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Secondary Causes of the Nephrotic Syndrome Sumit Kumar, MD Presbyterian Hospital Dallas Dallas, TX Normal Anatomy 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 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 Classification of Glomerular Diseases Diseases Associated With Nephritic ± Nephrotic Syndrome or RPGN Immune Mediated: Lupus; cryoglobulin related; antiGBM Pauci immune Proteinuria Proteinuria>150mg/24hr Dipstik Test: Urine protein:urine creatinine: >1(+) False positive: gross hematuria 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 Types of Proteinuria Glomerular Tubular Fanconi Syndrome, Tubulo-interstitial disease Overflow Primary and Secondary Diseases Charge selectivity (as in MCD) Hemodynamic (severe HTN and CHF) Monoclonal gammopathies Inflammatory Variants Transient: Usually disappears, No workup needed Orthostatic Associated with exercise, fever, stress Clinical Presentation of Glomerular Disease Asymptomatic Nephritic Syndrome Proteinuria 150 mg to 3 g Oliguria Hematuria > 5 RBC/ hpf Hematuria; RBC casts Non Nephrotic proteinuria Macroscopic Hematuria Brown/red urine, painless Synpharyngitic, or post infectious Asymptomatic hematuria ± proteinuria between episodes Edema, Hypertension Acute renal failure Nephrotic Syndrome Proteinuria > 3.5 g/1.73 m2 Hypoalbuminemia Edema; Lipuria Hypercholesterolemia Clinical Presentation of Glomerular Disease Rapidly Progressive Glomerulonephritis Acute Renal Failure (doubling of creatinine or 50% decrease in GFR in 3 months) Hypertension Hematuria; red cell casts Chronic kidney disease (low GFR) Hypertension Proteinuria > 50% crescent formation on biopsy Shrunken kidneys on US Other features of vasculitis Chronic Glomerulonephritis Clinical Pathways for the Pathogenesis of Glomerular disease Asymptomatic hematuria Macroscopic Hematuria Nephritic Syndrome RPGN Glomerular Disease Chronic Glomerulonephritis ESRD Nephrotic Syndrome Common Causes of Nephrotic Syndrome Disease Associations Serologic tests Minimal change Allergy, atopy, NSAIDs, Hodgkins None Focal sclerosing glomerulosclerosis African Americans, HIV, Heroin HIV Ab Membranous Drugs: gold, penicillamine, NSAIDs Lupus Nephritis Malignancy: breast, lung, GI Hep B surface antigen Hep C antibody Anti DNA Ab Membranaproliferative GN Type I C4 Nephritic factor C3 , C4 Membranaproliferative GN Type II C3 Nephritic factor C3, C4 normal Cryoglobulinemic MPGN Hepatitis C Anti HCV antibody, rheumatoid factor, C3 , C4, CH 50 Amyloidosis Myeloma Rheumatoid arthritis, bronchiectasis, Crohn’s disease, FMF SPEP, UPEP Diabetic nephropathy Other diabetic microangiopathy None Secondary Causes of the Nephrotic Syndrome Hereditary: Rare Infectious: Gold, Penicillamine, NSAIDs Metabolic: Diabetes Mellitus Amyloidosis Neoplasms: Viral: HBV, HCV, HIV Bacterial: 2 syphilis, SBE Protozoan: Ch malaria Immunologic: SLE Drugs: Myeloma Solid e.g. colon, lung, breast Lymphoma, leukemia Miscellaneous: Massive obesity, sleep apnea syndrome, chronic reflux nephropathy (FSGS) Secondary Glomerular Diseases Diabetic Nephropathy Lupus Nephritis Secondary focal segmental glomerulosclerosis Secondary membranous glomerulopathy Membranoproliferative Glomerulonephritis Paraproteinemia Collagen Vascular Disease Malignancy associated Doc…..I think I am not well!! Periorbital edema Pedal edema Weight gain 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 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 Diabetic Nephropathy 150 125 100 75 Counts Diabetes Glomerulonephritis Hypertension Cystic kidney 50 25 0 Rateper million population Number of patients (in thousands) Prevalent counts & adjusted rates, by primary diagnosis 500 Rates 400 300 200 100 0 81 83 85 87 89 91 93 95 97 99 01 81 83 85 87 89 91 93 95 97 99 01 Point prevalent ESRD patients; Medical Evidence form data; rates adjusted for age, gender, & race. Projected growth of the U.S. diabetic population, by race Percent change in population 300 250 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 2,941,056 200 150 1990-2000 2000-2030 100 50 0 White Black Other 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. The Natural History of Diabetic Nephropathy in IDDM Incipient Nephropathy Hyperfiltration Blood Pressure Poor glycemic control 0 2 Onset of Hypertension 5 10 -30 13-25 15-40 Time (yrs) Onset of Diabetes Functional Changes GFR Reversible albuminuria Kidney size Onset of Proteinuria Structural Changes GBM thickening Mesangial expansion GFR ESRD Natural History of Diabetic Nephropathy in NIDDM- Lessons learnt from the Pima Indians Nelson et al NEJM 1996;335:1636-1642 Natural History of Diabetic Nephropathy in NIDDM- Lessons learnt from the Pima Indians Nelson et al NEJM 1996;335:1636-1642 Diabetic Nephropathy Pathology of Diabetic Nephropathy Kimmelstein Wilson Nodular Sclerosis Major Therapeutic Maneuvers to Slow Loss of GFR in Diabetic Nephropathy Hyperglycemia Normotension Euglycemia Protein restriction ACEi, ARB Lipid Management Weight loss, exercise, smoking cessation Glomerulosclerosis Lupus Nephritis 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 Clinical Features of Lupus Nephritis % Proteinuria Nephrotic Syndrome Granular casts Red cell chasts Microscopic hematuria Macroscopic hematuria 100 45-65 30 10 80 1-2 Reduced renal function Rapidly deteriorating function Acute renal failure 40-80 30 1-2 Hypertension Hyperkalemia Tubular abnormalities 15-50 15 60-80 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, LibmanSacks arthritis, cerebral thrombosis 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 Clinicopathologic Correlations in Lupus Nephritis 100% 80% WHO Class V WHO Class IV WHO Class III WHO Class II 60% 40% 20% 0% Nephrotic Syndrome Proteinuria Normal Renal Function Diminished Renal Function WHO Class II Lupus Nephritis Mesangial disease – 1025% of all biopsies Mesangial expansion Clinically mild disease – non nephrotic proteinuria; normal renal function WHO Class III Lupus Nephritis Focal Proliferative 20-35% of biopsies Focal necrosis Clinically mild disease – proteinuria; hematuria ± 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 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 Secondary Focal Sclerosing Glomerulosclerosis (FSGS) Focal Segmental Glomerulosclerosis Focal Segmental Glomerulosclerosis Classification of Secondary FSGS Severe Nephrotic Syndrome Drugs: heroin; NSAIDs Viruses: Hep B, HIV, parvo Non Nephrotic Proteinuria Scarring Non Nephrotic proteinuria Reduced Mass Solitary kidney, allograft, surgical ablation, renal dysplasia, agenesis, segmental hypoplasia Hyperfiltration VUR, hypertensive nephrosclerosis, post infectious or inflammatory; lupus nephritis; vasculitides Obesity, sickle cell nephropathy, congenital cyanotic heart disease Other Causes Malignancies: lymphomas Misc: sarcoidosis, radiation nephritis; Charcot-Marie-Tooth Secondary FSGS HIV associated Nephropathy (HIVAN) Vesicoureteric reflux Obesity Renal Disorders in Patients with HIV Infection HIV Associated nephropathy Focal 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 failure Drugs, infection HIV infection in RRT Blood transfusions, IVDA, sexual contacts Allograft HIV associated Nephropathy Massive proteinuria Micro-hematuria Azotemia Rapid progression to ESRD African American Patients CD4 count low Normotensive Sonogram HIV associated Nephropathy Natural History Differential Diagnosis Malignant course ESRD within 3 to 4 months Less common now than 10 years ago Heroin associated Nephropathy Options Dialysis HIV treatment Transplantation?? 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 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 Paraproteinemia Glomerular Disease with Monoclonal Immunoglobulin Deposition Immunoglobulin Deposits Organized Fibrillar Microtubular Nonorganized: granular Glomerular Disease Amyloidosis (AL, AH) Cryoglobulinemia; immunotactoid GN Light chain deposition disease Heavy chain deposition disease Light and Heavy chain deposition disease Case Presentation - Amyloidosis HOPI PMH Meds 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 Case Presentation - Amyloidosis PE Labs 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 Case Presentation - Amyloidosis Hospital SG Catheter was placed - CI:3.8, PCWP:22, SVR:1535, PAP:48/20 Course 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 l spike in the g 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 Amyloidosis – an Infiltrative Disease Symptoms & Signs in Amyloidosis Macroglossia Lymphadenopathy Splenomegaly Hepatomegaly Gross Bleeding Purpura Pain Weight loss Fatigue 0% 20% 40% 60% 80% Median Wt loss ~ 23 # Renal insufficiency in 45% usually without hypertension Proteinuria in 73% 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 Amyloidosis Clinical suspicion Immmunoelectropheresis Tissue Biopsy Bone Marrow Biopsy 123I-SAP Scintigraphy Tissue Biopsy Abdominal Fat Pad Rectal Biopsy Bone Marrow Bone Marrow Gingiva Skin 60-90% 50-80% 30-50% in primary ALA 80% in FMF 60% 50% Months Outcome in AL Amyloidosis 60 Peripheral Neuropathy 50 CTS 40 Nephrotic Syndrome 30 Orthostatic Hypotension 20 Malabsorption 10 0 CHF Myeloma 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. Entities covered….. General discussion Diabetic Nephropathy Lupus Nephritis Secondary causes for FSGS: HIVAN Amyloidosis Entities we did not cover….. Hepatitis C related Glomerulonephritis Secondary causes of membranous nephropathy Rheumatologic causes of nephrotic syndrome Malignany related nephrotic syndrome