Drx 3

E. Multiple Myeloma and Light Chain Cast Nephropathy The overproduction of monoclonal light chains (Bence-Jones protein) by malignant B cells in multiple myeloma can lead to a spectrum of renal disorders that include glomerulopathies (light chain deposition disease, amyloidosis) as well as the following tubulopathies: 1. Fanconi syndrome (proximal tubular toxicity manifested by aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis, and low-molecular weight proteinuria) can occur due to proximal tubule cell uptake of filtered light chains 2. Light chain cast nephropathy (LCCN) or 'myeloma kidney' Urine dipsticks primarily detect albumin and are insensitive to excreted light chains; however, the combination of a positive test for protein in either a spot or a 24-hour collection, and a negative dipstick test for protein is highly suggestive of Bence-Jones proteinuria.

- LCCN is associated with advanced myeloma, with increased tumor burden and light chain excretion - obstruction of tubular flow results from the accretion of filtered light chains and Tamm- Horsfall protein (also known as uromodulin) - often presents acutely in the setting of extracellular volume depletion, infection, or hypercalcemia - casts appear glassy or crystalline by light microscopy of biopsy specimen, often with a fractured appearance - casts can also incite a giant-cell/foreign-body reaction and cause tubular rupture, leading to interstitial fibrosis - immunofluorescence shows light chain restriction (either kappa or lambda) - consider this diagnosis in all elderly patients with acute renal failure, especially in the setting of bone pain or otherwise-unexplained hypercalcemia - both serum and urine should be sent for protein electrophoresis and for immunofixation for the detection and identification of a potential monoclonal band - free light chain (kappa and lambda) levels can also be measured in serum/urine - initial treatment goal is to correct volume depletion and/or hypercalcemia - definitive treatment of the underlying malignancy is ultimately required

However the kidney can only lower urinary pH to about 4.4 and therefore urine has a maximum concentration of free acids of less than

0.04 mEq/L. At this concentration the kidney would have to excrete about 2,000 L of urine daily to eliminate the usual 80 mEq of nonvolatile acid produced! To avoid this problem hydrogen ion is excreted with buffers.

5. Examination of Sediment Twelve to 15 ml of freshly voided urine are placed in a thick-walled glass centrifuge tube and centrifuged at high speed for five to ten minutes. After centrifugation, the quantity and gross appearance of the sediment should be noted. The supernatant should be completely poured off and saved for the qualitative test for protein. The centrifuge tube should be held inverted so that any remaining urine does not run back down the inner wall of the tube and dilute the pellet of adherent sediment, which may be tiny. The concentrated bit of sediment is then taken up with a long medicine dropper pipette and transferred to a clean microscope slide. A cover slip is routinely used to prevent rapid drying. If a large plug of sediment is present, it may be diluted with some of the supernatant, but use of this maneuver when there is only a small amount of sediment may so disperse cells and casts that significant abnormalities are not seen. The entire area of the cover slip should then be systematically scanned, using the low power objective to locate cells and casts. The high power objective is used for their precise identification. A blue bulb or blue-glass filter should be used in the substage lamp of the microscope as yellow light obscures the characteristic color of red blood cell and hemoglobin casts. The iris diaphragm should be nearly closed and the substage condenser racked down to dim the light when the low power objective is being used since many formed elements may be overlooked with bright illumination. It is our opinion that careful qualitative examination of the urine sediment in this manner demonstrates the diagnostic abnormalities of significance and that more complex quantitative study of the sediment is not necessary. For detailed review, Lipmann's excellent monograph on urinary sediment should be consulted.

1. Bacteria Bacteria visible in the fresh unstained sediment of a ''clean-voided'' specimen indicate the strong likelihood of infection, but provide no substitute for a quantitative or semi-quantitative culture. A Gram stain may help to identify the bacterial type. 2. Cells A rough quantitation of cells is made by expressing the number ''per high power field'' (HPF). This method is obviously only semi-quantitative and will vary with the urine concentration, centrifuge, amount of suspending fluid, magnification of the microscope and other variables. a) Erythrocytes may occasionally be found in the normal sediment in small numbers (as 2-3/HPF) and particularly after exertion, trauma or febrile illness. Even small numbers, however, if persistently present, should arouse suspicion of urinary tract pathology. Larger numbers are characteristic of a wide variety of disorders including glomerulonephritis of any kind, infection, necrosis, tumors, stones and coagulation abnormalities. b) Leucocytes may normally appear in a clean-voided urine in amounts of 3- 5/HPF. Most of the white cells are polymorphonuclear and are distinguished by definitely identifying a multilobed nucleus. c) Epithelial cells are round mononuclear and difficult to specifically define as to point of origin in the urinary tract. Large epithelial cells from the vagina, bladder, ureter or urethra cannot be distinguished. Renal epithelial cells can be differentiated from those of the lower tract by their size, 1+-3 times that of a white blood cell, a round large nucleus and many cytoplasmic inclusions. They are seen rarely (0-1/HPF) in the sediment normally. d) Oval fat bodies are large epithelial cells laden with fat which are highly refractile. Viewed with the aid of polarized light, they resemble a Maltese cross. Fat may also be found free in the urine or in casts. 3. Casts Proteinaceous cylindroids may be precipitated in the tubules, either from protein of tubular origin (as Tamm-Horsfall protein) or from serum proteins or myeloma proteins filtered through the glomerulus. The protein matrix tends to dissolve, especially in warm alkaline urine, illustrating again the need for prompt examination. Casts may be distinguished from mucus strings or clumps of cells by their smooth parallel sides. a) Hyaline casts, with a refractive index much like that of water, are difficult to see unless the light is much reduced. A few of these casts may normally be present, and will be increased in number after exercise, fever or during proteinuria. b) Cellular casts are formed when erythrocytes, leukocytes or epithelial cells are included within the tubular protein precipitate. Their significance is the same as that of the cells themselves with the added certainty that the cells come from the renal parenchyma. c) Granular and waxy casts. It was postulated many years ago by Thomas Addis that coarsely and finely granular casts represented successive stages in the degeneration of cellular casts which could culminate in the formation of waxy casts. The latter were homogenous, often cracked, easily visible and of higher refractive index than hyaline casts. This hypothesis is still generally held though no definitive evidence for it has appeared. More recent work, however, has suggested that cast granules represent aggregated serum proteins. d) Broad casts, which are several times the diameter of ordinary casts, may be of any of the above-mentioned types - but are often waxy. They are thought to be formed in the wide collecting ducts when urine flow rate is very low. 4. Crystals A variety of crystals may be found in normal and pathologic urines, including phosphates, urates and oxalates.

Rarely, one can see a decreased anion gap.

1. hypoalbuminemia, 2. bromide ingestion 3. paraproteinemia such as multiple myeloma.

pH H ion range

10-8 to 10-7 moles/L or 16 to 160 nano-moles/L.

ACUTE INTERSTITIAL NEPHRITIS I. INFECTIOUS A. Bacterial pyelonephritis (covered in lecture on Urinary Tract Infections) B. Viral A number of viruses can lead to tubulointerstitial pathology. Two examples are given: 1. BK polyomavirus nephropathy - BK polyomavirus is acquired during childhood, but remains quiescent - increasingly common form of tubulointerstitial disease after renal transplantation due to reactivation of virus with immunosuppression - viral replication and tubular cell lysis cause cell-to-cell spread, introducing virus into interstitium and urine - elevated serum creatinine; no major urinary findings except for PCR-detectable virus and "decoy cells" (desquamated epithelial cells with viral inclusions in nucleus) - initial treatment is reduction of immunosuppression or a change to leflunomide, an immunosuppressant with anti-viral properties

2. HIV associated nephropathy (HIVAN) - largely a glomerular disorder leading to collapsing glomerulopathy and severe proteinuria - however, the proliferative effects of the virus on the tubules lead to large, ectatic tubules ("microcystic change" or "thyroidization of the kidney") characteristic of classic HIVAN - renal ultrasound shows very large, echogenic kidneys - urinary sediment shows massive casts, due to large diameter of microcystic tubules

D. Immune-Mediated Tubulointerstitial Nephritis 1. Sjögren's syndrome - a systemic autoimmune disorder primarily affecting the exocrine glands (lacrimal and salivary) leading to the 'sicca syndrome' (dry eyes and mouth) - non-exocrine organs (kidney, skin, lung, GI and nervous systems) can also be affected by lymphocytic infiltration of tissues - tubulointerstitial nephritis is the most common renal manifestation - can be associated with distal RTA, nephrogenic diabetes insipidus, and moderate renal failure - serological features may include hypergammaglobulinemia, and positive anti-Ro (SS- A) and anti-La (SS-B) antibodies - treatment of TIN with prednisone is usually effective, but maintenance therapy with immunosuppressive therapy (IST) may be required to prevent relapse

2. Tubulointerstitial nephritis with uveitis (TINU) - syndrome of unknown etiology characterized by inflammation of kidney and eye - extra-renal features include fever, anorexia, abdominal pain, arthralgia, and eye pain and redness, with blurred vision and photophobia - as in other tubulointerstitial diseases, there is mild proteinuria, elevated creatinine, and anemia - erythrocyte sedimentation rate (ESR) is often elevated as well - uveitis can occur prior to, concurrent with, or more commonly, after the initiation of the interstitial nephritis - typically self limited in children, but in adults, disease may follow a relapsing course and be more steroid-dependent - both renal and ocular manifestations generally respond well to prednisone but may require maintenance therapy with IST as above

2. Kidney recipient evaluation However, only one third of patients with new onset ESRD are medically suitable for transplantation. Candidates for kidney transplantation are tested rigorously for cardiovascular disease and other medical problems that might make transplantation surgery risky, and for occult malignancies or infections that could become life- threatening due to immunosuppression. A history of medication compliance is considered because of the critical importance of taking immunosuppressive agents consistently. Possible recipients are evaluated for underlying psychiatric disease and substance abuse as well as for their willingness to accept a kidney donated by potential living donors.

3. Living Donors Living donors also undergo a rigorous testing process to rule out any risk factors for themselves developing renal disease years later. In most transplant programs, diabetes mellitus or hypertension in a potential donor is a contraindication for proceeding with donation. Additionally, presence of hematuria or proteinuria in a donor warrants further workup possibly including kidney biopsy. GFR of the donor is measured (to ensure it is normal) by serum creatinine and the MDRD eGFR formula, but because this formula is inaccurate in patients with eGFR > 60 ml/min (one would hope a potential donor has a superb baseline GFR) a 24 hour urine is collected to determine creatinine clearance. Donors are evaluated for any occult infections that might be transmitted through transplantation (HBV, HCV, HIV, among others). Potential donors must be highly motivated to donate but without the expectation of any financial or other remuneration (except the psychological benefits of such an altruistic act, a benefit that should not be underestimated!). Different ethical issues may appear during the workup that are carefully evaluated by a series of professionals. Possible donors undergo imaging of their renal vasculature to ensure there are no anomalies that could preclude safe implantation of the new kidney. Finally, and arguably most importantly, donors must have ABO-compatible blood (without regard to the Rh factor) preferably with a high degree of HLA-matching. Typically, donors are related to the recipient, but may be emotionally related (spouses, best friends, mother-in-laws) if they are good ABO and HLA matches with the recipient.

3. Sarcoidosis - disease of unknown etiology characterized by non-caseating granulomata, T cells, and mononuclear phagocytes in involved tissues, such as the lung, lymph nodes, skin, and kidney - like Sjögren's and TINU, there may also be ocular involvement in sarcoidosis - granulomatous renal interstitial process is usually not clinically significant but may cause renal insufficiency - hypercalcemia (due to extrarenal 1-α-hydroxylation of vitamin D in granulomata) can lead to nephrocalcinosis and/or vasoconstriction-mediated renal failure - renal dysfunction is an indication for treatment with corticosteroids in patients with sarcoidosis.

4. IgG4-related systemic disease - a rare but interesting, recently described, multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into tissues (organ involvement is variable) o renal involvement manifests as tubulointerstitial nephritis o autoimmune pancreatitis (most well-described manifestation) o sclerosing cholangitis o sialadenitis (can be confused with Sjögren's syndrome) o retroperitoneal fibrosis and/or periaortitis - predominantly affects middle-aged men - excellent response to steroids

PCO2 of arterial blood is normally maintained at

40 mmHg and clinically is determined by the rate of alveolar ventilation (not the result of alterations in metabolic production or titration of bicarbonate to CO2). Thus, an increase in PCO2 is due to a decrease in alveolar ventilation. Conversely, a decrease in PCO2 is due to an increase in alveolar ventilation.

4. Deceased donors Donor selection for deceased donors requires that the family give permission for donation. Deceased donors typically die of head trauma, subarachnoid hemorrhages, etc., because other systemic illnesses such as disseminated infections would preclude the suitability of organ donation. Possible deceased donors are rapidly tested to rule out HIV and viral hepatitis, to improve the safety of donation from an infectious standpoint, but there is not time to rule out all rare infections. There are case reports of unusual infections in recipients of kidneys from donors with various infections, such as West Nile Virus. Donor and recipients pairs are determined by ABO-compatibility, HLA- matching, geography, and the by the length of time recipients have been on the kidney transplant waiting list (3-5 years in MA, depending on blood-type).

5. Immunosuppressive treatment: A number of agents are administered to suppress the immune response to enable the recipient to accept the foreign antigens of the renal graft. Immunosuppression for transplantation is a fine balance between adequate versus excessive immunosuppression. The former increases the risk of allograft rejection. The latter increases the risk of bacterial, viral and fungal infections as well as the risk of certain malignancies. Important infectious complications of renal transplantation include cytomegalovirus (CMV), tuberculosis, pneumocystis jirovecii, BK polyoma virus, as well as an increased prevalence of common infections also seen in immunocompetent individuals such as community acquired pneumonia and urinary tract infections (UTI). Immunosuppressed patients are also at increased risk of squamous cell cancers of the skin, head and neck, oral and vaginal mucosae, as well as B cell lymphomas that are associated with EBV infection. Common immunosuppressive regimens include three drug treatments including a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil more commonly than azathioprine) and prednisone. Transplant programs vary greatly on the specific regimen they tend to utilize. A more detailed discussion of immunosuppressive agents used in transplantation is covered in Dr. Walsh's lecture. Because immunosuppressive agents are used in higher doses during the first 6-12 months after transplant (due to a higher rate of graft rejection), various antimicrobial agents are administered as prophylaxis against CMV, UTI, and pneumocystis infections, among others.

range of arterial plasma pH

6.8 to 7.8.

Management of End Stage Renal Disease (ESRD) When the GFR falls below 20-30 ml/min, most patients have some of the laboratory abnormalities and some have mild, non-specific symptoms of CKD. At this point, in addition to managing these complications of CKD, patients should be prepared for the need for ''renal replacement therapy''. Guidelines recommend preparing for renal replacement therapy as early as the start of stage 4 CKD (eGFR <30 ml/min). ESRD is a term that encompasses chronic kidney failure requiring renal replacement therapy, in distinction to the use of dialysis for AKI. The term renal replacement therapy encompasses both dialysis and kidney transplantation. Education and planning are essential before patients become symptomatic because these allow the patient the required time to decide which form of renal replacement therapy to pursue. Early planning also permits orderly evaluation of family members as potential kidney donors and the patient as a kidney recipient, processes that can often take several months. It also allows time for maturation of a vascular access in the event that hemodialysis is selected as a treatment modality. We will first briefly review dialysis treatments and then kidney transplantation. There are several forms of chronic dialysis therapy that one should be aware of.

A. Hemodialysis: Hemodialysis employs solute diffusion down a concentration gradient across a semipermeable synthetic (dialysis) membrane to remove "uremic toxins", potassium, phosphorus, etc. Blood flows through the dialyzer countercurrent to the direction of dialysis fluid, allowing for maximal concentration gradients to efficiently remove solute from the blood into the dialysis solution (which contains no urea, creatinine, etc, so these molecules are removed rapidly). Smaller molecules such as urea, creatinine, and potassium are removed more rapidly than larger molecules such as beta-2 microglobulin (this is in sharp contrast to the glomerulus which filters smaller and larger molecules at the same rate). Phosphorus is dialyzed relatively slowly so patients have an ongoing need for phosphorus binders with all meals. Fluid (called "ultrafiltrate") is removed at a constant rate using carefully monitored pressure sensors in the dialysis apparatus that adjust hydrostatic pressure in the dialysis system to achieve precise rates of fluid removal (to avoid excessively rapid fluid removal which can cause hypotension). Hemodialysis is typically performed three times per week for 3-4 hours per session but can be performed nightly at home for motivated patients. This dialysis prescription is adequate for treating symptoms of uremia and obtaining adequate removal of toxins and adjustment of electrolytes to normal or near-normal values. The prescription requires modification for each individual patient depending on body size, presence or absence of residual kidney function, diet and other illnesses. Dialysis adequacy is determined by comparing pre- and post-dialysis urea concentration to ensure an adequate percentage of the pre-dialysis urea is cleared. To manage complications of ESRD, patients receive erythropoietin, vitamin D supplementation intravenously during HD treatment and take phosphorus binders with meals at home. Hemodialysis requires access to the patient's bloodstream and the blood flow rate must be rapid enough to provide adequate solute clearance. Either large bore intravenous catheters or arterio-venous access is required to achieve these high blood flow rates. through is ideally performed using an arterio-venous (AV) fistula, which is an artery anastomosed to a vein at the radiocephalic or brachiocephalic level. In patients whose blood vessels are too small to support an AV fistula, synthetic gortex can be used to create a bridge between larger vessels, called an AV graft. AV grafts have higher rates of becoming infected or thrombosed than AV fistulae, hence the preference for using AV fistulae. The least ideal option for hemodialysis access is placement of a tunneled hemodialysis catheter, typically in the internal jugular vein, but these have higher rates of infections, thromboses and central venous stenosis, so AV access is preferred, when possible. Dialysis is also more efficient (i.e. faster solute clearance per unit time) with AV accesses when compared with catheters. Despite this, a sizable percentage of HD patients use catheters. These complications of infection and thrombosis cause much of the morbidity and mortality of hemodialysis, although cardiovascular disease remains the number one cause of mortality. The annual mortality of HD is quite high, around 20%, despite years of efforts to improve all aspects of HD treatment. This likely reflects the numerous comorbidities of patients who develop kidney failure but also to limitations of the treatment itself.

,A buffer is best able to minimize pH changes when

A/HA = 1 or when pKa = pH

Acute tubulointerstitial disease often reflects a new pathological process in the kidney, from any of the causes listed in Table 1. Acute tubular necrosis and allergic interstitial nephritis are the most commonly encountered examples in routine practice. Chronic interstitial nephritis (CIN) is the end-product of any sustained renal damage or disease (infectious, toxic, obstructive, inherited, etc.) It may also result from a prolonged episode of acute interstitial nephritis that fails to adequately resolve, or as a consequence of the heavy proteinuria and tubular damage that accompanies glomerular disease.

ACUTE Sudden or rapid loss of GFR (evidenced by an acute increase in serum creatinine) Acute onset often evident due to symptoms Inflammation/edema or tubular obstruction can diminish urine output Renal inflammation and capsular distention can sometimes cause flank pain Hematocrit often normal or mildly low (in hospitalized patients) Depending on etiology, can see WBC casts, RTE, hematuria, or crystals in urine Echogenic, normal-to-enlarged kidneys on renal ultrasound CHRONIC Diminished GFR with slow but appreciable rate of further decline Insidious onset; often an incidental diagnosis Frequent urination, nocturia (enuresis in children) due to loss of concentrating ability Generally no pain, unless a form of CIN associated with nephrolithiasis Normocytic anemia due to loss of erythropoietin- producing interstitial cells Sediment with broad waxy casts, occasional WBCs or WBC casts; hematuria is uncommon Small or scarred kidneys on ultrasound, with increased echogenicity, loss of corticomedullary differentiation, prominence of renal pyramids

2. Diseases That Cause RPGN Anti-GBM Antibody Disease Autoimmune disease mediated by anti-GBM antibodies Crescentic GN with linear deposits of IgG on GBM Presents with RPGN ± hemoptysis from pulmonary hemorrhage (Goodpasture syndrome) Antigen: NC1 domain of 3 chain of type IV collagen Goodpasture syndrome - anti-GBM nephritis with pulmonary hemorrhage Predisposition - Smoking, volatile solvents, viral respiratory infection Treatment - plasmapheresis, steroids and immunosuppressive drugs

ANCA-Associated Vasculitis ANCA antibodies are found in a number of systemic vasculitides, including Wegeners (c-ANCA), polyarteritis nodosa and microscopic polyangiitis (p-ANCA) Leads to crescentic GN with few or no immune deposits (pauci-immune) Patients present with RPGN with or without systemic vasculitis (pulmonary hemorrhage, upper respiratory involvement, skin purpura) Testing for anti-neutrophil cytoplasmic antibodies (ANCA) is positive Treatment -steroids and immunosuppressive drugs ± plasmapheresis

. The other buffer, ammonia, is produced by the renal tubular cells via the metabolism of precursors such as glutamine.

Ammonia formed in these cells can readily diffuse into the tubular fluids where it can react with hydrogen ions as a weak base. Since NH4+ is charged and has a low permeability, it is trapped in the urine at high concentrations. The excretion of ammonium ions accounts for the remainder of acid excretion.

A decrease in bicarbonate concentration (e.g. increased production of an acid or GI/renal bicarbonate loss) is defined as metabolic acidosis.

An increase in bicarbonate concentration (e.g. a large alkali load or excessive excretion of acid vomitting) is defined as metabolic alkalosis.

Immune Complex Glomerulonephritis The granular deposits characteristic of immune complex nephritis may be seen at 3 different sites in the glomerulus either independently or in combination. 1. In the mesangium, in the focal proliferative nephritis seen in IgA nephropathy, Henoch-Schönlein purpura, lupus nephritis and some other diseases; 2. Along the subendothelial surface of the capillary wall in more severe cases of lupus and Type 1 membranoproliferative glomerulonephritis; 3. In the subepithelial space and slit pores as the ''humps'' characteristic of post- streptococcal glomerulonephritis or the diffuse, finely granular deposits seen in membranous nephropathy. Immune deposits contain antibody, and, in some cases, the pathogenic antigen can be identified as well. Such antigens may be exogenous, as in some post-infectious immune complex nephropathies (post-streptococcal, hepatitis C-associated), or endogenous antigens such as DNA, histones and possibly tumor antigens or intrinsic components of the glomerulus (the latter in membranous nephropathy). The clinical type of glomerular lesion appears to depend largely on the site and quantity of immune deposits in the glomerulus. In some cases the deposits may result from trapping of immune complexes formed in the circulation (e.g. lupus nephritis and mixed cryoglobulinemia), in others by in situ complex formation (e.g. membranous nephropathy). Subepithelial immune deposits form locally due to binding of circulating free antibody to antigens normally present on the glomerular epithelial cell, or previously localized on the sub-epithelial surface of the capillary wall.

Anti-GBM Nephritis About 3-5% of cases of glomerulonephritis are mediated by deposition of antibody to antigenic constituents of the GBM itself. Anti-GBM antibodies of the IgG class are found in a characteristic uninterrupted, linear pattern along the GBM by IF and can usually be detected in the circulation by an indirect IF assay or by a more sensitive radioimmunoassay or ELISA. The responsible antigen is part of the noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen. Type IV collagen is the predominant form of collagen in basement membranes and the alpha-3 chain is unique to the GBM and alveolar basement membranes. The events leading to anti-GBM antibody production in man are not understood, although association has been reported with smoking, hydrocarbon solvent exposure and influenza-A viral infection.

A. Autosomal dominant tubulointerstitial kidney disease (ADTKD) - rare group of disorders with an autosomal dominant pattern of inheritance - due to mutations in the genes for uromodulin (UMOD), renin (REN), hepatocyte nuclear factor 1β (HNF1B), or mucin-1 (MUC1) - affected individuals show a progressive loss of kidney function, associated with minimal proteinuria and a bland sediment - those with the UMOD mutation may have hyperuricemia and early-onset gout, while those with the REN mutation may have relative hypotension and be prone to acute kidney injury - kidney biopsy shows non-specific tubular atrophy and interstitial fibrosis - treatment is supportive; early referral to a nephrologist is recommended if identified in a child from an affected family

B. Mesoamerican (or 'Central American') nephropathy - a recently identified endemic form of chronic kidney disease found in young (age 30- 50) and otherwise healthy agricultural workers in Central America - seems to occur more often in sugar cane farmers working under extreme heat conditions - affected individuals have normal to mildly-elevated BP, low-grade proteinuria, and an asymptomatic but progressive decline in renal function - histology reveals chronic tubulointerstitial disease, often with secondary glomerulosclerosis - likely caused by repetitive cycles of dehydration and/or volume depletion, leading to progressive tubulointerstitial injury (although environmental toxins have also been proposed)

Regulation of HCO3-

Bicarbonate is freely filtered at the glomerulus into the tubular fluid at a rate of approximately 3,000 to 4,000 mEq/day. In order to preserve body base content this filtered bicarbonate must be reabsorbed.

B. Analgesic nephropathy - results from the long-term use of analgesics, commonly mixtures containing phenacetin or acetaminophen, aspirin, and caffeine or codeine that were previously available over-the-counter in Europe and Australia - cumulative dose often in the 2-3 kg range at the time CIN is noted - classically characterized by renal insufficiency, papillary necrosis (see section on Sickle Cell Nephropathy) due to the presumed concentration of the drug to toxic levels in the inner medulla, and papillary calcifications on CT scan - increased long-term risk of urothelial malignancy - current analgesic preparations in U.S. taken in moderate chronic doses do not appear to cause analgesic nephropathy - [ Note that analgesic nephropathy is due to chronic ingestion of such agents, whereas commonly-used NSAIDs may have acute renal effects such as decreased GFR in the setting of volume depletion; hyperkalemia; sodium and water retention ]

C. Aristolochic acid nephropathy - Encompasses two more traditional clinical entities: Chinese herbal nephropathy and Balkan endemic nephropathy - Chinese herbal nephropathy was initially identified in women taking Chinese herbal preparations as part of a weight loss regimen - Balkan nephropathy, an endemic chronic interstitial nephritis found primarily in towns along the tributaries of the Danube River, is now known to be due to contamination of local grain preparations with a certain weed - In both cases, the nephrotoxic agent has been identified as aristolochic acid - aristolochic acid, after prolonged exposure, produces a hypocellular, fibrotic interstitial lesion in the kidney, and importantly has also been associated with increased risk of bladder and ureteral cancers - urine sediment is bland, with rare leukocytes and only mild proteinuria

V. Metabolic causes of CIN Although not discussed in detail in this syllabus, be aware that there are several metabolic (inherited or other) causes of chronic interstitial nephritis: A. Hyperuricemia (leading to urate nephropathy) - while acute urate nephropathy due to tubular obstruction is established cause of AKI (as seen in tumor lysis syndrome), the existence of a chronic form of toxicity from uric acid is controversial B. Hypercalcemia - notably seen in primary hyperparathyroidism, but also may play a role in sarcoidosis and multiple myeloma - chronic hypercalcemia can lead to interstitial calcification (nephrocalcinosis), which can be seen by plain film (e.g., KUB) or non-contrast CT scan - nephrogenic DI, distal RTA, calcium oxalate stones, and interstitial damage can also occur with hypercalcemia

C. Hyperoxalosis - primary forms (due to deficiencies of specific hepatic metabolic enzymes) lead to increased urinary oxalate concentrations - extensive calcium oxalate deposition leads to nephrocalcinosis - secondary ('enteric') forms occur due to increased intestinal oxalate absorption D. Cystinosis - rare autosomal recessive disorder affecting cysteine transport from lysosomes - intracellular accumulation of cysteine causes early proximal tubular cell damage and Fanconi syndrome - hexagonal birefringent crystals on urinary sediment are pathognomonic

B. Peritoneal dialysis: In contrast to hemodialysis, the semipermeable membrane used in peritoneal dialysis is a biologic one, the patient's own peritoneum. Dialysis solution is introduced into the patient's abdomen (where it bathes the peritoneal membrane) via soft, flexible biocompatible catheters that are surgically inserted into the anterior abdominal wall (and can safely stay there for years). Peritoneal dialysis involves infusing 2-2.5 liters of sterile, warmed dialysis fluid into the peritoneal cavity. After being infused, the fluid is allowed to equilibrate (dwell) in the abdomen for a specified amount of time (discussed below) after which it is drained by gravity and discarded. The entire sequence of infusion, dwell and drainage is called an exchange. Solutes such as urea and creatinine are removed by diffusion along concentration gradients. In contrast tohemodialysis where ultrafiltration is accomplished by hydrostatic pressure, ultrafiltration in peritoneal dialysis is accomplished by the osmotic gradient created by adding dextrose to the peritoneal dialysis fluid. Available dextrose concentrations vary from 1.5% (83 mOsmol/L) to 4.25% (236 mOsmol/L), with higher % dextrose concentrations resulting in more rapid ultrafiltration of fluid. Peritoneal dialysis is usually a continuous therapy with 3-5 exchanges per day, leaving peritoneal dialysis fluid to dwell for 4-6 hours per exchange. These dwell times were determined because of a near-complete equilibration of urea and creatinine between blood and peritoneal dialysate after approximately 4 hours of dialysate dwell. The performance of 3-5 exchanges per day provides solute removal equivalent to 10-15 hours of hemodialysis per week. This form of PD is called continuous ambulatory peritoneal dialysis (CAPD). Patients can perform CAPD at home, allowing a greater freedom to work, travel, etc. An exchange takes 20-30 minutes to complete, but during periods of dialysate dwelling patients are able to proceed about normal daily activities (with 2-2.5L of dialysate in their abdominal cavity, but this is well-tolerated). A variation on this method is continuous cycling peritoneal dialysis (CCPD) where the exchanges are performed by a pre-programmed cycling machine, usually while the patient is asleep. Overnight, the machine can perform 5 or more exchanges while the patient sleeps and can even infuse a final "day dwell" of PD fluid after which the patient goes about his or her business until the next night when the process begins anew. Although it provides greater freedom, peritoneal dialysis is not without its problems including a risk of infection of the peritoneal cavity or catheter, the longer treatment time required, and risk of developing hyperglycemia, weight gain and diabetes from the dextrose containing fluid, among others.

C. KidneyTransplantation 1. Outcomes The first kidney transplants were performed here in Boston in 1954 between identical twins. With the development of immunosuppressive drugs, kidney transplantation from nonidentical twins began in the early 1960s. With current methods of tissue typing and immunosuppression, graft survival for well-matched living-related donor transplant is approximately 95% at one year; deceased-donor transplant graft survival rates currently are approximately 90% at one year. There has been a striking improvement in patient mortality over the past 30 years with the overall mortality less than 5% for the first year following a deceased-donor transplant. This low mortality rate represents a reduced likelihood of graft rejection, improvement in immunosuppressive agents, and a greater awareness of the infectious complications of immunosuppression. Second and third transplants carry a lower success rate than the first, although can be done safely for patients who lose a first allograft. After a transplant has functioned for >1 year, the half life of kidney survival (i.e. 50% of transplanted kidneys are still functioning is: 1) HLA identical living donor transplantation ~ 35 years 2) Haplo-non-identical living donor:15-20 years 3) Deceased donor kidney: ~ 10 years.As you can see, living donor transplants have better 1-year and long-term patient and graft survival but any type of transplant has superior patient survival compared with any form of dialysis.

1. A 76-year-old man with baseline chronic kidney disease stage 2 (baseline creatinine 1.3 mg/dL) undergoes abdominal aortic repair for a bleeding aneurysm located superior to the renal arteries. Surgery was successful but difficult and required 100 minutes of aortic cross clamping (necessary to prevent hemorrhage from the aorta during surgery). During the first 24 hours after surgery he excreted only 150 ml of urine despite intravenous fluids and diuretics. Urinary sediment immediately after surgery showed a few tubular epithelial cells, granular casts and many RBC's. Eighteen hours later the urinary sediment contained many RBC's, tubular epithelial cells, tubular cell casts and darkly pigmented granular casts. The next day the renal service is consulted because laboratory data demonstrated: Sodium 130 Potassium 6.4 Chloride 94 Bicarbonate 20 Creatinine 2.2 BUN 44 mEq/L mEq/L mEq/L mEq/L. mg/dL mg/dL His preoperative laboratory tests were within the normal range. a. What is the differential diagnosis of acute kidney injury? Which seems most likely in this patient? b. What tests could you order to clarify the etiology of acute kidney injury? c. Which fluid and electrolyte abnormalities are potentially life-threatening and should be treated? How would you treat each abnormality? What are the treatment options if he doesn't respond to these interventions? 14-1 d. What is the expected natural history of the disease you diagnosed? What is this patient's prognosis? e. What factors affect the rate of increase of BUN and creatinine? f. At what rate would you expect the bicarbonate to fall and potassium to rise in an uncomplicated case of acute kidney injury? Are these rates compatible with this case? Explain. g. What factors may play a role in the pathogenesis of acute kidney injury in this patient?

Case 1 Acute kidney injury (AKI) is divided into pre-renal, post-renal and intra-renal causes. Pre-renal causes include volume depletion but also disorders of fluid overload with decreased effective circulating volume (CHF, cirrhosis). Post-renal causes include obstruction to the flow of urine at the level of renal calyces, ureters or bladder. Intra-renal causes include glomerular, interstitial, vascular and tubular causes. He definitely has AKI given the combination of low urine output and rising serum creatinine. The most likely etiology of AKI in him is acute tubular necrosis (ATN). Evidence pointing towards ATN include the presence of darkly pigmented granular ("muddy brown") casts and tubular epithelial cells and casts. The fact that his urine output and kidney function didn't improve with IV fluids also favors this diagnosis. However, insufficient evidence is presented to fully exclude pre-renal causes. Post-renal obstruction is doubtful, particularly if he has an indwelling urinary catheter, but is an important cause to exclude at his age. The most helpful tests at this point would be to check a urine sodium (or calculate a fractional excretion of Na, FENa) to differentiate between pre-renal (UNa < 10 mEq/L, FENa < 1%) and intra-renal (UNa > 20 mEq/L, FENa >1%) causes, namely ATN for the latter. FENa is a valid test because this is oliguric (low urine output) AKI. A renal ultrasound is an easy test to exclude the unlikely diagnose of post-renal obstruction. Other reasonable tests include checking CPK levels to rule out the possibility of rhabdomyolysis (i.e. pigment-induced ATN) from concomitant ischemia to the muscles of his lower extremity during the surgery. Given what we know of the timing of the onset of AKI, we probably don't need to go on a wild goose chase looking for glomerular or vasculitic diseases. The hyperkalemia is the most threatening and should be treated (after an ECG is obtained) with medications to shift potassium into cells first and with medications to excrete potassium from the body (exchange resins or loop diuretics, the latter only if you don't think he's volume depleted). If these fail (and given the rapid rate of rising creatinine), dialysis can be considered. Although the low HCO3 and hyponatremia require monitoring, they are not life-threatening right now. Incidentally, calculate the anion gap and think about why he may have a metabolic acidosis. Assuming this is ATN, the natural history is to have an onset phase with rising BUN and creatinine and possible metabolic complications of the low GFR (keep in mind, that while BUN/creatinine are rising, the estimated GFR equations have no meaning. In fact, the GFR during severe AKI is probably considerably less than 10 ml/min). During this time, if AKI is severe enough, dialysis will be needed (during the plateau phase) but even if one can avoid starting dialysis, there are many fluid and electrolyte issues to manage in these patients. Fortunately, 75% of patients who survive an episode of ischemic ATN recover kidney function during the recovery phase. This is heralded by an increase in urine output which rapidly leads to polyuria because the tubules are still recovering and have difficulty concentrating the urine (as well as an osmotic diuresis from urea). The rate of increase of these factors depend on the baseline levels (i.e. pre-existing CKD), the severity of the AKI, and the underlying muscle mass for creatinine and liver function for BUN. In uncomplicated AKI with extremely low GFR, potassium rises at 0.5-1.0 mEq/L per day and bicarbonate falls at 1-2 mEq/L per day. These rates will be slower if the AKI severity is less (i.e. GFR is not < 10 ml/min). Faster rates of change of these two electrolytes should prompt a diagnostic workup for potential complicating problems such as tissue ischemia (lactic acidosis and potassium release from necrotic cells), multiple blood transfusions, rhabdomyolysis, severe infections/sepsis, among others. His risk of AKI was increased by baseline CKD stage 2, increased age, the prolonged time of aortic cross clamping (> 60 minutes). If the surgery was emergent, this would represent another potential risk factor for AKI.

Case Studies 1. A 48-year-old African American gentleman with a 15-year history of diabetes mellitus is seen in the office by you for fatigue and malaise of 3 months' duration. He denies dyspnea, chest pain, nausea, vomiting or diarrhea. On further questioning he does report some leg swelling at the end of his long day working in a construction site. Other than these symptoms, he recalls only good health previously. You review records from previous visits and the only abnormality was a urinalysis demonstrating 2+ protein five years earlier. On exam, BP is 140/90 mmHg, pulse 72, he is afebrile. His skin and conjunctivae are pale. Jugular venous distension noted in mid-neck. Lungs are clear to auscultation. Heart demonstrates a regular rhythm and rate. Trace lower extremity edema is present. Laboratory Data: Hematocrit 28% Urinalysis: specific gravity 1.014, pH 5, no glucose, 3+ protein, 2 + blood. Urine sediment: 5-10 RBC/hpf, 0-2 WBC/hpf, 1-2 hyaline casts/hpf, 2-4 oval fat bodies/hpf. You order a 24-hour urine collection. Urine volume 2000 mL Creatinine 80 mg/dL Protein 400 mg/dL. Sodium Potassium Chloride Bicarbonate BUN Creatinine Calcium Phosphorus 136 mEq/L 4.5 mEq/L 108 mEq/L 19 mEq/L 42 mg/dL: 2.4 mg/dL 8.8 mg/dL 4.4 mg/dL a. What is your best estimate of kidney function? What stage of chronic kidney disease is this? b. What is his kidney function? Is it consistent with his minimal symptoms? c. What is the likely acid base disorder? How did it develop? d. What mechanism(s) account for the normal plasma potassium concentration? e. What factors account for his low hematocrit? f. What treatments should be initiated now to slow the rate of CKD progression? g. What screening tests should have been employed many years earlier (given his known diagnosis of diabetes mellitus) to anticipate the onset of chronic kidney disease?

Case 1 a. There are two options for estimating kidney function based on the provided information. The first is to calculate the creatinine clearance based on the 24 hour urine collection. CrCl= [UCr]*(Uvol) / [SCr] or (80 mg/dL)*(2000 ml) / (2.4 mg/dL) but this result is ml/day so must divide by the 1440 minutes/day to get a CrCl measurement of 46 ml/min. If you enter his age, gender, ethnicity and creatinine into an online GFR calculator (www.mdrd.com is one example), estimated GFR is 37 ml/min. How do we account for the difference? Remember that creatinine is secreted in addition to filtered so the creatinine clearance is an overestimate of true GFR. The MDRD GFR equation functions reasonably well at this level of GFR (<60 ml/min). This is stage 3 of chronic kidney disease. b. Creatinine clearance is 46 ml/min, entirely consistent with few or no symptoms. Patients are not typically symptomatic until they've had a marked reduction of GFR. c. The likely disorder is a metabolic acidosis (although cannot prove this without an ABG as it could be a respiratory alkalosis). The anion gap (AG) is only 9 mEq/L. In CKD, metabolic acidosis with a normal AG is typically from a loss of the ability to increase ammonium production and net acid excretion. d. There are several possible mechanisms to explain the normal potassium level. First, increased distal delivery of sodium will lead to increased potassium secretion in the collecting tubules, a process known as adaptation. Aldosterone levels are also increased which enhance this effect and also increase colonic potassium excretion. e. His low hematocrit is likely multifactorial, including low erythropoietin levels, shortened RBC survival, and possible contributions of iron deficiency. f. Evidence exists for three treatments to slow the rate of CKD progression including 1) maintaining blood pressure < 130/80 mmHg, 2) glycemic control (HBA1c < 7%), 3) angiotensin converting inhibitors (ACE-I) or angiotensin receptor blockers (ARB) to lower glomerular hyperfiltration. Proteinuria is the intermediary marker used to monitor response to this treatment. 1 g. Starting when he was first diagnosed with diabetes, he should have been serially monitored with measurements of urinary albumin, the most sensitive way to detect diabetic nephropathy. Physicians should have measured serum creatinine and calculated eGFR to detect early stages of CKD. Once evidence of albuminuria was noted, ACE-I or ARB treatment should have been started to slow the progression of CKD.

Case Studies 1. A 56-year-old Caucasian male presents to the emergency department with shortness of breath and a cough productive of small amounts of blood-streaked sputum. Two months earlier an employment physical including chest x-ray and routine laboratory tests was entirely normal. Physical exam demonstrated BP of 148/92mmHg, pulse 72 bpm. Lungs had faint crackles at both bases. Heart exam was unremarkable. He had no lower extremity edema or skin rashes. Chest x-ray demonstrated bilateral alveolar infiltrates. Serum creatinine was 1.5 mg/dL and hematocrit was 28% on admission. He was treated with antibiotics for possible pneumonia. Three days later, you are asked to see the patient as part of the renal consult service. A renal consult was called because the serum creatinine increased to 2.8 mg/dL and the urine output has decreased to 500 ml/day. Laboratory studies reveal: Sodium Potassium Chloride Bicarbonate BUN Creatinine Hematocrit 25% Urinalysis: SG. 1.015, pH 5.0, 3+ blood, 1+ protein, otherwise negative Urine sediment revealed numerous dysmorphic RBCs, and rare RBC casts. 24-hour urine protein is 1.5 grams, creatinine 1400 mg. The renal fellow asks you to help schedule a kidney biopsy. a. What syndrome is this patient presenting with? b. What is the differential diagnosis? What clues help you narrow the differential diagnosis? c. Why did the fellow want to schedule a kidney biopsy? What would you expect a biopsy to show? d. What blood tests (if any) could be obtained to narrow the differential diagnosis? e. Why does he have pulmonary infiltrates? f. What is the prognosis of his disease?

Case 1 a. There is a high likelihood this is a glomerular disease (aside from the fact that it's a case during the glomerular disease small group session) because of the evidence of hematuria, proteinuria and RBC casts (and dysmorphic RBCs). This case is a nephritic disease of the glomerulus. Given the rapid fall in GFR over the course of a few days to weeks, the most precise description of the syndrome would be rapidly progressive glomerulonephritis (RPGN), a subset of the nephritic disorders with a poor renal prognosis. b. The differential diagnosis of RPGN is divided into 3 major classifications based on the immunofluorescence (IF) findings on kidney biopsy. 1. Anti- GBM antibody disease demonstrates linear IgG staining on IF. 2. Immune complex mediated diseases demonstrate a granular pattern of Ig staining on IF and includes diseases such as systemic lupus erythematosis, cryoglobulinemia, Henoch Schonlein purpura (all systemic diseases) but also renal-limited forms similar to the systemic diseases (membranoproliferative glomerulonephritis and IgA nephropathy are the renal-limited forms of cryoglobulinemia and HSP, respectively). 3. Finally, pauci-immune diseases that are usually associated with positive ANCA tests include Wegener's granulomatosis, microscopic polyangitis, and others. You will learn more about these in your rheumatology module. The renal-limited version of these is simply called pauci-immune GN, usually also with a positive ANCA. The presence of pulmonary alveolar infiltrates is your biggest clue to a pulmonary-renal syndrome (see 1e. below). c. A kidney biopsy will be key to identifying the etiology of the RPGN, as above, which has implications on the treatment (beyond the scope of this course). One would expect to see evidence of necrotizing and crescentic glomerulonephritis on light microscopy, regardless of the etiology, because of the RPGN clinical picture. The IF pattern may give a clue to the etiology. As above, linear IgG staining on IF suggests anti- GBM antibody disease, a granular pattern suggests one of the immune complex diseases (for instance, granular IgA staining would be consistent with either IgA nephropathy or HSP). Finally, severe crescentic GN with negative IF would be suggestive of one of the ANCA-associated pauci- immune causes of RPGN. Electronic microscopy (although it takes a few extra days for the results to return) often may also help clarify the etiology of RPGN. 1 d. Serological blood tests are often helpful when facing a possible case of RPGN but usually don't replace kidney biopsy because in these situations, you don't want to lose too much time waiting for blood tests to return (without specific treatment) and often can obtain results of a kidney biopsy in 24-48 hours, or less. That said, the serological tests are still helpful to the long-term management of these patients. One should send anti-GBM antibody levels, anti-nuclear antibodies (ANA), anti-double stranded DNA, ANCA, cryoglobulin levels, hepatitis B and C serologies. The tests perhaps most important to our thinking of the differential diagnosis are C3 and C4 complement levels, which are low in some of the above disorders (sometimes in patterns that help narrow the differential diagnosis, such as in cryoglobulinemia where C4 levels are characteristically low). Complement levels are normal in other disorders helping to focus one's approach to the diagnosis. e. The pulmonary infiltrates likely represent a pulmonary hemorrhage as part of a pulmonary-renal syndrome but we need to also consider volume overload from salt and water retention from the AKI. However, the hemoptysis described on admission points more strongly to a pulmonary- renal syndrome. Most of the causes of RPGN can cause pulmonary-renal syndromes but the classic among these are Goodpasture's syndrome (systemic version of anti-GBM disease) and Wegener's granulomatosis. However, SLE and some of the others on our list may also cause this. f. Untreated, RPGN is an extremely serious condition and inevitably proceeds to renal failure and dialysis dependency. Moreover, the extra- renal manifestations (pulmonary hemorrhage here) are life-threatening. Prior to effective treatments, mortality rates for diseases like Wegener's and Goodpasture's were extremely high. Now, with aggressive treatment including corticosteroids, other immunosuppressive agents and plasmapheresis, mortality rates are considerably lower (although there is a significant infectious risk of such heavy immunosuppression). Hopefully in this case, we've "caught" his disease early enough to prevent progression to complete renal failure and will start treatment quickly enough to salvage renal function and prevent other complications.

2. A 55-year-old woman is evaluated in your office. You recall that when you last saw her a few years ago she had stage 3 chronic kidney disease with an estimated GFR of 55 ml/min but no complications of CKD. She had proteinuria and hypertension and a 24-hour urine protein excretion was 0.5 grams. She declined kidney biopsy. She now reports that she has not seen any of her physicians in over a year because of the death of her mother. She comes to see you because of the recent onset of loss of appetite, nausea, occasional vomiting, a metallic taste in her mouth, leg cramps and tingling in her feet. Itching had begun about a week ago. On review of systems, she reports that she's developed a sharp chest pain in the left side of chest that's worse with deep inspiration and with lying down flat in bed. Physical Examination reveals a blood pressure of 168/95 mm Hg and a heart rate of 68 bpm. She appears chronically ill with pale skin and conjunctivae. Her lungs were clear to auscultation and heart exam reveals a harsh triphasic sound throughout the precordium but a normal rate, rhythm and no murmurs. Liver and spleen are not palpable. There is 2+ lower extremity edema. Laboratory Data: Sodium Potassium Chloride Bicarbonate BUN Creatinine Calcium Phosphorus Hematocrit 28% Urinalysis: SG 1.010, pH 5.0, protein 2+. Urine sediment exam showed a few broad granular casts but no cellular casts or cells. A twenty-four-hour urine collection had a volume of 1,100 mL, creatinine 80 mg/dL, protein 40 mg/dL. a. What is the estimated kidney function? What stage of chronic kidney disease does this represent? b. Why does she have hyperkalemia? What are the treatment options for her hyperkalemia? 19-3 142 mEq/L 5.9 mEq/L 111 mEq/L 15 mEq/L 89 mg/dL 7.5 mg/dL 7.9 g/dL 9.1 mg/dL c. Why is serum phosphorus elevated? How would you treat this? d. What factors account for the hypocalcemia? e. What would you expect the serum levels of following to be (high, normal or low)? Why? i. 25(OH) Vitamin.D ii. 1,25 (OH)2 Vitamin D iii. Intact parathyroid hormone (PTH) How do we treat these abnormalities? f. What is the acid-base abnormality? Should this be treated? How? g. Does she need dialysis? What form of dialysis would you initiate and why? h. Which symptom(s) would you expect to be ameliorated by instituting dialysis? i. What would you expect a renal ultrasound to show with respect to size of the kidneys? 19-4 j. What general group of kidney disease does this patient likely have? Why? k. What disease(s) would you suspect if his father had died at age 55 related to CKD and his brother developed ESRD and underwent kidney transplantation age 46? What questions would you ask to elucidate the etiology of CKD in the family?

Case 2 a. Creatinine clearance is (80mg/dL)*(1100 ml) / (7.5 mg/dL) (and divided by 1440 to get into familiar units of ml/min) = 8 ml/min. The eGFR by the MDRD equation is 6-7 ml/min (notice how much closer together the estimates are now with such a low GFR). This is stage 5 of CKD. The truth is you really didn't need to do these measurements because with her uremic symptoms (see below) she should start hemodialysis very soon. b. The efficacy of the mechanisms that maintained potassium in the normal range in Case 1 are markedly reduced at this level of GFR (except the colonic excretion). Even modest amounts of dietary intake of potassium may lead to hyperkalemia. At this level of potassium, first check an ECG and if this is normal, you can probably focus on potassium excretion from the body via loop diuretics or exchange resins (or dialysis, if you decide that this is indicated now, see below). c. Phosphorus is elevated because of the extremely low GFR and the difficulty in avoiding dietary phosphorus. This can be treated with using agents that bind phosphorus in the GI tract, calcium carbonate or acetate, sevelamer or lanthanum. d. In part the hypocalcemia is a response to the elevation in serum phosphorus (calcium-phosphorus tends to complex together) but also related to vitamin D deficiency. e. 25-OH vitamin D: low, due partly to reduced dietary intake of vitamin D and also to reduced sunlight exposure 1,25-OH vitamin D: very low, due to low 25-OH vitamin D levels as well as reduced 1-alpha hydroxylation due to loss of renal mass. Intact PTH: Very high, related to many factors including hypocalcemia, hyperphosphatemia (mediated through FGF-23), and also vitamin D deficiency Treatment is aimed at reducing phosphorus levels (see 2c.), administering pharmacologic doses of vitamin D (some recommend to begin with 25-OH vitamin D and after that's been supplemented to then give 1,25-OH vitamin D). Calcimimetic agents like cinacalcet can be used to lower PTH levels as well. 2 f. The likely disorder is a metabolic acidosis (although cannot prove this without an ABG as it could be a respiratory alkalosis). The anion gap (AG) is 16 mEq/L. In CKD, metabolic acidosis with an elevated AG is typically occurs due to a loss of glomerular filtration of phosphates, sulfates and other anions that contribute to an increasing anion gap. This should be treated to reduce bone and muscle complications of CKD with oral sodium bicarbonate (or by dialysis). g. In reality, the treatment of hyperkalemia and metabolic acidosis will be taken care of by dialysis, which is indicated in her for several reasons. First, she has multiple symptoms of uremia (see question 2h.) but more urgently she has pleuritic chest pain and evidence of a pericardial friction rub on physical examination, consistent with pericarditis. Uremic pericarditis is an urgent indication for dialysis initiation because of the risk of it converting to a life-threatening hemorrhagic pericarditis. h. All of the uremic symptoms would improve with dialysis beginning with the pleuritic chest pain but also the loss of appetite, nausea, vomiting, metallic taste, leg cramps and the itching. i. Kidney size would be quite small as her chronic kidney disease has slowly progressed to the point where renal replacement therapy is necessary. j. The low level of urine protein (40 mg/dL with 1.1 liters of urine output is equivalent to a daily protein excretion of 800mg) favors a tubulo-interstitial disease. She had this level of proteinuria a "few years ago" when she was last seen and refused to undergo a kidney biopsy. Most glomerular diseases would be associated with a higher level of proteinuria. k. This question asks you to consider the hereditary causes of kidney disease. The most common genetic disorder among patients with CKD is autosomal dominant polycystic kidney disease. One would need to get more family history about other involved or not involved relatives. Another consideration (if the patient were male) considering that all involved persons in the family are male would be Alport's syndrome, which is X- linked and also associated with hearing loss. One would want to ask if there's a family history of hearing loss.

2. You are asked to evaluate a 28-year-old African American woman patient referred to renal clinic for an elevated serum creatinine of 1.6 mg/dL. She reports that she has been relatively healthy with the exception of some recent fatigue. The only medical problem that she reports on full review of systems is that she has had 2 miscarriages and no successful pregnancies to term. She denies chest pain, shortness of breath, nausea, vomiting, lower extremity edema, or hemoptysis. Last summer, she had a facial rash that prompted her doctor to tell her to "stay out of the sun". On further questioning, she reports intermittent joint aches in her knees, fingers and elbows. Physical exam demonstrated BP of 160/92mmHg, pulse 72 bpm. Lungs were clear. Heart exam was unremarkable. She had no lower extremity edema or skin rashes. Laboratory studies reveal: Sodium Potassium Chloride Bicarbonate BUN Creatinine 135 mEq/L 4.6 mEq/L 104 mEq/L 26 mEq/L. 24 mg/dL 1.6 mg/dL Hematocrit 27% Urinalysis: SG 1.015, pH 5.0, 2+ blood, 3+ protein, otherwise negative Urine protein to creatinine ratio: 1.4 Urine sediment revealed some dysmorphic RBCs, and an occasional RBC cast . a. What syndrome is this patient presenting with? b. What is the differential diagnosis? What clues help you narrow the differential diagnosis? c. What blood tests (if any) could be obtained to narrow the differential diagnosis? d. What would you expect a renal biopsy to show? e. Why do you think she has anemia?

Case 2 a. This is a nephritic type of glomerular disease. Pointing towards this is the presence of hematuria, proteinuria, RBC casts and dysmorphic RBCs. The typical features of nephrotic syndrome (see cases below) are not present. b. The differential diagnosis of nephritic glomerular diseases can be organized into renal-limited vs. systemic diseases and diseases with low vs. normal complement levels. See table below, noting that adjacent systemic and renal-limited diseases share similar renal biopsy findings (table adapted from Madaio and Harrington, The Diagnosis of Glomerular Diseases, Archives of Int Medicine, 2001, a classic article in understanding both nephritic and nephrotic diseases of the glomerulus). Some clues towards a probable diagnosis of SLE nephritis in her include the facial rash (which may be the classic "butterfly" rash seen in SLE), the two prior miscarriages and the arthralgia symptoms. Systemic Renal-Limited Low complement levels Systemic lupus erythematosis Cryoglobulinemia Renal-limited SLE MPGN Post-infectious GN Normal complement levels Henoch-Schonlein purpura Wegener's granulomatosis Goodpasture's syndrome IgA nephopathy Pauci-immune GN (ANCA) Anti-GBM disease c. The same tests as above (1d.) are helpful in working up a nephritic glomerular disease. With SLE nephritis, we'd expect low complement levels, a high-titer positive ANA test and a positive anti-double stranded DNA. With stable kidney function, diseases like anti-GBM are less likely because it usually (but not always) presents with a RPGN pattern of disease. The other tests outlined in 1d are reasonable considerations here. d. SLE nephritis is divided into 6 categories by the World Health Organization. Given the nephritic picture and decreased GFR, class 3 or 4 SLE nephritis is the most likely. We need the biopsy results to clarify which form of SLE nephritis is present as this will guide treatment, but also because we can sometimes be fooled and this may not be SLE nephritis in the end. 3 e. If SLE is the underlying disorder, this could be related to the associated auto-immune hemolytic anemia that is seen with active SLE. Other possible explanations include anemia related to reduced EPO production (i.e. anemia of CKD) with perhaps a component of anemia of chronic disease.

3. A 70-year-old man is admitted with a history of confusion for the past week. His wife said he had been listless and lethargic for some time before that and had recently lost his previously hearty appetite. He had also complained to her of shortness of breath on mild effort and had been unable to take his usual daily walk. He had previously been well except for diabetes mellitus easily controlled by diet alone. He had noticed some hesitancy on urination for several weeks but points out now that he feels he hasn't urinated much in past 24 hours. Physical examination revealed a disoriented, agitated male with labored breathing. BP 160/100 mmHg, pulse 120/minute and regular. Jugular venous pressure was increased at 10cm. A third heart sound (S3) was heard and rales were present at both bases. The abdomen was mildly distended but bowel sounds were normal. A firmness was palpated in the suprapubic region. 2+ ankle edema was noted. Laboratory studies were significant for: Creatinine 5.8 BUN 140 Sodium 128 Potassium 6.0 Chloride 92 Bicarbonate 15 mg/dl mg/dL mEq/L mEq/L mEq/L mEq/L a. What further examination is needed? b. What is the most likely etiology of his acute kidney injury? What factors may have played a role in this? c. What treatment should be instituted now? Does he require dialysis? What manifestations of his condition may become evident after initial treatment? d. What other symptoms might be elicited from the patient when he is better? e. What is the prognosis of his kidney injury?

Case 3 The same differential diagnosis of AKI can be used. Pre-renal AKI from volume depletion is unlikely given the physical examination findings of hypertension, elevated jugular veins, the presence of a 3rd heart sound and other evidence of volume overload. However, pre-renal AKI from congestive heart failure and decreased effective circulating volume cannot be ruled out at this point. However, data seems to point towards a post-renal cause given the suprapubic firmness and recent lower urinary tract symptoms (urinary hesitancy). There's not enough information presented to start thinking about intra-renal causes but clinically one should first rule out post-renal obstruction with an ultrasound. Additional diagnostic studies that are needed include an ECG to look for abnormalities associated with the hyperkalemia and perhaps the placement of a urinary catheter to see if a large amount of urine is excreted (essentially a diagnostic maneuver). Post-renal obstruction likely related to benign prostatic hypertrophy (BPH) or less likely prostate cancer. The lower urinary tract symptoms that were present for weeks may have been a clue to this diagnosis. Also, remember for post-renal obstruction to cause significant AKI, it must be bilateral (or the patient must have only a single kidney) so typically these causes occur at the bladder or more distally (i.e. prostate). We cannot forget the possibility that he also may have underlying congestive heart failure (the volume overload symptoms may be from this and not all from the AKI and Na and water retention). As mentioned above, placement of a urinary (foley) catheter will be both a diagnostic and therapeutic maneuver. One would expect prompt excretion of large volumes of urine if post-renal obstruction at the level of the prostate was the etiology of AKI. Even though his laboratory tests suggest that dialysis might be imminent, the urine output that can be achieved through the urinary catheter should do an exceptional job of correcting volume overload, hyperkalemia and the acid-base disorder (dialysis can often be avoided in these patients, a gratifying outcome for both the patient and doctor). Patients, in fact, can have a "post-obstructive diuresis" related in part to a short-term tubular sodium wasting, concentrating defect and the elimination of previously retained salt and water. Clinicians need to monitor patients closely for the development of electrolyte abnormalities related to this diuresis. Urinary hesitancy, frequency, urgency, nocturia are among the lower urinary tract symptoms seen in patients with BPH. His prognosis is excellent particularly if we caught his symptoms early enough and initiated the appropriate therapy. Delays in recognizing post-renal obstruction can lead to long-standing damage to the kidney. Otherwise, his kidney function should return to baseline.

3. A 51-year-old man was evaluated for stage 3 CKD with hematuria and proteinuria six years ago. Kidney biopsy revealed IgA nephropathy. Despite managing this with increasing doses of ACE-inhibitors, angiotensin receptor blockers and other treatments, his GFR has slowly declined at about 3 ml/min per year. Six weeks ago he noted fatigue at the end of the day and insomnia. His wife convinced him to see his primary care physician who discovered further decline in e GFR (now 18 ml/min) and asked you to evaluate him promptly. When you see him, he has no additional complaints. Physical examination revealed a BP of 140/90mmHg with a heart rate of 80 bpm. There was no JVD. Lungs were clear to auscultation. The PMI was outside the midclavicular line. There was no hepatosplenomegaly. The extremities had a trace of edema. You order a variety of tests to assess for complications of CKD. These are pending during the visit. a. What stage of CKD is this? b. His wife asks you what his treatment options are now. What do you tell her? Does he need dialysis now? How would you counsel her about the different treatment options for dialysis? c. His wife asks about kidney transplantation. She wants to know if she can donate a kidney to him. What information do you need about him to decide if he is good kidney recipient candidate? d. What information do you need about her to decide if she is a good kidney donor? What information do you need to know to determine if she can donate to him? e. What would you counsel them about kidney transplantation? What are outcomes of transplantation when compared with dialysis? How about living donor kidneys vs. deceased donor kidneys?

Case 3 a. Based on his eGFR, this is stage 4 CKD, the point where we should begin planning for renal replacement therapy. b. You can reassure the wife that he doesn't need dialysis right now as he's relatively asymptomatic. Although his fatigue and insomnia might be early 3 uremic symptoms, they are more likely related to anemia related to CKD and can be treated. In the absence of any urgent indication for dialysis, we have time to think about his options. You should counsel her about the different options for dialysis, namely hemodialysis vs. peritoneal dialysis. Briefly, in-center hemodialysis requires 3-4 hours of treatment three times weekly in a dialysis center. Patient's blood is "cleaned" through a dialysis filter which removes uremic toxins through diffusion down their concentration gradients through the semi-permeable membrane of the dialyzer from the blood into dialysis fluid (which are running side by side in the hollow tubes of the dialysis filter). Fluid is removed using hydrostatic pressure created by the dialysis apparatus to achieve a steady rate of "ultrafiltration" Hemodialysis requires access to a patients blood through either an AV fistula, AV graft or a dialysis catheter. Infection and other complication rates are highest with catheters, lower with grafts and lowest with fistulae. Peritoneal dialysis (PD) utilizes the peritoneal cavity as the semi-permeable membrane, allowing diffusion of uremic toxins down their concentration gradient. Fluid is removed through osmotic actions of dextrose, which is a component of PD dialysate. Patients perform PD at home either performing 4-5 "manual exchanges" during the day (CAPD, see notes) or overnight using a automated cycler-machine to perform the exchanges. There are various advantages and disadvantages to the two techniques, discussed in part in the lecture notes and to a greater degree in various textbooks. c. Kidney transplantation is associated with better outcomes than either HD or PD (dialysis is associated with a 20% annual mortality). Living donor transplants have better outcomes as far as graft survival compared with deceased donor. Although most living donor transplants are performed between relatives (siblings, parents, children, etc.), they can be performed between unrelated but "emotionally related" individuals, such as spouses. There are even stories of individuals donating their kidney to their future mother-in-law and other interesting combinations. Kidney donation can only be performed between ABO-matched individuals (i.e. A to A, B to B, but remember blood type O are universal donors). Transplant outcomes are better the more HLA-matched donor and recipient pairs are, hence the desire to perform living related transplants because transplants between siblings who've inherited the same HLA genes from both parents ("0- mismatch kidneys") have better graft outcomes than those with 1- mismatch (typically seen with parents or children of the recipient). However, even without HLA-matching, transplant can be performed with good results (even better than deceased donor transplantation) due to advances in our immunosuppressive treatments. A more detailed discussion of HLA matching can be found in The Handbook of Kidney Transplantation (see reference from lecture notes). To determine if he's a good transplant recipient, we need to ensure he's not at risk for serious cardiovascular disease, doesn't have any occult but life-threatening 4 cancers or infections (which can become life-threatening once he's immunosuppressed) and also assess his ability to be compliant with the challenging treatment regimens he will have to take reliably to prevent rejection. d. We are extremely cautious with the process of selecting kidney donors because, although this amazingly altruistic act is associated with prolonged survival, improved mental-well being and is normally well tolerated, we need to ensure there's no long term risk to the donor. First, we make sure they're medically safe to tolerate surgery and that there's no risk of them transmitting infectious diseases to the recipient. Next, we carefully assess to ensure they are not at risk of themselves developing kidney disease in the future. So, people with diabetes, hypertension, evidence of glomerular disease, etc. are not appropriate kidney donors (they might need that kidney themselves years down the road!). With careful testing, appropriately selected donors can safely donate a kidney without long-term problems such as themselves developing kidney failure, proteinuria, etc. e. Kidney transplantation is associated with better outcomes than either HD or PD (dialysis is associated with a 20% annual mortality, although there are plenty of people who do exceptionally well with dialysis and live for > 20 years). The 1 year graft survival after transplant is over 90%. The kidney half life (the length of time at which half of kidney allografts are lost) is about 10 years for deceased donor transplantation and about 20-30 years for living donor transplant (depends on degree of HLA matching).

3. A 66-year-old Caucasian man presents with a chief complaint of increasing ankle edema and weight gain for several months. There is no recent history of respiratory or skin infection, rash, diabetes, arthritis, use of any medications or exposure to toxins. He denies shortness of breath, chest pain and nausea or vomiting. Physical examination reveals a BP of 140/86 mmHg, pulse of 80 bpm. He appears well and in no acute distress. Lungs are clear to auscultation. Cardiac examination reveals normal rate, rhythm and no murmurs. Abdominal exam is negative for liver or spleen enlargement. He has 3+ peripheral edema. Sodium Potassium Chloride Bicarbonate BUN Creatinine Albumin 138 mEq/L 4.6 mEq/L 103 mEq/L 24 mEq/L 17 mg/dl 1.1 mg/dl 2.3 g/dL Hematocrit 38% Urinalysis: SG 1.016, pH 6.0, no blood, 4+ protein. Urine sediment: No RBC or WBC's. Numerous oval fat bodies, rare fatty casts. 24-hour urine contained 9.7 grams of protein. a. What syndrome is this patient presenting with? What other laboratory abnormalities are seen with this syndrome? What complications might you anticipate occurring in him? b. What is the mechanism of edema in this syndrome? c. What is the differential diagnosis? 21-10 d. What blood tests (if any) could be obtained to narrow the differential diagnosis? e. What would you think biopsy might show? f. What do you think the biopsy might show if his ethnicity was African American?

Case 3 a. This is nephrotic syndrome which is characterized by proteinuria (>3.5 grams/24 hours), hypoalbuminemia, edema and hyperlipidemia. We should check a cholesterol panel to confirm the fourth part of the syndrome. Other characteristic findings in nephrotic syndrome are due to losses of various proteins in the urine. For instance, patients with nephrotic syndrome typically have low vitamin D levels (25-OH vitamin D) due to loss of vitamin D binding protein in the urine (along with bound vitamin D). Other important proteins excreted in the urine with nephrotic syndrome include proteins involved in the coagulation cascade (possibly contributing to the hypercoagulability seen with nephrotic syndrome) and immunoglobulins (possibly contributing to the observed increased susceptibility to infections). b. Althoughtheedemainnephroticsyndromeisoftenexplainedasarterial underfilling due to hypoalbuminemia (similar to decreased effective circulating volume described in cirrhosis and CHF) there is more recent convincing evidence for a direct increase in renal tubular sodium reabsorption playing the major role here. It is more complicated than simply thinking of hypoalbuminemia causing oncotic pressure difference to lead to fluid leaving capillaries into the interstitium. Experimental evidence suggests that in patients with nephrotic syndrome, there is increased activation of the epithelial sodium channel (ENaC) in the cortical collecting duct. The mechanism appears to be mediated via plasmin, a urinary serine protease, which activates ENaC. Plasminogen is one of the many proteins that are abnormally excreted in the urine in patients with nephrotic syndrome, where it is converted to plasmin by tubular urokinase- type plasminogen activator. Experimental evidence supports the concept that the plasmin then activates ENaC, leading to sodium reabsorption and resultant edema from volume overload. c. A simple way to think about nephrotic syndrome is to divide into systemic diseases and renal-limited diseases. Systemic diseases that cause nephrotic syndrome include 1) diabetic nephropathy (the most common glomerular disease worldwide, actually), 2) lupus nephritis (class 5), and 3) amyloidosis. Common renal-limited diseases that cause nephrotic syndrome include minimal change disease (MCD, most common in kids, 4 adolescents but also seen in adults), membranous nephropathy (most common in adults), focal and segmental glomerulosclerosis (FSGS, 2nd place in adults but rising quickly in prevalence), among others. In this case, there's not much pointing towards any systemic disorder such as diabetes or amyloidosis. The most likely non-systemic (i.e. non- diabetic) cause of nephrotic syndrome in adults in membranous nephropathy. This disorder can be seen in patients with HBV infection, SLE (WHO class 5), and other relatively rare associations with certain cancers, infections, and medications. However, the vast majority of membranous nephropathy patients have no such associations, and were previously described as "idiopathic" membranous nephropathy. However, decades of research by the renal section here at BUSM have identified phospholipase A2 receptor (PLA2R) as the target antigen in most cases of idiopathic membranous (and interestingly, antibodies to PLA2R are not present in secondary cases of membranous nephropathy). Keep your eyes out for possible future diagnostic tests and treatments based on this discovery. Certainly, FSGS and MCD are reasonable thoughts as well (in addition to other less prevalent disorders) and cannot really be excluded without a kidney biopsy. d. Serological tests are not quite as helpful in nephrotic diseases as they are in nephritic disease. However, checking ANA, anti-double stranded DNA, hepatitis B and C serologies (HBV associated with membranous nephropathy), HbA1c and serum/urine protein electrophoresis (SPEP, UPEP for paraproteinemia diseases like amyloidosis) are reasonable tests in general. In the past few years, our understanding of the pathogenesis of membranous nephropathy has evolved to where now testing for antibodies to PLA2R is a routine diagnostic test which is part of the workup of nephrotic range proteinuria and also a marker of disease activity and response to therapy. e. Themostlikelybiopsyfindingwouldbethickeningoftheglomerular basement membrane on light microscopy, "spikes" on silver staining of light microscopy, diffuse IgG and complement deposition on IF, and subepithelial electron dense deposits on electronic microscopy. Keep in mind though that focal and segmental glomerulosclerosis (FSGS) is rapidly increasing in prevalence and may some day overtake membranous in adults as the leading cause of renal-limited nephrotic syndrome. f. Focal and segmental glomerulosclerosis (FSGS) is the most common renal-limited cause of nephrotic syndrome in persons of African American ethnicity. Explaining this increased susceptibility has been an important area of research for years, culminating in a recent study demonstrating a 5 possible genetic association between ApoL1 gene variants and the development of FSGS and hypertension-attributed end stage renal disease (ESRD) in African Americans. This is an exciting area of investigation because these ApoL1 variants are responsible for killing trypanosomes, the cause of African sleeping sickness, and a pathogen that only exists in sub-Saharan Africa. The thought is that heterozygotes for the ApoL1 gene were protected from trypanosomes and thus rose in frequency in the population, however, that 2 copies increases susceptibility to renal dysfunction. This story is rapidly evolving in front of ours but is very reminiscent to what we see with sickle cell anemia, the hemoglobin genes and the protection from malaria. Stay tuned. Taken together with the data on PLA2R (membranous), these findings highlight the current tremendous excitement in nephrology as we are finally beginning to understand the pathogenesis of these disorders, which may lead to future diagnostic tests, treatments and further discovery.

3. A 50-year-old male sought medical care after three days of intractable vomiting of non-bloody, non-bilious emesis. The patient stated that he had recently been evaluated for epigastric pain that was relieved by antacids. He attributed these symptoms to a recently documented peptic ulcer. Physical examination revealed blood pressure 100/60 mmHg, pulse 100 bpm, dry oral mucosa, but no skin tenting. Abdominal examination demonstrated mild epigastric tenderness to deep palpation. Remainder of exam was negative. Laboratory data: Questions: HCT BUN Creatinine Sodium Potassium Chloride Bicarbonate Albumin 38% 35 mg/dl 1.3 mg/dl 137 meq/L 2.7 meq/L 93 meq/L 37 meq/L 4.3 g/dL Arterial blood gas pH 7.50 PCO2 49 mmHg PO2 91 mmHg Urinalysis Spec.Grav. 1.035 pH 5.0 a. What kind of acid-base disturbance does this patient have? b. Why is the PCO2 elevated? c. Describe the pathophysiological processes that resulted in this disorder? d. What urine test could confirm your hypothesis about the pathophysiology of this disorder? e. How would you treat this disorder? f. Some forms of this acid-base disorder are associated with hypertension. Describe the pathophysiology of their development?

Case 3 a. This patient has a metabolic alkalosis. The pH is elevated on the ABG. The elevated HCO3 would explain this, not the elevated PCO2. b. The PCO2 elevation represents the normal adaptation to metabolic alkalosis. For every 1 mEq/L rise in serum HCO3, the expected adaptation would be for a 3 0.6-0.7 mmHg increase in PCO2. His HCO3 is 13 mEq/L higher than normal (24), thus the expected PCO2 should be 8-9 mmHg higher than normal (40). Again, his PCO2 of 49 is an appropriate adaptation. c. Metabolic alkalosis is generated by the loss of hydrogen ions, in his case through the loss of HCl in his vomitus. However, if this was the only problem, his kidneys would quickly correct this problem through excretion of HCO3 in the urine. The maintenance of metabolic alkalosis in this setting requires enough volume depletion to stimulate aldosterone release. Aldosterone causes Na reabsorption and resultant H+ and K secretion in the collecting tubules (this is called paradoxical aciduria, note his low urine pH, which doesn't make sense given the alkalemia). Possibly more importantly, patients with metabolic alkalosis from volume depletion are chloride depleted. Reduced chloride delivery to the collecting tubules plays an important role because of Cl-HCO3 exchangers and H+ Cl co-secretion in this region of the nephron. The final factor that plays a role in the maintenance of metabolic alkalosis is the presence of hypokalemia, which stimulates the H+/K+ pump in the collecting tubules, exacerbating the metabolic alkalosis itself. d. Urine chloride should be low (<20 mEq/L) in this form of metabolic alkalosis. This is an also an important factor in its pathogenesis. This is called chloride responsive metabolic alkalosis. e. If urine chloride is low as we suspect, the treatment of this disorder is to replace chloride, with either sodium and/or potassium as the cation. Giving KCl makes intuitive sense because of the role of hypokalemia in the maintenance of this disorder, but giving too much potassium supplementation is risky. Adminstering NaCl also is intuitively appealing as this may correct the volume depletion that's leading to aldosterone secretion. Probably the best course of action is to give some NaCl and some KCl, so one can infuse normal saline with additional KCl added to the fluid. f. There are a large number of disorders of metabolic alkalosis, hypokalemia and hypertension, although they are less common than the volume depletion chloride responsive metabolic alkaloses. They all have common pathophysiology with excessive adrenal corticosteroids or mineralocorticoids playing the key role. A partial list of these disorders includes primary hyperaldosteronism, Cushing's syndrome, corticosteroid administration, among others. All of these conditions present with hypertension, distinguishing themselves from vomiting, where blood pressure is low-normal. Urine chloride levels are usually elevated, which gives these disorders the term chloride resistant metabolic alkalosis (administering chloride will not correct the electrolyte abnormalities). The treatment focuses on decreasing mineralocorticoid or corticosteroid levels, either medically or surgically.

4. A 5-year-old boy is referred to a pediatric nephrologist for edema. You are working in the office and evaluate the boy. His mother tells you that he has been well, without medical problems, until 2-3 weeks ago when he developed swelling in his legs, abdomen, arms and even his face. There is no history of respiratory or skin infection, rash, diabetes, arthritis, use of any medications or exposure to toxins. Family history is negative for any kidney diseases. Physical examination reveals a BP of 110/72 mmHg, pulse of 84 bpm. He appears well and in no acute distress. Lungs are clear to auscultation. Cardiac examination reveals normal rate, rhythm and no murmurs. Abdominal exam is negative for liver or spleen enlargement. He has 3+ peripheral edema as well as pitting edema on his abdominal wall and arms. His face and eyes look puffy. Laboratory studies are unrevealing except for a serum albumin of 1.6 gm/dL. Urinalysis: SG. 1.015, pH 5.0, No blood, 4+ protein, otherwise negative Urine protein to creatinine ratio: 12.3 Urine sediment revealed no cells or casts but does demonstrate oval fat bodies which polarize to form Maltese crosses under the polarizing lens of the microscope. a. What syndrome is this patient presenting with? b. What is the differential diagnosis of this syndrome? c. What blood tests (if any) could be obtained to narrow the differential diagnosis? d. Would you perform a kidney biopsy? What do you think biopsy might show? e. How would you treat this boy?

Case 4 a. Nephrotic syndrome. See 3a. b. See 3c. However, in the pediatric population the most likely diagnosis by far is minimal change disease. Less likely but possible is focal and segmental glomerulosclerosis (FSGS), including various recently described genetic disorders resulting in FSGS and nephrotic syndrome. Expect to hear more about these in the future as we further identify the cellular biology of the podocyte and slit diaphragm. c. See 3d. However, these are probably overkill in the pediatric population because of the extremely high likelihood of MCD. d. Intheoryyoucouldperformabiopsybutinpractice,pediatric nephrologists don't do this because of 1) the high prevalence of MCD (and its rapid and impressive response to corticosteroids) and 2) the difficulty of performing a biopsy in kids. Thus, in practice most would just treat this boy with prednisone and if his nephrotic syndrome remits with treatment, the presumptive diagnosis is MCD. If it doesn't get better in about 4 weeks, biopsy is then planned to look for other explanations, in particular the familial forms for FSGS. e. See4d.

4. A 40-year-old woman with known chronic alcohol use with resultant liver failure and cirrhosis had the following laboratory data obtained at the time of a routine medical evaluation. No further information is available: Serum electrolytes Sodium 134 mEq/L Potassium 3.1 mEq/L Chloride 104 mEq/L Bicarbonate 19 mEq/L Albumin 3.6 g/dL Questions: Urinalysis pH 7.0 Negative glucose, ketones 1+ bili a. b. c. Based on the serum electrolytes alone, what potential acid-base disorders does this patient have? Arterial blood gas showed the following results: pH 7.45, PCO2 28 mmHg, PO2 95 mmHg What acid-base abnormality does this represent? How can you explain these values? If instead, the arterial blood gas values were : pH 7.36, PCO2 35 mmHg, PO2 90 mmHg What acid-base abnormality does this represent? How can you explain these values?

Case 4 a. This case highlights the fact that one cannot distinguish between metabolic acidosis and respiratory alkalosis (with metabolic adaptation) based on just looking at the bicarbonate level. This statement is also true for elevated serum bicarbonate, where either a metabolic or respiratory process can be the primary disorder. b. The elevated pH with low PCO2 driving it, points towards a primary respiratory alkalosis. With end stage liver disease, the respiratory center is stimulated leading to increased alveolar ventilation. c. The ABG here helps diagnose a primary metabolic acidosis, perhaps related to decreased hepatic lactate metabolism leading to lactic acidosis.

Rapidly Progressive Glomerulonephritis (RPGN) Rapidly progressive renal failure Oliguria - variable (decreased GFR) Hematuria + red cell casts Hypertension - unusual Proteinuria - variable

Causes of Acute Nephritic Syndrome Primary (limited to the kidneys) • IgAnephropathy • Poststreptococcal GN • Membranoproliferative GN (MPGN) • Crescentic (rapidly progressive) GN Hereditary/Familial • Alport hereditary nephritis Secondary (associated with systemic diseases) • Systemic lupus erythematosus • HenochSchönleinpurpura • Postinfectious GN (e.g. infective endocarditis) • Anti-GBM nephritis (Goodpasture syndrome) • Systemic vasculitis (e.g. Wegener syndrome) • Hepatitis C-associated MPGN ± mixed cryoglobulinemia

The renal histopathology seen in acute cases is quite variable. It often reveals inflammatory changes, but may alternatively show necrosis or evidence of intratubular casts/obstruction. The pathology of chronic interstitial disease is non-specific and often unrevealing of the underlying etiology. Findings typically include: - tubular cell atrophy (flattened cells and tubular dilatation) - interstitial fibrosis; tubules separated by fibrotic material - patchy mononuclear cell infiltrate

Compared with glomerular disease, in tubulointerstitial disease: - there is a lack of significant proteinuria (urine protein-to-creatinine ratio is typically less than 1) and the serum albumin is relatively normal - sterile pyuria and WBC casts >> hematuria and RBC casts - tubular defects (renal tubular acidosis, concentrating deficit, etc.) predominate

An elevated arterial PCO2, increased mineralocorticoid, volume depletion and hypokalemia stimulate renal acidification and bicarbonate reabsorption.

Conversely, a depressed PCO2, decreased mineralocorticoid, volume expansion and hyperkalemia decrease renal acidification and bicarbonate reabsorption.

Membranoproliferative GN (MPGN) Clinical presentation: Mixed features of nephritic and nephrotic syndromes Hematuria and proteinuria are present in all RPGN (occasionally) HTN and decreased GFR are poor prognostic features Secondary MPGN: - any age and sex Often progresses to end stage kidney failure despite treatment MPGN Type I Immune complex disease Reduced C3, C1, C2 and C4 Idiopathic MPGN type I: - M:F 2:3; onset 10-30 years Secondary (esp. adults) o Hepatitis C ± mixed cryoglobulinemia o Other post-infectious e.g. infective endocarditis o Lymphoma

Dense Deposit Disease (MPGN Type II) Idiopathic Reduced C3; normal C1, C4, C2 C3 nephritic factor (C3NEF) - an autoantibody that causes unregulated activation of the alternate pathway of complement Dense deposit disease refers to the characteristic large and dense deposits seen on electronic microscopy in this disorder May be associated with partial lipodystrophy Often recurs after transplantation

Minimal Change Disease (MCD) Clinical features Main cause of nephrotic syndrome in children Renal function and BP usually normal No known serological abnormalities Steroid-sensitive nephrotic syndrome Named MCD because of absence of abnormalities on light microscopy and IF. Pathology Light microscopy (LM): Normal Immunofluorescence (IF): No immune deposits Electron microscopy (EM): Diffuse podocyte foot process effacement Course and treatment >80% respond to corticosteroid or immunosuppressive treatment Relapse is common Does not progress to chronic renal failure Secondary causes Hodgkin's lymphoma, NSAIDs

Diabetic Nephropathy (DN) Leading cause of ESRD and nephrotic syndrome in the Western world Incidence: Type 1 diabetes - ~ 35% Type 2 diabetes - 15-50 % Onset of proteinuria: Type 1 diabetes - 15-20 years after diagnosis of diabetes Type 2 diabetes - interval often much shorter Clinical features: Microalbuminuria - several years prior to overt proteinuria Nephrotic syndrome, in later stages of DN Hypertension Progressive renal failure, usually after the development of high levels of proteinuria Pathology: LM: diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) IF: No immune deposits EM: mesangial expansion and GBM thickening Therapy: Strict glycemic control ACE inhibitor or angiotensin II receptor blocker

Pauci-Immune Glomerulonephritis A high proportion of patients with a severe and Rapidly Progressive form of GN (RPGN) have extensive inflammation in the glomeruli but no immune deposits (so-called pauci- immune). They may have vasculitis (blood vessel inflammation) in other organs and typically have circulating Autoantibodies to Neutrophil Cytoplasmic Antigens (ANCA), but the initiator of glomerular inflammation is uncertain. In such cases cellular immunity, or endothelial damage by circulating anti-neutrophil cytoplasmic antibodies (ANCA) may play a role.

Diagnosis of Glomerular Diseases Clinical features: Renal - nephritic or nephrotic Systemic (other organs e.g. rash, arthritis, pulmonary or GI involvement) Serological abnormalities: Autoantibodies, complement levels, viral Abs, etc Histological features Light microscopy Immunofluorescence microscopy Electron microscopy Pathological terminology Focal - some glomeruli (usually <50%) are affected Diffuse - all or most (>50%) are affected Global - the whole glomerulus is affected Segmental - part of the glomerulus is affected and the rest is normal Proliferative - increased numbers of cells (usually infiltrating inflammatory cells) Sclerosis - there is an increase in extracellular matrix and loss of glomerular cells Collapsing - glomerular capillaries are collapsed Membranous - the GBM is thickened These terms are often combined when multiple patterns are visualized, for instance membrano-proliferative glomerulonephritis or diffuse proliferative glomerulonephritis. Clinical Syndromes Associated with Glomerular Injury Hematuria - micro- or macroscopic (RBC casts) Acute nephritic syndrome Rapidly progressive glomerulonephritis (RPGN) Asymptomatic proteinuria Nephrotic syndrome

Nomal Anion Gap (hypercholeremic) MA

Diarrhea Enterostomy drainage Uteroenterostomy Administration of Carbonic Anhydrase Inhibitors Renal tubular acidosis Ammonium Chloride ingestion

NSAID-induced AIN is a special case; it is often associated with the nephrotic syndrome (up to 75% of cases), and typically lacks most extra-renal features such as fever or rash.

Drugs can cause acute tubulointerstitial ("intrinsic") kidney injury in ways other than AIN: 1. Tubular toxicity e.g., aminoglycosides, cisplatin, amphotericin B, tenofovir 2. Tubular obstruction e.g., acyclovir, indinivir crystals; phosphate nephropathy (below) 3. Acute phosphate nephropathy - iatrogenic form of tubulointerstitial disease due to precipitation of calcium phosphate in/around tubules - occurs following administration of oral phosphate preparations that were commonly given prior to colonoscopy - most of ingested phosphate is excreted in stool (as intended), but a fraction is systemically absorbed and later excreted into the urine - many of the cases described are in elderly females, in whom a near-normal serum creatinine may mask a GFR that is actually quite low - volume depletion facilitates precipitation of filtered phosphate load, leading to tubular obstruction - urinary sediment is usually bland, without proteinuria - the creatinine may improve with time, but usually does not return to baseline - increased awareness and reduced doses of phosphate in bowel preparations should help reduce incidence - another possible etiology of phosphate nephropathy is acute tumor lysis syndrome with massive release of cellular phosphates

D. Several other medications are well established causes of chronic renal toxicity: - antiretroviral agents such as tenofovir - chemotherapeutic agents (ifosfamide, cisplatin) - calcineurin inhibitors (cyclosporine, tacrolimus)

E. Heavy metals (lead and cadmium) - prolonged exposure can lead to chronic interstitial nephritis - due to known health risks and consequent removal of lead from most commercial products and fuels, significant exposures are much less common - occupational exposure still possible: manufacture or destruction of batteries, shooting ranges, lead paint removal, or manufacture of alloys and electrical equipment (cadmium) - ingestion of moonshine whiskey distilled in lead-tainted containers has been one of the more frequent exposures to lead - early signs of chronic lead intoxication are due to proximal tubule dysfunction, particularly hyperuricemia due to diminished urate secretion - triad of 'saturnine gout' (from the hyperuricemia), hypertension and renal insufficiency, should prompt a practitioner to specifically ask about lead exposure - in those patients with CIN of unclear origin and an elevated total body lead burden, repeated treatments of lead chelation therapy may slow the decline in GFR

TUBULOINTERSTITIAL DISEASE Refers to a broad group of acute and chronic disorders that variably affect the tubular and interstitial components of the kidney Normal cellular components of the tubulointerstitium: - tubular cells (proximal, loop of Henle, distal, collecting duct) - interstitial cells (fibroblast-like) - peritubular capillary network (endothelium and pericytes) - dendritic cells (antigen presenting cells) and other resident immune cells

Functions (and clinical problems caused by failure to perform each of these functions): - Tubular o reclamation of filtered bicarbonate, electrolytes, amino acids, proteins, glucose (Fanconi syndrome - see section on Multiple Myeloma) o acidification of urine via generation of bicarbonate and secretion of H+ (distal renal tubular acidosis (RTA)) o water and sodium homeostasis (nephrogenic diabetes insipidus, the inability to concentrate urine) o 1α-hydroxylation of 25-(OH) vitamin D to 1,25-(OH)2 vitamin D (hypocalcemia, secondary hyperparathyroidism) - Interstitial o erythropoietin production to control red cell mass (anemia of CKD) o provision of vascular supply for perfusion of metabolically-active tubular epithelium and removal of reclaimed nutrients (ischemic ATN) o structural matrix for support of nephron (age- and disease-associated loss of renal mass) o antigen presentation (involved in interstitial nephritis)

All metabolic acidosis can be thought of as resulting from the equivalent of an increased amount of fixed acid. In other words,

GI or renal loss of bicarbonate is functionally the same as the overproduction of hydrochloric acid (for instance, as occurs with the ingestion of ammonium chloride).

Glomerular Basement Membrane (GBM) Composition Type IV collagen - GBM contains heterotrimers of 3, 4 and 5 chains of type IV collagen Provides structural integrity and tensile strength Gene for 5 is on X chromosome; 3 and 4 are on chromosome 2 Mutations in 5 chain - X-linked hereditary nephritis (Alport syndrome) Autoantibodies to 3 chain - anti-GBM nephritis (Goodpasture syndrome) Laminin - cell adhesion Heparan sulfate proteoglycans - determine porosity and confer charge, which limits negatively charged proteins such as albumin from penetrating the GBM.

Glomerular Disease - The glomerulus is the filtering unit of the kidney. Each day the glomeruli together produce ~180 L of protein-free plasma ultrafiltrate. The glomerulus is also critical in disease: it is the site of injury in over 50% of renal conditions. The hallmarks of glomerular disease are increased glomerular permeability to proteins (leading to proteinuria), hematuria, and reduced GFR (possibly leading to azotemia). There are a wide array of conditions that may injure the glomerulus. These conditions may be grouped in terms of the clinical syndromes that they cause (nephritic vs. nephrotic), grouped by their appearance on pathological examination (appearance on light microscopy, fluoroscopy, electron microscopy), or considered as isolated diseases.

RPGN from Immune Complex GN Several renal limited or systemic diseases shown in the figure above may present with RPGN, particularly when the underlying pathological lesion is a severe proliferative and crescentic GN. Among those listed, lupus nephritis is the most common. SLE nephritis IgA nephropathy Henoch Schonlein purpura Cryoglobulinemic vasculitis Membranoproliferative GN

Hereditary / Familial causes of Nephritic Syndrome Alport Hereditary Nephritis and Thin Basement Membrane Disease Mutations in 5 type IV collagen cause X-linked hereditary nephritis and account for ~85% of cases of Alport syndrome. Males - Hematuria from birth Proteinuria - adolescence Progressive renal failure Deafness Ocular defects Fragmented GBM Females - Hematuria from birth No proteinuria or renal failure Thin GBM Mutations in 3 or 4 type IV collagen Homozygous - autosomal-recessive Alport syndrome in either sex Heterozygous- autosomal-dominant microscopic hematuria with thin GBMs in either sex

Causes of Isolated Hematuria (none or minimal proteinuria, normal GFR) Primary (limited to the kidneys) Hereditary/Familial IgA nephropathy Thin basement membrane disease

Histopathology in Diseases that Cause Acute Nephritic Syndrome Diffuse proliferative GN e.g. Poststreptococcal GN Focal and segmental proliferative GN e.g. IgA nephropathy Crescentic GN e.g. Goodpasture syndrome, ANCA-associated vasculitis Membranoproliferative GN e.g. hepatitis C-associated MPGN

CHRONIC TUBULOINTERSTITIAL DISEASE (or chronic interstitial nephritis; CIN) Clinically important, since interstitial damage (as measured by the proportion of the kidney biopsy showing interstitial fibrosis and tubular atrophy) is a better predictor of future renal dysfunction than is the degree of glomerular injury. Due to similar clinical and biopsy features among the diverse etiologies of CIN, it is imperative to obtain a thorough clinical history including prescribed and over-the-counter medications, as well as other potentially toxic exposures.

I. Drugs and Toxins A. Lithium - used in treatment of manic-depressive illness; has very narrow therapeutic range - most significant effect is nephrogenic diabetes insipidus (renal concentrating defect) leading to polyuria and secondary polydipsia o lithium enters tubular cell via the ENaC sodium channel, inhibits adenylate cyclase, and leads to decreased luminal expression of aquaporin-2 water channels o the resulting free water losses (manifested by polyuria) lead to mild hyper- natremia, stimulating thirst (polydipsia) - the association with chronic interstitial nephritis is controversial and the mechanism unknown - biopsy findings in patients chronically treated with lithium reveal tubular atrophy and dilatation, characteristic microcyst formation, interstitial fibrosis and (to a lesser extent) glomerulosclerosis; there is little to no inflammatory infiltrate

II. Reflux nephropathy - historically, has (incorrectly) been referred to as chronic pyelonephritis - instead, it is a consequence of vesicoureteral reflux (VUR) or other urological anomalies in early childhood - pathophysiology: o VUR stems from abnormal retrograde urine flow from the bladder into the ureters and kidney due to an incompetent ureterovesical valve (primary reflux) or from any condition that leads to an abnormally high pressure in the bladder (secondary reflux) o high pressure reflux coupled with recurrent urinary infections in early childhood leads to patchy interstitial scarring, tubular atrophy and secondary FSGS, in part due to nephron dropout - affected adults are frequently asymptomatic and may be detected for the first time during pregnancy or during routine physical examination (e.g., elevated creatinine, proteinuria) - historical clues to the diagnosis include a history of recurrent urinary infections, nocturnal enuresis and hypertension in childhood - characterized clinically by variable renal insufficiency, hypertension, mild to moderate proteinuria and unremarkable urine sediment - when both kidneys are affected, the disease often progresses inexorably over several years to end-stage kidney disease (ESKD) despite the absence of ongoing urinary infections or reflux - renal ultrasound in adults characteristically shows asymmetric small kidneys with irregular outlines, thinned cortices and regions of compensatory hypertrophy - no indication for surgical intervention in adolescents or adults with reflux nephropathy - aggressive control of blood pressure with ACE inhibitors or AngII receptor blockers (ARB) and other agents is very effective in reducing proteinuria and may significantly forestall further deterioration of renal function

III. Sickle Cell Nephropathy - progressive disease attributable to chronic sickling of red blood cells in the kidney microvasculature, leading to regional occlusions as well as heme-mediated oxidative damage to the tubulointerstitium - advanced or end-stage kidney disease may develop in as many as 20% of patients with sickle cell disease - sickling occurs in the inner medulla, a site suited to such a phenomenon because of its relative hypoxia and high osmolality - microvascular occlusion leads to: 1. severe changes in the tubulointerstitial compartment 2. nephronloss,compensatoryhyperfiltrationinremainingnephrons,and secondary FSGS - first clinical manifestations are defects in urinary concentration, typically presenting in childhood and irreversible after the age of 15 - tubular damage is also manifested by an incomplete distal RTA and relative hyperkalemia, although often only in the setting of a superimposed decrease in GFR - chronic sickling, anemia, and degeneration of the medullary blood supply all contribute to papillary necrosis Papillary necrosis is usually a progressive, asymptomatic process due to infarction of, or other lethal/toxic injury to, the renal papillae; it can present acutely with gross hematuria, renal colic, or passage of sloughed tissue - the glomerular hyperfiltration that occurs early in the disease may initially cause relatively low serum creatinine values and thus obscure the degree of ongoing renal damage - with advancing disease, serum creatinine increases above the normal range and renal ultrasound may show increased echogenicity of the renal pyramids - clubbing of the calyces seen on IVP or CT urography can be a useful sign of papillary necrosis - avoidance of sickle crises as far as possible is paramount for preventing such changes, although initiation of ACE inhibitors and possibly hydroxyurea may be beneficial in patients with established disease

1. Diseases that cause the Nephritic Syndrome Post-streptococcal Glomerulonephritis Mainly affects children and adolescents Epidemic/endemic and sporadic cases Presents with acute nephritic syndrome 1 - 3 weeks after pharyngitis or impetigo with nephritogenic strains of group A, ß-hemolytic streptococci Serology: elevated anti-streptococcal antibodies; reduced C3; normal C1, C2 and C4 May develop acute renal failure but almost all epidemic/endemic cases resolve completely Some sporadic cases develop mild, long-standing renal dysfunction

IgA nephropathy Typical presentation - Recurrent macroscopic hematuria during or soon after URI ± persistent microscopic hematuria Normal BP, renal function, urine protein measurement and serologic tests Focal and segmental proliferative GN with mesangial deposits of IgA ± IgG and C3 Prognosis is good in ~60% of cases Progressive renal failure occurs in ~40% of cases Poor prognostic indicators - Heavy proteinuria, hypertension, or decreased GFR on initial presentation

Determinants of Glomerular Filtration Rate Transmembrane hydrostatic pressure (∆P) Filtration surface area (S) Hydraulic conductivity of the capillary wall (K) "Pore" length (GBM thickness) "Pore" density (slit pore frequency) GFR = ∆P x Kf (K x S) The glomerular capillary wall is a size- and charge-selective filter; i.e. plasma proteins are restricted from passage into the urine by both their molecular size and charge.

Immunopathogenesis of Glomerular Disease Many forms of glomerulonephritis (GN) in man are mediated by immunologic mechanisms. In minimal change disease, where glomerular injury is present without immune deposits, the underlying mechanisms are poorly understood, and there are no clearly analogous animal models. Many cases of GN, however, are associated with some form of immune deposits, the nature of which can be ascertained with reasonable certainty by comparison with findings in experimental models and, in some cases, by direct identification of antigens or antibodies in human tissue. The most common pattern of glomerular immune deposits by immunofluorescence (IF) and electron microscopy (EM) is the discontinuous, granular or "lumpy-bumpy" pattern characteristic of nephritis mediated by immune complex deposits. Immunoglobulin deposition in an uninterrupted, linear pattern along the GBM by IF is less common and is characteristic of anti-GBM antibody mediated GN (known as Goodpasture's Syndrome). Although there is substantial evidence that crescentic GN from systemic vasculitis is immune mediated, there are no (or few) glomerular immune deposits. Hence it is termed pauci- immune GN.

Anion Gap = Na+ - [Cl- + HCO-3]

In fact, the finding of an increased anion gap is diagnostic of the presence of a metabolic acidosis whether or not an acidemia exists (i.e serum pH is > 7.40, spend some time thinking about this important point).

The major buffers in urine are phosphate and ammonia.

In the collecting duct lumen the secreted hydrogen ions react with phosphate and ammonia (see right image) to form titrable acidity.

Systemic Amyloidosis Clinical: Primary (AL, Ig light chain) and secondary (AA) amyloidoses may affect the kidneys Nephrotic syndrome with progressive renal failure May also cause tubular dysfunction - renal tubular acidosis and nephrogenic diabetes insipidus Multisystemic involvement - e.g. heart failure, peripheral and autonomic neuropathy, gastrointestinal malabsorption, immotility and bleeding Pathology: LM: Congo-red positive deposits in glomeruli IF: Positive staining for lambda or kappa light chains EM: 8-12nm fibrils Serology: Free lambda or kappa light chains in serum and urine Treatment: Aggressive chemotherapy and autologous stem cell replacement

Light-chain-deposition disease Clinical: A systemic disease in which monoclonal immunoglobulin light chains, usually kappa, are deposited in vessel walls of multiple organs especially the renal glomeruli Heavy albuminuria is the rule accompanied by nephrotic syndrome in about 30% of cases Microscopic hematuria and hypertension are common Pathology: LM: nodular sclerosing glomerulonephritis indistinguishable from diabetic glomerulosclerosis. Congo red stain is negative IF: Positive staining for kappa (or lambda) light chains EM: Non-fibrillar deposits in mesangial nodules, GBM , tubular basement membranes and vessel walls Serology: Free kappa (or lambda) light chains in serum and urine May occur in patients with multiple myeloma Course and Treatment: Progressive renal failure develops in almost all cases within weeks to years Recurs after renal transplantation unless remission induced first Aggressive chemotherapy and autologous stem cell replacement can halt progression

Crescentic Glomerulonephritis Rapidly progressive GN (RPGN), also called crescentic GN (for the characteristic crescents of cellular debris found in glomeruli) can be caused by many of the diseases that cause nephritic syndrome; it presents with hematuria, red cell casts, rapidly deteriorating renal function and variable proteinuria, hypertension and oliguria. The underlying glomerular lesion is usually a proliferative or necrotizing glomerulonephritis with crescents in over 50% of glomeruli. The causes may be conveniently classified according to the pattern of immunofluorescent staining of glomeruli on renal biopsy (see above figure). Renal Biopsy

Linear GBM deposits 11% (anti-GBM antibody disease) With pulmonary hemorrhage • Goodpasture syndrome Renal limited • Anti-GBM GN Granular immune deposits 8% (immune complex disease) Systemic symptoms • SLE • HSP • Postinfectious • Cryoglobulinemia Renal limited • IgA nephropathy • MPGN No immune deposits (pauci-immune) 81% (ANCA-associated disease) Systemic vasculitis •Wegener granulomatosis •Microscopic polyangiitis •Churg-Strauss syndrome Renal limited •Pauci-immune GN

Lupus Nephritis Pathologic classification (ISN/RPS modification of WHO classification): Class I: minimal mesangial lupus nephritis Class II: mesangial proliferative lupus nephritis Class III: focal proliferative lupus nephritis (<50% of glomeruli involved) Class IV: diffuse proliferative lupus nephritis (>50% of glomeruli involved) o Class IV-S (segmental; <50% of glomerular tuft affected) o Class IV-G (global; >50% of glomerular tuft affected) Class V: membranous lupus nephritis Class VI: advanced sclerotic lupus nephritis Clinical features: Class I: No abnormalities Class II: Microscopic hematuria, mild proteinuria, normal renal function Class III and IV: Nephritic-nephrotic syndrome, variable renal insufficiency, ± hypertension, ANA+, anti-dsDNA+, anti-Smith+, reduced C3 and C4 Class V: Nephrotic syndrome, ANA+, C3/C4 often normal Class VI: Irreversible chronic renal failure Treatment: Classes III-V require corticosteroids and immunosuppressive drugs as well as anti- hypertensives to control BP, diuretics to control edema and ACE inhibitors or angiotensin receptor blockers (ARBs) to reduce proteinuria.

Membranoproliferative Glomerulonephritis (MPGN) Often has mixed nephritic/nephrotic presentation Covered in detail under the diseases that cause nephrotic syndrome

Focal and Segmental Glomerulosclerosis - FSGS Idiopathic FSGS Common cause of adult nephrotic syndrome esp. among Blacks Steroid-insensitive nephrotic syndrome; often progressive decline in GFR Pathology Light microscopy (LM): Glomeruli segmentally sclerosed Immunofluorescence (IF): No immune deposits Electron microscopy (EM): Diffuse podocyte foot process effacement Treatment Some patients respond after prolonged treatment with corticosteroids, others respond to immunosuppressive treatment e.g. cyclosporin Hereditary causes- podocin, a-actinin, TRPC6 mutations Secondary causes- chronic reflux nephropathy, sickle cell anemia, obesity, renal ablation HIV-associated nephropathy - collapsing glomerulopathy, a severe form of FSGS, with massive proteinuria and nephrotic syndrome and rapid deterioration of renal function; progression may be slowed by HAART.

Membranous Nephropathy (MN) Clinical features Main cause of idiopathic nephrotic syndrome in adults Renal function and BP usually normal initially Pathology Light microscopy (LM): GBM thickened Immunofluorescence (IF): granular glomerular capillary deposits of IgG and C3 Electron microscopy (EM): Subepithelial immune deposits, diffuse podocyte foot process effacement and GBM expansion between and around the deposits Serology Recent discovery by BUSM investigators of the target antigen - phospholipase A2 receptor (PLA2R) and circulating anti-PLA2R autoantibodies in patients with MN Course and treatment ~20-30 remit spontaneously; ~15-25% progress to ESRD Respond to immnunosuppressive treatment if given early in course Secondary causes Class V lupus nephritis, certain drugs, hepatitis B

Acute Nephritic Syndrome Acute onset of: Hematuria - macroscopic or microscopic + red cell casts Hypertension Oliguria Edema - moderate Proteinuria - mild to moderate Decreased GFR

Nephrotic Syndrome Insidious onset of: Severe proteinuria Hypoalbuminemia Edema - more severe than in nephritic syndrome Associated with: o Hyperlipidemia o Hypercoagulability o Lipiduria GFR often not reduced

The effectiveness of this buffer system derives from

PCO2, is regulated by the rate of alveolar ventilation and the other component, bicarbonate, is regulated by renal mechanisms. Both of these components are adjusted by physiological compensatory mechanism to minimize changes in pH.

Pathological Processes Involved in Tubulointerstitial Disease

Pathological process Examples Infection Immune-mediated Ischemia Iatrogenic/Medications Ingested/Inhaled toxins Inherited Malignancy Metabolic Mechanical / Physical Pyelonephritis, BK polyomavirus nephropathy of allograft Sjögren's syndrome, tubulointerstitial disease with uveitis (TINU) Acute tubular necrosis Acute allergic interstitial nephritis, acute phosphate nephropathy Heavy metal exposure, aristolochic acid Autosomal dominant tubulointerstitial kidney disease Lymphoma, myeloma Hypercalcemia, hyperuricemia Radiation, tubular obstruction

Classification and Causes of Nephrotic Syndrome Primary Minimal change disease (MCD) Focal and segmental glomerulosclerosis (FSGS) Membranous nephropathy (MN) Membranoproliferative GN (MPGN) Hereditary Congenital nephrotic syndrome (NPHS1) - nephrin mutation Steroid-resistant nephrotic syndrome (NPHS2) - podocin mutation Several others Secondary Diabetic glomerulosclerosis Lupus nephritis (class V SLE, membranous pattern) Infection - HIV, hepatitis B and C viruses Amyloid Drugs - NSAIDs, penicillamine, gold, other Cancer - lymphoma (MCD, MPGN seen on biopsies), solid tumors (MN) Pre-eclampsia

Proteinuria The majority of protein excreted in the urine in patients with glomerular disease is albumin. Normal Total urine protein excretion <150 mg/day Abnormal Microalbuminuria: 30 - 200 mg albumin/day (or mg albumin/g creatinine) Asymptomatic proteinuria: 0.2 - 2 g protein/day Nephrotic syndrome: > 2.5 - 3 g protein/day Urine protein/creatinine ratio (can be done on a single voided specimen - "spot" urine) < 0.2 ≈ < 0.2 g/day 0.2-2 ≈0.2-2g/day >2 ≈2g/day

II. NON-INFECTIOUS A. Acute tubular necrosis (discussed at length in lecture on Acute Kidney Injury) B. Acute allergic interstitial nephritis (AIN) - an immunologically-induced hypersensitivity reaction to an antigen (drug or infectious agent) - in the pre-antibiotic era, AIN most common with infection (scarlet fever, diphtheria) - now most likely to occur with therapeutic agents such as antibiotics (amoxicillin, ciprofloxacin), proton pump inhibitors (omeprazole), diuretics, NSAIDs, etc. - evidence that acute allergic interstitial nephritis is immune-mediated: o AIN usually occurs in only a small % of those taking the drug o AIN is not dose-dependent o associated with extra-renal manifestations of hypersensitivity (e.g., rash) o quickly recurs with accidental re-exposure to offending agent - mostly cell-mediated; immune deposits (which would suggest a humoral response) are not found on renal biopsy - can be distinguished from pyelonephritis by the relative absence of neutrophils in AIN as well as a failure to isolate any microorganisms from the kidney or urine - the prototypical drug causing AIN was methicillin (1960s and 1970s), and the 'classic' features of the disease come from these experiences

Renal features: - acute impairment of renal function - mild proteinuria (less than 1 g daily) - most patients will have some hematuria (and occasionally RBC casts) - pyuria (WBC in urine) is even more common; WBC casts often present - urinary eosinophils may be detected with Wright's or Hansel's stain, but finding is neither sensitive nor specific (can also be seen in glomerulonephritis, atheroembolic disease, ATN, rejection of renal allograft) - flank pain can occur in 1/3 of patients due to inflammation-induced capsular distention - blood pressure is usually normal, with no peripheral edema Extra-renal features (more common in "classic" AIN): - low-grade fever - maculopapular rash - mild arthralgia - peripheral eosinophilia Biopsy features: - inflammatory infiltrates within interstitium; often patchy and concentrated in deep cortex and outer medulla - T cells and monocyte/macrophages are typical - variable presence of eosinophils, plasma cells, and rare PMNs - tubulitis (WBCs within confines of tubular basement membrane) and granuloma formation may also be noted Treatment and prognosis - identification of the drug may be difficult, especially in hospitalized patients who are taking multiple medications - treatment is discontinuation of the offending agent, if it can be identified; early discontinuation carries a better prognosis - although a brief course of steroids such as prednisone may hasten and allow a more complete recovery, there are no randomized trials that show these effects - course of AIN not always benign; the creatinine may remain elevated in up to 40% of patients after an episode of AIN, due to interstitial fibrosis that results from maladaptive resolution of prolonged inflammation

The anion gap includes: sulfate, phosphate, anions of organic acids, and proteins.

Since blood is uncharged, the sum of the positive charges equals the sum of the negative charges. The anion gap can be estimated from the differences between the concentration of the principle cations and anions.

With this accumulation of acid the excess hydrogen ion is buffered by bicarbonate as depicted by the following equation: H+ + HCO-3 H2CO3 CO2 + H2O

Since respiration is stimulated in response, the CO2 is "blown off," lowering PCO2 to a value less than normal. Also, about half of the excess hydrogen ion diffuses into cells. This results in the counter-movement of a cation from the intracellular to the extracellular space. The cation is primarily potassium. Therefore, frequently one observes hyperkalemia in this disturbance. The longer-term adaptive response to metabolic acidosis will also include enhanced net acid secretion by the kidney.

Increased Anion Gap MA

Starvation Ketoacidosis Alcoholic Ketoacidosis Diabetic Ketoacidosis Ingestion of salicylate methanol, ethylene glycol Renal failure Lactic acidosis

b) Dipstick - test for protein (discussed below) 4. Dipstick is a chemically impregnated strip of cellulose that can be made responsive to protein, blood, glucose, ketones, hydrogen or urobilinogen in urine. In relative terms it is inexpensive, available, quick and informative. However, it is subject to error and misinterpretation. The dipstick has gained widespread acceptance in clinical practice. It is therefore important that this test be used and interpreted appropriately. Protein: At the bedside and in many laboratories the tetrabromphenol blue-citric acid impregnated dipstick has replaced other techniques - e.g., precipitation with sulfosalicylic acid (SSA) - as the method of choice in screening for proteinuria. This has occurred despite ample evidence that the dipstick responds primarily to albumin and may fail to detect Bence-Jones protein and other globulin fractions of potential pathological importance in the urine. The protein-sensitive dipstick is best used in conjunction with the SSA test. Together, the results of both procedures are more informative than those with either alone. A negative result with each is presumptive evidence of inconsequential proteinuria. Positive results with both indicate albuminuria. When SSA is strongly positive but the dipstick is negative or weakly reactive, globulinuria is suggested. Confirmation of its presence by immunodiffusion or electrophoresis may lead to consideration of otherwise unsuspected diagnoses - e.g., multiple myeloma. Red cells: When impregnated with orthotolidine blue and peroxide, the dipstick becomes sensitive to the presence of hemoglobin and myoglobin (organic iron) in urine. Too frequently its use is substituted for careful microscopic examination of the urinary sediment, despite evidence that the dipstick fails to detect small numbers of intact red cells. This job is better done by the microscope. The value of the dipstick lies in its capabilities to detect hemoglobin released from lysed red cells in the urinary supernatant and to alert the nephrologist to search for blood elements in the sediment. Both sediment and supernatant should be examined with the dipstick while urinary formed elements are scanned with the microscope. Only if all three approaches yield negative results can any urine be considered free of blood. The iron-sensitive dipstick is under-utilized in the differential diagnosis of red urine. Red supernatant in the presence of a negative dipstick reaction suggests prophyrins, beet pigment, pyridium or some other nonorganic iron containing pigment. A positive dipstick reaction in the supernatant and negative sediment examination should lead to a consideration of the diagnosis oh hemolysis or rhabdomyolysis. The dipstick has reagents that are also sensitive to glucose, ketones, bilirubin and urine pH.

Summary of different clinical tests available for proteinuria Semi-quantitative tests: Urine dipstick - sensitive to albumin; much less so to globulins - measures concentration not absolute excretion rate of albumin; - must be related to degree of urine concentration Salicylsulfonic acid (SSA) test - sensitive to all urine proteins albumin and globulin - measures concentration of protein - must be related to degree of urine concentration Quantitative tests: Total protein excreted per day: absolute quantity of all proteins in urine measured; normal < 150 mg/day requires timed (ideally 24 hour) collection of urine; Microalbuminuria - albuminuria below the range detectable by conventional tests; requires sensitive radio-immunoassay

Henoch-Schönlein Purpura (HSP) Renal involvement same as in IgA nephropathy Skin vasculitis with purpura, arthralgia and GI bleeding

Systemic lupus erythematosus (SLE) Autoimmune disease affecting many organ systems Classical features - "butterfly" rash, alopecia, polyarthritis, immune hemolytic anemia, leucopenia and thrombocytopenia, CNS vasculitis, nephritis. Serological features - antinuclear antibodies (ANA), anti-dsDNA, other autoantibodies, low serum complement C3 and C4.

The Anion Gap

The anion gap represents the anions usually not measured with a standard set of electrolyte determinations (that is, all anions but chloride and bicarbonate).

In respiratory acidosis the opposite renal response occurs. An increase in arterial PCO2 stimulates urine acidification. Therefore, bicarbonate reabsorption and de novo generation of bicarbonate by the kidney is enhanced. Both processes result in an increased serum bicarbonate concentration that will diminish the fall in pH.

The compensatory mechanism for respiratory acid-base disturbances rarely completely corrects the change in extracellular pH. The degree of compensation is also variable among different patients and is given in the acid-base nomogram.

The CO2 generated in this reaction is eliminated by ventilation and sodium bicarbonate is replaced by NaA, where A- is the anion of an organic acid such as acetate or lactate.

The decrease in serum bicarbonate is offset by an increase in unmeasured anions.

Since the stimulus for increased ventilation is acidemia, the drive for the compensation diminishes as correction occurs.Therefore, complete compensation is not possible.

The degree of compensation is somewhat variable, but in uncomplicated metabolic acidosis the PCO2 should certainly be reduced below normal. Nomograms have been constructed which define the usual degree of compensation.

2. A 50-year-old businesswoman with a history of chronic indigestion was admitted after three days of severe epigastric pain, nausea and vomiting. Physical examination revealed BP 90/60 mmHg, pulse 120 and regular. Skin turgor was decreased. There was a boardlike rigidity on abdominal examination with rebound tenderness. An abdominal CT scan with intravenous contrast demonstrated severe acute pancreatitis with pancreatic necrosis. She was given no food by mouth, intravenous fluids and pain medications, and was watched closely. Because she developed a fever of 103 degrees F, intravenous methicillin and gentamicin were administered to treat possible infected pancreatic necrotic material. Her urine output remained low during the first two hospital days between 5 and 15 ml/hr. Laboratory studies on hospital day 2 demonstrated: Urinalysis revealed specific gravity of 1.022, pH 5.0 but no protein, blood or glucose. Urine sediment demonstrated rare RBC and WBC and moderate number of hyaline casts. Urine sodium concentration was 5 mEq/L. Other laboratory studies included: Sodium Potassium Chloride Bicarbonate Creatinine BUN Hematocrit 45% 136 mEq/L 5.7 mEq/L 94 mEq/L 22 mEq/L. 1.4 mg/dL 45 mg/dL a. What is the differential diagnosis of acute kidney injury? Which seems most likely in this patient? b. What tests could you utilize to clarify the etiology of acute kidney injury? c. Why is this patient oliguric? Explain. 14-3 By the 5th hospital day, the patient was still experiencing some abdominal pain but was anxious to eat. Her oliguria had improved somewhat with intravenous fluids and she was producing about 600 to 800 ml of urine in 24 hours. Blood pressure and physical exam were normal. However, her laboratory studies showed a rising serum creatinine of 2.8 mg/dL with a BUN of 53 mg/dL. Urinalysis showed 5-10 WBC, 5-10 RBC, 4-8 renal tubular cells and a moderate number of darkly pigmented "muddy brown" casts. d. What are possible causes of her ongoing acute kidney injury (rising BUN and creatinine)? e. What additional urine tests may be helpful in differential diagnosis? f. What is appropriate management?

The differential diagnosis of oliguric AKI on hospital day 2 is similar to that of case 1. Post-renal obstruction is doubtful in a middle-aged woman but easily can be excluded by ultrasound. A pre-renal cause (volume depletion) seems most likely given the presented evidence (high specific gravity, low urine sodium and moderate number of hyaline casts). This diagnosis is also supported by the greater degree of BUN elevation than that of creatinine, although this is a non-specific diagnostic tool. Intrarenal causes that can be considered include ATN related to hypoperfusion of the kidneys and tubular ischemia related to the severe volume loss and marked elevation of inflammatory mediators that are caused by pancreatitis, but the urine tests point more towards a pre-renal etiology at this point. It's important to remember that aminoglycosides like gentamicin cause tubular injury and ATN, but usually not until after 5-7 days of treatment with this agent and the AKI typically is non-oliguric. Acute interstitial nephritis is associated with many medications (the classic descriptions are with methicillin, which she received), but usually doesn't develop until a longer duration of exposure to the agent, so isn't likely here. Actually most of the information we need including urine sodium, review of the urine sediment is presented in the case. A renal ultrasound should be checked to confirm no post-renal obstruction. Presence of oliguria (<400 ml of urine in 24 hours) denotes a worse prognosis in ATN than does non-oliguric ATN. However, oliguria, per se, is not always a worrisome finding. In this case, the patient may have been initially oliguric due to pre-renal AKI with stimulation of renal-angiotensin-aldosterone and (most importantly for understanding oliguria in pre-renal AKI) anti-diuretic hormone. High levels of ADH lead to insertion of water channels in the collecting tubules. High degrees of water reabsorption from the collecting tubules will lead to a high urine osmolality (note: specific gravity was 1.022) and excretion of a small amount of concentrated urine. She has ongoing AKI (rising BUN and creatinine) although is now non-olgiuric. The differential diagnosis is similar to question 2a although the probabilities of the various entities has changed. Pre-renal AKI is less likely as she no longer appears volume depleted, urine output has increased somewhat, and the hyaline casts have disappeared. The muddy brown casts point towards ATN as the most likely diagnosis. It's probably still too early to implicate gentamicin or methicillin-induced acute interstitial nephritis as etiologies, although as time passes, these become increasingly likely. Checking urine sodium concentration may be helpful as a level > 20 mEq/L would be supportive of the ATN hypothesis. Supportive management is all that is indicated. This means monitoring for electrolyte abnormalities, volume status and to avoid the use of medications that are toxic to the kidney (radiocontrast dye, aminoglycosides, NSAIDs). Medications should be adjusted for the relatively low GFR (it is difficult to know exactly what this is because the MDRD equation is valid only if serum creatinine has been stable for days and may not apply in a sick hospitalized person like her). The natural history of ATN as described in question 1d. is to have an onset phase, then a plateau phase and then a recovery phase. She probably doesn't need dialysis now although one cannot say this with certainty unless additional information was provided such as electrolytes, volume status, etc. She will hopefully experience an increasing urine output in the next few days followed by improved measures of renal function.

Essentially all the phosphate in the urine combines with hydrogen ions when the urine pH is below a value of 6.0.

The formation of titrable acid normally accounts for 40% of the net acid excreted in the urine

The defense of extra-cellular pH in the face of acid-base disorders is dependent on the total body buffering capacity and physiological adaptive responses.

The latter are commonly referred to as compensatory responses. These compensatory responses tend to minimize the pH change with a given acid-base disturbance but usually do not completely correct the pH.

In metabolic alkalosis, the compensatory response also involves pulmonary regulation by pH-sensitive chemoreceptors. In this circumstance however, the response is to decrease the ventilatory rate and thereby increase arterial PCO2.

The magnitude of the ventilatory compensatory response in metabolic alkalosis is often less than the response in metabolic acidosis. This limitation is thought to occur because hypoventilation not only results in a rise in PCO2 but also a fall in PO2. The rate of ventilation is also stimulated by hypoxemia (a low PO2). As PO2 levels fall to values below 60 mmHg, respiration will be stimulated. The range of compensation in this acid- base disorder is also given in the nomogram.

In metabolic acidosis the compensatory response is an increase in the rate of ventilation.

The stimulus for this response is the decrease in extracellular pH. Chemoreceptors both in the carotid body and in the central nervous system detect this pH change and signal the respiratory center to increase the rate of ventilation. As a consequence the PCO2 decreases and the pH change is diminished.

Thus the renal threshold or Tm for bicarbonate occurs at plasma bicarbonate concentrations greater than 24 mEq/L.

There are a number of factors that can stimulate or impair renal hydrogen ion secretion and thus alter this apparent threshold.

In the metabolic acidemias associated with an anion gap, the cause of the acidosis is the overproduction of a nonvolatile acid other than hydrochloric acid.

These acids titrate bicarbonate to CO2 such that bicarbonate is replaced by the anion of that organic acid. HA + NaHCO3 NaA + H2CO3 H2CO3 CO2 + H2O

Other forms of metabolic acidosis not associated with nonvolatile organic production will have an increase in the serum concentration of chloride.

These are referred to as hyperchloremic metabolic acidosis (or non-anion gap acidosis, see Table 2). In these circumstances the disorder is either caused by a loss of bicarbonate from the GI tract or kidney or by excess hydrochloric acid production.

In respiratory acid-base disorders the compensatory response involves renal mechanisms that adjust the serum bicarbonate concentration.

Unlike respiratory compensation, which requires only minutes to occur, the renal compensatory response requires hours before beginning and days before it is complete.

The capacity of the kidney to reabsorb bicarbonate is limited.

When plasma bicarbonate concentration is less than 24 mEq/L, filtered bicarbonate is usually completely reabsorbed. At higher bicarbonate concentrations bicarbonaturia will normally occur.

In respiratory alkalosis the primary change is a decrease in PCO2 secondary to hyperventilation.

With decreased PCO2, bicarbonate reabsorption in the kidney is diminished and bicarbonituria will occur. Thus, there is a decrease in the serum bicarbonate concentration. This change diminishes the degree of rise in arterial pH. In addition to this mechanism, arterial pH is also defended to a limited degree by the development of a mild lactic acidosis. This occurs because the increase in cellular pH stimulates glycolysis and an increase in the rate of lactic acid production.

2. A 20-year-old male is brought in by his college roommate after he was found unconscious face down on the floor of their dorm room. He is unable to provide any history but his roommate reports that he was "acting very strangely" the day before and that the roommate was concerned that he might have "taken something". The only other history the roommate can provide is that he had diarrhea for about 24 hours before being found unconscious. Physical examination reveals blood pressure 70/45 mmHg, pulse 120 bpm, temperature 101.0F, respiratory rate 24. He is confused, agitated with dilated pupils. Oral mucosa is dry but no skin tenting was observed. Lungs are clear to auscultation. Heart examination demonstrated tachycardia but no murmurs or gallops. Abdominal examination was unremarkable. Remainder of exam was negative. Laboratory data: Questions: HCT BUN Creatinine Sodium Potassium Chloride Bicarbonate Albumin 45% 35 mg/dl 1.6 mg/dl 135 meq/L 5.1 meq/L 99 meq/L 12 meq/L 4.0 g/dL Arterial blood gas pH 7.27 PCO2 24 mmHg PO2 91 mmHg Urinalysis Spec.Grav. 1.015 pH 6.0 a. What is the acid-base disturbance? b. Is this a simple or mixed acid-base disorder? How do you know? c. What is the differential diagnosis of this acid-base disorder? d. On morning rounds, your team has made some suggestions for the differential diagnosis. Think about each of these specific etiologies and whether they make sense or not. What tests could you send to confirm the various diagnoses you are entertaining? 1. Diabetic ketoacidosis. 2. Acidosis related to diarrheal losses of bicarbonate. 3. Ethylene glycol poisoning 4. Metabolic alkalosis from vomiting 5. Lactic acidosis from cardiovascular collapse due to cocaine ingestion 6. Uremic acidosis 7. Renal tubular acidosis

a. Metabolic acidosis. b. This is a simple metabolic acidosis. By Winter's formula for metabolic acidosis, for every 1 mEq/L decrease in HCO3, there is an adaptive 1.1-1.2 mmHg decrease in PCO2. Here, the HCO3 has decreased by 12 mEq/L, so the expected fall in PCO2 due to alveolar hyperventilation is about 14 mmHg (from 40 to 26 mmHg, close to the 24 mmHg seen on the arterial blood gas (ABG). c. Metabolic acidosis can be divided into causes that have a normal AG and those that have an elevated AG. This patient has an elevated AG of 24 mEq/L. The differential diagnosis of elevated AG metabolic acidosis includes DKA, lactic acidosis, uremic acidosis, and less frequently seen organic acid intoxications (ethylene glycol, methanol, etc.). The differential diagnosis of metabolic acidosis with a low AG includes severe diarrhea and renal tubular acidosis. d. Discussion of each of the diagnoses the team is considering 1. Diabetic ketoacidosis: possible diagnosis because of elevated anion gap. Urinalysis would provide information on whether glucosuria or ketonuria is present (this was left off urinalysis intentionally), serum glucose also would be helpful. 2. Acidosis related to diarrheal losses of bicarbonate: low AG acidosis. However, if volume depletion is sufficient to result in tissue ischemia and lactic acidosis, a 2 combined non-AG acidosis from diarrhea and an elevated AG acidosis from lactate is possible. However, an AG of 24 mEq/L is 12 mEq/L above the upper limit of normal for AG (12 mEq/L), equal to the decline in HCO3 of 12 mEq/L. Note, these are measured in the same units so whatever unmeasured anion is present is the sole cause of the acidosis; otherwise this so-called "delta-delta" calculation would not be equal to zero. 3. Ethylene glycol intoxication: conceivable diagnosis as it causes an elevation in the anion gap after ethylene glycol has been converted to its toxic metabolite, oxalic acid. One can check for an osmolar gap to diagnose organic acid poisoinings but with the caveat that it may be negative if all of the ethylene glycol has been converted to its metabolites (this is a much longer discussion for later in your medical school career). Can also look for calcium oxalate crystals in the urine or use a Wood's lamp to see if the urine fluoresces (if the source of the ethylene glycol was antifreeze, where fluorescent material is added to help auto mechanics find the source of leaks, and to help nephrologists make great diagnoses of ethylene glycol poisoning!). 4. Metabolic alkalosis: no, the patient has a metabolic acidosis. Can a patient have a metabolic acidosis and metabolic alkalosis at the same time? Sure, what about severe vomiting leading to lactic acidosis, as above. But then the aforementioned delta-delta calculation would not be equal to zero but instead would show the delta-AG to be greater than the delta-HCO3 (and the serum HCO3 would be much closer to 24 mEq/L) 5. Lactic acidosis from cardiovascular collapse due to cocaine ingestion: certainly, lactic acidosis is a frequent cause of an elevated AG acidosis. While we don't have enough information to determine whether lactic acidosis is due to cocaine, other illicit drugs, septic or cardiogenic shock or many other causes, lactic acidosis is a strong consideration in this case. Can check lactate level on arterial blood to confirm (lactate is measured in mEq/L, so the elevation in lactate should be equal or nearly equal to the elevation in AG). 6. Uremic acidosis: not plausible, because usually requires much lower GFR than this patient has given a serum creatinine of 1.6 mg/dL. 7. Renal tubular acidosis: similar to the diarrheal hypothesis, this doesn't make sense because it doesn't explain the elevation in AG.

1. A 23-year-old female with an 8-year history of type 1 diabetes mellitus was admitted because of fever, chills, dysuria and flank pain for two days duration. The significant physical findings are BP 100/60 mmHg; pulse 110 bpm, respirations 24/min; temperature 38°C. Skin turgor is decreased, oral mucosa is dry and she has left-sided flank tenderness on palpation. Laboratory data: Glucose Creatinine Sodium Potassium Chloride Bicarbonate Albumin Questions: 425 mg/dL 1.4 mg/dL 130 mEq/L 5.4 mEq/L 96 mEq/L 8 mEq/L 4.0 g/dL Arterial blood gas pH 7.25 pCO2 23 mmHg PO2 96 mmHg Urinalysis Numerous WBC / high power field Glucose 4+ Ketones 4+ a. What is the acid-base disturbance? b. Is this a simple or mixed acid-base disorder? How do you know? c. What pathophysiological process resulted in this disorder? d. Why is the serum potassium elevated? What is total body potassium for patients with this problem? e. Why is the serum sodium level low? f. How would you treat the underlying disease process and electrolyte abnormalities?

a. Metabolic acidosis. For any acid-base problem, first determine whether acidemia or alkalemia is present by looking at pH. Next, determine whether the PCO2 or the HCO3 is the process driving the acid-base disorder (i.e. whether acidosis or alkalosis is the primary disorder causing the patient's altered pH). In this case, the low HCO3 "fits" with the acidemic pH. b. This is a simple metabolic acidosis. For simple acid-base problems, the adaptive response should be in the same direction as the primary process (i.e. if low HCO3 is the primary disorder, the normal response is for PCO2 to decrease as well). One can confirm whether the disorder is simple (vs. mixed) by using readily available regression equations to determine the degree of change of the adaptive process for every unit change of the primary process. For instance, Winter's formula for metabolic acidosis tells us that for every 1 mEq/L decrease in HCO3, there is an adaptive 1.1-1.2 mmHg decrease in PCO2. Here, the HCO3 has decreased by 16 mEq/L, so the expected fall in PCO2 due to alveolar hyperventilation is about 18 mmHg (from 40 to 22 mmHg, extremely close to the 23 mmHg seen on the arterial blood gas (ABG). c. The next step in any acid base problem is to calculate the anion gap (AG), the formula of which is [Na] - [Cl] - [HCO3]. The normal AG is about 8-12 mEq/L. Metabolic acidosis can be divided into causes that have a normal AG and those that have an elevated AG. This patient has an elevated AG of 26 mEq/L. The differential diagnosis of elevated AG metabolic acidosis includes Diabetic Ketoacidosis (DKA), lactic acidosis, uremic acidosis, and less frequently seen organic acid intoxications (ethylene glycol, methanol, etc.). Here, the presence of glucosuria and ketonuria as well as hyperglycemia strongly suggests DKA. There are other ketoacidoses associated with 1) starvation and 2) alcohol ingestion, but the more likely explanation here is DKA. d. Serum potassium is elevated in DKA for three reasons, 1) solvent drag of intracellular K which follows water out of cells to the hyperosmolar extracellular space (due to hyperglycemia), 2) insulin deficiency results in less glucose and K uptake into cells (remember Dr. Borkan's train car analogy), 3) hydrogen-potassium exchange at the cellular level due to acidemia. Note that hyperaldosteronism seen with the related volume depletion counteracts this effect, in part. However, do not forget that total body K is markedly reduced in these patients due to K loss in the massive osmotic diuresis of DKA, which leads to Na loss and volume depletion as well as total body K (and phosphorus, for that matter) depletion. Care must be taken to replete K during DKA treatment as soon as serum levels return to the normal range. e. This is a result of the osmotic effect of marked hyperglycemia causing an increase in serum osmolality such that water moves osmotically out of cells, diluting the sodium concentration. One can determine the degree to which the Na concentration has fallen due to hyperglycemia (which is 1.6 mEq/L decrease inNa concentration for each 100 mg/dL that the glucose is above 100 mg/dL). In this case, 4.8 mEq/L (1.6 x 3) of the decline in Na concentration can be attributed to hyperglycemia-induced shifts in water. One can prove this point by checking serum osmolality to confirm the effect of hyperglycemia. f. Must treat both the insulin deficiency and hyperglycemia. The first step is administration of isotonic saline to correct volume depletion, an intervention that often helps quite a bit with the hyperglycemia. However, insulin is a crucial treatment to correct the insulin deficiency, arrest the ketogenesis process, etc. While treating, watch for the development of hypokalemia and hypophosphatemia.

In addition the kidney must regenerate

approximately 1-2 mEq/day/Kg body weight, or 80 mEq of bicarbonate each day, to compensate for bicarbonate loss as the result of normal metabolic production of acids.

Acid-base balance is primarily controlled by

bicarbonate-carbonic acid buffer system. Dissolved CO2 + H2O H2CO3 H+ + HCO-3

The process of bicarbonate reabsorption and bicarbonate regeneration is essentially identical:

both are achieved HCO3- Reabsorption by the Proximal Tubule through the secretion of hydrogen ions into the urine by the tubular epithelial cells

pH of arterial plasma, 7.4

is far removed from the pK value of the bicarbonate buffer system and represents at this pH a HCO-3/ PCO2 ratio of 20/1.

HH

pH = 6.1 + log HCO3/.03PCO3

85% of bicarbonate reabsorption happens in the

proximal tubule and the remainder of the process, including new bicarbonate production, occurs in the collecting duct.

pH is depicted by

ratio of bicarbonate to dissolved CO2

As noted, to regenerate bicarbonate lost as a consequence of nonvolatile metabolic acid production,

the kidney must secrete an amount of hydrogen ion equal to the amount of fixed acid produced each day.

if a patient's serum bicarbonate falls as a consequence of severe metabolic acidosis from 24 to 10 mEq/L with unchanged PCO2

the pH would decrease from 7.4 to a life- threatening value of 7.0. However, with stimulation of respiration, the PCO2 in a typical patient will decrease to about 25 mmHg; the pH will then be 7.25.

acidosis or alkalosis refers to

the process, which would, if unopposed, result in a change in pH. On the other hand, the terms acidemia or alkalemia refer to the change in pH of the blood itself.