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

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Presentation on theme: "Secondary Causes of the Nephrotic Syndrome Sumit Kumar, MD Presbyterian Hospital Dallas Dallas, TX."— Presentation transcript:

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 Asymptomatic Proteinuria 150 mg to 3 g Hematuria > 5 RBC/ hpf Nephritic Syndrome Oliguria Hematuria; RBC casts Non Nephrotic proteinuria Edema, Hypertension Acute renal failure Macroscopic Hematuria Brown/red urine, painless Synpharyngitic, or post infectious Asymptomatic hematuria ± proteinuria between episodes Nephrotic Syndrome Proteinuria > 3.5 g/1.73 m2 Hypoalbuminemia Edema; Lipuria Hypercholesterolemia

9 Clinical Presentation of Glomerular Disease Rapidly Progressive Glomerulonephritis Acute Renal Failure (doubling of creatinine or 50% decrease in GFR in 3 months) Hematuria; red cell casts Hypertension > 50% crescent formation on biopsy Other features of vasculitis Chronic Glomerulonephritis Hypertension Chronic kidney disease (low GFR) Proteinuria Shrunken kidneys on US

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

11 Common Causes of Nephrotic Syndrome DiseaseAssociations Serologic tests Minimal changeAllergy, atopy, NSAIDs, HodgkinsNone Focal sclerosing glomerulosclerosisAfrican Americans, HIV, HeroinHIV Ab MembranousDrugs: gold, penicillamine, NSAIDs Lupus Nephritis Malignancy: breast, lung, GI Hep B surface antigen Hep C antibody Anti DNA Ab Membranaproliferative GN Type IC4 Nephritic factor C3 , C4  Membranaproliferative GN Type IIC3 Nephritic factor C3 , C4 normal Cryoglobulinemic MPGNHepatitis CAnti HCV antibody, rheumatoid factor, C3 , C4 , CH 50  AmyloidosisMyeloma Rheumatoid arthritis, bronchiectasis, Crohn’s disease, FMF SPEP, UPEP Diabetic nephropathyOther diabetic microangiopathyNone

12 Secondary Causes of the Nephrotic Syndrome 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)

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 WhiteBlackOther ,325, , , ,475,204 1,319, , ,786,661 2,005, , ,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 Onset of Diabetes Functional Changes  GFR Reversible albuminuria  Kidney size 025 Structural Changes GBM thickening Mesangial expansion Onset of Proteinuria Onset of Hypertension  GFR ESRD Incipient Nephropathy Hyperfiltration  Blood Pressure Poor glycemic control Time (yrs) The Natural History of Diabetic Nephropathy in IDDM

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

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

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 Hyperglycemia Glomerulosclerosis Normotension Euglycemia Protein restriction Lipid Management Weight loss, exercise, smoking cessation ACEi, ARB

27 Lupus Nephritis

28 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 % Proteinuria Nephrotic Syndrome Granular casts Red cell chasts Microscopic hematuria Macroscopic hematuria Reduced renal function Rapidly deteriorating function Acute renal failure Hypertension Hyperkalemia Tubular abnormalities

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 - ½ of 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 – % 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

40 Classification of Secondary FSGS 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

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

42 Patients Renal Disorders in Patients with HIV Infection HIV Associated nephropathyFocal segmental glomerulosclerosis Minimal change disease Membranoproliferative GN Diffuse Proliferative GN HUS/TTP Amyloid Unrelated diseases in HIV infected patients Heroin associated nephropathy Obstructive uropathy Acute renal failureDrugs, infection HIV infection in RRTBlood transfusions, IVDA, sexual contacts Allograft

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

48 Glomerular Disease with Monoclonal Immunoglobulin Deposition Immunoglobulin Deposits Glomerular Disease Organized Fibrillar Microtubular Amyloidosis (AL, AH) Cryoglobulinemia; immunotactoid GN Nonorganized: granularLight chain deposition disease Heavy chain deposition disease Light and Heavy chain deposition disease

49 Case Presentation - Amyloidosis 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 HOPI 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, HCO 3, BUN 76 and Cr 6.7 CXRMild Pulmonary edema EKG: NSR, LVE, LAFB PE Labs

51 Case Presentation - Amyloidosis SG Catheter was placed - CI:3.8, PCWP:22, SVR:1535, PAP:48/20 She was started on dobutamine and dopamine with no appreciable change in hemodynamics. On day 3, HD was started for worsening azotemia, nausea & vomiting. Other w/up included Cardiac Echo: Restrictive cardiomyopathy with EF 25% Renal US: Normal sized kidneys with increased echogenicity IE: Monoclonal spike in the  region on serum and urine immunoelectropheresis Oral fat pad biopsy Rectal Biopsy: revealed a single vessel with amyloid deposits staining + with Congo Red with apple-green birefringence under polarized light She died 40 days later due to intra and post dialytic hypotension complicated by malignant ventricular arrhythmias Hospital Course

52 Amyloidosis – an Infiltrative Disease

53 Symptoms & Signs in Amyloidosis Median Wt loss ~ 23 # Median Wt loss ~ 23 # Renal insufficiency in 45% usually without hypertension Renal insufficiency in 45% usually without hypertension Proteinuria in 73% Proteinuria in 73%

54 Differentiate between Primary and Secondary Amyloidosis H/O inflammatory or infectious disease Family h/o amyloidosis, organ distribution Presence of a paraprotein in primary amyloid ALA pts may have one or more of the following Autonomic and peripheral neuropathy & CTS Restrictive cardiomyopathy Non thrombocytopenic purpura Large joint arthropathy Cutaneous plaques and nodules and macroglossia Isolated factor IX and X deficiency

55 Amyloidosis Clinical suspicion Immmunoelectropheresis Tissue Biopsy Bone Marrow Biopsy 123 I-SAP Scintigraphy Tissue Biopsy Abdominal Fat Pad60-90% Rectal Biopsy50-80% Bone Marrow30-50% in primary ALA Bone Marrow80% in FMF Gingiva60% Skin50%

56 Outcome in AL Amyloidosis Median Survival time of 229 pts was 12 m and less than 25% were alive at 3 yrs. Cardiomyopathy and arrhythmias accounted for ~ 40-50% of the deaths. Multivariate analysis of 168 patients - Cardiomyopathy, Urine LC, Hepatomegaly & MM affected survival in the 1st year.

57 Entities covered….. General discussion Diabetic Nephropathy Lupus Nephritis Secondary causes for FSGS: HIVAN Amyloidosis

58 Entities we did not cover….. Hepatitis C related Glomerulonephritis Secondary causes of membranous nephropathy Rheumatologic causes of nephrotic syndrome Malignany related nephrotic syndrome

59


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