GU/Renal Cards

A 21-year-old female presents with a recurrent rash near her vagina. She is G1P1 with a past medical history of allergic rhinitis. She spent the past college semester living in a submarine performing research. Physical examination demonstrates several small erosions surrounded by erythema near her introitus. She reports discomfort when the lesions are palpated. Cytology shows multi-nucleated giant cells with inclusion bodies. *What is the Dx?* A. Enveloped double-stranded DNA virus B. Gram-negative bacillus C. Gram-negative coccobacillus D. Gram-negative diplococcus E. Non-enveloped double-stranded DNA virus

*Enveloped double-stranded DNA virus* Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus. HSV causes multiple small vesicles on an erythematous base that may rupture to form painful erosions or shallow ulcers. Patients can also have dysuria, fever, tender local inguinal lymphadenopathy, and headache. HSV may be transmitted by sexual or non-sexual contact. A microscopic technique called a Tzanck smear may be utilized to characterize epithelial cells infected with HSV. It will show multinucleated giant cells with viral inclusion bodies. This image shows a patient with genital herpes caused by HSV-2 (red circles). Answer B: Granuloma inguinale is caused by a Gram-negative bacillus, Klebsiella granulomatis. This disease causes genital ulcers which have a beefy-red, friable base. Unlike genital herpes, ulcers of granuloma inguinale are not commonly recurrent. Also unlike genital herpes, this sexually transmitted infection is more common outside of the United States. Histologically, granuloma inguinale is characterized by Donovan bodies, which are clusters of bacteria within macrophages. Multinucleated giant cells are not characteristic. Answer C: Haemophilus ducreyi is a Gram-negative coccobacillus that causes chancroid. Like genital herpes, chancroid causes painful genital ulcerations. Unlike genital herpes, chancroid is more common outside of the United States. This patient does not report a recent international travel history. Chancroid does not demonstrate multinucleated giant cells on microscopy. Rather, these Gram-negative coccobacilli often form aggregates resembling a "school of fish" under the microscope. Answer D: Gonorrhea is caused by a Gram-negative coccus called Neisseria gonorrhea. Gonorrhea is a sexually transmitted infection characterized by urethritis, cervicitis, or salpingitis. Symptoms include dysuria, purulent discharge, or pruritus, although up to 50% of females are asymptomatic. Genital ulcers are not a typical cutaneous expression of gonorrhea. Multinucleated giant cells with inclusion bodies are not characteristic of gonorrhea. Answer E: Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. If it is sexually transmitted, it causes wart-like papules or plaques called condylomas. HPV does not cause ulcers. Microscopically, condylomas may demonstrate koilocytes, which are epithelial cells with perinuclear clearing. They do not demonstrate multinucleated giant cells with inclusion bodies. *Bottom Line*: Herpes simplex virus (HSV) is a common sexually transmitted infection in the United States that causes multiple small vesicles that may rupture to form painful erosions. HSV is characterized cytologically by multinucleated giant cells with inclusion bodies.

A 21-year-old female presents with a three-day history of two ulcerated papules on her labia majora. She has no past medical history. Social history is pertinent for unprotected sexual activity with a new partner and recent travel to Papua New Guinea. Physical examination demonstrates two ulcerated papules with friable, erythematous bases. Microscopy of ulcer exudate reveals macrophages containing bodies highlighted by bipolar stain. *What is the Dx?* A. Enveloped double-stranded DNA virus B. Gram-negative bacillus C. Gram-negative coccobacillus D. Gram-negative diplococcus E. Non-enveloped double-stranded DNA virus

*Gram-negative bacillus* This scenario is most compatible with infection by Klebsiella granulomatis, a Gram-negative bacillus. This sexually transmitted infection is called granuloma inguinale and is characterized by ulcers on or around the genitals. Ulcers usually have a beefy-red, friable base comprised of exuberant granulation tissue. Microscopic examination of exudate shows aggregates of bacilli, shaped like safety-pins, inside macrophages. These intracellular aggregates are highlighted by bipolar stain and have been named "Donovan bodies." Granuloma inguinale is uncommonly seen in the United States; it is more prevalent in countries such as South Africa, India, Australia, and Papua New Guinea. Other sexually transmitted pathogens may cause genital ulcers. Herpes simplex virus or Haemophilus ducreyi (chancroid) may cause painful genital ulcers. Treponema pallidum (syphilis) or Chlamydia trachomatis (lymphogranuloma venereum) may cause painless genital ulcers. Lesions of Klebsiella granulomatis (granuloma inguinale) may or may not be painful. Regardless, no other entity in the genital ulcer differential diagnosis would demonstrate Donovan bodies on microscopy. Answer A: Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus that causes grouped vesicles on an erythematous base. These vesicles may rupture, forming shallow, punched-out ulcers which are tender to palpation. HSV may be acquired through sexual or non-sexual contact. HSV-associated genital ulcers would not demonstrate Donovan bodies on microscopy. In contrast, a Tzanck smear of HSV-infected cells would show multinucleated giant cells with viral inclusion bodies. Answer C: Haemophilus ducreyi is a Gram-negative coccobacillus that causes chancroid. Chancroid is a painful genital ulceration, which is more common outside of the United States. While this patient has a history of recent international travel, chancroid does not demonstrate Donovan bodies on microscopy. Rather, these Gram-negative coccobacilli often form aggregates resembling a "school of fish" under the microscope. Answer D: Gonorrhea is caused by a Gram-negative coccus called Neisseria gonorrhea. Gonorrhea is a sexually transmitted infection characterized by urethritis, cervicitis, or salpingitis. Symptoms include dysuria, purulent discharge, or pruritus; however, up to 50% of affected females are asymptomatic. Genital ulcers are not a typical cutaneous expression of gonorrhea. Donovan bodies are not characteristic of gonorrhea. Answer E: Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. If it is sexually transmitted, it causes wart-like papules or plaques called condylomas. HPV does not cause ulcers. Microscopically, condylomas may demonstrate koilocytes, which are epithelial cells with perinuclear clearing. They do not demonstrate Donovan bodies. *Bottom Line*: Granuloma inguinale is caused by Klebsiella granulomatis, a Gram-negative bacillus. This sexually transmitted disease is characterized clinically by genital ulcers and histologically by the presence of Donovan bodies.

A 21-year-old female presents with a painful genital sore. She has no past medical history. Social history is notable for unprotected sexual activity with a new partner and recent travel to Venezuela. Physical examination demonstrates a soft erythematous ulcer on her vulva that is tender to palpation. Mild lymphadenopathy is palpable in her right inguinal basin. Light microscopy of ulcer exudate reveals microbes arrayed in aggregates and long parallel strands. *What is the Dx?* A. Enveloped double-stranded DNA virus B. Gram-negative bacillus C. Gram-negative coccobacillus D. Gram-negative diplococcus E. Non-enveloped double-stranded DNA virus

*Gram-negative coccobacillus* Haemophilus ducreyi is a Gram-negative coccobacillus that causes chancroid. A chancroid is a sexually transmitted infection that manifests as genital ulcerations. Lesions are typically soft and painful, and lymphadenopathy may be appreciated. This disease is rare in the United States so travel to equatorial areas is a suggestive clue. By light microscopy H. ducreyi forms clumps and long parallel strands, producing a "school of fish" appearance. Answer A: Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus. It may cause genital lesions which manifest as multiple small vesicles on an erythematous base. These vesicles may rupture to form shallow ulcers that are painful. Inguinal lymphadenopathy may or may not be present. Electron microscopy, not light microscopy, would be necessary to visualize HSV. Answer B: Granuloma inguinale is caused by a Gram-negative bacillus, Klebsiella granulomatis. This disease causes genital ulcers which have a beefy-red, friable base. Like chancroid, this sexually transmitted infection is more common outside of the United States. Histologically, granuloma inguinale is characterized by Donovan bodies, which are clusters of bacteria within macrophages. The question stem describes the characteristic "school of fish" appearance of Haemophilus ducreyi bacteria, not intracellular Donovan bodies. Answer D: Gonorrhea is caused by Neisseria gonorrhea, a Gram-negative coccus. Gonorrhea is a sexually transmitted infection characterized by urethritis, cervicitis, or salpingitis. Symptoms include dysuria, purulent discharge, or pruritus, although up to 50% of females are asymptomatic. Genital ulcers are not a typical cutaneous expression of gonorrhea. The "school of fish" appearance on microscopy is not characteristic of gonorrhea. Answer E: Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. If it is sexually transmitted, it causes wart-like papules or plaques called condylomas. HPV does not cause ulcers. Microscopically, condylomas may demonstrate koilocytes, which are epithelial cells with perinuclear clearing. They do not demonstrate the "school of fish" configuration, microscopically. Bottom Line*: Haemophilus ducreyi causes chancroid, which is characterized by painful ulcers. This sexually transmitted infection is associated with travel to tropical areas.

A 21-year-old female presents with acute pain in the left knee and rash of the right fifth toe. She has no past medical history. Social history is notable for recent unprotected sexual activity with a new partner. She also reports that she recently hiked the entire Appalachian trail. Vital signs are notable for a temperature of 38.4°C (101.2ºF), blood pressure of 115/55 mmHg, and heart rate of 63/minute. Physical examination demonstrates edema and erythema of the left knee, and her right fifth toe appears erythematous with a single pustule. *What is the Dx?* A. Enveloped double-stranded DNA virus B. Gram-negative bacillus C. Gram-negative coccobacillus D. Gram-negative diplococcus E. Non-enveloped double-stranded DNA virus

*Gram-negative diplococcus* The patient's presentation is indicative of disseminated infection with Neisseria gonorrhea, a Gram-negative diplococcus. The localized infection with N. gonorrhea is called gonorrhea, a sexually transmitted infection that causes urethritis in men, cervicitis or pelvic inflammatory disease in women, or pharyngitis in either sex. While most men exhibit symptoms, such as dysuria or urethral discharge, approximately 50% of women with gonorrhea are asymptomatic. When symptoms are present in women, they may include vaginal pruritus, mucopurulent discharge, or lower abdominal discomfort. Untreated, N. gonorrhea may enter the bloodstream and disseminate, causing fever, septic arthritis, and a localized rash. The arthritis may involve one or few joints in an asymmetric and migratory presentation. The rash typically has an acral distribution and is comprised of erythematous patches with solitary or few hemorrhagic pustules. Notably, disseminated N. gonorrhea (gonococcemia) is a common cause of acute-onset arthritis in healthy, young, sexually active adults. Although not included in this question stem, a deficiency in late complement components (C5 - C9) may predispose to infection with this Gram-negative diplococcus. Answer A: Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus that may also be spread by unprotected sexual contact. It causes multiple small vesicles on an erythematous base, which are classically painful. While these skin lesions may be included in the differential diagnosis of cutaneous lesions of gonococcemia, herpetic skin lesions are typically localized to the genitals, pubic skin, anus, oral cavity, or other skin or mucosal surfaces involved in sexual contact. Genital herpes would not commonly present on the fifth toe. Additionally, disseminated HSV is possible and may present with meningoencephalitis or generalized erythematous pustules; however, this is more commonly seen in the setting of immunosuppression, which this patient does not report. Patients with genital herpes may additionally report dysuria, fever, inguinal lymphadenopathy, and headache. Arthritis, as seen in this patient, is not associated with genital herpes infection. Answer B: A Gram-negative bacillus, Klebsiella granulomatis, causes the sexually transmitted infection granuloma inguinale. Typically, it presents as painless genital ulcers with regional lymphadenopathy with or without fever. Histologically, this disease is characterized by Donovan bodies, which are aggregates of bacteria within macrophages. Granuloma inguinale does not present with acute-onset arthritis or acral rash. Answer C: Haemophilus ducreyi, a Gram-negative coccobacillus, causes chancroid. Chancroid is a sexually transmitted infection that presents with painful ulcers of genital or perianal skin. Multiple ulcers are common, as is regional lymphadenopathy. Under the microscope, these Gram-negative coccobacilli often form aggregates resembling a "school of fish." This patient's presentation is not consistent with chancroid. Chancroid does not present with acute-onset arthritis or an acral rash. Chancroid is more common in tropical areas outside of the United States. Answer E: Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus that causes warts. There are many different types of HPV, which can be spread through sexual contact or non-sexual contact to infect squamous epithelium, including skin and mucous membranes. Sexually transmitted HPV includes types 6 and 11, which cause condylomas (benign genital warts), and types 16, 18, and 31, which cause genital warts with malignant potential. Condylomas are pink to skin-colored, verrucous papules or plaques. They are not pustules, as described in this case, nor are they acral in distribution. Furthermore, HPV is not associated with acute-onset arthritis. *Bottom Line*: Gonococcemia presents with asymmetric, oligoarthritis in a young, sexually active adult. An acral rash with scant erythematous pustules may also be observed.

A 21-year-old, sexually active female complains of pain in her wrists and ankles and a sore throat. The patient immigrated to the United States from South America as an 18-year-old and has not received the typical childhood/adolescent vaccinations. Physical examination reveals fever and a macular rash with ulcerations over the wrists and ankles. A detailed history reveals that 6 months ago she had a severe case of bacterial meningitis with an associated rash, for which she was successfully treated with ceftriaxone. Just as it was 6 months ago, the presence of a gram-negative diplococcus is once again identified. *Which of the following can best account for her symptoms?* A. improper microtubule formation B. inability to form the membrane attack complex C. inability to inactivate compliment component C1 protease D. inhibition of respiratory burst rxn E. lack of isotype switching resulting in high levels of IgM

*inability to form the membrane attack complex* This patient is presenting with a disseminated gonorrhea infection caused by Neisseria gonorrhoeae. Typical signs include arthralgia, tenosynovitis, and an ulcerative rash. Her previous bout of bacterial meningitis was most likely caused by Neisseria meningitidis since it was associated with a rash. Patients with a C5-C9 complement deficiency are at increased risk for Neisseria infections. C5-C9 are the final components of the cascade responsible for the membrane attack complex, which inserts holes in the microbial membrane. The complement cascade is an important mechanism by which the body can destroy microbes, especially encapsulated bacteria. Once activated, the complement cascade can fight infections by inducing inflammation, stimulating phagocytosis via opsonization, and attacking pathogens by poking holes within the microbial membrane, thereby causing cell lysis. There are 3 pathways by which the complement cascade can be activated; they are summarized in the figure. The membrane attack complex is noted at the bottom right of figure. *Gram-negative bacteria, especially Neisseria species, are highly susceptible to the membrane attack complex.* Answer A: *Microtubule dysfunction* is associated with *Chediak-Higashi syndrome*, which increases the risk of a variety of infections but is not particular for Neisseria. *The classic clue for Chediak-Higashi syndrome is immunodeficiency associated with albinism.* Answer C: Patients with *C1 esterase inhibitor deficiency* (also known as *hereditary angioedema*) present with *episodes of angioedema and severe laryngeal edema* that could be life-threatening. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases. Answer D: Neutrophils have *defective respiratory burst* in *chronic granulomatous disease (CGD)*. The deficiency in NADPH oxidase leads to a failure to generate the reactive oxygen radicals used to kill microbes during the respiratory burst phase of host defense. CGD patients are at *increased risk for infections caused by *catalase-positive organisms* such as *Staphylococcus, Pseudomonas, and Aspergillus*. Answer E: *Hyper-IgM syndrome* is seen in patients with a *CD40 ligand defect*. CD40 is a protein expressed on B cells. Without interaction with CD40L (CD154) expressed on T cells, the B cell does not receive proper activation signaling and does not class switch. As a result, high levels of IgM are found in the patient. Because IgM can still activate the classical pathway of complement activation, one would not expect an increase in incidence of Neisseria infections in these patients. Instead, *patients with hyper-IgM syndrome present with infections due to Pneumocystis jiroveci (fungi), cytomegalovirus, or Cryptococcus (fungi).* *Bottom Line*: Deficiency in the final components of the complement pathway, C5-C9, increases the risk for Neisseria infections.

A 16-year-old, sexually active female presents to the Emergency Department with a one-week history of urinary frequency and urgency and burning with urination. Physical examination reveals costovertebral angle tenderness on the right. A CT scan of her abdomen is obtained and reveals a horseshoe kidney. *Which of the following is the most associated with a horseshoe kidney?* A. absent thymus B. history of duodenal atresia C. hypocalcemia D. positive sweat test E. XO karyotype

*XO karyotype* Horseshoe kidney has a higher incidence in individuals afflicted with Turner's syndrome, which is characterized by an XO genotype. Turner syndrome is the most common sex-chromosome abnormality and is almost always associated with short stature and primary amenorrhea due to ovarian failure. Other physical features include a short neck, abnormal upper-to-lower segment ratio, cubitus valgus, short metacarpals, inverted and widely spaced nipples, webbed neck, nail dysplasia, renal dysgenesis, and cardiac malformation (coarctation, aortic valve disease, and aortic dissection) among many others. Females whose karyotype includes a Y chromosome (45X, 46XY mosaic) are at increased risk for gonadoblastoma requiring gonadectomy. Those with Turner syndrome are more likely to develop obesity, insulin resistance, and osteoporosis. Answers A & C: Absent thymus and hypocalcemia are both signs of DiGeorge syndrome, which is not associated with horseshoe kidney. Answer B: Duodenal atresia is not directly associated with horseshoe kidney. Answer D: A positive sweat test suggests cystic fibrosis, which is associated with sterility, lung disease, and pancreatic insufficiency, but not horseshoe kidney. *Bottom Line*: Turner syndrome (XO) has an increased association with horseshoe kidney development.

A 35-year-old Caucasian female presents to the office for progressively worsening left-sided flank pain that radiates to her left lower quadrant and urinary frequency. Her vital signs are stable. Physical examination reveals the bilateral flank areas and left lower quadrant to be tender to palpation. A urinalysis is obtained and is positive for leukocyte esterase and nitrites. CT of her abdomen and pelvis reveals a staghorn calculus. *The most likely composition of the stone is* A. ammonium magnesium phosphate B. calcium oxalate C. calcium phosphate D. cystine E. uric acid

*ammonium magnesium phosphate* A staghorn is a branched calculus that fills the entire intra-renal collecting system and is most commonly composed of struvite: ammonium magnesium phosphate. Struvite stones are highly associated with urinary tract infections due to urease positive bacteria such as Proteus mirabilis or Klebsiella species. These stones typically develop over a period of weeks or months, eventually developing into a staghorn calculus and causing flank pain, hematuria, and signs/symptoms of urinary tract infection (UTI). Women are more likely to form struvite stones than men because females are more likely to develop a UTI due to shorter urethra and proximity to vagina/rectum. Treatment includes percutaneous nephrolithotomy and/or shock wave lithotripsy. To diagnose a UTI, >100,000 CFU/mL of bacteria during a midstream clean-catch urine specimen in someone who is symptomatic (urinary frequency, dysuria) is required. A urine specimen found to be positive for nitrite, leukocyte esterase, or blood may also be indicative. A specimen with only leukocyte esterase positive is non-specific, but a specimen with both esterase and nitrites is a probable UTI. Answers B & C: Calcium stones are made of calcium oxalate, calcium phosphate, or both. These stones often form in conditions of hypercalcemia, i.e., hyperparathyroidism. Oxalate crystals can also result from ethylene glycol or vitamin C abuse. Calcium carbonate apatite may also cause a Staghorn calculus, but this type of stone is less likely considering the signs of a UTI displayed in the question stem. Answer D: Cystine stones are made of cystine and are due to cystinuria. Cystinuria is an autosomal-recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from the luminal fluid of the renal proximal tubule and small intestine. Cystine stones are the only manifestation of this condition. They are treated by alkalization of the urine. Answer E: Uric acid stones are made of uric acid and are associated with hyperuricemic conditions like gout. It is also seen in diseases with increased cell turnover, like leukemia. *Bottom Line*: Staghorn calculi most commonly contain ammonium magnesium phosphate.

A 48-year-old male presents to his primary care physician with hematuria. History indicates that this hematuria started yesterday and has not stopped since. He states that he has been unable to urinate regularly for a week, and it has gotten worse since the bleeding started. His medical history is significant for controlled hypertension of 4 years duration, and he reports a sore throat 3 weeks ago, which has since cleared. Physical examination shows lower limb edema and his eyelids appear to be swollen. Laboratory results indicate an elevated blood urea nitrogen/creatinine ratio. After hospital admission, a renal biopsy is taken and analysis under microscopy demonstrates bumpy deposits of immunoglobulin G on the renal basement membrane. Urinalysis reveals red blood cell casts and > 1500 mg/24 hrs (reference range: 50-80 mg/24 hrs) of protein. *Which of the following lab tests would most likely confirm the suspected diagnosis?* A. antistreptolysin O titer B. c-ANCA detection test C. hemaglobin A1C levels D. serum IgA detection test E. western blot

*antistreptolysin O titer* The test that helps confirm the diagnosis of postinfectious glomerulonephritis is an antistreptolysin O test. Postinfectious glomerulonephritis is caused by a group A streptococcus infection, and can follow strep throat or skin infections by 1-3 weeks. This disorder is more common in children, but can occur in adults. Symptoms include hematuria, hypertension, edema, and oliguria. Biopsy will show "lumpy bumpy" deposits of IgG and C3b on the renal basement membrane. Answer B: c-ANCA is used to detect granulomatosis with polyangiitis (GPA). Patients with GPA present with the triad of upper respiratory symptoms, lower respiratory symptoms, and kidney problems. Answer C: Hemoglobin A1C levels may be useful in detecting diabetic nephropathy. Patients with this disorder have a history of diabetes and hypertension. A biopsy should show Kimmelstiel-Wilson nodules in the glomeruli. Answer D: Serum IgA detection is used to help identify Berger disease, which is also known as IgA nephropathy. This is the most common nephropathy and it affects children and adults. Biopsy will show mesangial IgA immune complex deposits. Answer E: Western blot is used for detecting HIV. Patients with HIV are more at risk for focal segmental glomerular sclerosis. This is also commonly found in patients with a history of drug use. It is found mostly in adults. *Bottom Line*: Antistreptolysin O titers are helpful in identifying postinfectious glomerulonephritis, which is caused by group A streptococci. This kidney disorder presents up to 3 weeks after streptococcal infection.

A 28-year-old female comes to the office because she is planning a hiking trip in the mountains and does not want to "feel bad" like she did previously. Upon further questioning, she states the last time she went hiking through the mountains, she had a severe throbbing headache with associated nausea and lightheadedness. These symptoms ruined her trip and she had to go back down the mountain to recover. She wants to know if you can give her something that will prevent these symptoms from occurring. You prescribe a medication that would be effective in preventing these symptoms. *Which ion and nephron segment pair best explains why this medication is effective in preventing these symptoms?* A. bicarbonate; proximal convoluted tubule B. chloride; distal convoluted tubule C. potassium; ascending loop of henle D. sodium; ascending loop of henle E. sodium; collecting tubule

*bicarbonate; proximal convoluted tubule* The person in this clinical scenario suffers from altitude sickness. Altitude sickness refers to a group of syndromes that result from hypoxia. Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are manifestations of the brain pathophysiology, while high-altitude pulmonary edema (HAPE) is that of the lung. People who are hypoxic become tachypneic and develop a respiratory alkalosis as a result. Typically, AMS occurs in non-acclimatized persons in the first 48 hours after ascent to altitudes above 2500 m, especially after rapid ascent (1 day or less). Symptoms usually begin a few hours after arrival at the new altitude but may arise as much as a day later, often after the first night's sleep. Headache is the principal symptom, typically frontal and throbbing. Gastrointestinal symptoms (anorexia, nausea, or vomiting), and constitutional symptoms (weakness, lightheadedness, dizziness, or lassitude) are common. Acetazolamide, a carbonic anhydrase inhibitor, can be utilized in the primary prophylaxis of altitude sickness. Carbonic anhydrase inhibitors, such as acetazolamide, are weak diuretics. They decrease the secretion of hydrogen ions in the proximal convoluted tubule, with increased loss of bicarbonate and sodium. Since acetazolamide increases the loss of bicarbonate in the urine, people will develop a mild metabolic acidosis, which can help compensate for the respiratory alkalosis, accelerating acclimatization. It can both prevent these symptoms from occurring and quicken the resolution of these symptoms once they have occurred. Answer B: Thiazide diuretics remain the most widely prescribed medication for hypertension. Commonly prescribed thiazide diuretics include chlorthalidone, hydrochlorothiazide, and metolazone. These medications act by inhibiting the reabsorption of sodium and chloride in the early portion of the distal convoluted tubule, causing a natriuresis and an effective blood pressure response. These medications have no role in the prophylactic management of altitude sickness. Answers C & D: Loop diuretics, for example furosemide, inhibit the Na+/K+/2Cl- cotransporter, which is responsible for the transport of chloride across the lining cells of the ascending limb of the loop of Henle. This site of action is reached intraluminally after the medication is excreted by the proximal convoluted tubule. The effect of the cotransport inhibition is that chloride, sodium, and potassium all remain intraluminally and are lost in the urine. Loop diuretics are effective in the treatment of fluid overloaded states like congestive heart failure. They have no role in the treatment of altitude-related illness. Answer E: The collecting tubule is the portion of the nephron just distal to the end of the distal convoluted tubule. The potassium-sparing diuretics have their mechanism of action located here. Spironolactone and eplerenone are aldosterone receptor blockers, which block the action of aldosterone on this portion of the nephron, thus decreasing sodium reabsorption and decreasing potassium excretion. Spironolactone and eplerenone are utilized in the chronic treatment of heart failure and have no role in the prophylactic management of altitude sickness. Bottom Line: Acetazolamide decreases the secretion of hydrogen ions in the proximal convoluted tubule, with increased loss of bicarbonate and sodium.

A 50-year-old male presents to his primary care physician with nausea, vomiting, and pain in his right side. The pain, which "comes and goes," is very severe when present and started suddenly earlier this morning. He has never experienced this before. He states the pain often radiates down to his inner thigh and genitals. He takes furosemide for his blood pressure, smokes a pack of cigarettes per day, and has a glass of wine before bed. Vital signs are within normal limits. Physical examination shows a patient in distress due to pain. Urinalysis reveals 3+ hemoglobin with 100+ red blood cells, and a pH of 5.5 (reference range: 4.6-8.0). Abdominal radiographs display a stone in the proximal ureter. *Crystallization of which of the following is the most likely cause of his symptoms?* A. calcium carbonate B. calcium oxalate C. cystine D. magnesium ammonium phosphate E. uric acid

*calcium oxalate* This patient is presenting with symptoms consistent with nephrolithiasis, including acute, severe, colicky flank pain that may radiate into the inner thigh and genitals with associated nausea and vomiting. In addition, hematuria is a common finding. Calcium oxalate composes the majority of stones, accounting for > 75% of renal calculi. They display on x-ray as radiopaque calcifications. Hypercalciuria is the most common metabolic abnormality leading to calcium nephrolithiasis, which occurs as a result of increased intestinal absorption, excess resorption of calcium from bone (ie, hyperparathyroidism), or the inability of the renal tubules to properly reclaim calcium in the glomerular filtrate, as is seen with loop diuretic use. When clinical suspicion for nephrolithiasis is high, imaging confirms the diagnosis, evaluates for urinary obstruction, and detects the stone size in order to predict the likelihood of spontaneous stone passage. Different imaging modalities are discussed below. Abdominal x-ray: Radiopaque stones such as calcium oxalate, phosphate, struvite, and cysteine stones may display on abdominal x-ray, although there is lower sensitivity than with a CT scan. Uric acid stones are radiolucent and would not be seen on x-ray imaging. Computed topography: This is the preferred imaging modality, as it accurately determines location and evaluates for urinary obstruction. The study must be noncontrasted, as contrast obstructs the stones. This does expose the patient to radiation, which should be avoided during pregnancy. Ultrasound: This modality is able to determine if obstruction is present (displayed as hydronephrosis). It can visualize proximal stones, but has less sensitivity for mid or distal ureteral stones. It is the preferred initial imaging in pregnancy. Treatment differs based on stone composition but universally includes increasing fluid intake, pain control with NSAIDS or opioids, and ureteral muscle relaxation with alpha blockers such as tamsulosin, or calcium channel blockers. Straining the urine in order to catch and evaluate the stone composition is recommended, as prophylactic treatment differs based on the stone composition (alkalization versus acidifying urine, etc.) Indications for urology consult include urosepsis, failure to pass the stone, intractable pain, or stones unlikely to spontaneously pass (ie. ≥ 10 mm). *Bottom Line*: Nephrolithiasis presents with acute, severe, colicky flank pain that may radiate into the inner thigh and genitals with associated nausea and vomiting. Hematuria is common. Low dose CT scan of the abdomen without contrast is the preferred imaging modality, but should be avoided in pregnancy, where ultrasound would be preferred. Calcium stones are the most common stone composition, accounting for > 75% of renal calculi.

A 25-year-old female presents with vulvovaginal burning, itching and increased discharge. She admits to multiple male sexual partners in the past six months. She takes an oral contraceptive pill consistently and denies use of any barrier protection. Pelvic examination reveals severe cervical inflammation and a foul-smelling, thin, frothy discharge in the vaginal vault that is greenish-yellow in color. *What is the mechanism of action of the most effective treatment for the etiology?* A. forms free radicals that damage DNA and inhibit nucleic acid synthesis B. inhibit cell wall synthesis C. inhibit cell wall synthesis and has resistance to penicillinases D. inhibits ergosterol synthesis E. inhibits translation by binding the 50S subunit of the ribosome

*forms free radicals that damage DNA and inhibit nucleic acid synthesis* The most effective treatment against Trichomonas vaginalis is metronidazole. Metronidazole is a bactericidal and an antiprotozoal medication indicated for the treatment of Trichomonas, Giardia, Entamoeba, Gardnerella vaginalis, and anaerobes (Bacteroides, C. difficile). Metronidazole is also used in "quadruple therapy" for H. pylori infection. Its mechanism of action is the formation of free radical toxic metabolites in anaerobic bacterial and protozoal cells that irreparably damage DNA, inhibit nucleic acid synthesis, and lead to cell death. Answer B: Penicillin is the drug of choice for treating syphilis caused by the spirochete, Treponema pallidum. Its mechanism of action is the disruption of cell wall synthesis. Penicillin binds penicillin-binding proteins (transpeptidases) and block transpeptidase cross-linking of peptidoglycan. Many bacteria have acquired resistance to penicillin through penicillinase activity, a type of beta-lactamase that cleaves the beta-lactam ring and inactivates the antibiotic. Answer C: Ceftriaxone is a third generation cephalosporin used for the treatment of Neisseria gonorrhoeae as well as other serious gram-negative infections. Cephalosporins inhibit cell wall synthesis and are less susceptible to penicillinases than other beta-lactam drugs, such as penicillin. Answer D: Fluconazole is an anti-fungal used in the treatment of systemic mycoses, making it effective in treating infections caused by Candida albicans. Azoles inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol. Answer E: Azithromycin is a macrolide antibiotic that inhibits translation by binding to the 50S subunit of the bacterial ribosome. It is the drug of choice for Chlamydia trachomatis. Bottom Line: Metronidazole is the drug of choice in treating infections caused by Trichomonas vaginalis. Its mechanism of action is to damage DNA through the production of free radicals inside bacteria and protozoa.

A previously healthy 5-year-old male presents with a recent onset of flank pain, lethargy, and the development of multiple bruises without corresponding trauma. History indicates that a few days after a picnic 10 days ago, the child had bloody diarrhea and vomiting that has since resolved. The mother states that the boy ate a couple of hamburgers and potato salad at the picnic, and that despite drinking lots of water lately, he is not urinating as frequently. Urinalysis indicates proteinuria and hematuria, CBC shows a platelet count of 90,000/mcL (reference range: 130,000-400,000 mcL), and a peripheral blood smear displays many fragmented erythrocytes.* The patient's sequelae are most likely due to* A. disseminated intravascular coagulopathy B. hemolytic uremic syndrome C. Henoch-Schonlein purpura D. ideopathic thrombocytopenic purpura E. thrombotic thrombocytopenic purpura

*hemolytic uremic syndrome* This patient is most likely presenting with hemolytic uremic syndrome (HUS) following a prodrome of hemorrhagic colitis caused by enterohemorrhagic Escherichia coli (EHEC). HUS manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury that occur around a week after the onset of gastroenteritis. It primarily affects children < 5 years old, and patients will often present with hematuria and lower back and flank pain. EHEC is mainly transmitted through ingestion of undercooked beef, although cases have occurred through ingestion of contaminated leafy green vegetables and contact with animals at petting zoos. In addition, Shigella can cause HUS because it possesses the same toxin (shiga toxin) as EHEC. The EHEC toxin is now termed verotoxin, but may also be called shiga-like toxin. This toxin inhibits protein synthesis by cleaving the 28S RNA of the 60S ribosomal subunit, leading to cell death and bloody colitis. If the toxin enters the bloodstream, it can cause thrombosis of the glomerulus and renal cortical necrosis, leading to anuria and acute renal failure. The thrombi are composed primarily of platelets, causing thrombocytopenia. Central nervous systems complications such as seizures and strokes can also occur, albeit rarely, due to cerebral endothelial injury and clot formation. Diagnosis is typically made on clinical grounds from these sequelae, although definitive diagnosis can be made from the assay for the toxin in a stool sample, or less commonly via culture of the organism on sorbitol MacConkey agar. Answer A: Disseminated intravascular coagulation (DIC) results in fibrin deposition in vessels which leads to microvascular thrombi and multiple organ failure. Common manifestations include bleeding, petechiae, ecchymoses, and oozing from intravenous lines or catheters. The diagnosis of acute DIC is confirmed by thrombocytopenia, increased bleeding time, prolonged prothrombin time and partial thromboplastin time, decreased fibrinogen, increased fibrin degradation products, and an increased D-dimer. Many gram-negative organisms, including strains of E. coli, can lead to the development of DIC through the induction of septic shock by toll-like receptors binding to lipopolysaccharides, causing systemic inflammation. Some gram-positive organisms can also induce septic shock and DIC through the action of their superantigens. Answer C: Henoch-Schönlein purpura is a small vessel vasculitis that occurs in children between the ages of 2 and 11 years. Patients will present with purpura, arthritis, abdominal pain, and hematuria, often following an upper respiratory infection. The pathology of this disease involves the deposition of IgA and C3 immune complexes in arterioles, venules, and capillaries. Because the antibody is IgA, the alternate complement pathway is activated in these patients. This leads to immune complex deposition in the kidneys and results in an IgA nephropathy. Answer D: Idiopathic (also known as immune or primary immune) thrombocytopenic purpura manifests as bleeding and easy bruising due to autoimmune destruction of platelets by the spleen. This manifests as widespread petechiae, ecchymoses, purpura, and epistaxis. Immune thrombocytopenic purpura has an insidious onset and is most common in middle-aged women. It is due to IgG autoantibodies to platelets that result in splenic sequestration and phagocytosis by macrophages. Answer E: Thrombotic thrombocytopenic purpura is due to a deficiency of ADAMTS13 protease, which is normally responsible for the degradation of large von Willebrand factor multimers. This results in unusually large von Willebrand factor multimers that bind to platelets and cause the initiation of thrombotic events. A pentad of symptoms can be observed including fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, and renal abnormalities. Bottom Line: Hemolytic uremic syndrome is a secondary manifestation in children of primary infections with enterohemorrhagic E. coli, and usually begins 5-10 days after a prodrome of abdominal pain, vomiting, and bloody diarrhea. It results in the triad of hemolytic anemia, thrombocytopenia, and acute renal injury. COMBANK Insight : You now may see shiga-like toxin called verotoxin in some sources.

A 35-year-old female, with adult polycystic kidney disease, was taken to the University Hospital for a kidney transplant. The donor's kidney was from a 10-year-old female who was killed in a hit-and-run motor vehicle accident. The grafted kidney was placed in the recipient's left iliac fossa and appropriate vascular attachments were made. There were no acute changes to the donated kidney during the procedure and the patient was placed on immune suppressants to prevent transplant rejection. Additionally, the patient was treated with osteopathic manipulative medicine as an adjunct to medications, including a hyoid release, rib raising, diaphragm doming and a sacral myofascial release to promote bowel motility. Among the medications with which the patient is treated is sirolimus. *This medication has the capacity to* A. block interaction w/CD3 protein B. inhibit craniosacral motion, thus inc. CRI C. inhibit FK-binding protein D. inhibit mTOR E. inhibit action of calcineurin

*inhibit mTOR* The primary mechanism of action of sirolimus is that it creates a complex with intracellular immunophilins (FKBP) and binds to mTOR inhibiting T-cell proliferation in response to IL-2. This is normally given in conjunction with cyclosporine and corticosteroids after a kidney transplant to suppress organ rejection. This drug can cause hyperlipidemia, thrombocytopenia, and leukopenia. Answer A: This describes the action of muromonab-CD3 (OKT3). This drug is a monoclonal antibody that blocks CD3 protein, which is responsible for T-cell signal transduction. Answer B: Medications are not known to increase the cranial rhythmic impulse; factors which increase this include exercise, a systemic fever, or the application of osteopathic manipulative treatment (OMT). Answer C: Sirolimus binds to the FK-binding proteins to facilitate mTOR inhibition but does not inhibit the FK-binding proteins. Answer E: This describes the action of cyclosporine. This drug binds to cyclophilins preventing the production of IL-2 and its receptors. Additionally, tacrolimus can inhibit calcineurin, but this is not an effect of sirolimus. Bottom Line: The mechanism of action of sirolimus is that it binds to mTOR, inhibiting the proliferation of T-cells in response to IL-2.

A 70-year-old male presents to the office complaining of toe pain. He states that he woke up this morning with a red, swollen, painful toe. He denies previous similar symptoms and any recent trauma. He is being treated for hypertension and hyperlipidemia, and medical history also includes diverticulosis. He is up to date on all recommended vaccinations. Physical examination reveals a blood pressure of 126/68 mmHg and an erythematous and tender first digit on the right foot. The remainder of his musculoskeletal examination is within normal limits, with no visible deformity and full pain-free range of motion of the left foot and of the hands, wrists, elbows, shoulders, hips, knees, and ankles bilaterally. *What is the mechanism of action for the medication most likely responsible for the patient's condition?* A. blocking the actions of aldosterone B. calcium mediated smooth muscle relaxation C. inhibition of HMG-CoA reductase D. inhibition of the distal tubule Na+/Cl- symporter E. preventing conversion angiotensin I to angiotensin II

*inhibition of the distal tubule Na+/Cl- symporter* This patient presents with symptoms of hyperuricemic gout. Gout often presents with sudden onset of a painful inflammation of the metatarsophalangeal joint of the great toe. The inflammation is caused by the accumulation of needle-like crystals of monosodium urate which cause pain and inflammation. Hyperuricemia is a relatively common finding in patients treated with a thiazide diuretic and may, over a period of time, lead to such gouty arthritis. Thiazide diuretics are the most commonly used diuretic and recommended first-line antihypertensive, acting on the distal tubule by blocking the thiazide-sensitive Na+Cl− symporter. This decreases NaCl reabsorption and causes a diuresis as the tubular fluid will be drawn osmotically to follow the sodium being excreted. Thiazide diuretics induce hyperuricemia by increasing urate reabsorption, though the exact mechanism has not been elucidated. It has been noted that hyperuricemia occurs when diuretics produce sufficient salt and water loss to result in volume contraction. This volume loss stimulates solute reabsorption at the proximal tubule; at the same time they competitively inhibit the excretion of uric acid, thus causing hyperuricemia. Answer A: Spironolactone exerts its primary action antagonizing the effects of aldosterone by blocking its receptors at the collecting tubules. Although any diuretic may induce hyperuricemia as a result of volume contraction, spironolactone is less likely to cause hyperuricemia and gout than thiazide diuretics because it does not cause urate reabsorption. Answer B: Dihydropyridine type calcium channel blockers, such as amlodipine, are used to treat hypertension by relaxing arterial smooth muscle. Amlodipine, rather than causing hyperuricemia, is a uricosuric drug that decreases serum uric acid by blocking the reabsorption of urate. Although an off-label use, amlodipine can prevent hyperuricemia and uric acid crystals from being deposited into tissues. Answer C: HMG-CoA reductase inhibitors, or statins, are a group of drugs used for lowering serum cholesterol. Statins such as atorvastatin also stabilize plaque and prevent strokes through antiinflammation and other mechanisms. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body. Rather than causing hyperuricemia, atorvastatin has uricosuric effects. Answer E: Angiotensin converting enzyme (ACE) inhibitors, such as lisinopril, act by preventing the conversion of angiotensin I (which is essentially physiologically inert) to angiotensin II (which is a potent vasoconstrictor and inducer of aldosterone). ACE inhibitors thus lower blood pressure by disrupting the renin-angiotensin-aldosterone axis. Major side effects of ACE inhibitors include cough, rashes, leukopenia, and hyperkalemia. They are not associated with episodes of gout.

A 14-year-old female presents to her pediatrician with complaints of fatigue. She also notes recent weight gain, swelling of her ankles and feet, and dark and "foamy" urine. Urinalysis is remarkable for hematuria and proteinuria. Light microscopy of a renal biopsy shows proliferation of mesangial and endothelial cells of the glomeruli and expansion of the mesangial matrix along with immune deposits. *What is the Dx?* A. Alport syndrome B. Berger disease C. granulomatosis with polyangiitis D. membranoproliferative glomerulonephritis E. membranous glomerulonephritis

*membranoproliferative glomerulonephritis* Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephritis that occurs primarily in children and young adults. This disease refers to a pattern of glomerular injury based on characteristic histopathologic findings that include the following: 1) A proliferation of mesangial and endothelial cells and expansion of the mesangial matrix 2) Thickening of the peripheral capillary walls by subendothelial immune deposits and/or intramembranous dense deposits 3) Mesangial interposition into the capillary wall that gives rise to a double contour appearance on light microscopy In order to definitively diagnose this disease, a kidney biopsy needs to be performed. There are 3 different types of MPGN that are classified based on findings on electron microscopy. Classification Electron Microscopy Findings Type I =Subendothelial and mesangial deposits Type II = Dense deposits in the glomerular basement membrane (dense-deposit disease) Type III = Both subepithelial and subendothelial deposits Under light microscopy, the glomeruli are generally enlarged and hypercellular with an increase in mesangial cellularity and matrix. A mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of the lobular form that gives rise to the alternative name for this disease, lobular nephritis. Infiltrating neutrophils and monocytes contribute to the glomerular hypercellularity. The capillary basement membranes are thickened by the interposition of mesangial cells and matrix into the capillary wall. This gives rise to the classic "double contoured" or "tram-track" appearance of the capillary wall, which is appreciated with the methenamine silver stain or the periodic acid-Schiff reagent.

Blood urea nitrogen = 74 mg/dL; (6-20 mg/dL) Creatinine = 4.8 mg/dL; (0.7-1.3 mg/dL) Glucose = 315 mg/dL; (74-106 mg/dL) A renal biopsy is performed and the histology is shown in the exhibit. *What is the underlying pathophysiologic mechanism for these renal changes?* A. dec. aniotensin II B. dilation of the effernt glomerular arteriole C. hypofiltration of glomerulus D. isolated afferent hyline arterial scleroisis E. mesangial expansion

*mesangial expansion* The patient has newly diagnosed diabetes as evidenced by a nonfasting glucose level > 200 mg/dL with symptoms of diabetes (ie, polyuria, polydipsia, weight loss), with fundoscopic examination displaying findings consistent with diabetic retinopathy. Therefore, his abnormal renal findings are most likely representative of diabetic nephropathy, which causes mesangial expansion, glomerular basement membrane thickening, podocyte injury, and ultimately, glomerulosclerosis. He should also be advised to stop taking NSAIDs, which can cause tubulointerstitial nephritis in the long term. The renal biopsy demonstrates the Kimmelstiel-Wilson lesion, which is diagnostic for nodular glomerulosclerosis and diabetic nephropathy. It consists of nodules of pink hyaline material that form in regions of glomerular capillary loops in the glomerulus. This is due to a marked increase in mesangial matrix from damage resulting from nonenzymatic glycosylation of proteins. There are many causes of renal insufficiency, with diabetes and hypertension being the two most common causes in the United States. However, diabetes causes characteristic findings as discussed below Mesangial expansion: This is the earliest morphologic change seen and occurs due to increased mesangial matrix deposition and a mild increase in mesangial cellularity and hypertrophy of mesangial cells. Glomerular basement membrane: Diffuse thickening of the basement membrane occurs due to renal hyperfiltration. Podocyte injury: This leads to increased protein loss to the point of causing nephrotic range proteinuria. Glomerulosclerosis: As mesangial matrix continues to accumulate, the characteristic nodular glomerulosclerosis pattern, known as Kimmelstiel-Wilson nodules, is seen. Progression of diabetic nephropathy can be delayed by angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs). These medications work by dilating the efferent arteriole and, thereby, decrease the rate of renal damage. Diabetic retinopathy is another complication of diabetes that can lead to blindness if not intervened upon (laser therapy). It is characterized by retinal neovascularization, macular edema, and microhemorrhages as seen in the images below. Answer A: Increased (not decreased) angiotensin II plays an important part in the pathogenesis of diabetic nephropathy. It causes a preferential constriction of the efferent glomerular arteriole, increases glomerular capillary permeability to protein, stimulates advanced glycation end-product formation, and stimulates mesangial cell proliferation and accumulation of mesangial matrix by inducing many proinflammatory and fibrogenic cytokines, chemokines, and growth factors. Therefore, medications that inhibit angiotensin II activity (ACE-I/ARBs) are vital in preventing disease progression. This answer is incorrect. Answer B: Increased angiotensin II levels are seen in diabetes and cause a preferential constriction (not dilation) of the efferent glomerular arteriole that results in many of the histologic findings of diabetic nephropathy including accumulation of the mesangial matrix, ultimately causing the characteristic nodular glomerulosclerosis pattern termed Kimmelstiel-Wilson nodules. ACE-I/ARBs will cause arteriole dilation and, therefore, decrease the rate of damage. However, this patient was not receiving an ACE-I/ARB, and therefore, arteriole constriction, not dilatation, would be expected. This is not the best answer. Note: NSAIDs block prostaglandins and cause afferent glomerular constriction. Answer C: Many factors are involved in the pathogenesis of diabetic nephropathy. The glomerular hemodynamic changes include hyperfiltration (not hypofiltration) and hyperperfusion, which are in part due to decreased afferent arteriolar resistance that are mediated by the effect of various biochemical factors, including angiotensin II, nitrous oxide, glucagon, and insulin. Glomerular hyperfiltration and hyperperfusion play an essential part in mesangilisation and glomerular basement membrane changes seen diabetic nephropathy. Because there is glomerular hyperperfusion, not hypoperfusion, this is incorrect. Answer D: Isolated afferent hyaline arteriolosclerosis is seen in hypertensive nephropathy, whereas both the afferent and efferent arterioles are affected in diabetic nephropathy. In hyaline arteriosclerosis, there is fibrotic thickening of the intima, causing narrowing of the lumen. In the arteriole muscularis, there can also be atrophy and sclerosis (see images below). This patient is normotensive on examination, making isolated afferent hyaline arteriolosclerosis less likely. In addition, Kimmelstiel-Wilson nodules seen in the exhibit image are pathognomonic for diabetic nephropathy. This is not the best answer.

A 23-year-old G3P2103 female presents for her annual gynecologic exam complaining of a gray, distinct smelling vaginal discharge of three-weeks' duration. On wet mount, epithelial cells coated with bacteria are visible. *A vaginal swab reveals a pH of 4.7. The most appropriate treatment is* A. ceftriaxone B. ciprofloxicin C. doxycylcine D. metronidazole E. Pen G

*metronidazole* This image shows the characteristic "clue cells" seen in Gardnerella vaginalis (bacterial vaginosis). Note the stippled appearance (red circles). Bacterial vaginosis (BV), caused by the gram-negative rod Gardnerella vaginalis, typically presents as a gray-colored vaginal discharge. It is often described as having a "fishy odor," particularly after intercourse (although it is not considered to be a sexually transmitted infection). It is not usually painful or pruritic, and may be entirely asymptomatic. Diagnosis is confirmed on wet mount, when vaginal squamous epithelial cells covered in bacteria ("clue cells") are seen. Metronidazole is the treatment of choice for BV. Answer A: Ceftriaxone is a third-generation cephalosporin used to treat gram-negative infections. It is the treatment of choice for Neisseria gonorrhoeae. Like BV, gonorrhea may be asymptomatic in women. Answer B: Ciprofloxacin is a fluoroquinolone, which are used to treat gram-negative infections of the gastrointestinal and genitourinary systems. Ciprofloxacin is not used in the treatment of BV. Answer C: Doxycycline is a tetracycline used in the treatment of specific gram-negative infections, such as Chlamydia trachomatis, Helicobacter pylori, Ureaplasma urealyticum, and Borrelia burgdorferi. It is not used in the treatment of BV. Answer E: Penicillin G is the intravenous form of penicillin. Penicillins are typically used to treat gram-positive streptococcal infections. It is also the treatment of choice for Treponema pallidum. It is not used in the treatment of BV. Bottom Line: Bacterial vaginosis usually presents as gray vaginal discharge with a fishy odor. Clue cells on wet mount preparation are pathognomonic. Metronidazole is the treatment of choice. COMBANK Insight : Distinguishing between the color, consistency, and quantity of vaginal discharges and the microorganisms that cause them is high-yield for OB/GYN questions on COMLEX Level 1.

A 25-year-old female presents with vulvovaginal burning, itching and increased discharge. She admits to multiple male sexual partners in the past six months. She takes an oral contraceptive pill consistently and denies use of any barrier protection. Pelvic examination reveals severe cervical inflammation and a foul-smelling, thin, frothy discharge in the vaginal vault that is greenish-yellow in color. *Which of the following describes the most likely infectious agent?* A. budding yeast w/pseudohyphae & germ tubes B. gram-variable rods C. motile protozoan D. obligate intracellular parasite w/elementary bodies E. spirochete

*motile protozoan* The patient presents with vaginal irritation and her physical exam reveals cervicitis and a frothy, greenish-yellow discharge that is foul-smelling. This is the classic presentation of Trichomonas vaginalis. The cervical inflammation caused by T. vaginalis is often referred to as "strawberry cervix" and is visible as punctate hemorrhages in a small percentage of patients. Trichomonas vaginalis is a motile protozoan that is transmitted sexually. This patient admits to several sexual partners without barrier protection; thus, a sexually transmitted disease is likely. The infection is generally asymptomatic in men and may be asymptomatic in women as well. Answer A: Candida albicans is a budding yeast with pseudohyphae and germ tube formation at 37ºC. The classic presentation is vaginal itching with a thick white discharge, often described as being of a "cottage cheese" consistency. Usually there is not a strong or distinct odor, and it is not classified as a sexually transmitted disease. Women may describe having recently been treated with antibiotics prior to symptoms. Answer B: Gardnerella vaginalis is a pleomorphic, gram-variable rod that demonstrates squamous cells studded with bacteria, or "clue cells," upon microscopic examination and is a cause of bacterial vaginosis (BV). The classic presentation is foul-smelling watery, gray vaginal discharge with or without vaginal irritation. BV does not cause severe cervical inflammation and is not thought to be sexually transmitted. Answer D: An obligate intracellular parasite with elementary bodies describes Chlamydia trachomatis, a sexually transmitted disease that can cause urethritis, cervicitis and PID. It is the most common bacterial sexually transmitted infection in the United States. The discharge does not have a strong odor or distinct color as in Trichomonas vaginalis, and is often asymptomatic. Answer E: Syphilis is caused by Treponema pallidum, which is a spirochete. Syphilis is a sexually transmitted infection characterized by a painless chancre of the genitalia without any specific type of discharge. If untreated, syphilis can progress to disease affecting systems outside the genitourinary tract. Secondary syphilis is characterized by diffuse rash, classically involving the palms of the hands and soles of the feet, and condylomata lata. The next stage of the disease is a symptom free latent period lasting years to decades. Approximately a third of cases of chronic, untreated syphilis will develop into tertiary syphilis with cardiac, neurologic or cutaneous manifestations. *Bottom Line*: A sexually active female with frothy, foul-smelling greenish-yellow discharge should be suspected of having a Trichomonas vaginalis infection. The organism is a motile protozoan.

A 45-year-old woman is referred to a physician for complaints of bilateral pelvic pain, especially during intercourse. She has had mild dyspepsia for the past 2 months. Her sister was recently diagnosed with lobular carcinoma of the breast. On physical exam, the physician notes skin changes in both the axillae and groin, as shown in the exhibit. Pelvic exam shows both ovaries to be enlarged. CT scan of the pelvis reveals bilateral ovarian masses. *Pathologic examination of the ovarian tissue will likely show which of the following?* A. mucin producing signet ring cells B. papillary and cystic structures w/tiny calcifications C. small follicles w/eiosinophilic calcifications D. spindle shaped fibroblasts E. transitional-type epithelial cells resembling bladder tissue

*mucin producing signet ring cells* The patient likely has a Krukenberg tumor, which is bilateral ovarian metastases from a GI tract adenocarcinoma, usually the diffuse subtype of gastric adenocarcinoma composed of individually invasive, mucin-filled, signet-ring cancer cells. It is common for ovarian enlargement to be the first presentation of this cancer. The fact that a sister had lobular carcinoma of the breast suggests a familial mutation of CHD1 or BRCA2. The skin lesions seen in this patient are acanthosis nigricans, which in the absence of evidence of insulin resistance suggests a mucin-producing GI cancer. Remember these facts about the 2 types of gastric carcinoma: Diffuse type: Signet-ring cells filled with mucin, diffuse infiltration/"leather bottle"/linitis plastica, CHD1 and BRCA2 genes, no precursor lesion, no high- or low-risk geographic areas, frequency has stayed about the same. Acanthosis nigricans is occasionally seen. Intestinal type: Glands and/or sheets, APC and beta-catenin genes, strong link to helicobacter, chronic gastritis (helicobacter, autoimmunity) is a clear risk factor, nitrosamines and blood group A are still questionable; during the past 100 years it has become much less common in the US, except at the cardia from Barrett esophagus; it remains very common in Japan, Chile, and some other areas. This signet-ring cancer of the stomach shows crowded, but still-separate signet-ring cells. The bright-red structures are red blood cells in the tumor's vessels. Answer B: The most common (45%) primary ovarian cancer is papillary serous cystadenocarcinoma, often bilateral. They mimic the cells and fimbriae of the oviduct, and usually show papillary and microcystic growth patterns. Concentrically-laminated microcalcifications (psammoma bodies) are often seen. Answer C: Seen in an ovarian tumor, miniature follicles (Call-Exner bodies) indicate granulosa-cell origin. Granulosa cell tumors can secrete estrogen, causing precocious puberty in girls and irregular menses, endometrial hyperplasia, and endometrial carcinoma in adult women. The photo of a granulosa cell tumor on the left shows several miniature follicles. Answer D: Fibromas of the ovary are benign, firm, white tumors but can be troublesome if they undergo torsion or produce the mysterious Meigs syndrome, which is ovarian fibroma, ascites, and hydrothorax. Histologically, you will see bundles of spindle-shaped fibroblasts. If they have luteinized, it's a thecoma instead, likely to produce hyperestrogenism. The fibroma in the picture, however, is classic and produced Meigs. Answer E: Brenner tumors of the ovary are almost always benign and are made of fibrous tissue containing nests of cells that mimic urothelium (transitional epithelium), which is obvious only to experienced histopathologists. Both granulosa tumors and Brenner tumors may show coffee-bean nuclei. You might be able to appreciate the resemblance to urothelium in panel C below. *Bottom Line*: Krukenberg tumors are ovarian metastases from GI tract primary cancers. Histologically, the tumor will show mucin-producing signet ring cells.

A 22-year-old female complains of burning with urination, increased urinary frequency, and lower abdominal pain. She is sexually active and reports no abnormal discharge. There is inhalation somatic dysfunction of the pelvic diaphragm R > L, and paravertebral hypertonicity and tenderness from T11-L1. A urinalysis is performed and yields the following results: Leukocyte esterase = 2+ Urine culture demonstrates catalase-positive, coagulase-negative, gram-positive cocci in clusters. Which of the following additional findings is associated with the most likely causative organism?* A. beta hemolysis on blood agar B. fruit smell in culture C. growth on Thayer-Martin agar D. lactose fermentation E. novobiocin resistance

*novobiocin resistance* The patient's symptoms of dysuria, increased frequency, and lower abdominal pain are clues to a urinary tract infection (UTI). The urinalysis reveals a cloudy specimen (a clue to pyuria) and positive leukocyte esterase, both consistent with a UTI. The most common cause of UTI's in young sexually active females is Escherichia coli. However, E. coli is positive for urine nitrites. This patient's urine nitrites are negative. So the cause of this patient's UTI is not due to the most common cause but rather, to the second most common cause of UTI's in young sexually active females: Staphylococcus saprophyticus. S. saprophyticus is a catalase-positive, coagulase-negative, gram-positive cocci in clusters. Since it does not produce coagulase it is placed with several other species of staphylococci called the coagulase-negative staphylococci, or CoNS. To differentiate S. saprophyticus from the other CoNS species, a novobiocin resistance test is performed. S. saprophyticus is resistant to novobiocin. Other CoNS species, like Staphylococcus epidermidis, are novobiocin sensitive. S. saprophyticus is nonhemolytic (gamma hemolytic) on blood agar plates. Osteopathic findings can include viscerosomatic reflexes for the lower urinary tract as TART changes from T11-L1. There may also be pelvic diaphragm dysfunction as a result of local inflammation due to the urinary infection. Answer A: There are several organisms that are beta-hemolytic on blood agar and can cause UTIs. Several gram-negative rods, including E. coli and Klebsiella pneumoniae, are beta-hemolytic. Staphylococcus aureus is also beta-hemolytic and can cause UTIs, but is not the cause in this case as the organism responsible is coagulase-negative, and S. aureus is coagulase-positive. Answer B: Pseudomonas aeruginosa is an aerobic, gram-negative rod that is nonlactose fermenting and is oxidase-positive; it produces a blue-green pigment in culture as well as a characteristic fruity odor. Since the causative organism in this case is a gram-positive coccus, P. aeruginosa is not causing her infection. Answer C: Neisseria gonorrhoeae is a common sexually transmitted infection and is associated with pelvic inflammatory disease, septic arthritis, and neonatal conjunctivitis. N. gonorrhoeae is a gram-negative coccus that ferments glucose but not maltose, and grows on Thayer-Martin chocolate agar. Since this patient has a gram-positive infection, N. gonorrhoeae is not the cause. Answer D: E. coli is a lactose-fermenting gram-negative rod and is the most common cause of UTIs overall (> 80% of community acquired UTIs). Urine nitrites are positive in patients with a UTI caused by E. coli. This patient's urine nitrites are negative. This patient's organism is gram-positive. E. coli is a gram-negative organism and is not causing her infection. Bottom Line: The second most likely cause of urinary tract infections in sexually active young women is Staphylococcus saprophyticus, a gram-positive coccus that is catalase-positive, coagulase-negative, and resistant to novobiocin. The most common cause of UTI's in this group is E. coli. However, the urine nitrites (negative) and gram staining reaction (gram-positive cocci) indicate that this patient's current condition is due to S. saprophyticus, not E. coli. COMBANK Insight : Several uropathogens are negative for urine nitrites and include Staphylococcus saprophyticus, Enterococcus, and Candida albicans. The second most common uropathogen of young sexually active females after Escherichia coli is the catalase-positive, coagulase-negative, and novobiocin resistant S. saprophyticus. On COMLEX, these bacteria should always be considered in a young, sexually active female patient.

A 56-year-old postmenopausal female presents to the community health clinic for lower back pain of two weeks' duration. Past medical history is positive for esophageal cancer 10 years ago. On exam you note paravertebral hypertonicity and tenderness to palpation from T2-4, tenderness in the breast tissue, and decreased range of motion in the lumbar spine without step-off deformity or midline tenderness. Imaging studies of the lower back reveal radiolucency, suggestive of demineralization in the cortical bone of the lumbar vertebrae. Laboratory studies reveal a calcium level of 10.0 mg/dL. *The most appropriate pharmacologic treatment for this patient's conditions is:* A. alendronate B. calcitonin C. raloxifene D. tamoxifen E. trastuzumab

*raloxifene* *Selective estrogen receptor modulators (SERMs)* are a class of drugs that have estrogen agonist and antagonist properties at different target sites. The SERMs, raloxifene and tamoxifen, have potent antiestrogenic effects in the breast while improving mineralization and preventing loss of bone. In regards to estrogen receptor positive breast cancer, *raloxifene is indicated for prevention and tamoxifen is indicated for treatment*. The important difference between the two drugs is their effect on the uterus. Tamoxifen's estrogen-like effects stimulate endometrial tissue (increasing the risk of endometrial carcinoma) while raloxifene has minimal effects on the endometrium. Raloxifene is approved for use in osteoporosis in women past menopause because it was only studied in these women. Although not used to diagnose osteoporosis, plain radiography can reveal osteoporotic changes. Bone demineralization can be seen in the cortical bone when greater than 30% of bone has been lost. The presence of osteoporotic fractures or reduction in the ratio of cortical compared to medullary bone width is also radiographic features of osteoporosis. Although bone resorption and calcium loss are the major players in primary osteoporosis, calcium levels may be normal in these individuals because bone remodeling does not determine the equilibrium of extracellular fluid calcium concentrations measured by the serum. This patient exhibits TART changes from T2-4 likely representative of viscerosomatic reflexive changes from the breast tissue 2/2 the cancer. Answer A: Alendronate is a bisphosphonate that inhibit osteoclastic bone resorption by binding to hydroxyapatite and interfering with osteoclast adherence. According to the 2010 guidelines from the American Association of Clinical Endocrinologists (AACE), bisphosphonates are first-line agents used in osteoporosis unless the patient has a past history of esophageal cancer (may have increased risk) or esophageal disorders (esophagitis, Barrett's esophagus, esophageal stricture). Unless cancer has infiltrated the bone causing hypercalcemia, they are ineffective agents in this scenario. Answer B: Calcitonin directly inhibits osteoclastic bone resorption by binding to osteoclasts. The 2010 guidelines from the AACE list this as a last line agent when treating osteoporosis. Unless cancer has infiltrated the bone causing hypercalcemia, they are ineffective agents in this scenario. Answer D: Tamoxifen, also a SERM, is used to treat breast cancer and has traditionally been useful to prevent osteoporosis. Tamoxifen differs from raloxifene in that it is an antagonist in the breast and agonist in the bone and endometrium. However, tamoxifen may increase the risk of endometrial carcinoma via its estrogen-like effects on endometrial tissues, and it may cause "hot flashes." Tamoxifen has an indication for estrogen receptor positive breast cancer treatment. This would not be the best choice in a postmenopausal woman when raloxifene is available. Answer E: Trastuzumab is a monoclonal antibody against HER-2 (erb-B2). This agent helps eliminate cancer cells that overexpress HER-2, a protein associated with more aggressive breast cancers. Although used for HER-2 positive breast cancer, it is not an agent used for osteoporosis. *Bottom Line*: Raloxifene, a SERM, is an effective agent for osteoporosis without increasing the risk of endometrial cancer, as is the case with tamoxifen. Raloxifene is also useful in the prevention of estrogen receptor positive breast cancer. Raloxifene is used first before alendronate in this patient due to past history of esophageal cancer and must avoid bisphosphonates in this case.

A 55-year-old female with a history of poorly controlled type 2 diabetes mellitus and hypertension presents to her primary care physician for a routine physical examination. She checks her glucose in the morning and it is consistently > 200 mg/dL. She continues to drink soda, but has started to go on walks at night. She has no prior alcohol, tobacco, or drug use. Her medications include metformin, atorvastatin, and lisinopril. Vital signs reveal a blood pressure of 125/80 mmHg, heart rate of 78/min, and respiratory rate of 20/min. Fasting finger stick blood glucose is 225 mg/dL (reference range 74-106 mg/dL) and hemoglobin A1c is 12% (reference range 4.2%-5.9%). Routine electrolytes, blood urea nitrogen, and creatinine are normal. Routine urinalysis shows no hematuria, but microalbuminuria is present at 300 mg/day (reference range < 30 mg/day) consistent with prior testing. *Which of the following findings would be expected if renal biopsy was performed?* A. basement membrane thickening w/tram-track appearance B. immunoglobulin deposited along the glomerular basement membrane C. loss of podocyte foot processes w/o other pathology D. spike and dome basement membrane thickening E. uniform basement membrane thickening

*uniform basement membrane thickening* Patients with long-standing or uncontrolled diabetes mellitus (DM) are at risk for developing complications related to the disease. Diabetic nephropathy is a term that encompasses albuminuria, hyperfiltration, and glomerulosclerosis. Findings on biopsy would display uniform glomerular basement membrane thickening and perhaps, mesangial nodules (ie., Kimmelstiel-Wilson nodules). In diabetes, the basement membranes in the glomeruli and elsewhere in the body thicken and become more permeable to protein. In some diabetics, the mesangial matrix becomes more abundant and forms distinctive Kimmelstiel-Wilson nodules — masses of pink-staining, hyaline material among the capillary loops. Nonenzymatic glycosylation of receptors is most likely the cause, but the exact molecular biology remains poorly understood. Other common complications of diabetes include the following: 1. Neuropathy: Symmetrical, lower extremity, axonal neuropathy is common. Monofilament and vibration testing are screening tests. 2. Retinopathy: This is usually asymptomatic until late in the disease. An annual dilated funduscopic exam looking for macular edema and proliferative or nonproliferative diabetic retinopathy should be initiated 5 years after diagnosis for those with type 1 DM, and at time of diagnosis for type 2. 3. Gastroparesis: Delayed gastric emptying due to impaired neural functioning can lead to symptoms of nausea, vomiting, abdominal pain, early satiety, and postprandial fullness. Diagnosis is with a gastric-emptying study. Treatment is often with metoclopramide. 4. Vasculopathy: Both coronary and peripheral arterial disease has a high rate of mortality and morbidity in those with DM. Statin therapy is indicated in diabetic patients age 40-75 years, with statin intensity based on their 10 year cardiovascular risk. 5. Ulcers: Diabetic foot wounds occur due to neuropathy causing delayed recognition. Nightly foot checks are important to prevent progression. In those with hypertension with proteinuria and chronic kidney disease, angiotensin converting enzyme inhibitors or angiotensin receptor blockers are first-line medications, regardless of ethnicity, to prevent further progression and worsening of the disease. Note: The term "moderately increased albuminuria" has now replaced the term "microalbuminuria," referring to 30-300 mg/d albumin excretion. The image displays a hematoxylin and eosin stained photomicrograph showing visible, thick basement membranes. Notice that the capillary lumens are correspondingly narrowed. The Kimmelstiel-Wilson nodules are also visible in the glomerulus. Answer A: Membranoproliferative glomerulonephritis is an uncommon cause of chronic nephritis that occurs primarily in children and young adults. This diagnosis refers to a pattern of glomerular injury based on histopathologic findings, especially proliferation of mesangial and endothelial cells with extension of the mesangial matrix around capillary loops creating the appearance of a double glomerular basement membrane or tram track as in the image below. Membranoproliferative glomerulonephritis may be idiopathic, result from antibodies against complement components, or be secondary to chronic infections, especially hepatitis B or C. It would not be seen in diabetes. Answer B: Antibodies directed against the glomerular basement membrane typically cause rapidly progressive glomerulonephritis with hematuria and increasing azotemia (increased blood urea nitrogen and creatinine). In most cases, these antibodies also attack the pulmonary basement membranes, causing hemoptysis (Goodpasture disease). On biopsy, expect a crescentic glomerulonephritis and an immunostaining pattern that is linear along the glomerular basement membrane (see image below). Immunoglobulin deposit is not seen in diabetic patients. Answer C: While glomerular foot processes tend to be lost/obliterated in heavy glomerular proteinuria from any cause, this is the sole finding in minimal change disease, in which proteinuria tends to be selective for the small albumin molecules rather than the larger globulin molecules, and light microscopy of the glomeruli is normal (see image below). This is the most common cause of nephrotic syndrome in children and is effectively treated with steroid treatment. In contrast, diabetic nephropathy is characterized by uniform glomerular basement membrane thickening and mesangial nodules. Answer D: Spike and dome basement membrane thickening is seen in membranous glomerulonephritis, which tends to cause heavy proteinuria/nephrotic syndrome. Antibody-rich granules form on the subepithelial surface of the glomerular basement membrane (domes), and the membrane itself grows up between them (spikes). Membranous glomerulonephritis is usually primary, caused most often by autoantibodies against the phospholipase A2 receptor 1 protein gene. In contrast to spike and dome thickening of the basement membrane, diabetic patients have uniform thickening. *Bottom Line*: In diabetic nephropathy, the basement membranes in the glomeruli become more permeable to protein (albuminuria). Renal biopsy would display uniform thickening of the basement membranes. In addition, the mesangial matrix may become more abundant and form distinctive mesangial nodules called Kimmelstiel-Wilson nodules. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers prevent progression of kidney disease.

A 25-year-old female presents with vulvovaginal burning, itching and increased discharge. She admits to multiple male sexual partners in the past six months. She takes an oral contraceptive pill consistently and denies use of any barrier protection. Pelvic examination reveals severe cervical inflammation and a foul-smelling, thin, frothy discharge in the vaginal vault that is greenish-yellow in color. *Which of the following is the most appropriate diagnostic test for the etiology?* A. culture organism using Thayer-Martin agar B. dark-field microscopy C. direct microscopic visualization following KOH prep D. PAP smear to visualize koilocytes E. wet mount and microscopy

*wet mount and microscopy* The patient is most likely infected with Trichomonas vaginalis given her history, symptoms, and characteristic vaginal discharge. A common and cost-effective method of diagnosis of trichomoniasis in the female is the examination of a wet mount (also known as wet prep or saline prep) of vaginal fluid to view motile trophozoites. However, the sensitivity of this test is only 60% and may be even less so in asymptomatic women. When wet mount is inconclusive there are other tests based on availability and cost including a new nucleic acid amplification test (NAAT), various rapid diagnostic kits that are antigen or DNA hybridization based, or culture. The two available culture media on which T. vaginalis can be cultured are Kupferberg's STS and Diamond's medium (modified). This image shows the typical appearance of the flagellated trophozoite form of T. vaginalis. Answer A: Thayer-Martin media is designed to grow Neisseria gonorrhoeae, it would not be effective in testing for Trichomonas vaginalis. There is also a new dual urine NAAT that detects both Neisseria and Chlamydia. Answer B: Dark-field microscopy would not be helpful in visualizing T. vaginalis. It is useful in analyzing spirochetes, such as Treponema pallidum in the diagnosis of syphilis. A swab from a chancre would be obtained for this microscopic examination. Answer C: A KOH (potassium hydroxide) prep can be used to identify Candida albicans in a vaginal sample under direct microscopic visualization. Trichomonas vaginalis can be directly visualized under a microscope on a wet mount but not on the KOH prep. The KOH lyses bacteria and epithelial cells from the vagina but not fungi, due to the fungal cell wall, leaving only budding yeast and/or hyphae for easier detection of a yeast infection. KOH is also used for the "whiff test." When a drop of KOH solution is added to a sample of vaginal discharge with bacterial vaginosis, a classic fishy odor may be produced by the release of amines due to elevated vaginal pH in these patients. Answer D: Visualizing koilocytes by a Pap smear is indicative of HPV infection, an etiology of genital warts and cervical, head, and neck cancers. Koilocytes are seen as vacuolated cells with enlarged, irregular nuclei upon H&E staining. *Bottom Line*: Trichomonas vaginalis is an STI caused by a motile protozoan. Several diagnostic tests are available to aid in the detection of T vaginalis including direct microscopic visualization on a wet mount slide, nucleic acid amplification test, rapid diagnostic kits, and culture.