Secondary Causes of the Nephrotic Syndrome

1. Secondary Causes of the Nephrotic Syndrome Sumit Kumar, MD Presbyterian Hospital Dallas Dallas, TX

2. Normal Anatomy

3. Classification of Glomerular Diseases • Primary glomerular diseases • Nephrotic Syndrome • Non Immune Complex • Immune Complex • Nephritic syndrome • Post infectious glomerulonephritis • Ig A nephropathy / Henoch Schonlein purpura

4. Classification of Glomerular Diseases • Diseases Associated With Nephrotic Syndrome • Monoclonal Immunoglobulin Deposition Disease (MIDD) • Amyloidosis • Light chain deposition disease • Others • Infections • Deposition diseases • Secondary FSGS • Malignancies

5. Classification of Glomerular Diseases • Diseases Associated With Nephritic ± Nephrotic Syndrome or RPGN • Immune Mediated: Lupus; cryoglobulin related; anti-GBM • Pauci immune

6. Proteinuria • Proteinuria>150mg/24hr • Dipstik Test: • >1(+) • False positive: gross hematuria • Urine protein:urine creatinine: • Normal <0.15 • Ratio of 1 correlates with proteinuria of 1g/24hr • Most accurate is 24 hr urine collection for protein and creatinine • Pitfalls of spot protein testing: False positives and negatives

7. Types of Proteinuria • Glomerular • Primary and Secondary Diseases • Charge selectivity (as in MCD) • Hemodynamic (severe HTN and CHF) • Tubular • Fanconi Syndrome, Tubulo-interstitial disease • Overflow • Monoclonal gammopathies • Inflammatory • Variants • Transient: Usually disappears, No workup needed • Orthostatic • Associated with exercise, fever, stress

8. Clinical Presentation of Glomerular Disease

9. Clinical Presentation of Glomerular Disease

10. Clinical Pathways for the Pathogenesis of Glomerular disease Asymptomatic hematuria Macroscopic Hematuria Nephritic Syndrome Nephrotic Syndrome RPGN Glomerular Disease Chronic Glomerulonephritis ESRD

11. Common Causes of Nephrotic Syndrome

12. Hereditary:Rare Infectious: Viral: HBV, HCV, HIV Bacterial: 2 syphilis, SBE Protozoan: Ch malaria Immunologic:SLE Drugs: Gold, Penicillamine, NSAIDs Metabolic: Diabetes Mellitus Amyloidosis Neoplasms: Myeloma Solid e.g. colon, lung, breast Lymphoma, leukemia Miscellaneous: Massive obesity, sleep apnea syndrome, chronic reflux nephropathy (FSGS) Secondary Causes of the Nephrotic Syndrome

13. Secondary Glomerular Diseases • Diabetic Nephropathy • Lupus Nephritis • Secondary focal segmental glomerulosclerosis • Secondary membranous glomerulopathy • Membranoproliferative Glomerulonephritis • Paraproteinemia • Collagen Vascular Disease • Malignancy associated

14. Doc…..I think I am not well!! • Periorbital edema • Pedal edema • Weight gain

15. Approach to the Patient with Nephrotic Syndrome • Make the diagnosis Proteinuria > 3.5 g/1.73 m2 Hypoalbuminemia Edema Lipuria Hypercholesterolemia • Screen the patient for secondary etiologies

16. Assessment of a Nephrotic patient • History: medications, drugs, surgeries, infections, obesity, travel, family history • Serologies • Hepatitis B and C, HIV • ANA, C3, C4, SPEP, UPEP, Cryoglobulins • VDRL, ASO titer • Imaging • Chest Xray • Renal sonogram

17. Diabetic Nephropathy

18. Prevalent counts & adjusted rates, by primary diagnosis Point prevalent ESRD patients; Medical Evidence form data; rates adjusted for age, gender, & race.

19. Projected growth of the U.S. diabetic population, by race White Black Other 1978 4,325,230 824,354 117,175 1990 6,475,204 1,319,594 385,756 2000 8,786,661 2,005,805 773,134 2030 18,441,647 5,539,283 2,941,056 Prevalence rates of diabetes in 1980–1998 obtained from National Health Interview Survey (NHIS) data. These data are linearly extrapolated to obtain prevalent rates for 1978–2030, & estimates are then multiplied by census projections to obtain estimated numbers of individuals with diabetes for 1978–2030.

20. The Natural History of Diabetic Nephropathy in IDDM Incipient NephropathyHyperfiltration  Blood Pressure Poor glycemic control Onset of Hypertension 15-40 0 2 5 10 -30 13-25 Time (yrs) Onset of Diabetes Onset of Proteinuria GFR ESRD Functional Changes GFR Reversible albuminuria  Kidney size Structural ChangesGBM thickening Mesangial expansion

21. Natural History of Diabetic Nephropathy in NIDDM- Lessons learnt from the Pima Indians • Nelson et al NEJM 1996;335:1636-1642

22. Natural History of Diabetic Nephropathy in NIDDM- Lessons learnt from the Pima Indians • Nelson et al NEJM 1996;335:1636-1642

23. Diabetic Nephropathy

24. Pathology of Diabetic Nephropathy

25. Kimmelstein Wilson Nodular Sclerosis

26. Major Therapeutic Maneuvers to Slow Loss of GFR in Diabetic Nephropathy Normotension Hyperglycemia Euglycemia Protein restriction ACEi, ARB Lipid Management Weight loss, exercise, smoking cessation Glomerulosclerosis

27. Lupus Nephritis

28. Lupus Nephritis • Renal involvement • Early Course: 30-50% of unselected patients • Later Course: 60-80% • Most patients present with proteinuria • Hypertension ± • Hyperkalemic renal tubular acidosis

29. Clinical Features of Lupus Nephritis

30. Lab tests in Lupus Nephritis • ANA, Anti DNA antibody, Anti Smith antibody • Anemia of moderate degree, Coombs + in minority, severe hemolytic anemia – rarely • Leukopenia, thrombocytosis • Hypocomplementemia: C4 and C1q are depressed more than C3 suggesting classic pathway activation (never occurs in idiopathic MPGN • Antiphospholipid antibody - ⅓ - ½of patients with lupus nephritis • Renal arterial, venous and glomerular cap thrombosis, Libman-Sacks arthritis, cerebral thrombosis

31. Diagnosis and Differential Diagnosis • Suspect in • Middle aged, nephrotic male • Idiopathic membranous nephropathy in a young woman • Routine screening of all nephrotic patients with ANA • Differential: Rheumatoid arthritis; Henoch Schonlein purpura; Ig A nephropathy; vasculitis

32. Clinicopathologic Correlations in Lupus Nephritis

33. WHO Class II Lupus Nephritis • Mesangial disease – 10-25% of all biopsies • Mesangial expansion • Clinically mild disease – non nephrotic proteinuria; normal renal function

34. WHO Class III Lupus Nephritis • Focal Proliferative • 20-35% of biopsies • Focal necrosis • Clinically mild disease – proteinuria; hematuria ±

35. WHO Class IV Lupus Nephritis • Diffuse proliferative (DPGN) • 35-60% of biopsies • Hypercellularity • Intense inflammation • Clinically – hematuria, red cell casts, proteinuria, hypertension, acute renal failure. • Most amenable to treatment • Rx: NIH Protocol

36. WHO Class V Lupus Nephritis • Membranous • 10-15% of biopsies • Silver positive “spikes” – subepithelial • Clinically nephrotic, often normal renal function • Rx: Difficult to treat; Steroids; Ponticelli protocol

37. Secondary Focal Sclerosing Glomerulosclerosis (FSGS)

38. Focal Segmental Glomerulosclerosis

39. Focal Segmental Glomerulosclerosis

40. Severe Nephrotic Syndrome Drugs: heroin; NSAIDs Viruses: Hep B, HIV, parvo Non Nephrotic proteinuria Reduced Mass Solitary kidney, allograft, surgical ablation, renal dysplasia, agenesis, segmental hypoplasia Non Nephrotic Proteinuria Scarring VUR, hypertensive nephrosclerosis, post infectious or inflammatory; lupus nephritis; vasculitides Hyperfiltration Obesity, sickle cell nephropathy, congenital cyanotic heart disease Other Causes Malignancies: lymphomas Misc: sarcoidosis, radiation nephritis; Charcot-Marie-Tooth Classification of Secondary FSGS

41. Secondary FSGS • HIV associated Nephropathy (HIVAN) • Vesicoureteric reflux • Obesity

43. HIV associated Nephropathy • Massive proteinuria • Micro-hematuria • Azotemia • Rapid progression to ESRD • African American Patients • CD4 count low • Normotensive • Sonogram

44. HIV associated Nephropathy • Natural History • Malignant course • ESRD within 3 to 4 months • Less common now than 10 years ago • Differential Diagnosis • Heroin associated Nephropathy • Options • Dialysis • HIV treatment • Transplantation??

45. Secondary FSGS • Vesicoureteric reflux • May not occur for several years • Often a poor prognostic sign – strong correlation between extent of glomerular involvement and the magnitude of proteinuria and GFR decline\ • Hypertension occurs late • Histology: Hyalinosis in unscarred areas of the kidney or in the contralateral normal kidney

46. Secondary FSGS • Obesity • Proteinuria is fairly common (upto 40%) • Likely to be part of the endothelial dysfunction syndrome a.k.a. dysmetabolic syndrome X • Remission of proteinuria often occurs with weight reduction • Association with sleep apnea

47. Paraproteinemia

49. Case Presentation - Amyloidosis HOPI • B.J.A., a 56 AA female with a long standing h/o HTN for the past 30 years was in good health until about 8 weeks prior to presentation. • Insidious onset of fatigue; 5 kg lost over a 2 m period. She had a baseline Cr of 1.6 three m prior. • About a week prior, she was started on Atenolol and HCTZ for recent difficulty in controlling her BP. • at that time, a Captopril renography was performed after Captopril 25 mg was given - Study was negative. • Over the course of the next week, her symptoms of fatigue worsened and she was admitted to DGH with progressively worsening SOB, 3-4 pillow orthopnea, and 2 episodes of syncope. • Hypertension for 30 yrs • Nifedipine XL 90 mg po qd, HCTZ 25 po qd, Atenolol 25 mg po qd and ASA PMH Meds

50. Case Presentation - Amyloidosis • 94/56; Wt 54 kg nd Ht 5’2” Eyes revealed Gr II HTNsive retinopathy JVP : 13 cm Chest had rales on the bases Precordial heave and a PSM was heard at the apex 3/6 rad to axilla Liver was 3cm BCM, Firm and non tender • Urine: SG 1.020, Protein 2+, Normal sediment Chem-7: Na 135, K 4.3, Cl 96, HCO3, BUN 76 and Cr 6.7 • CXRMild Pulmonary edema • EKG: NSR, LVE, LAFB PE Labs