WBR0283

Author	[[PageAuthor::Ayokunle Olubaniyi, M.B,B.S [1] (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [2])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathology
Sub Category	SubCategory::Renal
Prompt	[[Prompt::A 5-year-old boy is brought to the emergency department (ED) by his mother. She reports that her boy has generalized swelling with decreased urine output, and she is concerned his condition is serious. She explains that 3 days ago, he had a mild swelling around the eyes, but soon his condition worsened and involved the rest of his body. The boy does not report any obvious exacerbating or alleviating factor. The patient has no past medical history and no family history for chronic diseases. Upon further questioning, the mother recalls that the patient was stung by a bee ten days ago. In the ED, the patient's temperature is 36.7 °C (98 °F), his blood pressure 110/72 mmHg, and his heart rate is 82/min. Physical examination is remarkable for generalized pitting edema and a bee sting mark in the left upper extremity. Chest x-ray is remarkable for pleural effusion. 24-hour urine collection demonstrates oval fat bodies and profound proteinuria. The physician suspects the patient's condition is caused by a renal disease. On renal biopsy, which of the following findings on light microscopy is consistent with this patient's diagnosis?]]
Answer A	AnswerA::Segmental sclerosis and hyalinosis
Answer A Explanation	[[AnswerAExp::Segmental sclerosis and hyalinosis are characteristics of focal segmental glomerulosclerosis (FSGS). FSGS is a common cause of nephrotic syndrome among adults and is associated with HIV and sickle cell disease.]]
Answer B	AnswerB::Diffuse capillary and glomerular basement membrane thickening
Answer B Explanation	AnswerBExp::Diffuse capillary and glomerular basement membrane thickening are findings observed in membranous nephropathy (MN). MN is a slowly progressive kidney disease prevalent among Caucasians between 30 and 50 years of age.
Answer C	AnswerC::Normal glomeruli
Answer C Explanation	[[AnswerCExp::A renal biopsy of minimal change disease typically shows no abnormalities on light microscopy. In contrast, electron microscopy shows effacement (fusion) of podocytes, which are visceral epithelial cells, with slit-pore membrane obliteration between podocyte foot processes.]]
Answer D	AnswerD::Enlarged, hypercellular glomeruli with proliferation of mesangial and endothelial cells
Answer D Explanation	[[AnswerDExp::Enlarged, hypercellular glomeruli with proliferation of mesangial and endothelial cells are findings suggestive of acute post-streptococcal glomerulonephritis, a common cause of nephritic syndrome among pediatric patients. Electron microscopy in PSGN demonstrates subepithelial immune complexes that have a "lumpy-bumpy" appearance. Patients with PSGN typically present with hematuria, hypertension, and periorbital edema with or without oliguria.]]
Answer E	AnswerE::“Wire looping” of capillaries
Answer E Explanation	[[AnswerEExp::“Wire looping” of capillaries is a feature suggestive of diffuse proliferative glomerulonephrits, which is frequently observed among patients with systemic lupus erythematosus (SLE).]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::Minimal change disease (MCD) is considered a disease of childhood. It is responsible for up to 70-90% of nephrotic syndrome in patients less than 10 years of age, and up to 50% of older children. MCD is much less common in the adult population. Nonetheless, it still accounts for 10-15% of nephrotic syndromes in adults. The hallmark of minimal change disease in children is acute-onset proteinuria that progresses into nephrotic syndrome. Fatigue and subsequent edema develops with symptoms of periorbital edema and weight gain. The majority of MCD cases occur sporadically with no obvious trigger. In contrast, adults are more likely to present with hypertension and hematuria in approximately (30 - 40% of cases) or with infections, such as pneumonia in an otherwise healthy individual. Physical examination may be remarkable for signs of nephrotic syndrome, such as facial, scrotal or vulvar edema, ascities, or pleural effusion. Additionally, subungual edema may show a paradoxically pink lunulae and white nail beds. Finger abnormalities may be evident, showing Muehrcke lines, which are horizontal white lines of toenails and fingernails. Genetic mutations that have been implicated in MCD include mutations in NPHS1, NPHS2, and ACTN4 genes that encode nephrin, podocin, and alpha-actinin 4, respectively. In addition, environemental factors have been associated with the development of MCD, including: upper respiratory infections, bee sting, medications (NSAID, gold, penicillamine, ampicillin, and mercury), hematologic malignancies (leukemia and Hodgkin's and non-Hodgkin's lymphoma). The exact pathogenesis of minimal change disease is not well-understood. However, it is hypothesized that the disease is mediated by T-cell dysfunction, release of pro-inflammatory cytokines, and damage to the polyanion barrier of the renal-glomerulus. Animal studies have demonstrated that secretions of T-cell products are associated with significant proteinuria, which are findings that further suggest the role of T-cell dysfunction in the pathophysiology of the disease. Several factors have been associated with the development of MCD, including hemopexin, IL-3, VEGF, heparinase, sialidase, cardiotrophin-like cytokine, soluble urokinase plasminogen activator receptor, CD80, and beta-3-integrin. In MCD, albumin excretion is significantly elevated with consequential hypoalbuminemia, increased protein catabolism, and hyperlipidemia that may be extensive and irreversible. A decrease in nephrin and dystroglycan, two important podocyte proteins, and slit-pore membrane obliteration between podocyte foot processes occur with effacement or fusion of the foot processes. The loss of important proteins also includes immunoglobulin and complement proteins, such as factor B. Concomitantly, serum concentrations of IgA and IgG may be low in patients with MCD while IgM levels are typically elevated, suggesting abnormal immunological capacity of immunoglobulin switching and predisposition to infections. Other significant losses include thyroid-binding globulin (TBG) and iron and copper-binding transferrin. Loss of protein S and anti-thrombin III lead to excessive production of factors V and VIII, making minimal change disease a hypercoagulable state. Patients with MCD typically have elevated hematocrit levels due to volume contraction, hypoalbuminemia, and an abnormal lipid profile. Serum electrolytes may show pseudohyponatremia due to elevated serum lipids. In addition, hypocalcemia and hypovitaminosis D are common findings. 24-hour urine collection typically shows elevated urinary specific gravity, profound proteinuria that may be in nephrotic range (> 3 g/day), and tubular lipid laden cells (oval fat bodies). A renal biopsy of minimal change disease typically shows no abnormalities on light microscopy, but lipid-laden cells may be observed in the proximal tubular epithelium. In contrast, electron microscopy shows effacement (fusion) of podocytes (visceral epithelial cells) with slit-pore membrane obliteration between the podocyte foot processes. However, podocyte effacement is not specific and should not be considered pathognomonic of the disease. Patients have excellent renal outcomes when they are still steroid-responsive and virtually all patients survive with a normal creatinine clearance. Age at disease onset is strongly associated with the frequency of relapses in children. Up to 80% of children with nephrotic syndrome respond to corticosteroids and are in full remission within 1 month of steroid therapy. Steroids are often administered empirically among children with nephrotic syndrome to avoid unnecessary renal biopsies among responsive patients. As such, renal biopsy is reserved for patients who do not demonstrate signs of remission and thus require further investigation for appropriate diagnosis and management. Educational Objective: Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, and edema. Minimal change disease (MCD) is the most common cause of NS in children. A renal biopsy of minimal change disease typically shows no abnormalities on light microscopy. In contrast, electron microscopy shows effacement (fusion) of podocytes, which are visceral epithelial cells, with slit-pore membrane obliteration between podocyte foot processes. The majority of cases of MCD are responsive to steroid therapy. References: Beck L, Bomback AS, Choi MJ, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis. 2013;62(3):403-41. Ali AA, Wilson E, Moorhead JF, et al. Minimal-change glomerular nephritis. Normal kidneys in an abnormal environment? Transplantation. 1994;58(7):849-52. Saha TC, Singh H. Minimal change disease: a review. South Med J. 2006;99(11):1264-70. First Aid 2014 page 536]]
Approved	Approved::Yes
Keyword	WBRKeyword::Nephrotic syndrome, WBRKeyword::Minimal change disease, WBRKeyword::Proteinuria, WBRKeyword::Renal, WBRKeyword::Kidney, WBRKeyword::Lipoid nephrosis, WBRKeyword::Bee sting, WBRKeyword::Renal disease, WBRKeyword::Glomerulopathy, WBRKeyword::Light microscopy, WBRKeyword::Edema, WBRKeyword::Swelling, WBRKeyword::Oval fat bodies, WBRKeyword::Lipid laden cells
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