Clinicopathologic Conference OS 214 - Renal Module

1. ClinicopathologicConferenceOS 214 - Renal Module Group IV Tan-Tanchuling-Te-Teo-Tindoc-Tugano-Urquiza-Uy-Velasco-Ventigan-Ventura-Verdolaga-Villanueva-Villanueva-Visperas-Yabut-Yambot-Yap-Yap

2. General Data

3. R.V. • 45 y/o, F • Separated • Filipino, Roman Catholic • From Port Area Manila • CC: Bipedal Edema

4. History of Present Illness Overview

6. History of Present Illness One Month Prior to Consult

7. LBM (2 episode, 1 cup/ episode) Generalized Body Weakness/Palpitations/Easy Fatigability Enzyme/Hormone Panel ↑ ALT ↑ TSH ↔ FT4 ↓ FT3 Urinalysis Color: Yellow pH: 6.8 Slightly Turbid Albumin +3 ↑ WBC ↑ RBC Trichomonas CBC ↔ Hemoglobin ↔ Hematocrit ↑ WBC ↑ Neutrophils ↓ Lymphocytes ↔ Platelets Prescribed with silymarin 140 mg BID for 1 month Norfloxacin 400 mg BID for 7 days

8. History of Present Illness Two Weeks Prior to Consult

9. Generalized Body Weakness/Palpitations Urinalysis Proteinuria ↑ WBC Prescribed with Metronidazole 500 mg TID Ciprofloxacin 500 mg BID Developed Edema on the 3rd day of intake of antibiotics Consulted another physician and was prescribed with: Potassium Citrate / Diltiazem / Spironolactone / Methylprednisone / Furosemide Laboratory Work-up was requested

10. Laboratory Work-up was requested Urinalysis Color: L. Yellow pH: 6.0 Slightly Turbid (-) Glucose (-) Crystals Protein +4 ↑ WBC ↑ RBC + Cast (Coarse/Fine) Bacteria – Moderate Blood Chemistry ↔ ALT ↔ AST ↔ BUN ↔ Creatinine ↔ Total Protein ↔ Globulin ↔ Sodium ↔ Potassium ↓ Albumin ↑ ALP CBC ↔ Hemoglobin ↔ Hematocrit ↔ Platelets ↑ WBC ↑ Neutrophils ↓ Lymphocytes Tumor Markers ↔ CEA ↔ AFP Serology HBsAg – non-reactive AntiHCV – non-reactive Thyroid Hormone ↔ FT3 ↔ FT4 ↑ TSH

11. Radiological Findings UTZ Liver normal size with solid mass (3.5x3.3x3.9cm) in left lobe normal portal vein, tributaries, intrahepatic and CBD Gallbladder normal findings Pancreas and Spleen normal KUB X-Ray Normal Kidneys Urinary Bladder Normal Patient was lost to follow up

12. Patient was lost to follow up Seek Consult with a GI consultant Referred to a Nephrologist Advised a CT Scan with Triple IV 24 hr Urine ↑ Protein ↑ Total Volume ↑ Protein Excretion Lipid Profile ↑ Cholesterol ↑ Triglyceride ↑ LDL ↑ VLDL ↓ HDL Prothrombin Time 9.5/11.90/>100%/INR 0.78 Normal

13. Day of Consult

14. History Physical Exam Review of Systems (+) Hair Loss (thinning) No joint pains Malar rash Family History (+) DM - Mother No intake of NSAIDS and other nephrotoxic drugs or previous Blood Transfusion Personal/Social History Worked as a photographer Claims Ex-husband was promiscuous hence separated No vices OB/Gyne History G1P1 (1001) BP: 110/80 HR: 76 bmp Bipedal Edema Grade 2 Periorbital Edema

15. Laboratory Results Urinalysis Color: Yellow SG: 1.020 Slightly Turbid ↔WBC ↔ RBC (-) Glucose (+) Cast (Waxy/Fine Granular) Bacteria – Moderate Protein +4 Laboratory ANA Negative Anti dsDNA Negative ↔ BUN ↔ Creatinine ↔ Sodium ↔ Potassium ↓ C3 ↓ Albumin ↓ Calcium CBC ↔ WBC ↔ MCV ↔ MCH ↔ Neutrophils ↔ Lymphocytes ↔ Platelets PT: Noramal PTT: Normal ↓ Hgb ↓ Hct

16. Radiologic Findings X-Ray/UTZ Non-obstructing Nephrolithiasis in left kidney Pelvocaliectasis in right kidney, normal urinary bladder .

17. Differential Diagnosis

18. Proteinuria Hyperlipidemia Edema Nephrotic Syndrome IgA Nephropathy Membranous Glomerulonephritis Minimal change disease Focal Segmental Glomerulonephritis Membranoproliferative Glomerulonephritis Post-streptococcal Glomerulonephritis

19. Nephrotic Syndrome IgA Nephropathy Membranous Glomerulonephritis • Rule in: • Nephrotic syndrome(80%) • Microscopic hematuria(~50%) • Peak incidence 30-50 y/o • Non-spcific complaints – fatigue, malaise • Rule out: • Hypertension – not characteristic but absence makes it unlikely • Normal C3 Complement • Edema usually generalized • Rule in: • Nephrotic syndrome(10%) • Onset following GI infection/UTI • Lethargy(if renal function is impaired) • Rule out: • Frank hematuria following infection(most common presentation) • Normal to increased C3 complement

20. Nephrotic Syndrome IgA Nephropathy Membranous Glomerulonephritis Minimal change disease Focal Segmental Glomerulonephritis Membranoproliferative Glomerulonephritis Post-streptococcal Glomerulonephritis

21. Nephrotic Syndrome Minimal change disease Focal Segmental Glomerulonephritis • Rule in: • Proteinuria • Hypoalbuminemia • hyperlipidemia • Benign urinary sediments – casts • Dependent edema • Facial edema (Periorbital) • Microscopic Hematuria (<15%) • Rule out: • More common in children • Normal C3 Complement • Rule in: • Nephrotic syndrome(~60%) • RBC’s and leukocytes in urine • Rule out: • Gross hematuria is more commonly seen • Hypertension is found as a presenting feature in one third of patients • Normal C3 Complement

22. Nephrotic Syndrome Minimal change disease Focal Segmental Glomerulonephritis Membranoproliferative Glomerulonephritis Post-streptococcal Glomerulonephritis

23. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Post-streptococcal Glomerulonephritis • Rule in: • Nephrotic syndrome • Hematuria(may be microscopic) • Low C3 Complement • Periorbital or dependent edema • Fatigue • Rule out: • Can’t be ruled out • Rule in: • Hematuria • Malaise • Weakness • Low C3 Complement • Rule out: • Gross hematuria is more commonly seen • Hypertension • No history of infection weeks prior to edema (no latent period)

24. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Post-streptococcal Glomerulonephritis

25. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Type II • Rule in: • Nephrotic syndrome • Hematuria(may be microscopic) • Low C3 Complement • Periorbital or dependent edema • Fatigue • Rule out: • Can’t be ruled out • Rule in: • Hematuria • Low C3 Complement • Rule out: • More Nephritic • Red cells • Red call casts • Hypertension • No history of infection weeks prior to edema (no latent period)

26. Primary Impression Nephrotic Syndrome 2○MembranoproliferativeGlomerulonephritis Type I

27. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Idiopathic HIV Nephropathy Cryoglobulinemia Scleroderma Infective endocarditis Hepatitis C and B Sjögren syndrome Lymphoma Sarcoidosis Visceral abscesses Carcinoma Systemic lupus erythematosus Leukemia

28. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Infective endocarditis Hepatitis C and B Scleroderma No Evidential Findings in the History and PE Negative for Serologic Tests No Evidential Findings in the History and PE

29. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Sjögren syndrome Lymphoma Sarcoidosis Leukemia No Evidential Findings in the History and PE No Lymphadenopathy No other Evidential Findings in the History and PE No Evidential Findings in the History and PE Anemia No other evidential findings in the History and PE

30. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Visceral abscesses Carcinoma Systemic lupus erythematosus No Evidential Findings in the History and PE Liver Mass No weight loss Negative CEA Negative AFP No Malar Rash Negative ANA Negative Anti-dsDNA

31. Nephrotic Syndrome Membranoproliferative Glomerulonephritis Type I Idiopathic HIV Nephropathy Cryoglobulinemia More Common in Type I EBV Infection Promiscuous Husband Anemia Predisposition of repeated Infection

32. Primary Impression Nephrotic Syndrome 2○MembranoproliferativeGlomerulonephritis Type I 2○ to EBV Infectious Mononucleosis vs. HIV Infection

33. Pathophysiology

34. Epstein-Barr Virus Cryoglobulin MPGN Type 1 HIV Nephropathy Liver mass Nephrotic Syndrome Low C3 Complement

35. MPGN Type 1 Nephrotic Syndrome Hypothyroid state Proteinuria Decrease in TBG Easy fatigability; weakness Hypoalbuminemia leading to Edema Hyperlipidemia Hypocalcemia Increase in Cholesterol, Triglycerides, LDL, VLDL Decrease in HDL Nephrolithiasis due to increased excretion of calcium

36. HIV Infection • Most have low CD4 counts <200 and advanced HIV • Mechanism is not well understood but in vitro study suggested HIV can infect glomerular endothelial cells, mesangial cells and tubular cells. • Presents with renal insufficiency with heavy proteinuria (>10g), few red or white cells in urine sediment and hypoalbuminemia, nl to large hyperechogenic kidneys on US. HTN and peripheral edema is not common. • Rapid decline in renal function due to severe glomerular injury and marked damage to the tubular cells • In histology, tendency to collapse and sclerosis of the entire glomerular tuft rather than segmental injury.

38. EBV Infectious Mononucleosis • Epstein-Barr virus (EBV) is ubiquitous. It is estimated that more than 90% of adult humans demonstrate serologic evidence of a prior infection with EBV. • Most cases of IM are due to EBV, but the vast majority of EBV infections do not result in infectious mononucleosis. • The most common mode of transmission of EBV is through exposure to infected saliva from asymptomatic individuals, often as a result of kissing. • Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic • Prodromal symptoms consisting of 1-2 weeks of fatigue, malaise, and myalgia are common.

39. Management Confirmatory Diagnostics

40. HIV Infection • Rapid HIV tests • Test for HIV antibodies with an enzyme-linked immunosorbent assay (ELISA). • Next steps if rapid test positive • Confirm reactive tests with Western blot or immunofluorescent assay (IFA). • Nonreactive tests with high suspicion for acute HIV infection should be followed up with a virologic test such as HIV RNA assay (viral load). • Viral load is very high (>100,000 copies/mL) in acute HIV infection. • If virologic test is positive, then repeat antibody testing in 3 months after seroconversion.

41. EBV Infection • Patient should undergo the heterophile test to diagnose EBV with IM. • Human serum is absorbed wth guinea pig kidney. • Heterophile titer is defined as greatest serum dilution that agglutinates sheep, horse or cow erythrocytes. • A titer of greater than or equal to 40-fold is diagnostic of acute EBV infection in a person with symptoms of IM with atypical lymphocytes. • The patient can also undergo the monospot test which is slightly more accurate and more commercially available. • The patient can also choose to undergo EBV-specific serologic studies which is considered the “gold standard”.

42. Biopsy • Renal Biopsy • Liver Biopsy

43. Management Therapeutics

44. Nephrotic Syndrome Treatment of nephrotic syndrome involves: • Specific treatment of the underlying morphologic entity • General measures to control proteinuria if remission is not achieved through immunosuppresssive therapy and other specific measures • General measures to control nephrotic complications

45. Nephrotic Syndrome • Corticosteroids • Immunoregulators • Diuretics • Anticoagulation to prevent thromboembolic complications • Hypolipidemic agents may be used, but if the nephrotic syndrome cannot be controlled, there will be persistent hyperlipidemia. • In secondary nephrotic syndrome, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers are used. These may reduce proteinuria by reducing the systemic blood pressure and by reducing intraglomerular pressure.

46. Nephrotic Syndrome Diet • For patients with nephrotic syndrome, their diet should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d). Supplemental dietary protein is of no proven value. • A diet with no added salt will help to limit fluid overload. • Management of hyperlipidemia could be of some importance if the nephrotic state is prolonged.

47. Type 1 MPGN • 1/3 of patients with Type 1 MPGN will have spontaneous remission, 1/3 will have progressive disease, and 1/3 will have a disease process that will wax and wane but never completely disappear. The goals of treatment: • reduce symptoms • prevent complications, and • slow the progression of the disorder.

48. Type 1 MPGN • There is no clearly defined treatment for Type 1 MPGN. • After ruling out secondary causes, it consists of corticosteroid therapy (there is no standard dosage for adults) and antiplatelet drugs (aspirin, 500–975 mg/d orally, plus dipyridamole 225 mg/d orally). The rationale for antiplatelet therapy is that platelet consumption is increased in MPGN and may play a role in glomerular injury. • Prednisone – low dose, alternate-day may have salutary effect on improving renal function. • However studies for this have been limited to children.

49. Type 1 MPGN • a host of other forms of immunosuppressive and anti-coagulant treatment has been used in the management of type I MPGN. • Ex. dipyridamole, aspirin, and warfarin with and without cyclophosphamide • A study using acetylsalicylic acid with dipyridamole demonstrated a slight decrease in urine protein excretion by 3 years without differences in renal function. • Important to treat the associated diseases, if any. • Treatment with inhibitors of the renin-angiotensin system is prudent if there is proteinuria.

50. EBV-associated IM • Clinical course is generally self-limited • Does not usually require specific therapeutic intervention beyond the use of aspirin or acetaminophen for antipyresis and mild pain relief • Short courses of corticosteroids have been used to hasten symptomatic recovery in cases in which the symptoms are severe or refractory. • Excessive physical activity during the first month should be avoided. • Antiviral agents (like acyclovir) have not been demonstrated to significantly accelerate resolution of symptoms or prevent complications of the disease.