First International Renal Conference Brugge Clinicopathological Conference

Transcription

1 2014 MFMER MFMER First International Renal Conference Brugge Clinicopathological Conference Fernando C. Fervenza, MD, Ph.D Division of Nephrology and Hypertension Mayo Clinic College of Medicine Rochester, MN

2 "I have endured a great deal of ridicule without much malice, and have received a great deal of kindness not quite free from ridicule." 2014 MFMER MFMER

3 What does not kill me makes me stronger 2014 MFMER MFMER

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6 2014 MFMER MFMER Case 1: Ben Sprangers, KU Leuven Female, 30y, adopted, Indian ancestry, smoker Relevant medical history: 1992: M pneumoniae infection 2003: non-alcoholic steatohepatitis (NAFLD) 2006: hyperthyroidism (Graves) 2008: chronic back pain (lumbo-ischialgia L5-S1) G4P3A1M2 P1: normal delivery, 40w, 2700g (<P5) P2: mors in utero on 36w, hypertension, 1950g (<P5) A1: first trimester miscarriage, torsion of the left ovary P3: induction of labour (persistent proteinuria and previous mors in utero), 35w, 2320g (P25)

7 2014 MFMER MFMER Early during her 4 th pregnancy she was diagnosed with pregnancy-related diabetes and was started on a diet and insulin. She developed proteinuria (2g/24h) at 30w of gestation. There was no hypertension at that moment. Delivery was induced because of persistent proteinuria and previous mors in utero at 36w of gestation (second pregnancy). She was first seen at the nephrology clinic in April 2012 because of persistent proteinuria of >1g 2 months after delivery. Clinical exam unremarkable: BP normal, no edema, no skin lesions

8 2014 MFMER MFMER Serum creatinine 0.78 mg/dl Sodium mmol/l, Potassium 4.22 mmol/l, Chloride mmol/l, Bicarbonate 23.1 mmol/l Serum albumin 41.7 g/l, Serum protein 81 g/l HbA1c 5.8 %, Liver set normal ANF, ANCA, complement, EE/IF normal Urine analysis Sediment uprot 39 rbc/hpf (dysmorphic) 15 wbc/hpf 1.43 g/24h or 1.32 g/g creat 2+ on albustix

9 2014 MFMER MFMER Echo/duplex kidneys Size right 10cm cortex 17mm left 10 cm cortex 17 mm Normal appearance of cortices, no parenchymal lesions, no dilatation of excretion system Normal intrarenal indices Evolution Because of persistent proteinuria it was decided to perform a kidney biopsy in September 2012

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11 2014 MFMER MFMER Differential Diagnosis Preeclampsia HELLP Syndrome Active Lupus Nephritis Timing in Pregnancy (Weeks Gestation) After 20 weeks After 20 weeks Any gestational age Complement (C3, C4) Normal Normal May be decreased Thrombocytopenia & Neutropenia Absent Present May be present Active urine sediment or Other organ involvement Absent Absent Commonly present Anti-dsDNA or Anti-C1q Absent Absent May be present Abnormal liver function tests Absent Present Absent Serum uric acid Increased Increased Normal* Hypertension (>140/90mmHg) Present Absent in 10-15% Variable Serum creatinine >1.2mg/dL Typically absent <10% of patients Commonly present Smyth & Garovic, 2013

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13 2014 MFMER MFMER Other Glomerular Disease in Pregnancy Antiphospholipid Syndrome Scleroderma Diabetic nephropathy Atypical HUS Vasculitis Post-Infectious GN Atypical? IgA Nephropathy Minimal Change Disease Focal Segmental Glomerulosclerosis Membranous Nephropathy

14 2014 MFMER MFMER Hematuria and proteinuria Normal kidney function No Hypertension Proteinuria but No Nephrotic Syndrome Hematuria after birth but what now?

15 2014 MFMER MFMER It should also be recognized that nephrotic-range proteinuria (>3.5 g/24 h) and nephrotic syndrome (>3.5 g/24 h and serum albumin <3.5 g/dl) are not necessarily synonymous. This is an important clinical distinction particularly in patients with nephrotic-range proteinuria in which a kidney biopsy shows FSGS, but who do not have full-blown nephrotic syndrome. These patients are more likely to have FSGS due to a secondary process while patients with primary FSGS are more likely to present with nephrotic syndrome and marked edema and hyperlipidemia. On the other hand, patients with secondary FSGS are less likely to have edema or hyperlipidemia.

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17 2014 MFMER MFMER NEPHROTIC SYNDROME REDUX A Clinical Perspective by Richard J. Glassock, Fernando C. Fervenza, Lee Hebert and J. Stewart Cameron

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19 Other Glomerular Disease in Pregnancy Antiphospholipid Syndrome Scleroderma Atypical HUS Vasculitis Post-Infectious GN Atypical? Diabetic nephropathy Minimal Change Disease Membranous Nephropathy IgA Nephropathy Focal Segmental Glomerulosclerosis CASE MFMER MFMER

20 2014 MFMER MFMER Case 2: Steven Van Laecke, UZ Gent Female, 64 y Caucasian History of hypertension and CKD stage 3a (with a negative family history) Admitted fever, coughing, a sore throat, urticaric rash, and oligo-anuria since a few days. BP 80/40 mmhg; P 110; T 38.5C Hemocultures were positive for Streptococcus pyogenes Tonsillitis as potential focus Ultrasound: kidneys of 110 mm slightly increased hyper echogenicity.

21 2014 MFMER MFMER Sedimentation 98; CRP 12.3 ml/dl (<0.5) Hemoglobin 11.4 g/dl; WBC 7500/mm 3 ; Thrombocytes /mm 3 Serum creatinine 10.4mg/dL LDH 840; Haptoglobin 560mg/dL; Schistocytes negative; PTT 100% C3 40 mg/dl (90-180); C4 9 mg/dl (10-40) ANF negative; ANCA negative; Anti-GBM negative; Cryoglobulins negative Urine 10 RBC/hpf; 8 WBC/hpf; Proteinuria 1.5g/L

22 2014 MFMER MFMER No renal recovery despite antibiotics and corticosteroids. Peritoneal dialysis was initiated. During PD peritonitis and one episode of sepsis low C3 concentrations were noticed.

23 2014 MFMER MFMER Differential Diagnosis Hypocomplementemic GN: Post-Infectious SLE MPGN/Cryoglobulinemia Cholesterol emboly Post-infectious glomerulonephritis Atypical

24 Acute post-streptococcal glomerulonephritis is an ancient and well-defined renal disease. 24

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26 However, in a small % of patients the GN takes longer to resolve, results in persistent hematuria and proteinuria, or even progresses to end-stage kidney disease. In these patients, kidney biopsies shows findings consistent with post-infectious glomerulonephritis. 26

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28 28 Sethi, Fervenza, Zhang et al., Kidney Int 83: , 2012

29 29 Sethi, Fervenza, Zhang et al., Kidney Int 83: , 2012

30 30 Sethi, Fervenza, Zhang et al., Kidney Int 83: , 2012

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32 Most patients diagnosed with atypical post-infectious GN have an underlying defect in regulation of the alternative pathway (AP) of complement. Defects include mutations in complement regulating proteins and antibodies to the C3 convertase = C3 nephritic factors (C3Nefs) affecting regulation of the AP that is not brought under control even after resolution of the infection. The result is continual glomerular deposition of complement factors with inflammation and development of an atypical postinfectious GN 32

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36 36 Sethi, Fervenza, Zhang et al., Kidney Int 83: , 2012

37 Atypical post-infectious GN mimics post-infectious GN on kidney biopsy, yet behaves differently in that these patients have persistent proteinuria and hematuria and may progress to end stage kidney disease. Atypical post-infectious GN is associated with an underlying abnormality in the AP of complement. 37 Sethi, Fervenza, Zhang et al., Kidney Int 83: , 2012

38 Atypical post-infectious glomerulonephritis = C3 GN 38

39 Am J Kidney Dis. 60 (1): , 2012 Am J Kidney Dis. 60 (6): ,

40 2014 MFMER MFMER Four years latter she receives a kidney graft, induction basiliximab, corticosteroids, tacrolimus and MMF Shock, DGD Serum creatinine 0.8mg/dL at discharge. Four months posttransplantation, diarrhea, vomiting, low-grade fever, oliguria with AKI Gastroscopy - normal

41 2014 MFMER MFMER Sedimentation 98; CRP 42.3 mg/dl Hemoglobin 6.1 g/dl; WBC 5930/mm 3 ; Thrombocytes /mm 3 ; Reticulocytes 22/1000; Fragmentocytes 7/1000 Serum creatinine 5.3 mg/dl LDH 270 U/L ( ); Haptoglobin 2.43 g/l (0.3-2) PTT 63% C3 43 mg/dl; C4 15 mg/dl (10-40) Urine: 6RBC/hpf; 12WBC/hpf; Proteinuria 0.8/L

42 The patient was successfully treated with IV corticosteroids, IV Ig, and 7 sessions of plasmapheresis with partial recovery 2014 MFMER MFMER

43 Differential Diagnosis 2014 MFMER MFMER

44 In DEAP-HUS autoantibodies bind to the C-terminal surface binding region; In MPGN one case is reported in which a mini-autoantibody binds to the N-terminal complement regulatory region of Factor H and blocks complement regulatory function in fluid phase and on cell surfaces. C3NeF apparently acts on C3 convertases assembled in the fluid phase and on surfaces MFMER MFMER

45 Fervenza & Sethi, Am J Kidney Dis. 2012;60(1): MFMER MFMER

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48 2014 MFMER MFMER Case 3: Bart Maes, AZ Delta Roeselaere Female, 54 y, Caucasian, history of psoriasis General malaise, myalgia, arthralgia, dyspepsia and abdominal discomfort without diarrhea, and without fever or chills. Normal vital signs and physical findings (150/80 mmhg). The GP started ciprofloxacin 500 mg bid the day before. Urine: proteinuria (+) and massive dysmorphic erythrocyturia with erythrocyte casts. No WCC Chest X-ray was normal. Ultrasound showed two kidneys of 115 mm with increased parenchymal density and cortical thickness.

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50 2014 MFMER MFMER Serum creatinine 6 months earlier 0.7 mg/dl Despite aggressive therapy (pulse CYC + steroids), the patient immediately became anuric. One week after admission: profound microangiopathic hemolytic anaemia, with multiple schistocytes and thrombocytopenia. Despite daily plasma exchange in combination with oral steroids, hemolysis remained active, no recovery of renal function was noted.

51 2014 MFMER MFMER Differential Diagnosis - Nephritic Syndrome Hematuria - rbc casts, dysmorphic rbc Oliguria Edema Hypertension Proteinuria < 3.0 g/24h

52 2014 MFMER MFMER RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS Days to weeks to months Hematuria: dysmorphic red cells - red cell casts Proteinuria: Usually <3 g/day Frequent oliguria with pulmonary-renal syndrome Blood pressure often normal Fibrinoid necrosis & crescentic (>50% crescents)

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54 Crescentic Glomerulonephritis 2014 MFMER MFMER

55 Common Glomerular Diseases Presenting as Rapidly Progressive Glomerulonephritis Disease Association Tests helpful in diagnosis Goodpasture s disease Lung hemorrhage Anti-GBM antibody [occasionally ANCA present] Vasculitis GPA (Wegener) Upper and lower respiratory canca (cytoplasmic) involvement Microscopic polyangiitis Multisystem involvement panca (perinuclear) Immune complex Systemic lupus Other multisystem features ANA, anti-ssdna, C3, C4 of lupus Poststreptococcal Pharyngitis, impetigo ASO titer, streptozyme glomerulonephritis C3, C4 normal IgA nephropathy/ Characteristic rash ± Serum IgA (30%), C3 and Henoch-Schönlein abdominal pain in HSP C4 normal purpura (HSP) CP

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57 Frequency of Different Types of Crescentic GN in Consecutive Native Renal Biopsies at the UNC Pauciimmune Immunecomplex Anti-GBM Others % No. % No. % No. % No. All (n=632) / / / /632 Age 1-20 yr (n=73) 42 31/ / / Age yr (n=303) / / / /303 Age yr (n=256) / / / /256 Jennette JC: Kidney Int 63:1166, 2003 CP CP

58 2014 MFMER MFMER Signs and Symptoms of Necrotizing Small Vessel Vasculitis Cutaneous purpura, nodules and ulcerations Peripheral neuropathy (mononeuritis multiplex) Abdominal pain and blood in stools Hematuria, proteinuria and renal failure Hemoptysis and pulmonary infiltrates or nodules Necrotizing (hemorrhagic) sinusitis Myalgias and arthralgias Muscle and pancreatic enzymes in blood

59 2014 MFMER MFMER Ernest W. Goodpasture CP

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63 2014 MFMER MFMER Distribution of the Goodpasture antigen Kidney Lung Eye Ear Brain Muscle Other GBM, distal TBM, and Bowman s capsule Alveolar basement membrane Bruch s and Descemet s membranes, basement membranes of retinal capillaries, lens capsule, and cornea Cochlear basement membrane Basement membrane of choroidal epithelium Basement membrane at the neuromuscular junction Basement membranes of adrenal, breast, pituitary, and thyroid Sources: Cashman et al. (1988); Kleppel et al. (1989); and Miner and Sanes (1994).

64 Microangiopathic hemolytic anaemia 2014 MFMER MFMER

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68 Following the third dose of ciprofloxacin, the patient experienced muscle pain and cramping. His symptoms worsened following ingestion of the 4 th dose MFMER MFMER

69 Int Med J 2009; 9: MFMER MFMER

70 2014 MFMER MFMER Crescentic Glomerulonephritis ANCA-Associated Anti-GBM disease ANCA + Anti-GBM TTP Vasculitis Quinolone

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73 Chapel Hill Consensus Nomenclature of Vasculitis Large to medium sized artery Small artery Capillary Arteriole Venule Vein Cutaneous leukocytoclastic vasculitis Aorta Henoch-Schönlein purpura Cryoglobulinaemic vasculitis Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis Microscopic polyangiitis Wegener s granulomatosis Churg-Strauss syndrome Arthr & Rheum 37: 187, 1994 CP

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75 2014 MFMER MFMER A common pathological principle which develops into a spectrum of related events The association of different molecules with different surface binding characteristics could be one reason why different organs are affected in TTP vs HUS/MPGN.

76 IF showed intense glomerular deposits of C3 and IgM, while IgG and C1q were negative. On ultrastructural analysis, the deposits were electron-dense and located in the sub-endothelial part of the GBM, consistent with type I MPGN MFMER MFMER

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