Renal Disease in HIV/AIDS


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Theodoros Katsivas, MD (UC San Diego Owen Clinic), Shira Abeles, MD (UC San Diego Owen Clinic) and Robyn Cunard, MD (UC San Diego) present "Renal Disease in HIV/AIDS"

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Renal Disease in HIV/AIDS

  1. 1. AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.
  2. 2. Renal Disease in HIV/AIDS Theodoros Katsivas, M.D. Assistant Clinical Professor; UCSD Owen Clinic Robyn Cunard, M.D., FRCP Assistant Professor, Nephrology Shira Abeles, M.D. ID Fellow, UCSD Owen Clinic AIDS Clinical Rounds, UCSD AVRC Jan 4, 2013
  3. 3. Renal disease in HIV infection Prevalence of renal disease in European HIV cohorts ranges 0.31% – 0.5% US cohorts report higher rates with incidence ranging 3-8 per 1,000 patient-years Burden of renal disease expected to increase as the HIV infected population survival rates increase
  4. 4. Renal disease in HIV infection Acute kidney injury (AKI)  Pre-renal states (hypovolemia, cirrhosis)  Acute tubular necrosis  Ischemic  Sepsis  IV contrast  Nephrotoxic  Post-renal causes  Nephrolithiasis  Cancer  Infectious  Interstitial nephritis  HIV associated thrombotic microangiopathy
  5. 5. Medication nephrotoxicity in HIV infection Antiretrovirals  PIs: indinavir, atazanavir  NRTIs: tenofovir Other antivirals: acyclovir, foscarnet, cidofovir, adefovir Other antibiotics: SMX/TMP, pentamidine, aminoglycosides Antifungals: amphotericin
  6. 6. Renal disease in HIV infection Chronic kidney disease (CKD)  HIV associated nephropathy  Immune complex mediated GN (HIVICK)  Hepatitis C co-infection related renal disease  Post infectious GN  Membranous GN  Membranoproliferative GN  IgA nephritis  Lupus like diseases  Cryoglobulinemic GN  Thrombotic microangiopathy  HTN nephrosclerosis  DM nephropathy
  7. 7. Advanced renal disease in HIV infection • N=8817 with median f/u 4.5 years • ARD: advanced renal disease: eGFR<30 ml/min • ESRD: HD or PD >1 mo or renal transplantRyom, JIAS, 2012, Advanced renal disease, end-stage renal disease and renal death among HIV-positive individuals in Europe
  8. 8. Renal disease and HIV progression or AIDS death In a cohort with 5,824 person years of follow-up 22% were female, 34% African American, 38% on HAART, and 3% had CKD at baseline CKD at presentation was not independently associated with increased risk of AIDS defining illness or AIDS related death(Alves, Clin Nephrol, 2012)
  9. 9. Advanced renal disease in HIV infection Most studies suggest improved mortality in HD patients receiving ART Kidney transplant recipients infected with HIV and receiving ART now have survival rates that are similar to uninfected allograft recipients.
  10. 10. Antiretroviral treatment in HIVAN and advanced renal disease No RCTs on use of ARVs for HIVAN Observational studies show cART benefit, but not clear on:  Which agents are more beneficial?  Magnitude of beneficial effect?  Durability of beneficial effect? Limited dosing options for renally adjusted ARVs combinations
  11. 11. Case Presentation:HPI 45 yo M with HIV, Hep C, DM2, and HTN who presented after leaving prison for care of HIV and medical issues 2009 diagnosed with HIV and Hep C, CD4 was 50s VL Unknown; Started on atripla Developed disseminated Tb (lungs, gut, renal, sinuses) in Jan 2010, M. bovis; stenotic L ureteral orifice, ? Tb – stent placed (ultimately removed 6/2011)
  12. 12. HPI cont’d 10/2011 released from jail, began care at San Ysidro – no acute issues. On atripla and insulin regimen Cr 1.3, 3+ protein in urine 11/2011 developed L CVAT and found to have hydronephrosis, Cr 1.4 Seen by urology 3/2012 Creatinine 1.5  Underwent cystoscopy – stent placed, AFB cultures negative
  13. 13. HPI cont’d SBO 4/23 – biopsies of ileocecal valve c/w chronic active ileocolitis – no cultures of biopsies sent (CMV staining negative),  AKI with this, Cr 3.07, resolved Atripla changed to Efavirenz/Abacavir/3TC Following switch, Cr bumped 1.3 -> 1.8 (resolved) Referred to renal Followed by urology for stenotic L ureteral orifice with reflux
  14. 14. PMH HIV CD4 412, VL UD, dx in 2009 with AIDS  RF ? exposure while nurse in Mexico vs MSM, last neg HIV test 1999 Disseminated TB dx 2010 - M. Bovis, possibly in kidneys/ L ureter. He was hospitalized at Alvarado for 1 1/2 months, treated for 1 year 4 meds/then 2 med. CKD with proteinuria Ileocecal SBO, iliocolitis HCV (1a), VL 292k - dx in 2009, no tmt DM2 - since 1999, on insulin since 2008, + diabetic retinopathy s/p laser tmt, + PN in hands and feet HTN - dx 2012 HL - dx 1999 Hydronephrosis: Stenotic left ureteral orifice, dilated with stent, removed the stent in 5/12, first dilatation in 2010, stent left in for 6 months
  15. 15. History cont’d NKDA Meds:  Atripla, gemfibrozil, bactrim ppx, azithro ppx, insulin, citalopram Fam Hx: No renal disease Soc Hx: From Monrovia, CA; in MCC (prison) 21 months 2009-2011, CA-1 9/2011, then in half-way house. Has a cat. No other travel, MSM, no IV drugs, not currently sexually active
  16. 16. PE Exam notable for BP 138/86 Thin, well-appearing Otherwise unremarkable, no peripheral edemaPertinent Studies CD4 418, VL UD BUN 34, Cr 1.6, K 4.6; A1c 7.5 >3g proteinuria; protein/cr ratio 10,903 UA gluc 1+, 3+ protein, 2+ occ blood but no RBCs or WBCs Renal US - unremarkable
  17. 17. Renal Biopsy 1) Review some normal histology slides 2) Review our patients’ pathology
  18. 18. Renal Biopsy
  19. 19. EM
  20. 20. Discussion:HIV and Renal Disease HIV often combined with DM, HTN, Hep C ARF and CKD more likely in HIV than non-HIV  ARF HIV-related RF include AIDS/AIDS-defining illness, high VL, or use of indinavir, tenofovir, nevaripine  CKD HIV-related RF higher VL and lower CD4, use of tenofovir or indinavir Immune activation – inflammatory cascades and Ig complex deposition, some IL enhance viral replication (IL-6, TNFα)
  21. 21. Glomerular disorders associated with HIV 1) HIVAN  Form of FSGS with collapse of entire glomerular tuft (not focal) but podocytes proliferate instead of atrophy/die  Dilated/microcystic tubules, various levels of fibrosis and edema  immune cell infiltrates – CD4 and CD8 cells and macrophages 2) HIVICK (HIV-immune complex kidney disease), immune complex glomerulonephridities  Subepithelial and/or subendothelial immune deposits of HIV Ags, Ig complexes (IgA), complement  Glomerular lesions w mesangial expansion w crescents  Immune cell infiltrates mostly B cells 3) Thrombotic microangiopathy  Rare. Damage to glomerular microvascular endothelium, occurs often with thrombocytopenia or hemolytic anemia.
  22. 22. HIVAN: Clinical Features Typically in setting of high VL Rarely in acute HIV infection or in 1st few months Typically rapid decline in renal function with significant proteinuria – nephrotic range Typically lack peripheral edema, HTN UA typically bland US with b/l echogenic & enlarged kidneys Dx requires bx
  23. 23. HIVAN: Epi EPI: more common in African descent  Of 102 HIVAN cases, 97 in black pts (Laradi et al 1998)  Of 17 cases of HIV and renal disease, 7 with HIVAN, all of African origin (Williams et al 1998)  120 autopsies of Caucasian AIDS pts: 68% with renal disease, 0% HIVAN (Monga et al, 1997) Inrig et al. Renal Complications of HIV Infection. AIDS 2013
  24. 24. HIVAN Pathogenesis: HIV in renal cells  Bruggerman – murine model: HIV-1 expression in renal epithelial cells necessary for devpt of HIVAN  Since mice don’t develop AIDS, shows independent of immune suppression and suggested viral gene expression in renal cells important (proteins)  Also showed that in HIV+ pts with HIVAN, HIV infected tubular and glomerular epithelial cells  Unclear how HIV enters epithelial cells  PCR suggests CD4 and CXCR4 can be detected in cultured renal epithelial cells
  25. 25. HIVAN Pathogenesis Marras – renal tubular cells supported viral replication and subsequent divergence (separate from blood) Winston – renal parenchymal cells can serve as reservoir for HIV, can persist in glomerular and tubular epithelial cells despite ART
  26. 26. HIVAN: Pathogenesis Note – HIV DNA seen in glomeruli even in absence oh HIVAN so another factor involved  Viral expression: Nef  Genetic predisposition
  27. 27. HIVAN Pathophysiology: Nef Nef implicated; interferes with host signaling pathways in renal cells Nef – accessory protein involved in modulation of host immune system by controlling T cell receptor responses, downregulation of CD4 and CD28 In mice, Nef production results in phenotypic changes seen in HIVAN  likely from Nef’s effects on host cell transduction pathway involving Src Kinases and STAT3 and activation of NF-kB  Induces podocyte dysfunction
  28. 28. HIVAN – Genetic RF Almost exclusively in African Americans  Associated with gene MYH9 which codes for non-muscle myosin on chromosome 22  Genome-wide association analysis using >1million SNPs in AAs and European Americans with FSGS. Variants in 60kb area on chromosome 22 containing MYH9 and Apolipoprotein L1 (ApoL1) genes were strongly associated with increased risk for FSGS in Aas only.  DNA sequence in larger cohort showed 2 ApoL1 variants (G1 and G2) associated with FSGS, not MYH9. G1 and G2 variants absent in European Am genomes.  ApoL1 encodes serum factor that lyses Trypanosoma brucei  Subspps (gambiense and rhodesiense) produce ApoL1 inhibitors; inhibited by G1 and G2 ApoL1 mutations Genovese et al. Science 2010
  29. 29. Antiretroviral treatment in HIVAN and advanced renal disease No RCTs on use of ARVs for HIVAN Observational studies show cART benefit, but not clear on:  Which agents are more beneficial?  Magnitude of beneficial effect?  Durability of beneficial effect? Limited dosing options for renally adjusted ARVs combinations
  30. 30. HIVAN: Treatment Prior to ART, patients progressed to ESRD within 1-4 months of dx, now slower with ART  Increased risk of worsening renal function with  Low CD4  Elevated Serum Cr  Increased proteinuria  Higher VL  Hep C coinfection In general worse renal survival compared with non- HIVAN
  31. 31. HIVAN: Treatment Other therapies  ACE-I – improved renal survival in early disease  Steroids – unclear benefit, high infectious complications – not recommended  Dialysis  Renal transplant
  32. 32. Points of Discussion Patient Diagnosis Patient management  Hep C treatment  Antiretroviral choices
  33. 33. Thank you! Thank you Boris Shlopov of pathology for taking pics of slides Thank you Robyn Cunard of nephrology