Nephrotic and Nephritic SyndromeJanuary 22, 2008Pamela J. Fall, M.D.Section of Nephrology

ObjectivesDefine nephrotic syndrome and glomerulonephritisIdentify clinical features of both syndromesIdentify causes of each syndromeEvaluation of glomerular diseaseManagement of glomerular diseases

CaseA 65 year old Caucasian man presents with several months of lower extremity edema.PMH is unremarkable. No medications.ROS is notable for fatigue and some weight loss. Appetite remains good.BP is 150/100 mm Hg, pulse 92, periorbital plaques, edema and guaiac +

CaseLab: Cr 1.4 mg/dL, Hg 8 g/dL, MCV 70, cholesterol 450 mg/dL, albumin 2.0 g/dL UA with 4+ protein, no blood and bland sediment. 24 hour urine 6 g proteinUltrasound shows 11 cm kidneys bilaterally with increased echogenicity

CaseThe most likely cause of his nephrotic syndrome is?Hypertensive nephrosclerosisDiabetic nephropathyFocal segmental glomerulosclerosisMembranous nephropathyMembranoproliferative glomerulonephritis

Nephrotic SyndromeProteinuria > 3.5 g/day/1.73 m2 Hypoalbuminemia < 3.5 g/dLEdemaHyperlipidemiaLipiduria

Nephrotic SyndromeCauses of primary idiopathic NSMinimal change diseaseMembranous nephropathyFocal segmental glomerulosclerosisMembranoproliferative glomerulonephritis (overlap)

Nephrotic SyndromeCauses of secondary NSMinimal change diseaseMembranous nephropathyFocal segmental glomerulosclerosisMembranoproliferative glomerulonephritisDiabetic nephropathy (unique pathology)Amyloid (unique pathology)Light change deposition disease (unique pathology)

Minimal Change DiseaseMost cases primary/idiopathicSecondary causesNonsteroidal anti-inflammatory agentsMalignancies (hematologic)

Focal Segmental GlomerulosclerosisSecondary causesHealing of previous glomerular injuryMassive obesity? OSASickle cell anemia HIV (other viruses)Pamidronate Heroin abuse

Membranous NephropathySecondary causesMalignancy, primarily solid tumorsClass V lupus nephritisRheumatoid arthritisHepatitis B and CDrugs (penicillamine, gold, NSAIDs, captopril)Syphilis

CaseThe most likely cause of his nephrotic syndrome is?Hypertensive nephrosclerosisDiabetic nephropathyFocal segmental glomerulosclerosisMembranous nephropathyMembranoproliferative glomerulonephritis

CaseC.G. is a 33 year old white male who presents with right flank pain and gross hematuria. PMH: 3-4 episodes of hematuria per year, 6 hospitalizations for pain control, multiple evaluations with no diagnosis.

CaseExam: BP 140/95 mm Hg, pulse 78, chest, abdomen, extremities are normal. He has no rash or arthritis.Lab: Cr 1.1 mg/dL, Hg 14 g/dl, UA shows numerous RBCs, no casts. 24 hr urine protein is 1.5 g. Ultrasound is normal.

CaseWhat is his diagnosis?Lupus nephritisIgA NephropathyMembranous nephropathyMembranoproliferative glomerulonephritis from hepatitis CNephrolithiasis

Glomerular DiseaseAccounts for 51% of ESRD in the US38% diabetic nephropathy13% nondiabetic glomerular diseaseDefinition of glomerulonephritisIntraglomerular inflammationCellular proliferationHematuriaExcludes nonproliferative disorders

GlomerulonephritisRefers to that variety of kidney disease in which proliferation and inflammation of the glomerulus is secondary to an immunologic mechanism.Presentation of GN varies from microscopic asymptomatic hematuria or proteinuria to acute nephritis, to rapidly progressive nephritis.

Nephritic SyndromeHematuria dysmorphic red blood cells, red blood cell castsAzotemiaOliguriaHypertensionVariable proteinuria (usually < 3 g/day)

Focal Proliferative GlomerulonephritisIgA nephropathyHenoch-Schonlein purpuraLupus nephritis (class II and III)Heriditary nephritis (Alports)

Diffuse Proliferative GlomerulonephritisPoststreptococcal glomerulonephritisBacterial endocarditisLupus nephritis (Class IV)Membranoproliferative glomerulonephritisCrescentic glomerulonephritisVasculitis

IgA NephropathyCommon cause of glomerulonephritisMesangioproliferative glomerulonephritisAsians and CaucasiansRare in African-Americans Age 20-30Males > FemalesPathogenesis altered regulation of IgA

IgA NephropathyClinical presentation50-60% episodic gross hematuria (synpharyngitic) 30-40% persistent microscopic hematuria

Henoch-Schonlein PurpuraSystemic IgA nephropathyArthralgiasPurpuraAbdominal painGastrointestinal bleedingHematuria

Poststreptococcal GlomerulonephritisClinical presentationChildren 2-10 yearsUncommon over age 40 (< 10%)Symptoms develop 7 days to 12 weeks after the infectionLow complement levels (C3 and CH50)Spontaneous recovery is the ruleHematuria can persist 6 monthsProteinuria, mild can persist years

Poststreptococcal GlomerulonephritisPathogenesisNephritogenic strains of streptococciPlanted antigenNephritis associated plasmin receptor (GAPDH)Zymogen (cationic protein-subepithelial deposits)Host immune response (ab/ag)Alternative pathway of complement activationIgG and C3 found in glomeruli

CaseT.G. is a 47 year old white man who presents with 3 weeks of malaise, anorexia, weight loss, cough and dark urine.PMH: mild asthma, nonsmokerExam: BP 145/70, lungs with diffuse rhonchi, heart, abdomen normal, no rash, 2+ edemaLab: Cr 6.3 mg/dL, UA 3+ blood and protein, dysmorphic rbcs

CaseWhat is his diagnosis?Lupus nephritisIgA nephropathyPoststreptococcal glomerulonephritisAnti-GBM diseaseFocal segmental glomerulosclerosis

Rapidly Progressive GlomerulonephritisClinical syndromeGlomerulonephritis (nephritic syndrome)Rapid decline in renal functionRare 2-4% of all glomerulonephritisPathologic hallmark crescentsClassified based on presence or absence of immune complexes

Rapidly Progressive GlomerulonephritisImmune complex mediated:Henoch-Schonlein purpuraCryoglobulinemia (often associated with hepatitis C)Lupus nephritisAcute postinfectious glomerulonephritisBacterial endocarditis

Rapidly Progressive GlomerulonephritisDirect antibody attack mediatedAnti-GBM disease/Goodpastures syndromePauci-immune (ANCA associated)Wegeners granulomatosisMicroscopic polyarteritis

Anti-GBM DiseaseClinical presentation:Bimodal age distribution (3rd and 6th decades)60-70% present with pulmonary hemorrhageSystemic symptoms - malaise, fatigue, anorexia, weight loss, arthralgias, myalgiasCaucasiansRare in African-Americans

Anti-GBM DiseasePathogenesisAntibodies develop against 3 chain type IV collagen in GBMLinear deposition of IgG along GBMAntibodies detected by ELISAANCA found in ~30% of patients

Anti-GBM DiseaseOutcome poor without therapyTreatmentCorticosteroids alone insufficientCyclophosphamidePlasma exchange with albumin 14 daysRenal recovery rare if patients present needing dialysis

Case24 year old black female presents with hypertension and edema. Two weeks prior she developed a cough, chest pain, nasal congestion and pain in her right ear and received a course of amoxicillin. One week prior she noted a rash on her face and chest and complained of some pain in her hands.

CasePMH: unremarkableExam: BP 180/126 mm Hg. She has periorbital edema, normal oropharynx. Heart, lungs and abdomen are normal. She has lower extremity edema and an erythematous maculopapular rash over her chest.

CaseLab:Cr 1.6 mg/dLUA 3+ blood, 4+ protein, > 50 RBCs/HPF, many dysmorphicWBC 3.0, Hg 10, platelets 120Complements C3 low, C4 low

CaseWhat is your diagnosis?Poststreptococcal glomerulonephritisIgA nephropathyLupus nephritisMembranous nephropathyWegeners granulomatosis

Systemic Lupus ErythematosisComplex multisystem autoimmune disease11 criteria 4 present for diagnosisKidney is most common organ involved (50-75%)Females > MalesAfrican-Americans have higher rates of lupus nephritis and worse renal survival

Lupus NephritisClinical spectrumMild urinary abnormalitiesAcute and chronic kidney failureUsually develops within 3 yearsPathogenesis of renal involvementHistone-DNA complex planted antigenAnti-dsDNA antibodies eluted from nephritic kidneys WHO recognizes 6 classes

Classification of Lupus NephritisClass InormalClass IIvariable mesangial hyper-cellularity and immune depositsClass IIIfocal proliferative glomerulonephritisClass IVdiffuse proliferative glomerulonephritisClass Vmembranous nephropathyClass VIchronic glomerulosclerosis

Lupus Nephritis10-20% mesangial or focal proliferative40-60% diffuse proliferative10-20% membranous nephropathyTreatmentCorticosteroidsAzathioprineCyclophosphamideMycophenolate

Evaluation of GlomerulonephritisHistory and examUrinalysis blood, protein and dysmorphic rbcs +/- rbc castsComplements Additional serology as dictated by presentation

Laboratory Tests - ComplementsLow serum complement levelSystemic diseasesSLE (75-90%)Subacute bacterial endocarditis (90%)Cryoglobulinemia (85%)Renal diseasesAcute poststreptococcal glomerulonephritis (90%)Membranoproliferative glomerulonephritis (90%)

Laboratory Tests - ComplementsNormal serum complement levelSystemic diseasesVasculitisHenoch-Schonlein purpuraRenal diseasesIgA nephropathyIdiopathic rapidly progressive glomerulonephritisAnti-GBM diseaseIC disease

SummaryGlomerular disease is an important cause of CKD and ESRD.Patients can present with a variety of clinical syndromes.A good history, exam and certain lab tests in conjunction with renal biopsy can often lead to a diagnosis.