The UC San Diego AntiViral Research Center sponsors weekly presentations on HIV, HBV, HCV, TB and other infectious diseases to provide current research, clinical practices and trends. This presentation was on renal disease in HIV/AIDS patients. It discussed the various causes of acute and chronic kidney disease seen in this population, including HIV-associated nephropathy. Treatment focuses on antiretroviral therapy to suppress HIV viral load, though options are limited in advanced renal disease. The case presentation involved a patient with multiple comorbidities where a renal biopsy showed findings consistent with HIV-associated nephropathy.

1. AIDS CLINICAL ROUNDS
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.

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. 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. 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. 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. 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. 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
transplant
Ryom, JIAS, 2012, Advanced renal disease, end-stage renal disease and renal death among HIV-positive individuals in Europe

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. 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. 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. 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. 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. 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. 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. 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. PE
 Exam notable for BP 138/86
 Thin, well-appearing
 Otherwise unremarkable, no peripheral edema
Pertinent 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. Renal Biopsy
 1) Review some normal histology slides
 2) Review our patients’ pathology

24. Renal Biopsy

32. EM

38. 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)

39. 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.

40. 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

41. 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

42. 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

43. 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

44. HIVAN: Pathogenesis
 Note – HIV DNA seen in glomeruli even in absence oh
HIVAN so another factor involved
 Viral expression: Nef
 Genetic predisposition

45. 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

46. 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

47. 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

48. 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

49. HIVAN: Treatment
 Other therapies
 ACE-I – improved renal survival in early disease
 Steroids – unclear benefit, high infectious complications –
not recommended
 Dialysis
 Renal transplant

50. Points of Discussion
 Patient Diagnosis
 Patient management
 Hep C treatment
 Antiretroviral choices

51. Thank you!
 Thank you Boris Shlopov of pathology for taking pics of
slides
 Thank you Robyn Cunard of nephrology