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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 5  |  Page : 1106-1111
Renal transplantation in HIV-positive patients – No more a scare!


Department of Nephrology, M. S. Ramaiah Memorial Hospital, Bengaluru, Karnataka, India

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Date of Web Publication21-Sep-2017
 

   Abstract 


Human immunodeficiency virus (HIV) infection has posed as a major global health epidemic for almost three decades. With the advent of highly active antiretroviral therapy in 1996 and the application of prophylaxis and management of opportunistic infections, acquired immunodeficiency syndrome mortality has decreased markedly. The most aggressive HIV-related renal disease is end-stage renal disease due to HIV-associated nephropathy. Presence of HIV infection used to be viewed as a contraindication to renal transplantation for multiple reasons; concerns for exacerbation of an already immunocompromised state by administration of additional immunosuppressants; the use of a limited supply of donor organs with unknown long-term outcomes. Multiple studies have reported promising outcomes at three to five years after kidney transplantations in patients treated with highly active antiretroviral therapy, and HIV is no longer a contraindication for renal transplant. Hence, we present eight HIV-positive patients who received live-related renal transplantation at our center and their follow-up.

How to cite this article:
Mahesh E, John MM, Konana GC, Parampalli RM, Bande SR, Suryadevara S. Renal transplantation in HIV-positive patients – No more a scare!. Saudi J Kidney Dis Transpl 2017;28:1106-11

How to cite this URL:
Mahesh E, John MM, Konana GC, Parampalli RM, Bande SR, Suryadevara S. Renal transplantation in HIV-positive patients – No more a scare!. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Jan 26];28:1106-11. Available from: http://www.sjkdt.org/text.asp?2017/28/5/1106/215132



   Introduction Top


Since the early years of the acquired immunodeficiency syndrome epidemic, the medical and scientific community has recognized various renal diseases that develop in patients with human immunodeficiency virus (HIV).[1] Renal diseases, as a direct consequence of HIV infection, include HIV-associated nephropathy (HIVAN), immunocomplex diseases, and thrombotic microangiopathy. The emergence of highly active antiretroviral therapy (HAART) has decreased the incidence of HIV-related renal disease although the overall prevalence of renal disease continues to increase among this subset of patients.[2]

Probable explanations include inadequate HAART, drug toxicity, increased survival rates leading to an increase in the proportion of elderly patients, and chronic viral coinfections (i.e., viral hepatitis).[3] End-stage renal disease (ESRD) is common in the setting of HIV infection with a multifactorial etiopathogenesis.

The most aggressive HIV-related renal disease is HIVAN, which affects approximately 10% of patients with HIV.[4] Direct infection of HIV-1 of renal epithelial cells is associated with the onset of the disease. Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is also common, and affected patients are at risk of developing viral hepatitis-associated glomerulonephritis.

With the widespread use of HAART, overall survival and morbidity for HIV-positive patients on dialysis have improved although it is far less than patients who do not require any form of renal replacement therapy. This coupled with the challenges of antiretroviral therapy, dose adjustments in patients with reduced renal clearance and dialysis dependency has prompted consideration of renal transplantation for this group of patients.

The earlier concerns about the requirement of additional immunosuppression and its effect on HIV replication and risk of further opportunistic infections caused the European Best Practice Guidelines[5] to consider HIV as an absolute contraindication to renal transplantation. These fears have been allayed over the past decade as survival of patients on dialysis who have HIV, have improved owing to potent HAART (e.g., those with high CD4+ T-cell counts), and are now similar to that of patients who are not infected with HIV.[6]

Given the advances in the treatment of HIV over the past decades, investigating the safety and efficacy of renal transplantation in patients with HIV has become a research priority. Hence, we undertook the follow-up of eight HIV positive renal transplant recipients from our center.


   Subjects and Methods Top


We enrolled eight consecutive HIV-positive patients with ESRD, who underwent renal transplantation.

Inclusion criteria were in adherence to the Guidelines for Kidney Transplantation in patients with HIV disease[7] and included:

  1. CD4 count of >200 cells/microliter for at least six months
  2. Undetectable HIV viremia (<50 copies/mL) for at least six months
  3. Demonstrable adherence and a stable HAART regimen for six months
  4. Absence of AIDS defining illness following successful immune reconstitution after HAART
  5. Available antiretroviral treatment options in the future


Exclusion criteria[7] included:

  1. Documented history of progressive multi-focal leukoencephalopathy
  2. Extracutaneous Kaposi’s Sarcoma
  3. EBV and HHV8-related lymphoproliferative disorders – lymphomas and multicentric Castleman’s disease
  4. CD4 count <200 cells/μL
  5. Persistent HIV viremia despite HAART
  6. Continuing noncompliance with antiretro-viral therapy
  7. More than three class HIV resistance and lack of future HIV treatment options
  8. Previous or current infections that are at high risk of re-activating with immune suppression
  9. Advanced cardiopulmonary disease
  10. History of neoplasms except solid tumors adequately treated and disease-free survival documented for >5 years
  11. HTLV-1 positive patients
  12. Patients with significant human papilloma virus-associated cervical and anal disease including CIN/AIN III and carcinoma in situ.
  13. Hepatic cirrhosis (F4 fibrosis by Metavir if HBV/HCV coinfection)
  14. Evidence of active viral replication if co-infected with HBV/HCV
  15. Pregnancy.


At the time of enrollment, two patients were on abacavir and efavirenz, three patients were on abacavir, efavirenz, and lamivudine, and another three patients were on abacavir, raltegravir, and lopinavir/ritonovir, as a part of HAART.

Patients received Valganciclovir prophylaxis, for a period of three months posttransplant and trimethoprim-sulfamethoxazole for a period of 12 months.

Recipients were vaccinated with pneumo-coccal, influenza, hepatitis B, and varicella zoster before transplant.

Induction agent used was basiliximab and was the same for all eight patients.

All patients posttransplantation received triple immunosuppression which included steroids, tacrolimus, [calcineurin inhibitors (CNI’s)] and mycophenolate mofetil.

Enrolled patients were followed up every two weeks, for a maximum period of 24 months. Demographic data, CD4 counts, change in mean serum creatinine posttransplantation, and serum tacrolimus levels were among the variables that were serially recorded [Table 1].
Table 1: Recipient descriptive parameters.

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   Statistical Analysis Top


Median value calculation was done for demographic details of the patient, change in serum creatinine posttransplantation, and serum tacro-limus levels during the follow-up period. “P <0.05 was considered statistically significant.


   Results Top


Eight consecutive HIV-positive ESRD patients who underwent live-related kidney transplantation were enrolled. They were all of African descent. Median age of the patients was 48.5 years, and they had a median dialysis vintage of nine months. Duration of hospital stay encompassing the transplant surgery and post-transplant recovery was observed as a median of 12.5 days. The reason for ESRD among the recipients included two patients with diabetic kidney disease, three patients had HIVAN, and three had hypertension-chronic interstitial nephritis.

Four patients received live unrelated renal transplants and were at high immunological risk and received induction therapy before to transplant. The remaining four patients received live-related transplants (sibling donors) and were at low immunological risk [Table 2]. Triple immune suppression was started two days before transplant, in addition to HAART, and titrated as required, to attain adequate CNI levels, which was checked once every 72 h.
Table 2: Donor parameters.

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We noted a maximum follow-up period of 24 months and a minimum follow-up of seven months duration. Among posttransplant infections, four episodes of urinary tract infections (UTI) were noted among the transplant recipients during the follow-up period, one developed esophageal candidiasis, and two developed bronchopneumonia, of which one patient expired [Table 3]. The patient who expired had tacrolimus levels well within acceptable range and degree of immune suppression does not seem to contribute to his death. One recipient developed lower limb cellulitis. Among the recipients, seven patients had good primary graft function and one patient had delayed graft function [Table 4].
Table 3: Posttransplant complications.

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Table 4: Mean decline in serum creatinine level posttransplant.

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No rejection was seen in any of the recipients. Median change in CD4 counts pre-and post-transplantation were 353 mm3 versus 302 mm3, which did not reach statistical significance [Table 5].
Table 5: CD4 count levels.

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Two recipients demonstrated very high tacrolimus levels on day-2 posttransplantation (53.5 ng/mL and 36.2 ng/mL). Both were on protease inhibitors and were started on oral phenytoin for a period of five days till adequate tacrolimus levels were reached [Table 6]. Donors had a median age of 42 years, with a mean GFR of 107 mL/min and had a median hospital stay of 5.5 days.
Table 6: Mean values of serum tacrolimus level posttransplant.

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   Discussion Top


In a study conducted by Suarez et al,[7] baseline CD4+ cell count of <200 cells/mm3 had the highest probability of serious infections during first six months of transplant. In our study, all the eight patients had stable HIV disease on HAART regimen with undetectable HIV RNA and CD4 cell count of ≥200/mm3 before transplantation and satisfied the guidelines laid down by British HIV Association and endorsed by the British Transplantation Society Standards Committee.[8]

All our patients were of African origin. A 20fold increased susceptibility of HIV collapsing glomerulopathy, in this racial population is noted, as compared to the Europeans.[9] Reasons include, genetic polymorphisms in MHY9, a component of nonmuscle Myosin IIA and coding region polymorphisms in APOL1 (encoding apolipoprotein L1), which is a constituent of high-density lipoprotein. The reason for ESRD among the recipients included two patients with diabetic kidney disease, three patients had HIVAN, and three had hypertension-chronic interstitial nephritis.

A study by Locke et al[10] suggested that HIVpositive transplant recipients ideally should have less than or equal to three HLA mismatches. Similarly, in our study of four related donor transplants, none had HLA mismatch of >3.

In a study conducted by Kucirka et al,[11] patients with high immunological risk received induction with antithymocyte globulin, had a lower rate of acute rejection and graft loss, hence recommended the use of induction agent. Similarly, in our study, the four patients with high immunological risk (unrelated donor) received basiliximab induction, and they had a similar outcome as those who did not receive induction therapy.

All our patients received “triple-immunosuppression” with steroids, tacrolimus, and MMF which was started two days before transplant. The protease inhibitors are substrates of CYP (cytochrome CYP3A4) and also act as inhibitors of Pgp (a transmembrane glycoprotein) that functions as an energy-dependent efflux pump for a wide variety of structurally unrelated compounds. Calcineurin inhibitors are also metabolized by liver by CYP3A4 thus when used concurrently with PI the drug levels of calcineurin inhibitor may be increased. Frequently, the dose of CNI requires to be reduced to 85% when the patient is on protease inhibitors as these are very potent inhibitors of CYP3A4 which metabolizes the CNIs.[12] Two recipients demonstrated very high tacrolimus levels on day-2 post transplantation (53.5 ng/mL and 36.2 ng/mL) in spite of being on minimal doses. Both were on protease inhibitors and were started on oral phenytoin (CYP3A4 inducer) for a period of five days till adequate lower levels of tacro-limus were reached.

In view of the higher rejection rates observed in HIV transplant recipients, owing to their ability to mount an alloimmune response, as compared to their counterparts,[13] induction therapy with interleukin-2 receptor inhibitor, Basiliximab was used for all of our patients. The longest period of follow-up was 24 months and the shortest being seven months. Preliminary data of renal transplant in HIV positive recipients suggest that patient survival rates are similar to those of HIV-uninfected transplant recipients, with an increase in the prevalence of opportunistic infections.[6],[14] The largest series, till date is from the United States of 150 kidney transplants, reports patient and graft survival of 88% and 74% respectively, at three-year follow-up,[14] despite high rates of acute rejection, kidney transplantation has proven a successful renal replacement treatment modality for patients with HIV. Although patient and graft survival rates at three years are comparable with those observed in patients without HIV, the high number of early rejection episodes might have a negative effect on the long-term graft function of patients with HIV.[15] We did not encounter rejection in any of our patients although keeping in mind the small cohort.

Only one patient succumbed to broncho-pneumonia in the posttransplant period. Other infections such as UTI, cellulitis, pneumonia, and esophageal candidiasis encountered in the other seven patients were treated with specific antibiotic/antifungal therapy, satisfactorily. No rejection was seen in these patients.


   Acknowledgment Top


We thank Dr. Mohan Keshavmurthy, Dr. Seetha Belavadi, and Mr. Thomas of Lalitha health care foundation, Bangalore, for their support.

Conflict of interest: None declared.



 
   References Top

1.
Pardo V, Aldana M, Colton RM, et al. Glomerular lesions in the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101:429-34.  Back to cited text no. 1
[PUBMED]    
2.
Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol 2002;13:2997-3004.  Back to cited text no. 2
[PUBMED]    
3.
Fine DM, Perazella MA, Lucas GM, Atta MG. Renal disease in patients with HIV infection: Epidemiology, pathogenesis and management. Drugs 2008;68:963-80.  Back to cited text no. 3
[PUBMED]    
4.
Shahinian V, Rajaraman S, Borucki M, Grady J, Hollander WM, Ahuja TS. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis 2000; 35:884-8.  Back to cited text no. 4
[PUBMED]    
5.
EBPG (European Expert Group on Renal Transplantation). Evaluation, selection and preparation of the potential transplant recipient. Nephrol Dial Tranplant 2000;15 Suppl 7:3-38.  Back to cited text no. 5
    
6.
Abbott KC, Swanson SJ, Agodoa LY, Kimmel PL. Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression. J Am Soc Nephrol 2004; 15:1633-9.  Back to cited text no. 6
[PUBMED]    
7.
Suarez JF, Rosa R, Lorio MA, et al. Pre-transplant CD4 count influences immune reconstitution and risk of infectious complications in human immunodeficiency virus-infected kidney allograft recipients. Am J Transplant 2016;16:2463-72.  Back to cited text no. 7
[PUBMED]    
8.
Bhagani S, Sweny P, Brook G; British HIV Association. Guidelines for kidney transplantation in patients with HIV disease. HIV Med 2006;7:133-9.  Back to cited text no. 8
[PUBMED]    
9.
Centers for Disease Control and Prevention. HIV and AIDS in the United States, Factsheet. Available from: http://www.cdc.gov/hiv/ resources/factsheet/PDF/us.pdf. [Last accessed on 19/06/2010].  Back to cited text no. 9
    
10.
Locke JE, Shelton BA, Reed RD, et al. Identification of optimal donor-recipient combinations among human immunodeficiency virus (HIV)-positive kidney transplant recipients. Am J Transplant 2016;16:2377-83.  Back to cited text no. 10
[PUBMED]    
11.
Kucirka LM, Durand CM, Bae S, et al. Induction immunosuppression and clinical outcomes in kidney transplant recipients infected with human immunodeficiency virus. Am J Transplant 2016;16:2368-76.  Back to cited text no. 11
    
12.
Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl 2002;8:841-5.  Back to cited text no. 12
[PUBMED]    
13.
Kumar MS, Sierka DR, Damask AM, et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIVpositive patients. Kidney Int 2005;67:1622-9.  Back to cited text no. 13
[PUBMED]    
14.
Roland ME, Barin B, Carlson L, et al. HIV- infected liver and kidney transplant recipients: 1-and 3-year outcomes. Am J Transplant 2008;8:355-65.  Back to cited text no. 14
[PUBMED]    
15.
Roland ME, Stock PG. Review of solid-organ transplantation in HIV-infected patients. Transplantation 2003;75:425-9.  Back to cited text no. 15
[PUBMED]    

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Correspondence Address:
Eswarappa Mahesh
Department of Nephrology, M. S. Ramaiah Medical College, Bengaluru - 560 054, Karnataka
India
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PMID: 28937070

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
   Discussion
   Acknowledgment
    References
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