This document summarizes research on kidney transplantation between HIV-positive donors and recipients. A study in South Africa found that outcomes for 27 HIV-positive recipients of kidneys from 15 deceased HIV-positive donors were comparable to recipients of HIV-negative organs over 2-3 years. However, applying this approach in the U.S. may pose challenges due to higher rates of antiretroviral resistance and limited access to dialysis in South Africa altering risk-benefit calculations. While expanding access to transplant, ethics require caution given limited long-term outcomes data from HIV-positive donors.

1. HIV in Kidney Transplantation
Wisit Cheungpasitporn
May 22, 2015

2. Disclosure
• None

4. Adults Living with a Diagnosis of HIV
Year-End 2008—United States

5. Classic pathologic features of HIVAN
Wyatt CM et al. Annu Rev Med. 2012;63:147-59.

6. Naicker S et al. Clin Nephrol. 2015;83(7 Suppl 1):32-8.

7. Age- and sex-standardized incidence of
ESRD among HIV-infected adults
Abraham AG et al. Clin Infect Dis. 2015;60(6):941-9.

8. Trullas JC et al. Kidney Int. 2011 Apr;79(8):825-42

9. HIV and ESRD
• Nearly 90% of U.S. patients living with ESRD
attributed to HIVAN are African-American.
• Nearly 900 patients with a presumptive
diagnosis of HIVAN progress to ESRD each
year.
• With improved survival of HIV-infected dialysis
patients and increasing prevalence of HIV
related ESRD.
United States Renal Data System 2010

10. HIV+ on dialysis vs. HIV- on dialysis
87%
54%
79%
41% HIV+
HIV-
Ahuja TS et al. J Am Soc Nephrol. 2002;13(7):1889-93.
USRDS data

11. Probability for kidney transplant
HIV-
HIV+
-National, multicenter,
retrospective cohort
study of HIV infected
patients starting dialysis
in Spain (1999–2006).
-66 HIV+ and 66 HIV-
patients on dialysis
-Matching for dialysis
center, year of starting
dialysis, age, sex, and
race.
Trullàs JC et al. J Acquir Immune Defic Syndr. 2011;57(4):276-
83.

12. Factors Associated with Failure to List
HIV+ Kidney Transplant Candidates
Sawinski D et al. Am J Transplant. 2009;9(6):1467-71.

13. Outcomes: HIV-Infected Recipients
Stock PG et al. N Engl J Med. 2010;363(21):2004-14.
150 patients
CD4+ >200
Undetectable HIV RNA levels
Treated with a stable ARV regimen

14. Outcomes: HIV-Infected Recipients
Stock PG et al. N Engl J Med. 2010;363(21):2004-14.
31%
41%
12.3%

15. • SRTR; 2002–2011
• 510 adult kidney transplant recipients with HIV
(median follow-up, 3.8 years) matched 1:10 to
HIV-negative controls
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

16. The number of kidney transplants
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]

17. Graft survival
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]
HR 1.06; 95% CI, 0.85-1.33; P=0.61
HIV-/HCV-
HIV+/HCV-

18. Graft survival
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]
HR 1.38; 95% CI, 1.08-1.77; P=0.01
HIV-/HCV+
HIV+/HCV+

19. Patient survival
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]
HIV-/HCV-
HIV+/HCV-

20. Patient survival
Locke JE et al. J Am Soc Nephrol. 2015. [Epub ahead of print]
HIV-/HCV+
HIV+/HCV+

21. Wyatt CM et al. AIDS 2008, 22:1799–1807
Non-transplant
HIV+ pts

22. Gonzalez VD et al. J Virol. 2009;83(21):11407-11.
T-cell activation in co-infected individuals
• CD38 is expressed selectively during the activation of a subset of
mature T cells

23. Wyatt CM et al. AIDS 2008, 22:1799–1807

24. HIV-Positive–to–HIV-Positive Kidney
Transplantation?

25. • November 2013: Organs infected with HIV may be
transplanted only into individuals who are: (1) infected
with such virus before receiving such an organ; and (2)
participating in clinical research approved by an
institutional review board.
HIV Organ Policy Equity (HOPE) Act approved by US Congress. 2013
HOPE

26. HIV-Infected Donor Eligibility and Selection
in the USA
Richterman A et al. Curr Infect Dis Rep (2015) 17: 17

27. Moreno CN et al. Rev Assoc Med Bras. 2011;57(1):100-6

28. • Nationally, approximate 356 potential HIV+
deceased donors yielding 192 kidneys and 247
livers annually.
Richterman A et al. Am J Transplant. 2015 May 14. [Epub ahead of print]

29. Muller E et al. N Engl J Med. 2010;362(24):2336-7.
-In South Africa
-HIV+ recipients to HIV+ donors
-September to November 2008
-None had access to dialysis
-4 transplants from 2 deceased
donors
•not received ART
•no opportunistic infection or
cancer
•had normal renal biopsies
•without evidence of proteinuria
-ATG as induction therapy
Maintenance: prednisone,
mycophenolate mofetil, and
tacrolimus.
7.7 6.6 19.4 8.2
1.3 1.3 2.0
1.2
1.1
1.0 1.2 1.0
-A patient receiving tacrolimus
had calcineurin toxicity and was
switched to sirolimus.
-At 12 months after
transplantation, all patients had
good renal function, did not have
clinically significant graft
rejection.

30. N Engl J Med. 2015 Feb 12;372(7):613-20.

31. Method
• Prospective nonrandomized study
• Groote Schuur Hospital, Cape town, South Africa
• 50-70 KTx/year
• Donor: living (30%) vs deceased (70%)
• All HIV-positive patients with stage 5 CKD who
underwent KTx from HIV-positive donors
• September 2008 – February 2014

32. Donor selection
Inclusion
• HIV-infected deceased
donors
• Not on ART or received
first-line treatment
• Undetectable plasma HIV
RNA viral load (<50
copies/mL)
Exclusion
• Severe sepsis
• Active tuberculosis
• WHO stage 4 HIV disease
(AIDS)
• Abnormal renal function
• Proteinuria on urine
dipstick
• Alb:Cr ratio ≥ 300 µg/g

33. Recipient
Inclusion
• HIV-infected
• Receiving ART for ≥ 3 Mo
• CD4 T-cell ≥ 200 /mm3
• Undetectable plasma HIV
RNA viral load
Exclusion
• History of opportunistic
infection (AIDS)

34. Immunosuppression
• Induction: rabbit antithymocyte globulin
• Thymoglobuline (1.5 mg/kg/d for 5-7 days) or
• ATG (2 mg/kg/d for 5 – 7 days)
• Maintenance: start on day 0
• Prednisone (30  5 mg/d over the first 3 Mo after KTx)
• MMF (1 g q 12 hr)
• Tacrolimus (0.2 mg/kg adjusted for trough level 6-8 ng/mL)

35. Antiretroviral therapy
• Initially, NNRTI-based ART were switched to a boosted
PI-based regimen at the time of KTx
• To increase the suppression of donor-virus replication
• To lower the costs of immunosuppressive Tx by the inhibitory
effect of ritonavir on calcineurin-inhibitor metabolism
• Due to concern regarding calcineurin-inhibitor toxicity,
recipients continued to receive their pre-KTx regimen
• Prophylaxis for opportunistic infection
• TMP 80 mg and SMX 400 mg daily for PCP
• Isoniazid 300 mg/d for TB
• Valganciclovir 900 mg/d for the first 3 Mo for CMV

36. Clinical protocol
• Follow-up: weekly for 1st
month and monthly thereafter
• Lab
• Monthly: Urea .Cr
• Every 6 Mo: CD4 T-cell count, plasma HIV RNA viral load
• Allograft biopsy
• Performed yearly
• When clinical suspicion of acute rejection
• Acute rejection: biopsy proven using Banff classification

37. Statistical analysis
• Kaplan Meier method was used to estimate patient
survival, graft survival and allograft rejection
• Data regarding graft survival were censored at the time
of patient’s death

38. Result - Donor
• 15 eligible donors
• Median age 30 (IQR 23-36) years
• Cause of death
• 13 trauma
• 1 overdose
• 1 subarachnoid hemorrhage
• ART therapy before death
• 1 NNRTI-based first-line therapy
• 14 no ART

39. Result - Recipient
• 27 recipients
• Survivors were followed
for a median of 2.4 yr

40. RESULTS – Patient and graft survival
• 2 had delayed graft function and required dialysis during
the 1st
week after KTx
• 1 graft failure due to venous thrombosis on day 1
• 1 acute severe Ab-mediated rejection , refractory to
plamapheresis, which necessitated graft removal after 2 weeks
• 25 well-functioning graft at the end of 1st
year
• Median Cr at 1 year 1.3 (1.2-1.3 mg/dL)

41. RESULTS – Patient survival
Time
(Yr)
HIV +ve HIV -ve
1 84 91
3 84 -
5 74 85

42. RESULTS – Patient survival
• 5 patients died after KTx
• 1 Sepsis (E.coli and pseudomonas) and acute pancreatitis
• 1 MI
• 1 recurrent klebsiella pneumoniae septicemia due to UTI
• 1 rapidly progressive, invasive pulmonary aspergillosis
• 1 pulmonary squamous cell carcinoma
1 month
6 months
1st year
1st year
5 years

43. RESULTS – Graft survival
Time
(Yr)
HIV +ve HIV -ve
1 93 88
3 84 -
5 84 75

44. RESULTS – Allograft rejection
• 8 episodes of biopsy-confirmed acute rejection
• 6 were successfully reversed using steroid, ATG, or
plasmapheresis
• 2 graft failure
• 1st
week: acute severe Ab-mediated rejection
• 2 years: chronic scarring and fibrosis
• Rejection rate; 8% at 1 year and 22% at 3 years

46. RESULTS – Pharmacologic interactions
• Type of ART regimen had a consierable effect of the
tacrolimus dosing
• The median tacrolimus dose was 0.5 mg q 7 – 10 days
in PI-based regimen vs 8.5 mg q 12 hours in NNRTI-
based regimen
• Side effect of tacrolimus were more pronounced in PI-
based regimen
• 5 renal biopsy of calcineurin-inhibitor toxicity

47. RESULTS – Progression of HIV disease
• CD4 T-cell count
• Median was 179 (IQR 141-310) in 1st
year and 386 (IQR 307-
484) at 3 years
• Viral load
• All had undetectable viral load (<50 copies/mL) during F/U
• Histologic finding
• 3 routine renal biopsy revealed typical change of early HIV-
associated nephropathy; none had clinically significant renal
impairment, proteinuria or required dialysis

48. Discussion
• Outcomes in HIV+ patient who received kidneys from
HIV+ donors were comparable with those who received
from HIV- donor
• Concerns
• The risk of transmission of a new and possibly
resistant strain of HIV from donor to recipient
• The appearance in the postoperative biopsy
specimens of early changes related to HIV-
associated nephropathy that were not present in the
baseline biopsy specimens
• Interaction between medications

49. Discussion
• The patients in this study did not have any increase in
plasma viral load, and viral levels remained
undetectable after transplantation.
• All the donors in this study had not received ART
previously or had received first-line treatment with no
known virologic evidence that would suggest resistance,
although genotyping was not performed.

50. • Protocol renal transplant
biopsies performed at 3
months from 19
recipients with HIV-1
• Undetectable levels of
plasma HIV-1 RNA at
transplantation
• HIV-1 infected the kidney
allograft in 68% of these
patients
• Podocyte infection
associated with a faster
decline in allograft
function compared with
tubular cell infection.
Canaud G et al. J Am Soc Nephrol 2014;25:407-19
in situ hybridization of HIV-1 RNA

51. Discussion
• The interaction between ART and immunosuppressants
• Ritonavir and TAC
• Decreases the metabolism of TAC, resulting in a decrease
of more than 80% in the clearance of TAC
• Required minimal doses of TAC every 7 to 10 days to
maintain adequate levels.
• A higher incidence of CNI nephrotoxicity
• The NNRTIs and TAC
• Induce the cytochrome P450 enzyme system
• Increases the metabolism of tacrolimus, necessitating
higher doses (median, 8.5 mg twice daily) to maintain
adequate levels.

52. Discussion
• Rejection rates among HIV-positive recipients have
been reported to be approximately 3 times as high as
those among HIV-negative recipients: unclear reasons
• Immune dysregulation
• Challenge of managing the drug interactions
Stock PG et al. N Engl J Med. 2010;363(21):2004-14.

53. Conclusions
• Kidney transplantation from an HIV-positive
donor appears to be an additional treatment
option for HIV-infected patients requiring renal-
replacement therapy.

54. Questions & Discussion

55. Apply to the United States?
• Lack of access to dialysis severely limits
options for HIV-infected individuals with ESRD
in South Africa, altering the risk–benefit
dynamic.
• South African donors have been untreated for
HIV; given the homogeneity of HIV infection in
South Africa, it is unlikely that there will be
resistance issues complicating management of
the recipients.

56. Apply to the United States?
• The population of HIV-infected individuals in
U.S.- higher rates of antiretroviral exposure and
resistance:
• making it less likely that a single empiric
choice of antiretrovirals will be sufficient to
treat both donor and recipient.

57. Ethics of HIV-Infected Donation
• Attitudes of HIV-Infected Patients on waiting list-
No data available
• Beneficence- strive to expand access to
transplant in novel ways because of the
discrepancy between the need for transplant
and organ shortage.
• Non-maleficence-requires a cautious process
forward because of limited outcomes data from
HIV-infected donors.
• Informed consent