Morning Report

1. Morning Report August 10th, 2010 Neil Iyengar, MD

2. MKSAP • A 19-year-old woman is evaluated for a 3-month history of periorbital edema, ankle edema that worsens towards the end of the day, and foamy urine. Medical history is unremarkable, and she takes no medications. • On physical examination, temperature is normal, blood pressure is 112/70 mm Hg, pulse rate is 60/min, and respiration rate is 12/min. BMI is 24. Funduscopic examination is normal. There is 2+ bilateral pedal edema. • Laboratory studies: Serum creatinine: 0.8 mg/dL (70.7 µmol/L), Urinalysis: 4+ protein; no blood; no bacteria, Urine protein-creatinine ratio: 10 mg/mg • Kidney biopsy is performed. Electron microscopy of the specimen reveals diffuse foot process effacement. Light microscopy is normal. Immunofluorescence testing shows no immune complex deposits.

3. Which of the following is the most appropriate treatment for this patient? • A. Cyclophosphamide • B. Cyclosporine • C. Prednisone • D. Tacrolimus

4. This patient most likely has minimal change disease. MCD is the most common cause of the nephrotic syndrome in children and commonly causes this syndrome in young adults. MCD is characterized by the sudden development of nephrotic syndrome (urine protein-creatinine ratio that may exceed 9 mg/mg). Additional manifestations include edema, hypoalbuminemia, and hyperlipidemia. • The creatinine may be normal or slightly elevated, light microscopy reveals no abnormalities, and immunofluorescence shows no immunoreactants. Effacement or flattening of glomerular epithelial cells seen on EM is diagnostic. • Few trials have been performed in adults and treatment mirrors that used in children. steroid therapy is the initial treatment of choice. • Approximately 25% of patients are resistant to steroids. Cyclophosphamide, cyclosporine, or tacrolimus are indicated for patients who are steroid resistant, steroid dependent, or have frequent relapses.

5. 58 year-old female with SLE and rheumatoid arthritis presents with SOB x1 week • Right-side chest pain • Fatigue • Worsening dyspnea and palpitations • SOB & new DOE • Non-productive cough • Recent 6 hour flight

6. 58 year-old female with SLE and rheumatoid arthritis presents with SOB x1 week PMHSLEHTNGERD PSHTAH Family HxSister – SLEMother – DMFather – MI age 55 SocialNo Tob/EtOH/IVDAOccupation: Auditor Lives with her 2 children Home MedicationsNorvasc 10mg dailyKCl 20 mEq dailyToprol XL 50mg dailyASA 81mg dailyPrednisone 7.5mg dailyNexium 40mg dailyMethotrexate 2.5mg daily – DC’d 3 months agoPlaquenil 200mg daily – DC’d 3 months ago

7. Physical Exam Gen: Obese AAF in NAD VS: T 36.5 HR 103 RR 25 BP 105/66 95% on 4L NC HEENT: PERRLA, EOMI, anicteric, mmm, O/P clear Neck: Supple, trachea midline, no LAD, no thyromegaly CV: Regular rhythm, s1/s2, II/VI systolic murmur at LLSB, JVD @ 14cm, warm ext, no peripheral edema Lungs: Good effort, Bibasilar crackles GI: Soft, NT/ND, NABS, no masses MSK: No joint effusions, full ROM throughout Neuro: A&Ox3, CN II-XII intact, strength 5/5 throughout, reflexes symmetric Skin: No rashes/lesions

8. Differential Diagnosis

9. Initial Labs/Studies

10. Labs Ca 7.3 Mg 1.5 Ph 4.4 103 9.6 140 41 N 87% L 4% 381 112 12.5 21 3.7 3.7 27.9 MCV 83.2 GFR 13 CK 94 CKMB 6.5 Trop T 0.36 BNP 20166 C3 113 C4 28 UA: pH 5.5 LE + Nitrite – 3+ Protein 3+ Blood, >20 RBC >20 WBC Many granular casts Occasional WBC casts Many bacteria 3.1 FENa: 0.4% FEUr: 29.8% Ur Eos: 0% 8.5 0.4 0.1/0.3 31 17 47

11. Further Studies • CXR: clear, no pathology • V/Q Scan: Numerous unmatched perfusion defects in both lungs, consistent with extensive pulmonary embolism • TTE: Normal LV, no thrombus. Flattened septum. Moderately dilated RV with severely reduced performance. Interatrial septum bows toward LA. • Renal U/S: Echogenic kidneys c/w medical renal disease. No evidence of renal v. thrombosis or hydronephrosis.

12. NEJM. 7/2010

13. Hospital Course • Heparin gtt initiated • UTI treated, IVF for ARF • But renal failure worsening • Cr 3.7  5.2 • FENa 1.4% • UA: 3+ protein, 3+ blood, RBC casts • 24-hour urine protein: 4.58 gm • UOP: continues to be adequate at 50-100 cc/hr

14. Additional work-up/ Differential

15. The Glomerulus

16. Approach to Proteinuria • 3 types: • Glomerular – increased filtration of macromolecules across glomerular capillary wall. Only glomerular proteinuria is identified on urine dipstick. • Tubular – interference with proximal tubule reabsorption of smaller proteins • Overflow – increased excretion of low molecular weight proteins exceeds proximal tubules reabsorptive capacity (i.e. myeloma)

17. Approach to Glomerular Disease • Focal nephritic: inflammatory lesions in less than half the glomeruli on light microscopy • Red cells (often dysmorphic), occasional RBC casts, mild proteinuria (<1.5 g/day) • Diffuse nephritic: Affects most or all the glomeruli. Same findings as above in addition to heavy proteinuria (often nephrotic range) • Nephrotic: Heavy proteinuria and lipiduria, but few cells or casts

18. Focal Glomerulonephritis • Mild postinfectious • IgA nephropathy • Thin basement membrane disease • Herediatry nephritis • HSP • Mesangial proliferative • SLE nephritis • Nephrotic • Minimal change • Focal segmental glomerulosclerosis • Mesangial proliferative • Membranous nephropathy • Diabetic nephropathy • Postinfectious (later stage) • Preeclampsia • Amyloidosis • Benign nephrosclerosis • Diffuse Glomerulonephritis • Postinfectious • Membranoproliferative • SLE nephritis • Rapidly progressive • Fibrillary • Vasculitis • Cryoglobulinemia • Anti-GBM • Wegener’s granulomatosis

19. Further studies RF 165 (<14) Anti-CCP 5 (<20) Anti-dsDNA <10 ANA 2560, speckled SSA 4 (<20) SSB 2 (<20) Anti-smith 10 (<20) Anti-RNP >100 ANCA IFA >1:40 titer Anti-MPO ANCA >100 (<20) Anti-PR3 ANCA 5 (<20) Mixed connective tissue disease with ANCA Vasculitis

20. Hospital Course • Preparation for renal biospy • LE doppler studies: Multiple bilateral DVTs • IVC Filter placed • Heparin held and reversed with FFP • Patient developed respiratory failure and was intubated

21. CT scan

22. Hospital Course • CT read: Multiple new ground glass centrilobular opacities in LUL. Viral versus fungal differential. Honeycombing prominent in lower lung zones with traction bronchiectasis in UIP-like pattern. • Bronchoscopy reveals diffuse pulmonary hemorrhage

23. How do you put this together?

24. Renal biopsy • Light microscopy: Diffuse crescentic glomerulonephritis • Electron microscopy: Normal organization and thickness of GBM with normal podocytes • Immunofluorescence: • Strong linear staining of GBM

25. Additional Labs • Anti- Glomerular basement membrane IgG: 2.1 (nl <1.0) • Serologic evidence of antiphospholipid antibody syndrome: • Mod elevated Anticardiolipin IgM • Elevated anti-beta2 glycoprotein IgA

26. Crescentic Glomerulonephritis(Rapidly progressive GN) • Type 1: Anti-GBM • Type 2: Immune complex • Pattern of deposition is not diagnostic of a specific disorder (rare) • Type 3: Pauci-immune • Few or no immune deposits • MPO-ANCA vasculitis • Wegener’s granulomatosis • Type 4: Double antibody positive disease • Features of Type 1 and 3

27. Antibody directed against NC1 domain of the alpha-3 chain in Type IV collagen • Alpha-3 chain expression is highest in alveolar and glomerular basement membranes • Alveolar hemorrhage occurs in 60-70% of patients • Diagnosis is confirmed by biopsy and serology • Treatment: Plasmapheresis, steroids, and cyclophosphamide

29. Follow-up • Patient responded well to 8 cycles of plasmapheresis • Also treated with prednisone and cyclophosphamide • Anti-GBM level zero by time of discharge • Discharged on warfarin, prednisone taper, and cyclophosphamide • Seen in clinic last month, one year after hospitalization: Anti-GBM and MPO-ANCA levels undetectable, resolution of hematuria, but still with proteinuria. Now on maintenance immunosuppression with azathioprine. Nonspecific antiproteinuric treatment with ACE-I to preserve remaining glomerular function