Chronic kidney disease
discuss strategies for medication dosing in patients with CKD GQ 17 ) how would you go on about adjusting dosage regimens in repsonse to renal disease?
-average number of meds people with CKD are on: 12 +/- 5 - estimate renal function using the 3 formulas >Consider patient factors: obesity, age, amputation, etc. CONSIDER DOSAGE ADJUSTMENT OF DRUGS AFTER STAGE 3a down (make sure drugs arent accumualting and causing toxicity) >>SICKNESS ACUITY ASSESSMENT • Should therapy be more or less aggressive? • Risk versus benefit (consequences of over versus under treating) • Will dose adjustment really make a difference? (Evidence of outcomes) >>ASSESS THE DRUG • Cl total = Cl renal + Cl nonrenal , also t 1⁄2 = (VD)(0.693)/Cl • Evidence for dosing: product monographs (specify the equation type to use ), published guidelines, original PK studies, textbook guidelines • Active metabolites? Toxic metabolites? • Wide or Narrow Therapeutic Drug Window (downside of too little or too much) • Therapeutic monitoring available? • Drug interactions alter systemic exposure? >>DETERMINE INITIAL DOSAGE - Adjusted dose ± frequency • Dose reduction>>>> maintains more constant [drug] but is associated with ↑risk of toxicities if dosing interval is inadequate to allow for drug elimination • Lengthening dosing interval >>>> associated with lower risk of toxicities but a ↑risk of sub-therapeutic [drug] - Further adjustments based on patient response and therapeutic drug monitoring if available >>DRUGS PRESCRIBING IN RENAL FAILURE -divided into 3 GFR categories <10, 10-50, >50 ml/min __________________________________________________________________________________ >>>>>>DRUG DOSAGES IN CKD ORAL ANTICOAGULANTS -Alot depend on renal elimination -do not use dabigatran and rivaroxaban crcl<30 ml/min and apixaban crcl <15 ml/min -no antidote expect for dabigatran "idracruzumab" LMWH -TX: enoxaparin, deltaparin, tinzaparin... dosage adjustment crcl<30 ml/min -DVT PROPHYLAXIS: USE DELTAPARIN (ok to use in short term and do not accumulate) -DIALYSIS CIRCUIT ANTICOAGULATION: use deltaparin FONDAPARINAUX TX: CI when crcl<30 ml/min _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _. __ _. ___. _ ANTIMICROBIALS AND CKD • Most antibiotics require either a reduced dose or increase in dosage interval (exceptions: cloxacillin, azithromycin, clindamycin, metronidazole, doxycycline, moxifloxacin) >>Therapeutic drug monitoring • Aminoglycosides ( minimize concomitant ototoxic agents such as furosemide) • Vancomycin ***Many dialyzable: dose after dialysis _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _. __ _. ___. _ ANALGESICS -use acetaminophen and avoid NSAIDS because... NSAIDs cause acute kidney injury... inhibits prostaglandings in the afferent arteriole thus this causes constriction and reduced blood flow to the kidneyes (specially if dehydrated and advanced CKD this can cause kidney injury) -do not use codeine, morphine and meperidine.... they have neurotoxic metabolites that are renally excreted, and that accumualte in CKD and may cause toxicity _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _. __ _. ___. _ GOUT DRUGS -require dosage adjustment based on GFR _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _. __ _. ___. _ OTHERS.. -Gabapentin is often prescribed but not reassesd. should be deprescribed!
GQ 15 ) based on your assessment, what is the most likely cause of Ricks ARF? what risk factors does he have? could this have been prevented?
-infection (pyelonephritis) -ASA
NEW TARGETS FOR IMPROVING HEMOGLOBIN
-may replace ESA agents -oral ****HIF Stabilizers (HIF Prolyl hydrolylase inhibitors), regulation of HIF coordinates erythropoiesis • Oral agents in the pipeline...... Roxadustat, Vadadustat, Daprodustat MOA -these drugs are involved in the gene regulation of the EPO gene and increase epoesis -these have been shown to lower hepcidin thus the iron that the patients are on works better(people will need less iron) —>lower hepcidin and requirement for hepcidin has gone down —>regulation of genes brings the concern about tumor growth
Urea levels in CKD
-normally urea in the blood gets excreted into the urine. but when the GFR rate is decreased less urea gets filtered out thus it builds up the blood "condition called Azotemia" >>The general sxs of this include: nausea and loss of appetite. as the urea levels keep building up they start to affect the fucntions of the NS causing encehalopathy "resuting in Asterixis which is a tremor of the hand".. build up can also lead to endocarditis, coma and death, bleeding "as less clot formation", uremic frost "crystals in the skin"
Symptoms
-often asymptomatic (malaise) until 80% of the kidney function is lost!
Renal anatomy
-outer cortex, inner medulla -urine collects in the calyxes that converge in the renal pelvis and they exit via the ureter -the renal capsule protects the kidneys -the functional unit is the nephron. bowmans capsule houses the glomerulus. though connective capilaries are the site of filtration. -blood is filtered (enters via the afferent arteriole) and leaves via efferent arteriole. The glomerular filtration barrier: >>the normal ultrafiltrate should not contain proteins (kidney injury indicative) 1. Capillary Endothelium (has million holes which allow for cellular layer which screens for blood cells and not letting them to get into the urine filtrate) 2. Basement Membrane (specialized connective tissue layer. allows for the movement of small solutes and water but not plasma proteins) 3. Epithelial (Podocyte) Layer (foot like proceses which circle around the capilaries which allows the ultrafiltrate to pass through)
Goals of TX in CKD
-slow the progression of CKD >>the items to target to slow down the progression of diabetic nephropathy include: A) BP < 130/80 B) AIC ≤ 7% C) ACR ≤ 3 mg/mmol D) LDL ≤ 2.0 mmol/L or ≥ 50% reduction in LDL -Manage reversible CV risk factors -Treat the complications of CKD -educate the patient and caregivers on CKD
Sodium Bicarbonate slows progression of CKD?
**Bicarbonate suppl. had a mean decline in CrCl of 1.88 ml/min/1.73 m2 vs. 5.98 ml/min/1.73m2 among controls --> Five times as many patients in the control group progressed to ESRD, compared with patients who received bicarbonate suppl.
Complications of CKD
**Until recently, CKD was thought to be progressive, with the patient experiencing a decline in function over time and ultimately requiring dialysis. With the development of new interventions and prevention strategies, patients with CKD, particularly those without proteinuria, may have little progression of their kidney disease; however, they remain at high risk for cardiovascular events and death.** - electrolyte abnormalities - toxin buildup -hypertension... EVENTUALLY AFTER ALL NEPHRONS DIE, the level of renin will decrease causing BP to fall. -decreased EPO "anemia" -weak bones "renal osteodystrophy"
CARDIOVASCULAR medications and CKD look at slides 79-81
- Dose adjustment (% of usual dosage) based on GFR ml/min ACE-I : All dialyzable except fosinopril. Dose after dialysis (often tell people do not take BP meds before they come in for dialysis) -ARBs, CCB and α blockers do not require dose adjustment and none are dialyzed -BBs: Removed by dialysis, dose after dialysis -Diuretics: HCTZ usually ineffective at GFR <30 but they still have some benefit
Diagnosis of CKD
- changes in GFR over time ---> in healthy people, the GFR is 100-120 mL/min/1.73 m2 **this value is slightly less in women than men and decreases slowly as we get older** - in CKD, the GFR is less than 90 ml/min/1.73 m2 (over at least 3 months) - irreversible kidney damage may occur in GFR less than 60 ml/min/1.73m2 >>>Criteria for CKD: include any of the following present for greater than 3 months • Albuminuria ACR ≥ 3 mg per mmol (in diabetes canada guidlines this number is 2) • Urine sediment abnormalities (e.g. RBC casts, RBCs, WBC casts,WBCs) • Electrolyte and other abnormalities due to tubular disorders • Abnormalities detected by histology • Structural changes detected by imaging • History of kidney transplantation • eGFR less than 60 ml/min/1.73m2 SCREENING RECOMMENDATIONS: >> Random urine ACR (Preferably 1st am void, at least 2 out of 3 elevated in order to be considered abnormal) >> Serum Creatinine that is converted to eGFR • Calculate yearly in all diabetic patients • Calculate every 6 months in patients with nephropathy • Screening should commence at diagnosis of diabetes in T2DM and 5 years after diagnosis of T1DM and repeated yearly thereafter ***• eGFR ≤60 mL/min Or 2 out of 3 ACRs ≥2.0 or 3.0 mg/mmol for > 3 months → CKD diagnosis confirmed**** >>>>>>• The degree of risk of CV events or progression to ESRD INCREASE as albuminuria levels rise and as eGFR falls, with the combination of albuminuria and low eGFR predicting a very high level of risk
Vitamin supplements in CKD
-CKD patients are at high risk of developing nutrient deficiencies -Indications for use of Replavite renal vitamin • Eating less than 50% of meals and/or consuming <1500 Kcal/day • Chronically poor or erratic eating habits • Reduced appetite, nausea, vomiting, taste changes or food aversions • Undesirable weight loss • Dialysis >>>Replavite • Vitamins B1 (thiamin), B2 (riboflavin), B3 (niacin), B6 (Pyridoxine) • Folic acid • Vitamin C ***shouldnt be on it if they are not on dialysis....once patients start dialysis the water soluble vitamins get dialyzed off and they need to have a vitamin that replaces Bs, C and folic acid (dose after dialsysis) avoid herbal remedies >>nephrotoxic side effects.... most NHPs are not studied in CKD patients
NON PHARMS for CKD
-Encourage exercise for 30-60 mins 4-7 days/ week to reduce the possibility of becoming hypertensive or to lower BP in those with BP -Encourage smoking cessation to slow progression of CKD and to reduce the risk of cardiovascular disease -Alcohol intake should be limited to 2 drinks or less per day and should not exceed 14 standard drinks per week for men and 9 standard drinks per week for women so as not to increase blood pressure. DIET -Patients with CKD and hypertension should follow a low sodium diet: <90 mmol/day Na, or 2 g Na or 5 g NaCl/day. -If serum potassium >5 mmol/L, first consider medications that can be discontinued, such as potassium supplements and potassium-sparing diuretics. If these medications are not present, advise dietary potassium restriction. Note that ACE inhibitors (ACEIs), ARBs and aldosterone antagonists may also contribute to the hyperkalemia; continue these agents if being used to decrease proteinuria, and restrict dietary potassium instead -Dietary protein intake has been the focus of several trials; however, there is a lack of convincing evidence that a long-term protein-restricted diet (<0.7 g/kg/day) delays the progression of CKD. Referral to a dietitian to provide a diet that is protein-controlled (0.8-1 g/kg/day) is recommended. -Encourage weight loss if obese (BMI >30 kg/m2) or overweight (BMI 25-29 kg/m2) to lower the risk of CVD.
Physical exam of CKD patients
functionally: - dec GFR - dec urine output - inc nitrogenous waste in blood (urea, creatnine) structurallly: - cell death (apoptosis, necrosis) - loss of adhesion to intrinsic renal cells (obstruction) PHYSICAL EXAM -general appearance: in advanced stages of CKD, patients develop cachexia or loss of muscle mass; advanced uremia is often accompanied by a sallow, greyish complexion and so-called "uremic fetor," which is secondary to breakdown of urea to ammonia in saliva -weight: measure at each visit to assess fluid and nutritional status; large changes are usually associated with fluid gains or loss -vitals: lying and standing blood pressures and pulse, assessment of the jugular venous pressure and the presence of edema -abdominal exam: palpation for enlarged, cystic kidneys, and auscultation for renal artery bruits at a position approximately 2 cm above and 2 cm lateral to the umbilicus; among patients with known hypertension, a bruit audible in both systole and diastole is moderately specific for renal artery stenosis
GQ 3 ) Stages of CKD - GFR categories
stage of our patient in the case : G2a2 >>EXAM TIP: will be asked to calculate renal function ad stage the patient based on their GFR. **usefulness of eGFR... screening, staging, predicting prognosis and management of progression and complications of CKD - prognosis of CKD is determined by GFR and albuminuria Persistent albuminuria categories A1 : normal to mildly increased <3 mg/mml A2: moderately increased 3-30 mg/mmol A3: severely increased >30 mg/mmol >>there is a direct relationship between what their eGFR is and stage of CKD and when they will show up complications of CKD.
LDL Lowering Trials and CKD -->no benefit of sttain use in dialysis patients -->huge benefit in people with CKD (as observed in the secondary analysis from JUPITER in CKD patients)
the following studies were done in hemodialysis patients... >>4D Trial: No difference, potential increased risk of fatal stroke? (by chnace? dunno!) >>AURORA: NS primary endpoint >>Why no benefit? Patient selection? Drop outs? (10-15%) Cardiac deaths often related to sudden death, arrhythmias (62%), not typical CV events such as MI. Are all statins the same >>Dialysis patients are truly different? Vascular calcification Non-traditional risk factors play a greater role Too little too late? -->they have non traditional CVD risk factors which play a big role. • Albuminuria • Homocysteine • LP(a) and apo (a) isoforms • Lp remnants • Anaemia • Abnormal Ca/PO4 metabolism • ECF overload • Oxidative stress • Inflammation (CRP) • Malnutrition • Thrombogenic factors • Endothelial dysfunction SHARP -final trial detrmiend what to do with dialsis patients (tx with statin or not) • reduced major vascular event by 16% (NNT = 37) • reduced major atherosclerotic event by 15.3 % (NNT = 40) • No benefit on kidney disease progression • All cause mortality did not change TAKE HOME MESSAGE • Patients with CKD have a tremendous risk for developing CVD or having a second event if they have established CVD. • Predialysis patients (stage 3 and 4) benefit from LDL lowering treatment particularly if no prior MI or revascularization (SHARP) and/or no DM (JUPITER). • Dialysis patients do not appear to benefit from LDL lowering. • KDOQI 2012: • In adults CKD stage 5D (dialysis), suggest statin or statin/ezetimibe combination not be initiated. • In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued • In adult kidney transplant recipients we suggest treatment with a statin
Pathophysiology
the kidneys role: - regulates whats in the blood (remove waste, steady electrolytes, regulate water) - make hormones >>Blood gets into the kidney via the renal artery. once inside, arteriole in side the glomerus filter it. Once filtration occurs, the filtrate moves into the renal tubule. the rate at which this filtration occurs is called the glomerular filtration rate (GFR)
GQ 6 ) TREATING HYPERTENSION IN CKD ACE Inhibitors and ARBs >Moderate to high doses of ACEIs and ARBs have been associated with slowing the progression of CKD. Begin with low doses and increase at 4- to 6-week intervals while monitoring for side effects and hypotension
who should recieve ACEI or ARB therapy? (regardless of baseline BP) -clinical CVD -age ≥55 years with an additional CV risk factor or end organ damage (albuminuria, retinopathy, left ventricular hypertrophy) -microvascular complications -ACEIs and ARBS are the preferred agents for certain types of CKD because they have the following effects: -ACEi and ARB decrease efferent arteriole tone and thus decrease intraglomerular pressure. this leads to an intial decrease in eGFR followed by stabilization. this leads to deceased albuminuria and THUS renal protection. >Reduction of blood pressure and intraglomerular pressure: in controlled trials, the beneficial effect of ACEIs and ARBs on the progression of CKD was greater than would be expected based on their antihypertensive effects alone. >Reduction of proteinuria: ACEIs and ARBs reduce proteinuria more than any other antihypertensive even when the effect of blood pressure reduction on urinary protein excretion has been taken into account. >Other mechanisms: ACEIs and ARBs alter the function of mesangial cells and interfere with angiotensin-mediated generation of free radical formation, which also help slow the progression of CKD. >>>>THUS: reductions in proteinuria, doubling of SrCr, progression to ESRD. (the study was conducted in DM nephropathy and proteinuric CKD) USING ACEI AND ARB COMBINATION ((NOT RECOMMENDED) The ONTARGET trial also found that while the combination of an ACE inhibitor with an angiotensin receptor blocker had some extra blood pressure lowering it had more side effects such as hyperkalemia, hypotension and renal impairment and did not improve patient outcomes compared to the ACE inhibitor alone. In people with stage 3 chronic kidney disease (GFR > 30 ml/min) the combination of an ACE inhibitor with an ARB reduced urine protein levels and had better BP control but did not reduce cardiovascular outcomes (death, Mi, stroke or hospitalization for HF) and did increase adverse renal outcomes including the need for acute dialysis, doubling of SrCr, greater decline in eGFR, hyperkalemia and hypotension compared to the ACE inhibitor alone >>>>>the use of combination of ACE inhibitor and ARB therapy should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. For people already on the combination and stable, clinicians need to consider that prescribing just one of the two classes reduces cardiovascular events to the same extent and that other therapeutic regimes have the potential to reduce cardiovascular events and blood pressure to a greater degree. MONITORING FOR ACEIS: - SrCr, K+ in 1-2 weeks - rise in SrCr (up to 30%) -nutrition counseling on k+ restricted diet -persistent cough -angioedema >>>>WHAT ABOUT COMBIANTION OF ACEI/ARB PLUS ALISKIREN (DIRECT RENIN INHIBITOR) - ALTITUDE study: incresed incidence of nonfatal stroke, renal complications, hyperkalemia, hypotension (((ALSO NOT RECOMMENDED)
Bowel Preparation in CKD
• Adequate colon cleansing is necessary for successful visualization and detection of suspicious lesions of the colon during colonoscopy - ideal agent should be safe, tolerable, reliable and effective RECOMMEND: PEG 2 liters plus bisacodyl 10-15 mg enteric coated tablets AVOID • Fleet phospho- Soda, phoslax, phosphate solutions (Health Canada warning) • Magnesium citrate (MAG) • Sodium picosulphate, citric acid, magnesium oxide containing preparations (PSMC)
RLS
• Affects 25-40% of people on dialysis • Characterized by irresistible urge to move legs (Significant insomnia, impaired QOL -drug induced RLS --NONPHARMS - limit or avoid caffeine alcohol and smoking - practice good sleep hygiene -massages and warm baths -engage in mental alertness activities (puzzles..) --PHARM TX -Ropinirole (0.25 mg PO qhs... titrate 0.125mg/week to a max of 4 mg/day) -Pramipexole -try gabapentin for refractory cases
Pruritis
• Affects 40% of dialysis patients >>>Causes -- Uremic-related • xerosis, HD inadequacy, anemia, secondary hyperparathyroidism -- Uremic-unrelated • Infestations,allergy,drug hypersensitivity, contact dermatitis, inflammation, hepatitis, hypothyroidism, neoplasm >>Management ---->(Non-Pharm) • Skin hydration (Glaxal base [eg emollient cream 15% glycerin and 10% paraffin (CJASN 2011; 6: 748-52)], Uremol cream, Nivea Cream) • Tepid baths • Minimize scratching ---->(pharm) ..... consider renal dosing -- Localized pruritis: • Hydrocortisone1%cream,betamethasone valerate 0.1% cream -apply sparingly • Capsaciancream0.025% -- Generalized pruritis: • Antihistamines (hydroxyzine , diphenhydramine, cetirizine , loratadine, desloratadine) • Gabapentin • Pregabalin -- Refractory pruritis: • Doxepin(noCI) • UVB phototherapy • Acupuncture
Prevalance of CKD
• CKD affects >2 million Canadians • 22,000 Canadians on dialysis • 15,000 approximately living with functional renal transplants • Health care costs ~2% of Canadian health care budget being spent on this small (0.1%) segment of the population >>the number of people receiving renal replacement therapy (dialysis) is projected to double world wide.
DIABETES AND CKD
• DELAY onset and/or progression with glycemic and blood pressure control and ACE inhibitor or angiotensin receptor blocker (ARB) • Check serum creatinine and potassium at baseline and within 1-2 weeks of initiation or titration of therapy and during time of acute illness • Should be given a "sick day" medication list that outlines medications that should be held during times of acute illness (SADMANS - sulfonylureas, aceinhibitors, diuretcs and direct renin inhibitors, metformin, ARBS, NSAIDS, SGLT2 inhibitors.... these meds will have reduced cleraance and increased risk of ADRs) • Immunization (influenza, hepatitis B vaccine and pneumococcal vaccine) • Avoid dual RAAS blockage (ACE-I, ARB, DRI) GLYCEMIC TRGETS: • Recommend a target HbA1c of ~7.0% to prevent or delay progression of the microvascular complications of diabetes, including DKD. • Recommend not treating to an HbA1c target of <7.0% in patients at risk of hypoglycemia. • Recommend a target HbA1c >7.0% in patients with co- morbidities or limited life expectancy and risk of hypoglycemia. >>IF CLINICAL CVD -START ANTIHYPERGLYCEMIC AGENTS WITH DEMONSTARTED CV BENEFITS. (empagliflozin, liraglutide, canagliflozin) >>KNOW which antihyperglycemic options are avaialble in end stage kidney disease (stage 5) -insulin (dosage adjusted) -repeglinide -some DPP4Is -->sitagliptin (dosage adjusted) -never use pioglitazon and rosiglitazone (people with low albumin have lots of edema dont wnat to risk furthur issues) **SGLT2 inhibitors: mechanism prohibits it from working once eGFR gets down to 45 (but usually use for CV and renal benefits not because they aid in hyperglycemia) METFORMIN -Discontinue metformin when ClCr or eGFR <30 mL/min/1.73 m2 due to an increased risk of lactic acidosis. Metformin should also be discontinued when there are acute decreases in kidney function, and illnesses or procedures that could lead to acute kidney injury (e.g., nausea/vomiting, dehydration, administration of IV contrast dye) or cause hypoxia (e.g., cardiac or respiratory failure), as these are also risk factors for lactic acidosis. -Patients with CKD are at higher risk of developing hypoglycemia because the ability of the kidney to metabolize insulin is impaired. In patients with eGFR <30 mL/min/1.73 m2, emphasize how to recognize and treat hypoglycemia. Gliclazide is the preferred sulfonylurea because, with a shorter half-life and no renally excreted active metabolite, it causes less hypoglycemia. Doses of insulin and some oral diabetes medications may need to be reduced as CKD progresses
GQ 2 ) -what is meant by CrCl? -discuss the limitations of creatnine as a marker for GFR. -calculate Rick's crcl using CG. -what are the advantages and disadvanatges of CG, MDRD and CKP-EPI for estiamting renal fucntion? -discuss the limitations of 24-hour urine collections.
• Standard measure of kidney function has been GFR 1) Use exogenous compounds (e.g. inulin or iothalamate) • Non practical for routine use (time and lack of availability) 2) Measured 24 hour creatinine clearance (CLCR), • Limited value, prone to errors, analytical interference and time required 3) Use of serum creatinine and GFR-estimating equations routinely available, fast and more accurate - kidney function is described using the GFR or creatinine clearance >GFR is the sum of the filtration rates in all of the functioning nephrons -estimated at 125 ml/min (180 L/d).. this cannot be measured directly. (but emasured through other means) >>>>usefulness of GFR: screening, staging, predicting prognosis and management of progression and complications of CKD >>>MEASUREMENT OF GFR: >Exogenous substances: urinary clearance of inulin, iothalamate, iohexol.... limitations. >Endogenous substances: creatinine**, cystatin C -urinary clerance of creatnine (CrCl) derived from a 24 hour urine collection... limitations. ****serum creatnine (Scr) combiend with patient factors to estimate GFR using equations....limitations.***** >>Discuss the LIMITATIONS of creatinine as a marker for GFR: - factors affecting creatinine generation: extremes of muscle mass, race/ethnicity, diet(high protein diet, creatinine supplements), indigestion of cooked meat, -factors affecting tubular secretion of creatinine: decrease by drug induced inhibition(trimethoprim, cimetidine, fenofibrate) -factors affecting extra renal elimination of creatinine: dialysis -Interference with creatinine assay: chemical interferences (glucose, ketones, bilirubin) -High GFR: higher biological variability in non-GFR determinanats relative to GFR(higher measurement error in SCr and GFR) the Cockcroft-Gault (CG): (ml/min) • Derived from 249 caucasian (small number of individuals) males with mean CrCL of 73 ml/min. Validated against 24 hour CrCl measurement • Assumes SS creatinine. 4-variables: Age, Sex, Wt, Scr • Reported using total body weight • Authors recommended to use IBW in obese patients or volume overload (generally ideal body weight is used. the weight is given on exam... wouldn't have to calculate for adjusted body weight) • 15% reduction in CrCL for females >>>>FORMULA: [ 1.2 (140-age) x wt(kg) / serum ceatinine ] x 0.85 for females >>>>>SERUM CREATININE ASSAYS WERE STANDARDIZED in 2009, before that there was a lot of variability in reporting serum creatinine. • To reduce variability - Scr assays were callibrated to be traceable to an isotope dilution mass spectrometry (IDMS) reference. • The standardized creatinine is 11 umol/L less than previous non- standardized creatinine. ((the effect: slightly higher calculated CG estimated CrCL..... • Non-standardized creatinine: 102 umol/L; ClCr = 46 mL/min • Standardized creatinine: 91 umol/L; ClCr = 52 mL/min)) MODIFICATION OF DIET IN RENAL DISEASE (MDRD) (ml/min per 1.73 m2) > variables used: src, age , gender, multiplication if african american The MDRD study was based on a multicenter trial to evaluate the effect of dietary protein restriction and blood pressure control on progression of renal disease in 1628 patients with CKD, with the added objective of developing an equation that could improve the prediction of GFR from plasma creatinine -in patients whose BSA is considerably larger or smaller than 1.73m2: • eGFR IND (ml/min) = eGFR MDRD x BSA per 1.73 m2 • Performs well when GFR is < 60 ml/min/1.73m2 • Not recommended if GFR > 60 ml/min/1.73m2 (people get diagnosed with CKD earlier than they should have been as GFR is underestimated) CKD-EPI (ml/min per 1.73 m2) The CKD-EPI equation was developed to be more accurate and has less bias than the MDRD equation, especially when actual GFR is >60 mL/min/1.73m2. -Given that the MDRD equation was developed in a population with sub-optimal kidney function, its accuracy in predicting GFR is best reflected in those with mild kidney impairment. It is recognised that MDRD tends to underestimate renal function in those with a normal eGFR >90 mL/min/1.73m2. In response to these concerns, the CKD-Epidemiology Collaboration group (CKD-EPI) developed and validated a new equation in 2009 designed to match the accuracy of the MDRD equation at GFR <60 mL/min/1.73m2 and to offer greater accuracy at higher GFR, minimising the over-diagnosis of CKD with the MDRD equation --->Extrapolated to whole populations, it means that fewer individuals will be assigned as having CKD and thus resources can be more appropriately targeted. • Data pooled from several studies • As accurate as MDRD for GFR < 60 ml/min/1.73m2 • More accurate than MDRD for GFR > 60 mL/min/1.73 m2 • KDIGO (Evidence level IB) recommends reporting eGFR in adults using the 2009 CKD-EPI creatinine equation • In Nova Scotia, eGFR will automatically be reported on all Scr using CKD-EPI equation in June 2016 • Multiply eGFR by 1.159 if patient african descent >>>BSA NORMALIZATION BSA normalization will result in: ↑ doses for smaller people and ↓ doses in bigger people LIMITATIONS OF 24 HOUR URINE COLLECTION -not always reliable. (challenging for people to do) -In the past, a 24 h urine creatinine clearance has been regarded as a more sensitive tool for the detection of kidney failure than a single plasma creatinine measurement. However, the inconvenience of a timed urine collection, failure to collect the entire specimen, and the wide (11%) within-subject variability, restrict the usefulness of this procedure. Furthermore, there is some tubular secretion of creatinine and as a result, healthy individuals could have a creatinine clearance regularly exceeding that of inulin clearance by 10 to 40%, thereby overestimating GFR and masking any future renal impairment USEFULNESS OF eGFR... GUIDING DRUG THERAPY Rule of Thumb - If the patient looks pretty standard for their age the eGFR will be pretty close to whatever formula you use to calculate it. • For elderly use CG IBW (take out the normalization) • For obese use CGIBW or CG Adj or CKD-EPI IND and Compare! (take out the normalization) • Convert ml/min/1.73m2 TO ml/min • eGFRIND (mL/min) = CKD EPI eGFR (mL/min/1.73m2 ) x estimated BSA or use GFR calculator
Calcium and phosphorus homeostasis
>> 4 target organs -parathyroid gland -kidneys -GI tract -Bones >>Hormones/Minerals involved -PTH -Ca -PO4 -Calcitriol -others...
GQ 18 ) what are the various factors (drug and tx) that would determine how the dialysis method would impact upon the pk of drugs that Rick is currently receiving (hemodialysis)?
>>>>Dialyzability of Drugs -Drug Factors > Molecular size -The smaller the size of the drug, the more likely it will be dialyzed. -HD can dialyze drugs < 20 000 Da -PD can dialyzed drugs < 30 000 Da - Most dialyzability data derived from studies using conventional membranes _ _ _ __ __ __ __ _ _ __ _. __ __ _ _ __ _. _. _ _ _ _ _ _ >Protein binding • Primary drug binding proteins are albumin and ἀ1 - acid glycoprotein • MW albumin: 69,000 • MW ἀ1 - acid glycoprotein : 44, 000 • Only unbound drug is dialyzable • Highly protein bound drugs have low dialyzability _ _ _ __ __ __ __ _ _ __ _. __ __ _ _ __ _. _. _ _ _ _ _ _ > Volume of distribution • Drugs with a large Vd are typically lipophillic. (For example: digoxin, atorvastatin, LMWH) • Lipophillic drugs distribute widely into tissues leaving less free drug in the vascular space to be dialyzed • Drugs with a large Vd have low dialyzability _ _ _ __ __ __ __ _ _ __ _. __ __ _ _ __ _. _. _ _ _ _ _ _ > Water solubility • Dialysate used in PD and HD is an aqueous solution. • Drugs with high water solubility increases dialyzability ________________________________________________________________________________ -Dialysis Factors > Pore size • Pore size can vary among HD dialyzers. A high-flux dialyzer will allow bigger drugs to pass through • In general, the pore size of the peritoneal membrane is larger than in hemodialysis. So bigger drugs can potentially be dialyzed _ _ _ __ __ __ __ _ _ __ _ __ __ _ _ __ _ _ _ _ _ _ _ _ _ _ > Blood and dialysate flow rates • Drug movement across the membrane is concentration dependent. • Higher blood flow rates (HD) will present more drug to membrane. Blood flow rates in PD can not be altered. • High dialysate flow rates will maximize drug concentration gradient across the membrane. • Increasing PD frequency will increase drug dialyzability ________________________________________________________________________________ > Other Factors • Non-renal clearance (PLASMA CLEARANCE) • Sum of renal and non-renal clearance. ClP=ClR + ClNR • In dialysis, CLR is replaced by dialysis clearance (ClD) • If ClNR is large compared to Cl R, Cl D of a drug is minimal • If ClR (or ClD) accounts for >30% of ClP then the amount of drug cleared by dialysis becomes important.
Treatment options for electrolyte imbalances
>>>>PHARMACOTHERAPY SUMMARY: (((manage phosphate level by using phosphate binders. start with the calcium based agents (can only use up to 2 g of elemental ca per day), there is also the option to add on sevelamer. if someone is highly calcified just use sevelamer, OR lanthanum. If the PTH level is high (above 55) try one of the vitamin D analogs (one-alpha) to bring these levels down... however if the phosphate or calcium levels go up we will watch our use of vitamin D analogs. cincalcet is only sued if someones PTH level is elevated (needs 2-6 month time)... there should be 2 elevated consecutive PTH levels for patients on dialysis, then this is an option. >> phosphate binders (((((TAKE with meals. they only work if taken with food))))) ---> calcium based binders (ca carbonate, ca acetate.... know the amount of elemental calcium and cap the amount at 2g of ca/day. EX TUMS: regular has 200 mg, extra strength has 300mg and Ultra strength has 400 mg. "remember to space specific meds by at least 2 hours... cipro,oral iron, doxycycline, synthroid") vs non-calcium based binders (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate) —> Non calcium based phosphate binders: **SEVELAMER HCL **SEVELAMER CARBONATE -Take with meals -do not chew,crash -common ADRs: nausea, vomiting, diarrhea, constipation **LANTHANUM - Take with meals -Chew tablets completely before swallowing -common ADRs (nausea, vomiting, diarrhea/constipation) >> magnesium hydroxide (milk of magnesia, various brands) >> new agents (sucroferric oxyhydroxide) _____________________________________________________________________________ >> Vitamin D analogs ((dont require the kidney to actiavte them.. thus solves the problem!)) ***works directly on the PTH. it lowers PTH levels and promotes reabsoprtion of ca fro the gut... as a result people ca increases. if calcium levesl start to rise (once at 2.5-2.6 we are done) either reduce the dose or change things"change calcium in dialysate fluid". this can also increase phosphorous reabsorption. high phosphorous also means readjustament of dosing!!! > Calcitriol (oral"Rocaltrol" , injection"Calcijex") -directly increases the amount of activated vitamin D in your body. -Dose titrate: Q 4-12 weeks, monitor calcium, phospahte, PTH level > Alfacalcidiol (oral"One-Alpha") -bypasses conversion step required by kidneys and increases the amount of active vitamin D in your body -Dose titarte: Q 6-12 weeks, monitor calcium, phosphate, PTH level -this one is used the most as its the cheapest -requires activation by the liver.. dont use if they have liver dysfunction _____________________________________________________________________________ >> Cinacalcet (sensipar) -works directly on PTH and reduces PTH levels "reduces calcium and phsopahte". This agent is ONLY approved in dialysis (also not covered by public and private insurance... it is VERY expensive) - calcimimetic agent that increases the sensitivity of the calcium sensing receptor on the parathyroid gland to calcium. THUs it decreases serum parathyroid hormone, calcium and phosphate concentrations ((USED FOR SECONDARY HYPERPARATHYRODISM)) -ADRS: N/V/D (COMMON... limits dosing), HYPOcalcemia (if calcium levels are low to begin with do not start this med due to the risk of hypocalcemia.. or do it slow and very carefully. generally monitor calcium and phsopahte weekly) - Drug Interactions: • Strong inhibitor of CYP 2D6 (e.g. amitriptyline, metoprolol) • Metabolized by CYP 3A4 (erythromycin, ketoconazole, itraconazole {may need less of sensipar}, rifampin, phenytoin {may need more sensipar} -Not removed by HD or PD (doesnt matter if you take before or after) -Dosing: 2-4 week dose titration - Take with food or shortly after largest meal, swallow whole, do not split tablet • Assess trough PTH (4-6 weeks); Ca and PO4 (weekly x 3 weeks) >>>>>NON-PHARMACEUTICAL - diet - surgery (if patient can get their parathyroid gland removed that is our first option ) - dialysate additives (add things to the fluid that circulates through the dialysis machine (add calcium or remove it)
Renal physiology
>>>Primary Functions of the Kidney • Removal of metabolic wastes • Fluid balance • Electrolyte balance • Acid base regulation • Blood pressure control • Hormone production
Causes of CKD ---> irreversible loss of nephron... thus blood flow shifts to nephrons that are still alive (leading to glomerular hyperfiltration). during the early stages this is tolerated (increase in GFR in fucntional nephron). after a while this hyperfiltration leads to sclerosis because there is so much pressure and eventually sclerosis will lead to that nephron as well and the cycle continues! in the late stage you loose so mcuh of the kidneys fucntion that the GFR and urine decerases and you start to retain waste reuslting in uremia! MODIFIABLE RISK FACTORS -hyperglycemia -albuminuria (U ACR) -hypertension -dyslipidemia -smoking -anemia?? (not sure (correcting calcium and phosphorus) may prevent renal disease) -calcium and phosphorus NOT MODIFIABLE -age -ethnicity -gender
>>many causes are hereditary, genetic or associated with other conditions (patient and family history are very important)... patients with risk factors diabetes and CVD should be screened for CKD. >>>>>>>the number 1 cause of starting dialysis is diabetes, then HTN then glomerulonephitis, then cystic kidney ACUTE KINDEY FAILURE HYPERTESNION - Walls of the arteries supplying the kidneys start to thicken in order to withstand the pressure. this results in a narrow lumen which results in less blood and O2 getting delivered to the kidneys.(leads to ischemic injury to the glomerulus) -immune cells like macrophages and foam cells get into the glomerulus to secrete growth factors (TGF-beita 1 ). this causes the mesangial cells to transform to mesangioblasts. the mesangiobasts secrete extracellular matrix....the excess of this leas to glomerulo-sclerosis(hardenign and scaring... cant filter the blood) --thus less blood is entering the kidneys and the kidney thinks by increasing the BP 9production of renin) it will receive more blood however this just causes more vessel thickening and vessel narrowing. leading to glomerulosclerosis!!! DIABETES (most COMMON cause) -diabetic nephropathy eventually will lead to chronic kidney failure -hyperglycemia will lead to over production of reactive oxygen species(ROS)...... leading to activation/production of unecessary growth factors, proinflamamtory cytokies and oxidative stress!... all of this leads to diabetic nephropathy changes -excess glucose in blood starts sticking to proteins (non enzymatic glycation).. this process affects the efferent arteriole the most causing it to get stiff and narrow.. this causes a situation where it makes it hard for the blood to leave the glomerulus. this increases the pressure inside the glomerulus which leads to hyperfiltration. due to the increased pressure in the glomerulus the mesangial cells produce more and more extracellular matrix which expands the size of the glomerulus. the glomerulosclerosis over the years diminishes the nephrons ability to filter the blood leading to CKD ((• Hyperglycemia leads to afferent arteriole vasodilation and an increase in glomerulus pressure • Diabetics have a higher sensitivity to ATII (potent vasoconstricotr) and therefore have more efferent arteriole constriction • Results in increase flow and increased interglomerular pressure • Results in increased permeability of the glomerular basement membrane (or basal lamina) to protein which leads to a decrease in functioning nephrons) >>>>stages of diabetic nephropathy: the urine dipstick for protein is positive for overt nephropathy but not for micoralbuminuria. in microalbuminuria the urine ACR is 2-20 but in overt nephropathy it is >20 KIDNEY DISEASE -polycystic kidney disease (hereditary disease) SYSTEMIC DISEASES SUCH AS: LUPUS, RHEUMATOID ARTERITIS (which can also cause glomerulo-sclerosis) INFECTIONS (HIV) MEDICATIONS -NSAIDs, Acetaminopehn, lithium, cyclosporine, tacrolimus, contrast dyes TOXINS -Tobacco RECURRENT EPISODES OF DEHYDRATION
Effect of CKD on ADME GQ 16 ) how might renal disease affect the ADME of the drugs Rick is taking
ABSORPTION >>>Drug bioavailability (fraction of drug that gets into systemic circulation) varies more in renal than healthy patients --->Decrease Bioavailability • ↑ in gastric pH (from salivary urea converted to ammonia by urease) will minimize absorption of drugs that require an acidic environment (oral iron "switch to parental iron", furosemide) • Slowed absorption rates due to reduced peristalsis and bowel wall edema (due to low albumin which keeps the hydrostatic pressure) • Phosphate binders that form complexes with drugs, making them insoluble for absorption (quinolones) --->Increase Bioavailability (altered first pass metabolism) • ↓ in metabolism during drug's first pass through the GI tract and liver resulting in ↑ amounts of active drug in systemic circulation (greater exposure and longer half life) _________________________________________________________________________________________________ DISTRIBUTION • Plasma protein binding (Pb) is a key determinant of volume of distribution (Vd : the amount of drug absorbed/[Cp]) • Drugs that are highly Pb will stay in the vascular space and have a low Vd • Pb drugs are largely inactive • CKD may ↑ or ↓ Pb of drugs • Reduced PB (low albumin)may result in more free drug available at the site of drug action⁄toxicity >>>Misinterpretation of measurements of total drug concentrations • Example: Dialysis patient with [Total phenytoin] of 20 umol/L and albumin 20 g/L ......adjusted [Total phenytoin] = 67 umol/L (target range 40-80 umol/L)... if we didnt know we have adjust for albumin we would think the dose of the drug needs to be increased. • Organic acids that accumulate in RF will compete with acidic drugs for Pb, and a larger fraction of acidic drugs will exist in the unbound active state (warfarin, sulfonamides, salicylate, phenytoin) _________________________________________________________________________________________________ METABOLISM/ELIMINATION • CKD impacts Cl"nonrenal" of drugs • Reduction in hepatic and/or intestinal cytochrome (CYP) P450 enzymes and drug transport proteins --↑ oral bioavailability, greater systemic exposure, ↑ t 1/2 -- In 2010, FDA published a draft guidance document for industry recommending that PK studies be conducted to assess renal and non-renal clearances of drugs in patients with CKD • CKD impacts Cl"renal" of drugs • Drugs may accumulate due to impaired glomerular filtration and decreased tubular secretion • Decrease in elimination of parent drug, drug metabolites
QUESTION: Which of the following drugs would be the most likely culprit in a patient with newly diagnosed renal intratubular obstruction? A) Ibuprofen B) Losartan C)Acyclovir D) Amphotericin B
C)Acyclovir --->FORMS CRYSTALS
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
CASE • RD is a 59 year old male with Autosomal Dominant Polycystic Kidney Disease (ADPKD) who has been followed in the Pre-dialysis clinic. He has been on Tolvaptan (Jinarc®) for 4 years. His CKD has progressed to stage 5 and his eGFR is now < 10 ml/min. Why is Tolvaptan used to delay progression of CKD? WHAT IS ADPKD? •Is a dominantly inherited, systemic disease •Is a form of obstructive nephropathy (KIDNEYS GROW) characterized by multiple kidney cysts •Causes slow, gradual, and massive bilateral kidney enlargement •Results in kidney failure in the majority of individuals by the fifth or sixth decade •Birth prevalence: 1:400 to 1:1000 ( Affects ~ 30,000 Canadians) TOLVAPTAN >>MOA: - Vasopressin promotes cyst growth in the kidneys in patients with ADPKD - Tolvaptan blocks these effects through inhibition of the vasopressin V2 receptor (INHIBITS CYST GROWTH) >>EFFICACY: - Tolvaptan showed benefits across a spectrum of CKD stages (TEMPO STUDY looked at CKD stages 1 to 3a, and REPRISE STUDY looked at CKD stages 2 to 4) -Tempo study: Tolvaptan decreased the rate of TKV(total kidney voume) growth by 49% over 3 years compared to placebo in subjects with CKD stages 1 to 3.... AND Tolvaptan slowed eGFR decline by 26% over 3 years compared to placebo -REPRISE study: Tolvaptan slowed eGFR decline by 35% over 12 months compared to placebo >>Conclusions on Safety and Efficacy: • Together, TEMPO 3:4 and REPRISE show that tolvaptan slows eGFR decline over a broad range of disease stages and may delay time to ESRD • Transaminase elevations occurred more frequently in the tolvaptan arms of these studies • There were 2 cases meeting Hy's Laboratory criteria for hepatic injury in TEMPO 3:4 • There were no such cases in REPRISE (attributed to the monthly transaminase monitoring in the latter study) ***this drug helped to delay dialysis!! :) >>ADRs - drives the thirst by alot (alot of uriantion) -DOSE: 2 doses daily: one (larger dose) upon waking and one (smaller dose) 8 hours later ... the later people do take it the greater the chnace they will have nocturia. -the dose is titrated based on urine osmolality and how well they are doing. >>MONITORING: Adequacy of vasopressin suppression at a given dose of tolvaptan can be monitored through measurement of urine osmolality and may be used to optimize the clinical benefit of tolvaptan in ADPKD patients. >>INTERCATIONS: - With cyp3A4 inhibitors and inducers -grapefruit juice -PGP inhibitors
Therapeutic goals of electrolytes
Ca - avoid ypercalcemia -correct for albumin level • [(40-Alb)*0.02+pt Ca level PO4 - lower phosphate levels towards normal range PTH - optimal PTH is unknown • CKD stage 3a-5: optimal PTH unknown. Patients with levels of intact PTH rising or persistency above the upper normal limits be evaluated for modifiable risk factors. (↑ Phosphate, calcium, high phosphate intake and vit D deficiency). Use of calcitriol and vitamin D analogues not to be routinely used (reserved for more severe cases) • CKDstage5D:inpatientsrequiringPTH lowering therapy, suggest calcimimetics, vitamin D analogue or a combination
GQ 7 ) what is the evidence for the use of SGLT2 inhibitors and GLP1 agonist (eg liraglutide) medication in patients with T2DM with CKD? are there also cardiovascular or renal benefits?
GLP1 AGONSIST: Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. --> when liraglutide is added to usual care, it resulted in lower rates of the development and progression of diabetic kidney disease than placebo - liraglutide had superiority in T2DM with clinical CVD -not that impressive comapred to the empa. SGLT2 INHIBITORS SGLT2 inhibitors might have beneficial effects on the kidneys because they reduce glomerular hyperfiltration and restore tubule-glomerular feedback -cana and empa: superiority in T2DM patients with clinical CVD >>>>SGLT2 inhibitor trials: • Renal effects were not the primary focus of the CV outcomes trials • CV outcomes trial results suggested possible attenuation of renal effects in patients with reduced kidney function - the three trials: EMPA-REG outccome, CANVAS program, DECLARE ((the populations had low renal risk )) - in the trial CREDENCE ((higher renal risk population)) -comapring the studies head to head: (in the credence many more composite renal outcomes were prevented comapred to palcebo )
Acute renal failure
GQ 12 ) what is ARF? how frequently does it happen? how serious is it? >> reversible decrease in GFR ((IN BEST CASE SCENARIO WE HOPE THAT THE KIDNEYS RECOVER BUT SOMETIMES THEY DONT)) • Rapid deterioration of renal function - azotemia (a medical condition characterized by abnormally high levels of nitrogen-containing compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds) in the blood.) CLASSIFICATION BASED ON DAILY URINE OUTPUT Anuric: <50 ml/day (poor prognosis) Oliguric: 50-400 mL/day Nonoliguric: >400 ml/day THERE IS ALSO A GFR CRITERIA GQ 13 ) what is the etiology and pathology of ARF? how would you classify the different types of ARF? What evaluations are helpful in determining the cause of ARF? *pre-renal causes: sudden or severe drop in BP or flow obstruction in kidnyes! -renal stenosis, HF and hemorhage *intra-renal causes: Direct damage to the kidnyes, inflamamtion within kidneys, infection, drugs, autoiimne disease -acute glomerulonephritis: due to SLE -acute tubular necrosis: death of cells within nephron -acute intrastitial nephritis: inflamamtion of interstitial space within the kidnyes (mostly due to infection or allergy) -vascular changes: endothelial dysfunction, vasocontriction, increased adhesion of inflammatory cells *post-renal causes: obstruction of urine flow -BPH, renal stones, tumors >>pre and post renal causes often lead to intra-renal causes
Chronic Kidney Disease (CKD)
KDIGO 2012 defines CKD as abnormalities of kidney structure or function, present for greater than 3 months with implications for health. --> chronic kidney failure is the end stage of CKD
SICK DAY medication managament SADMANS
KDIGO 2013 Recommends temporary discontinuation of potentially nephrotoxic and renally excreted drugs in people with GFR < 60 ml/min/1.73m2 who have serious intercurrent illness that increases the risk of AKI. •Contrast media dye poses a risk fo AKI in patients with CKD. If procedure necessary, monitor renal function pre and post dye. Cessation of ACEi, ARB, diuretics as well as metformin recommened prior to procedure.
Bone disease in CKD
MANAGEMENT: -dialysis (taking away phosphorus, givving calcium) -diet -drugs (phosphate binders, vit D, calcium) -monitor skin/bone (complication: calciphylaxis)>> rashes and ulcerations easily develop due to imbalance of calcium and phosphorus. leads to calciphylaxis (is a serious, uncommon disease in which calcium accumulates in small blood vessels of the fat and skin tissues. Calciphylaxis causes blood clots, painful skin ulcers and may cause serious infections that can lead to death.)
Electrolyte balances and CKD
Na+ and H2O BALANCE - decrease in GFR leads to incerase in Na and water retention which then leads to an increase in BP and peripheral edema. -it is important to restrict fluid intake for these patients thus when vomiting or diarrhea occurs this can be very dangerous POTASSIUM LEVELS - Normally the kidney aids in K+ excretion. - in CKD less potassium is excreted and more builds up in the blood. leading to hyperkalemia (problematic as it can cause cardiac arrhythmias, muscle weakness, ECG changes) -loss of nephrons eventually leads to a decrease in renin production which leads to a decrease in aldosterone. when you have a decrease in aldosterone, the distal sodium/potassium pump does not work, which leads to potassium retention. THUS, using potassium sparing diuretics and ace inhibitors can further aggravate the problem. >>hctz and furosemide should be used for edema don't use K sparing ones like spironolactone • Goal 4.5-5.5 mmol/L • Minimize potassium-containing foods • Attend dialysis regularly if on • Kayexalate (sodium polystyrene sulfonate) -30 grams powder only (mix with 125 ml water, not fruit juice as it may contain K).... you can only drink 500 mls of water between dialysis days :( -Avoid oral suspension that contains sorbitol (colonic necrosis -Health Canada warning) -Space 3 hours from other oral medications • Newer agents coming: Zirconium Cycosilicate, Patiromer (taste a bit better and have lower Na content) CALCIUM LEVELS - normally the kidney helps to activate vitamin D "calcitriol", (which then helps to absorb the calcium from the diet.) -in CKD there is less activated vitamin D thus less ca is absorbed to blood leading to hypocalcemia -as calcium levels in the blood fall, parathyroid hormone is released causing bones to lose ca! (over time this resorption of ca from the bones causes the bones to become brittle and weak. >>>Renal osteodystrophy -decease in calcitriol will lead to hyperparathyroidism. this state leads to osteodystrophy. (stimualtes bone breakdown) METABOLIC ACIDOSIS -kidneys regulate the pH of the blood by producing bicarbonate or hydrogens when necessary. -diminished capacity to excrete hydrogen and to generate bicarbonate which leads to acidosis -acidosis leads to bone decalcification >>TREAT with sodium bicarbonate tablets or Shohl solution (citric acid/sodium citrate). Start at 0.5 mmol/kg/day in 2-3 divided doses and titrate to achieve a CO2 level ≥22 mmol/L. Monitor closely since some patients will experience fluid retention and heart failure. BICARBONATE LEVELS - low in CKD • Bicarbonate goal >22 mmol/L • AVOID baking soda! (dose uncertainity) • Discontinue once dialysis begins as bicarbonate added to dialysate bath PHOSPHATE LEVELS -loss of nephrons will lead to a decrease in GFR leading to hyperphosphatemia -phosphate retention will lead to increased ca and PO4 product leading to soft tissue calcification. -TREATMENT: If serum phosphate is progressively or persistently elevated despite a low phosphate diet (800-1000 mg phosphate/day), start therapy with a low dose of calcium-containing phosphate binder (calcium carbonate or calcium citrate) if hypercalcemia is not present. If hypercalcemia develops, reduce the dose of calcium-containing phosphate binders and vitamin D analogues if used. If hyperphosphatemia is still present, the patient may be changed to a non-calcium-containing phosphate binder, such as lanthanum, sevelamer carbonate or sevelamer hydrochloride.
Cefazolin dosing
Nephrotoxicity has been reported rarely with cephalosporins, and is more likely in older individuals, or in patients who are taking other nephrotoxic drugs concomitantly or have pre-existing renal impairment. Since cefazolin is cleared renally, dosage adjustment is recommended in patients with impaired renal function DOSING IN RENAL IMPAIREMENT GFR >50 (mL/min) ........ usual dose GFR 10-50 (mL/min) ....... 100% of dose, Q12H GFR <10 (mL/min) ........ 50% of dose, Q24-48H In patients receiving hemodialysis, cefazolin should be administered at a dose of 15-20 mg/kg after each dialysis session. In patients receiving continuous ambulatory peritoneal dialysis, cefazolin should be administered at a dose of 500 mg Q12H.
Hormone balances and CKD
RENIN LEVELS -normally when the kidneys start sensing a lower than normal amount of fluid being filtered, they respond by releasing the hormone renin to increase the BP. -in CKD the falling GFR rate leads to more and more renin secretion. leading to hypertension. ((hypertension also causes CKD!!! visious cycle))
Anemia in CKD
THE ROLE OF THE KIDNEYS: - the kidneys produce a hormone called EPO. EPO prompts the bone marrow to make red blood cells which then carry oxygen through the body. Pathophysiology (many factors may disrupt iron homeostasis) -When kidneys are diseased or damaged, they do not make enough EPO. As a result, the bone marrow makes fewer red blood cells, causing anemia. When blood has fewer red blood cells, it deprives the body of the oxygen it needs. -blood loss in dialysis is common IN CKD HEPCIDIN EXPRESSION IS INCREASED.... -CKD = functional iron deficiinecy (they often have iron but it is not available.... Iron is held as ferritn in the liver and not released as functional iron) -try to find a target for hepcidin to reduce it for CKD patients -increased expression of hepcidin will lead to inadequate absorption of iron, impaired iron utilization. hepcidin binds to ferroportin and inhibits iron from being absorbed. IRON THERAPY The first step in treating anemia is raising low iron levels. Iron pills may help improve iron and hemoglobin levels. However, for patients on hemodialysis, many studies show pills do not work as well as iron given intravenously!!! >>Oral Iron • 200 mg elemental Fe per day (ferrous sulfate, ferrous gluconate, ferrous fumarate, polysaccharide-iron complex, [Feramax®] Proferrin) >>IV Iron **this becomes the drug of choice in end stages • Iron Sucrose (Venofer®) >> used alot • Iron Dextran (Infufer®) >>not used anymore due to reaction... if used TEST DOSE(25mg) • Sodium Ferric Gluconate Complex (Ferrlecit®) • Iron Isolmaltoside 1000 (Monoferric®) >> if you had previous allergic reaction with other irons this product is contraindicated. Doses up to 1000 mg must be administered over 20 minutes or more.(this is advantages!) ***for all iv irons Observe for signs and symptoms of hypersensitivity for at least 30 minutes following each IV iron administration. ****Most CKD patients will require a minimum cumulative dose of 1,000 mg of EI over sequential sessions and may continue to require IV iron therapy at the lowest dose necessary to maintain target Hb and iron storage parameters (TSAT and Ferritin) TIMING OF IV IRON ADMIN AND MEASUREMENT OF IRON STUDIES "TSAT and FERITIN" - iron dextran, iron sucrose and sodium ferric gluconate (7 days post dose) -iron isomaltoside 1000 (wait atleast 1 month as the iron is released much more slowly from the iron oxide core) >>NOTE: During maintenance phase, TSAT/Ferritin at least every 3 months. ERYTHROPOIETIN -If CKD is the cause of anemia, tx can include injections of a genetically engineered form of EPO. -iron must be present for this to work -Studies have shown the use of EPO increases the chance of cardiovascular events, such as heart attack and stroke, in people with CKD. The health care provider will carefully review the medical history of the patient and determine if EPO is the best treatment for the patient's anemia. Experts recommend using the lowest dose of EPO that will reduce the need for red blood cell transfusions. Additionally, health care providers should consider the use of EPO only when a patient's hemoglobin level is below 10 g/dL. Health care providers should not use EPO to maintain a patient's hemoglobin level above 11.5 g/dL.2 Patients who receive EPO should have regular blood tests to monitor their hemoglobin so the health care provider can adjust the EPO dose when the level is too high or too low >>Darbepoetin alfa (Aranesp)... reenginered improved formualtion and doesnt need to be dosed that often! this is mainly due to the additional carbohydrate side chains • t 1⁄2 IV = SC (~ 30 hours) >>Epoetin alfa (Eprex) • t 1⁄2 IV (5-11 hours) - requires dosages of 20-30% with more frequent dosing to achieve similar Hb targets as Subcut. • t 1⁄2 Subcut. ( ~20-25 hours) >>>>>>DOSING: in dialysis patients given weekly. if non dialysis/ peritonealD get this SC at home. these agents must be refrigirated! .... dont see impact of dosage change until 4 weeks! no dosage adjustment sooner than 4 weeks! CKD targets for anemia >>2 guidelines (international KDIGO and commentary from the Canadian society of nephrology) -the target hemoglobin for CKD patient is 95-115 g/L (alot lower than what it is in healthy individual.. this is beacsue of the results of studies that found; when they used erythropoetin to target near normal levels in CKD patients bad things happened (eg stroke).... if you are above or below this range dose the ESA agent differently -Target TSAT: there is good evidence to support administartion of iron when the TSAT is <20% and ferritin <200ug/L •Uncertainty in definition of ESA hyporesponsiveness •Issue of hyporesponsiveness is important since these patients are at exceedingly high risk of CV events and mortality even after adjustment for patient comorbidity. •~ 15% of ESRD patients have ESA resistance, trials are required to determine the optimal strategy for anemia management in this population. •In absence of definitive clinical trials of hyporesponders, and given the safety concerns with higher Hb targets, a maximum weekly dose of ESA seems prudent! CKD MANAGEMENT OF ANEMIA (Targets) - ferritin>200 ug/L (The ferritin level helps assess the amount of iron stored in the body).... not very reliable biomarker it is impcated by inflammation and patients with CKD are often inflammed - TSAT >20% (The transferrin saturation score indicates how much iron is available to make red blood cells) - •For patients on ESAs: an acceptable range for Hb is 95-115 g/L with a target of 100-110 g/L. OKKKKKURRRRRRR IMPORTANT TAKE HOMES IN ANEMIA CKD • ESA appear to have a maximum benefit on hemoglobin • Classify patients as ESA hyporesponsiveness if have no increase in Hgb from baseline after the first month of ESA therapy on appropriate weight-based dosing • Adverse events occur at > 120 g/L (TREAT, CREATE, CHOIR, RTC Studies) • Complete mechanism unknown • Target hemoglobin has yet to be determined • New guidelines target lower hemoglobin (95-115 g/L) • Guidelines target TSAT ≤30% and Ferritin ≤500 ng/ml (KDIGO 2012) but CSN Target TSAT ≤20% and Ferritin ≤200 mg/ml)
GQ 14 ) pharmacists need to be familiar with common drug induced diseases. what drugs can cause each of the types of ARF? how do they cause it? how do patients present? what are the risk factors? how can you prevent/manage it?
TYPES OF ARF >>PRE-RENAL (MOST COMMON TYPE) •Reduced intravascular volume (hypovolemia) [eg NSAIDS, ACE-I/ARB, Diuretics, Sepsis] •Cardiac failure or hypotension •Vascular obstruction >>INTRINSIC ATN (ACUTE TUBULAR NECROSIS) •Drugs (AGs, cyclosporine, radiocontrast dyes, Lithium, acyclovir, amphotericin B, cisplatin etc) AIN (ACUTE INTERSTITAL NEPHRITIS... immune reaction) •Drugs (beta-lactams, sulfonamides, rifampin, allopurinol, ranitidine) GLOMEROLURNEPHRITIS •Infections, immune-mediated conditions >>POST-RENAL •Obstruction (eg stones, tumor, BPH, Acyclovir crystals)
Hypertension and CKD
Taregts: <140/90 nondiabetic CKD <130/80 Diabetic CKD KDIGO • <140/90, urine albumin excretion <30 mg per 24 hours (non-diabetic and diabetic CKD) or ACR < 3 mg/mmol • <130/80, urine albumin excretion 30-300 mg per 24 hours (nondiabetic and diabetic CKD) or ACR > 3 mg/mmol • NOTE: Exception in ADPKD ≤110/75 (in most) **Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics**
SMOKING CESSATION
The incidence of developing ESRD based on cigarrete consumption. -->The higher the number of cigs/day the higher the risk for developing ESRD. -if on ace-inhibitor and smoked (the ace inhibitor seems to be kidney protective)
GQ 4 ) what is microalbuminuria and macroalbuminuria? what are their roles in diabetic kidney disease? what are the risks associated with this condition?
The term microalbuminuria is no longer used on lab reports in NSHA, IWK. ----> Term replaced by Urine Albumin Excretion expressed as Urine Albumin to Creatinine Ratio ( U ACR). • Clinical terminology is changing to focus on albuminuria rather than proteinuria. Albumin is the principle component of urinary protein found in most kidney diseases. >>>Earliest clinical sign of diabetic nephropathy is albuminuria • not detected by dipstick • albumin has smallest MW of proteins • Usually after 5-10 years after onset • Up to 50% of diabetics progress to this stage • Rate of GFR decline slow 1-2 mL/min/1.73 m2/year • Important because of association between albuminuria and CV morbidity and mortality >>>Next stage is macroalbuminuria or overt nephropathy • Detectable with urine dipstick • Rate of GFR decline 5-10ml/min/1.73 m2/year • GFR decline is highly variable from individual to individual URINE ALBUMIN EXCRETION (U ACR) >>>THE DIFFERENT LEVELS: Normal or mildly increased: less than 3 mg per mmol Moderately increased: 3.0-30 mg per mmmol Severely increased: greater than 30 mg per mmol
Dialysis >Dialysis is a treatment that does some of the things done by healthy kidneys. It is needed when your own kidneys can no longer take care of your body's needs. What does dialysis do??? -removing waste, salt and extra water to prevent them from building up in the body -keeping a safe level of certain chemicals in your blood, such as potassium, sodium and bicarbonate -helping to control blood pressure
WHEN TO START DIALYSIS? -You need dialysis when you develop end stage kidney failure --usually by the time you lose about 85 to 90 percent of your kidney function and have a GFR of <15 Recommended to start when you start developing SXs of kidney failure (fatigue, nausea, SOB, decreased appetite -make decision 3-6 months before you start it **People that end up on dialysis have high mortality rates CONSERVATIVE CARE "Do nothing" -preserve kidney function as long as possible. (this will not stop the slow decline in kidney function and will ultimately lead to death) DONATED KIDNEY -This is the best tx option (live longer and better than dialysis) - either from deceased donor or living donor. the ones from living donors last longer! REASONS FOR DIALYSIS A acid : base abnormalities E electrolyte disturbances (eg INCREASED K) I intoxication O overload(not responding to ceiling dose diuretics) U uremia 2 TYPES OF DIALYSIS: >>Hemodialysis: happens outside the body. blood is passed through an artificial kidney. this requires diet changes and fluid restrictions -usually done for 4 hours 3-4x/week -swings in blood chmeistry and strict diet/fluid restrictions -fistula/gaft or CVC (peripheral vein wouldnt be enough blood supply) - theres also home based HD >>>>>>Advantages • Greater solute clearance, better defined adequacy goals • Technique failure rate low • Close monitoring of patient >>>>>>Disadvantages • "loss" of control to take care of self • HD complications (hypotension, cramps, etc.) • Vascular access - infection, thrombosis • Decline of RRF (RESIDUAL RNAL FUNCTION) _ _ _. _. _ _ _ _ __ _ _ _ __ _ __ _ __ _ _ >>Peritoneal dialysis: happens inside the body (uses the peritoneal memebrane and man made dianeal solution to remove waste and fluid (exchnage process that atkes 20-30 minutes) -7 days a week -may hae increased control of diet, blood chmeistries and fluid balannce -PD catheter -two types.... continous ambulatory peritonela dialysis and atutomated peritoneal dialsis >>>>>>>>Advantages • Hemodynamic stability • Preserve RRF • Convenience - do not "lose" control of self • Less blood loss, iron deficiency >>>>>>>>>Disadvantages • Protein and amino acid loss in PD fluid • Infectious (peritonitis, exit site ) • Mechanical problems (dialysate leaks) • Inadequate solute removal (UF) • Patient burnout, technique failure • High glucose load exposure (obesity, lipids, DM) • Abdominal hernia >>>>>>>DRUGS AND PD -in general drugs removed by PD must be small in size, low PB, and have low Vd -drug clerance likeley around 5-7.5 ml/min-factor in RRF -use dose recommendations for crcl or eGFR <15 ml/min -IP administation of drugs (stability and compatibility of IP drug and PD solution).... works way better than iv if the site of infection is the peritoneum ***AVF CREATION -aneuresims form after they used the artery for so long for HD HOW DOES DIALYSIS WORK -diffusion and osmosis -ultrafiltration -convection >>maintains electrolytes and acid base balance (most end up in metabolic acidosis thus bicarbonate is given through dialysis). also removes wste products from blood DIALIZER (artificial kidney) -smaller moelcules move through the fibers but the larger ones like almumin do not pass through -contain postassium, mg, glucose in the dilayzer (we dont want them to lose to much of this and we want their levels to be maiantianed within normla level during the process) COMPLICATIONS OF DIALYSIS -hypotension -leg cramps (mostly HD) -perionitis (PD) -bleeding from hemodialysis site -exit site infection -failure to drain (PD) -constipation (PD).... must have bowel moveemnets for PD to work. most are on senna and most recently people have been put on PEG -hernia (PD) -fluid deficit/overload (PD/HD)