7/12/16 Disclosures • I am site PI for the REPRISE study evaluating efficacy of ABIM CERTIFICATION tolvaptan in autosomal dominant polycystic kidney EXAM: NEPHROLOGY disease (Otsuka pharmaceuticals) JULY 2016 UCSF CME Division of NephroloGy Department of Medicine Meyeon Park, MD MAS As s is tant Pr ofes s or Roadmap for today • Glomerular diseases (30 min) ---------Scheduled 15 min break------- • Common electrolyte abnormalities (30 min) • Acid-base (45 min) • Acute kidney injury (20 min) GLOMERULAR DISEASES • Secondary hypertension (10 min) 1 7/12/16 Case Laboratory studies A 74 yo man is evaluated for a 5-month history of sinusitis • Hemoglobin 11.5 g/dl and intermittent otitis media. He has lost 9 lbs (4.1 kg) • Leukocyte count 10.8x10^9 /L and has occasional joint pains. • Blood urea nitrogen 28 mg/dl Physical exam: Afebrile • Creatinine 1.6 m/dl HEENT: crusting in right nares; opaque right tympanic • Albumin 3.8 g/dl membrane; bilateral maxillary sinus tenderness • C3 100 mg/dl CV: 2/6 systolic murmur • C4 32 mg/dl Lungs: rhonchi • Urinalysis: 18 dysmorphic erythrocytes and 1 erythrocyte Extremities: 2+ edema bilateral lower ext cast/hpf • CXR: nodule in RUL, hazy density in LLL Case Question Case answer review A. Antinuclear antibody – lupus nephritis – wrong age / Which one of the following studies is most appropriate? sex – low complements A. Antinuclear antibody B. Anti-glomerular basement membrane antibody – wrong B. Anti-glomerular basement membrane antibody history; usually younger men; no respiratory C. Myeloperoxidase antineutrophil cytoplasmic antibody involvement D. Proteinase-3 antineutrophil cytoplasmic antibody C. Myeloperoxidase ANCA – can exist in granulomatous E. Anti-double-stranded DNA antibody polyangiitis (Wegener’s) but less specific D. Proteinase-3 ANCA – right answer – granulomatous polyangiitis E. Anti-double-stranded DNA antibody – lupus nephritis – wrong age / sex 2 7/12/16 Granulomatous polyangiitis (GPA) Glomerular diseases: ‘nephritic’ • Formerly known as Wegener’s granulomatosis • Hematuria, tea-colored urine • Granulomatous inflammation involving respiratory tract • Hypertension (often acute) and necrotizing vasculitis affecting small to medium sized • +/- Edema vessels • +/- Rapid loss of GFR • Necrotizing glomerulonephritis is common • Active urine sediment • Dysmorphic red blood cells • Red cell casts Glomerulonephritis: many ways to Vasculitis approach approach • Small vessel: microscopic polyangiitis, GPA, Churg- • Renal limited (mostly): IgA nephropathy, post-strep GN, Strauss, cryoglobulinemic, Henoch-Schonlein purpura– anti-GBM antibody disease inflammation / leukocyte infiltration; crescentic • Pulmonary-renal: Goodpasture’s syndrome, microscopic glomerulonephritis polyangiitis, Churg-Strauss, granulomatous polyangiitis • Renal-dermal: Henoch-Schonlein purpura; ANCA- • Medium-vessel: kawasaki’s disease, polyarteritis nodosa associated vasculitis; cryoglobulinemia; systemic lupus – renal infarctions / renovascular hypertension erythematosus • Systemic: systemic lupus erythematosus; HUS/TTP • Large-vessel: giant cell arteritis, Takayasu’s arteritis- renal ischemia due to narrowed abdominal aorta / renal arteries • Rapidly progressive GN: 50% eGFR loss in <30 days 3 7/12/16 ImmunoloGic approach Rapidly proGressive Glomerulonephritis Ser ologic analy s is • Immune complex mediated: Henoch-Schonlein purpura; cryoglobulinemic vasculitis; lupus; serum sickness; Anti-neutrophil cytoplasmic Anti-GBM Immune c omplex rheumatoid; polyarteritis nodosa; infection-induced; viral autoantibodies (ANCA) autoantibodies disease markers (hep B/C), bacterial (strep); Goodpasture’s (anti-GBM Others antibodies) No extra- Systemic Pulmonary Asthma Lung Anti-DNA Anti-pathogen renal necrotizing necrotizing and hemorrhage autoabs abs Cryoglobulins/ disease HCV • ANCA mediated (non-immune-complex mediated): GPA, arteritis granulomas eosinophilia No lung MPA, Churg-Strauss hemorrhage IgA Renal Microscopic Granulo- Churg- Goodpasture's Lupus GN Post-strep Cryo- • Cell-mediated: allograft cellular vascular rejection; giant limited polyangiitis matosis Strauss syndrome GN globulinemic vasculitis GN / MPGN cell arteritis; Takayasu’s with syndrome Anti-GBM polyangitis GN ANCA GN Anti-GBM GN Immune complex GN (‘pauci-immune’) Immune complex GN Immune complex GN • Post-streptococcal GN • SLE nephritis • Hematuria 2-3 weeks after pharyngitis or skin infection • Usually occurs within first 3 years of SLE diagnosis • Elevated ASO and anti-DNase B antibody • ANA, anti-dsDNA, anti-Smith antibodies • Low C3 / low-normal C4 • Immunosuppression: • No direct therapy available • Mycophenolate (CellCept) or cyclophosphamide • IgA nephropathy • Steroids (combined with above) • Synpharyngitic gross hematuria • Henoch-Schonlein Purpura (HSP) = Abdominal pain, diarrhea, often seen in kids, rarely in adults • Rx: steroids, fish oil(?), ACEi/ARB 4 7/12/16 Immune complex GN Anti-GBM antibody disease • Membranoproliferative glomerulonephritis (MPGN) type I • Antibodies to noncollagenous portion of type IV collagen causes autoantigen response • Secondary to cryoglobulinem ia, neoplasms, or chronic infections (eg HCV) • Renal limited: Anti-GBM Disease (older women) • Cryoglobulin deposits in vessels -> mesangiocapillar y GN • Pulmonary renal syndrome (hemoptysis / pulmonary hemorrhage + RPGN): Goodpasture’s Syndrome (young Caucasian men) • Low complements; + C3 nephritic factor (autoantibody against C3 convertase of alternative complement activation pathway) • Anti-GBM titer, kidney biopsy • Cryos: arthralgias, purpura, livedo reticularis • Rx: Plasmapheres is, steroids, cyclophosphamide • Rx: Underlying HCV à interferon and ribavirin ANCA Pauci-Immune GN /ANCA Vasculitis • Antineutrophil Cytoplasmic Antibodies • Diagnosis: ANCA +, normal complements, no • ANCAs react with cytoplasmic antigens (PR3 and MPO) that are immunohistologic evidence for vascular immune complex present at surface of cytokine-stimulated leukocytes, causing localization on biopsy leukocytes to adhere to vessel walls, degranulate, and generate toxic oxygen metabolites • Microscopic polyangiitis (p-ANCA) • Specific for proteins within granules of neutrophils and monocytes • Necrotizing vasculitis; no granulomas • Cytoplasmic (c-ANCA) versus perinuclear (p-ANCA) • Granulomatosis with polyangiitis (c-ANCA) • Cytoplasmic = PR3 (serine proteinase) = more common in GPA • Lung disease, upper airway disease, granulomas (Wegener) • Churg-Strauss Disease (p-ANCA or ANCA neg) • Perinuclear = myeloperoxidas e (MPO) = more common in MPA • Eosinophilia, asthma, sinus disease, peripheral neuropathy, (microscopic polyangiitis) granulomas • Treatment: Steroids, cyclophosphamide (+/- pheresis if hemoptysis, GPA) 5 7/12/16 IgA and SLE: Chameleons Case Both IgA Nephropathy and SLE can be… A 67 yo man with a h/o osteoarthritis, BPH, hyperlipidemia • Indolent or rapidly progressive is evaluated for new-onset joint pain in shoulders • Crescentic GN accompanied by lower extremity swelling. 3 months ago, • Nephritic and/or nephrotic baseline kidney function was normal. Meds include tamsulosin, simvastatin, naproxen. IgA Nephropathy Physical examination reveals BP 132/68. • More common in Asians and Hispanics HEENT: pale conjunctivae • Episodic macrohematuria Cardiac: S3 gallop SLE Pulmonary: decreased breath sounds at bases • More common in Asians, Hispanics, African-Americans Ext: 3+ LE edema • Up to 75% with SLE have renal disease; usually presents with proteinuria Case, continued Case Question Labs Which of the following studies is most likely to confirm the • Hemoglobin 8.2 g/dl cause of this patient’s kidney failure? • Leukocyte count 8.1 x10^9/L • Platelets 132k/mcL A. ANCA antibodies • BUN 68 mg/dl, Creatinine 5.6 mg/dl B. Serum protein electrophoresis / urine protein • Na 131 / k 3.5 / Cl 110 / Bicarb 18 / Albumin 3 / Anion electrophoresis gap 3 C. Urine eosinophil measurement • Ca 10.5 / Phos 5.4 • UA: pH 5, SG 1.015, no blood, 2+ protein D. Hepatitis C antibody assay • Urine protein:creatinine ratio 5 mg/g E. kidney ultrasonography 6 7/12/16 Case answer review Nephrotic disease: Amyloidosis A. ANCA antibodies – no hematuria • Pathology B. Serum protein electrophoresis / urine protein • β pleated structure that forms 8-10 nm fibrils electrophoresis – right answer – amyloidosis, multiple • Congo Red stain has apple-green birefringence with polarized light myeloma – low anion gap (increase in unmeasured • Classification cations including immunoglobulins) • ~ 20 unique amyloidoses • AL (primary) amyloidosis C. Urine eosinophil measurement – wrong history; test no • myeloma and monoclonal gammopathies longer favored even in AIN • AA (secondary) amyloidosis D. Hepatitis C antibody assay – MPGN can be nephrotic • chronic infections, inflammatory states (inflammatory bowel disease, rheumatoid arthritis, familial Mediterranean fever) and associated with RPGN, but no hematuria E. kidney ultrasonography – dx obstructive uropathy in older man with BPH, but more going on here Nephrotic Disease: Amyloidosis Nephrotic Disease: Amyloidosis • Clinical findings • Treatment • Large kidneys and massive proteinuria • AA Amyloidosis: Treat underlying infection or inflammation, • Multi-organ involvement colchicine for Familial Mediterranean Fever • Periorbital hemorrhage (raccoon sign), macroglossia • AL Amyloidosis: Treat underlying myeloma, melphalan, prednisone, • Cardiac deposits stem-cell transplant • GI involvement, hepatomegaly • Adjuvant therapy: ACEi/ARB, blood pressure control, diuretics,