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IgA Nephropathy Pathogenesis, Diagnosis and Treatment
- 1. Noon Conference Aaron Cheung, MD PGY1 8/20/2018
- 2. © 2016 Virginia Mason Medical Center 2 Objectives IgA Nephropathy • Pathogenesis • Etiology • Clinical Presentation • Diagnosis • Treatment • Prognosis • Illness script
- 3. © 2016 Virginia Mason Medical Center Pathogenesis 1. Pathogenic IgA 2. Poor clearance of IgA immune complexes 3. Mesangial cell affinity and reaction 4. Progressive renal injury response 3
- 4. © 2016 Virginia Mason Medical Center Etiology • Most cases idiopathic • Often associated with URI • CMV, H.parainflu, S.aureus, toxoplasmosis, ?mycoplasma? • Other clinical associations: • Chronic liver disease • Celiac • HIV • Familial IgA nephropathy 4
- 5. © 2016 Virginia Mason Medical Center Clinical Presentation 5 • 40-50%: • Gross hematuria with upper respiratory infection • 30-40% • Microscopic hematuria, mild proteinuria • <10%: • Nephrotic syndrome, RPGN • Edema, HTN, renal insuff, hematuria
- 6. © 2016 Virginia Mason Medical Center QUESTION 1 24 hour urine protein in nephrotic syndrome: A. >3500mg B. >2000mg C. >2500mg D.>9000mg 6
- 7. © 2016 Virginia Mason Medical Center QUESTION 1: answer Urine protein in nephrotic syndrome: A. Urine protein >3500mg/24 hrs B. Urine protein >2000mg/24 hrs C. Urine protein >2500mg/24 hrs D. Urine protein>9000/24 hrs Nephrotic syndrome defined as: - Urine protein excretion >3500mg/24 hours OR random urine protein/creatinine ratio >3000mg/g - AND hypoablbuminemia <3.5 g/dL 7
- 8. © 2016 Virginia Mason Medical Center Diagnosis • Kidney biopsy ONLY way to confirm • IgA deposits in glomerular mesangium • Indications for kidney biopsy: severe or progressive dz • Urine protein >500mg/day • Elevated serum creatinine • New-onset HTN or significant elevation 8
- 9. © 2016 Virginia Mason Medical Center Diagnosis Oxford Classification of IgA nephropathy • Standardized grading features • MEST-C: • Mesangial hypercellularity • Endocapillary hypercellularity • Segmental glomerulosclerosis • Tubular atrophy • Crescents • Correlates with adverse renal outcomes independent of clinical features • Utility of guiding therapy remains uncertain* 9
- 10. © 2016 Virginia Mason Medical Center Question 2 Most common cause of death in ESRD patients in the US: a. Cardiac arrhythmias b. Acute MI c. Septicemia d. Withdrawal from dialysis 10
- 11. © 2016 Virginia Mason Medical Center Question 2: answer Most common cause of death in ESRD patients in the US: a. Cardiac arrhythmias-38.7% b. Acute MI c. Septicemia d. Withdrawal from dialysis 11
- 12. © 2016 Virginia Mason Medical Center 12 NIDDK, 2016
- 13. © 2016 Virginia Mason Medical Center Treatment • No gold standard disease-targeted treatment • Optimal approach is uncertain • General approach: decrease progression of renal disease • 1. Nonimmunosuppressive • 2. Immunosuppressive • Serial monitoring through serum creatinine, GFR, protein excretion 13
- 14. © 2016 Virginia Mason Medical Center Treatment: Nonimmunosuppressive • BP and proteinuria control • ACE-I and ARBs • Indications: • Proteinuria >1g/day or >500mg/day • Normal or slightly reduced GFR • Mild/mod histologic findings 14
- 15. © 2016 Virginia Mason Medical Center Treatment: Immunosuppressive • Treat underlying inflammatory disease • Glucocorticoids • Indications: severe, rapidly progressive disease – Nephrotic range proteinuria – Proteinuria AFTER 3-6mo of ACE-i/ARB therapy – Severe histologic findings • Combined immunosuppressive • More severe disease – GC + (cyclophosphamide, azathioprine) 15
- 16. © 2016 Virginia Mason Medical Center Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines 16
- 17. © 2016 Virginia Mason Medical Center Prognosis • Majority benign course • 15-20% develop ESRD within 10 years • 25-30% develop ESRD by 20 years 17
- 18. © 2016 Virginia Mason Medical Center Illness Script 18 IgA Nephropathy Henoch Schonlein Purpura Pathophysiology Abnormal IgA complex deposition in mesangium and inflammatory response “ “ , large IgA complexes Epidemiology 5-50% Children, 10-40% Adults; 15-70% Children, 4-13% Adults; Clinical presentation hematuria more common with mucosal infection hematuria less common, purpura Diagnostics Labs: UA: RBC casts, proteinuria Kidney Biopsy: IgA Mesangial Deposition “ “ Therapeutics Supportive therapy, ACE-I, ARBs, immunosuppressants “ “ Clinical remission more common
- 19. © 2016 Virginia Mason Medical Center Citations 1. Cheung,CK. Clinical presentation and diagnosis of IgA nephropathy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com 2. Cattran, Daniel. Treatment and prognosis of IgA nephropathy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com 3. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402- 2414. 19
- 20. © 2016 Virginia Mason Medical Center Thanks! 20
- 21. © 2016 Virginia Mason Medical Center Histological 21
Editor's Notes
- Abnormal IgA, Poor O-gaglactosylation, alterations of IgA1 sialylation, favor mesangial deposition, genetic predipsoition related to these abnormal creations Reticuloendothelial system cannot clear IgA, abnormal handling, over production Even with deposition, body should be able to clear it, IgA deposits cleared with kidney transplantation, some innate deficiency of clearance, impaired binding and clearance Progress to glomerulosclerosis and interstitial fibrosis rather than resolution of inflammation
- IgA nephropathy consequence of aberrant IgA immune response rather than antigen itself, loci in genes that influence the immune response to intestinal pathogens
- Gross hematuria Synpharyngitic hematuria Provoked by bacterial tonsillitis, viral URI Thought to represent the start of disease Micrscopic hematuria often incidentally found on routine examination or during a dx evaluation of CKD Unknown how long disease has been going on <10% Patients in these cases have longstand disease that was not detected bc patient did not have gross hematuria or undergo routine UA 3-16% reported incidence of IgA deposits in healthy individuals
- Histological features are similar to that of Henoch-Schonlein purpura nephritis but without palpable purpura due to leukocytoclastic vasculitis with IgA in the walls of dermal capillaries the consensus recommendation is that every biopsy report of IgA nephropathy should include numerical scores based upon the presence or absence of these variables. the following variables correlated with adverse renal outcomes independent of the clinical features at baseline and the degree of proteinuria and blood pressure control during follow-up:
- M1- Worse outcomes than M0 E1- Worse renal survival in patients not on immunosuppression and improved renal survival with immunosuppression S1- Predictive of worse outcomes T- Strongest predictor of worse outcomes C1 - Predictive of worse outcomes if no immunosuppression is given, but not if immunosuppression is used; C2 is predictive of worse outcomes regardless of Immunosuppression Other predictors of worse outcomes: High serum creatinine level (>120 mmol/L) at presentation Hypertension (diastolic >95 mm hg or need for antihypertensive treatment) Proteinuria: Urinary protein excretion 3.5 g/24 hr with 7% renal survival [15] Extensive interstitial fibrosis and tubular atrophy on renal biopsy C4d staining on biopsy
- Optimal approach to tx of IgA nephropathy is uncertain Slow rate of loss of GFR seen in patients hinders ability to perform adequate studies no specific serologic markers to identify continued immunologic activity in IgA nephropathy.
- General intervention to slow progression that are not specific to IgA nephropathy ACE inhibitor or ARB slows the rate of progression of most proteinuric chronic kidney diseases, an effect that is mediated at least in part by lowering both the systemic blood pressure and the intraglomerular pressure, thereby minimizing both proteinuria and secondary glomerular injury Statin therapy for patients w/ elevated LDL cholesterol, no evidence that it slows rate of progression of disease, CKD associated with increased cardiovascular risk Fish oil and tonsillectomy have been studied roles less clear. Tonsillectomy source of abnormal IgA that forms immune complexes and deposits in glomeruli IVIG needs more studies, has shown decrease in proteinuria in small sample sizes Budesonide: delayed release targets Peyer patches (source of production of galatosylated IgA1 proteinuria goal of less than 1000 mg/day, which is similar to the K/DOQIrecommendation of 500 to 1000 mg/g creatinine. we recommend that blood pressure be lowered to below 130/80 mmHg.
- we suggest not treating with glucocorticoids in patients with a chronically elevated serum creatinine or morphologic evidence of prominent glomerulosclerosis and tubulointerstitial atrophy or fibrosis
- 48-72 hours after infection begins, persists less than 3 days and loin pain