Epidemiological and Immunological Characteristics of HIV-Infected Patients on the Cadaveric Kidney Donor Waiting List at the Johannesburg Renal Transplant Program

Abstract

HIV infection was previously considered an exclusion criterion for renal dialysis and transplant. Recent research has prompted policy changes, allowing for transplantation in this subgroup of patients. Theoretical risks with transplantation include the immune dysregulation associated with post-transplantation immunosuppression and immune activation with possible organ rejection. Assessments for eligibility to renal transplantation rely on a point system, which allocates points based on a patient's age, previous transplants, and time on the waiting list as well as panel reactive antibodies among other parameters. This study aimed at quantifying and defining the clinically relevant characteristics of HIV-infected patients on the cadaveric donor waiting list on the Johannesburg renal transplant program. Clinical records for patients on the transplant list from November 2016 to October 2017 were accessed from existing databases and clinical records. A total of 248 patients were analyzed during the study period. There were a total of 215 HIV-uninfected patients, and 33 HIV-infected patients were on the waiting list. The median age for patients at listing was 39 years (interquartile range 29–47). There were no significant differences in the median age of listing between the HIV-infected and HIV-uninfected groups (p = .7). Hypertension was the most common cause of renal failure in both study groups. The study did not show any significant differences in age or immunological characteristics between the HIV-infected and HIV-uninfected groups. This suggests that for immunological risk stratification purposes, these two groups of patients could be considered equivalent. A possible explanation for this could be that antiretroviral therapy has a significant role in mitigating the effect of the virus on the immune system. Further studies looking at a larger study population are required to corroborate these findings. These data do provide reassurance that HIV-infected patients are suitable candidates for transplantation.

Introduction

Since its first description more than three decades ago, HIV-related kidney disease is now recognized as a common condition in HIV-infected individuals.¹ Although HIV-associated nephropathy (HIVAN) was previously the most important cause of chronic kidney disease (CKD), increasing contributions are expceted from noncommunicable diseases such as diabetes and hypertension as antiretroviral therapy (ART) becomes widely available.² CKD is defined as a glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m² and albumin greater than 30 mg/g of creatinine for more than 3 months.³ End-stage renal disease (ESRD) is said to be present when the GFR is less than 15 mL/min.⁴

Renal transplantation has only recently become more widely available as a treatment for ESRD in HIV-infected patients. Recent studies demonstrate both its utility^5,6 and outcomes, which are comparable to those seen in HIV-uninfected individuals^7,8 (Table 1). Cadaveric donations, also know as nonliving donations, refer to organ donations that are obtained from clinically brain dead donors⁹ and are the most common types of donation for HIV-infected recipients.¹⁰

Table 1.

Outcomes in HIV⁺ Renal Transplantation Recipients

Author (location)	No. of patients (n)	Deceased donor (%)	Donor infections	Acute rejection (%)	Survival (1 year)
Stock⁷ (San Francisco, USA)	150	68	HBV 3%, HCV 19%	41	92%
Touzot¹¹ (Paris, France)	27	93	HBV 7%, HCV 7%, CMV 96%	15	100%
Mazuecos¹² (Cadiz, Spain)	20	100	HCV 40%	40	85%
Malat¹³ (Philadelphia, USA)	92	91	HIV 100%, HCV 45%	45
Gómez¹⁴ (Madrid, Spain)	7	71	HIV 100%, HCV 71.4%	40	Not stated
Muller^8,10,15,16 (Cape Town, South Africa)	27	26	HBV 3%	22	84
Alfano¹⁷ (Modeno, Italy)	19	Not reported	Not reported	32.9	Reduced

CMV, Cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus.

Previously in South Africa, HIV infection was considered an exclusion criterion for renal dialysis and renal transplantation.⁸ Recent research, both locally and internationally,^7,15,16,18 has prompted policy changes across centers in South Africa, allowing these patients to be included on waiting lists for cadaveric kidney allocation.⁸ Although these studies are encouraging, there are a number of theoretical concerns regarding transplantation into HIV-infected patients, including the possibility of a second viral transmission event (in the case of HIV-HIV transplantation) and immune dysregulation associated with post-transplantation immunosuppression.¹⁹ In addition, the number of HIV-infected patients with ESRD requiring transplantation is expected to increase as higher numbers meet the qualifying criteria for listing.^20,21 Cadaveric organs remain a scarce resource, with only 234 adult patients in the private and public sector receiving kidney transplant across South Africa in 2016 (https://www.odf.org.za). A number of interventions have been tried to ameliorate this shortage, including transplanting organs from HIV-infected donors into HIV-infected recipients. The first HIV-to-HIV renal transplants were performed in Cape Town in 2008 with a 100% 1-year survival.¹⁶ A follow-up study of 27 patients reported a 5-year survival rate of more than 74% in HIV-infected recipients of HIV-infected deceased donor organs.¹⁵

In the Johannesburg transplant program, cadaveric organ allocations are based on a point system, which scores various parameters, including recipient age, previous transplants, and time on the waiting list as well as a panel reactive antibody (PRA) score. Panel reactive antibodies, scored between 0% and 100%, estimate the percentage population with which preformed antibodies in the donor will react, possibly mediating an acute rejection episode.²² Acute transplant rejection (AR) is a serious immunological complication that carries a high mortality. The majority of antibodies mediating AR are directed against human leukocyte antigens (HLA antigens), although other minor histocompatibility antigens including (MHC Class 1-associated antigen) MIC-A may also be targeted. PRAs can be measured by various methods, including serological and through bead-based testing (Luminex™ technology).^23,24 Two service providers, the South African National Blood Services (SANBS) and the National Health Laboratory Service (NHLS), currently conduct testing for PRAs. Patients with high PRAs (referred to as “highly sensitized” patients) exhibit a higher-than-normal incidence of AR. Testing for donor-specific antibodies can also provide a basis for a virtual crossmatch where compatibility is estimated.²⁵ PRAs also can be used for immunological risk stratification²²

In HIV-infected kidney recipients, AR rates are reportedly higher than in noninfected individuals, although the exact cause for this occurrence is unknown.⁶ Possible mechanisms could include chronic inflammation, which results in a dysregulated immunological responses in HIV-infected patients.¹³ This could result in nonspecific polygammaglobulinaemia with higher PRA levels in HIV-infected individuals with consequent higher immunological risk.

We predict that the number of HIV-infected individuals qualifying for transplantation in our program will increase. To inform our organ allocation system, we decided to assess the HIV-infected patients for both epidemiological characteristics and immunological risk.

Materials and Methods

This study was a retrospective cohort study and was conducted at the teaching hospitals attached to the University of the Witwatersrand, Johannesburg, South Africa. Ethical approval for the study was obtained from the Ethics Committee at the University of the Witwatersrand, Johannesburg (M171016).

Clinical records for patients on the transplant list from November 2016 to October 2017 were accessed from various sources, which included the patients' prelisting forms, medical files and various electronic databases held at the NHLS, the transplant unit at Charlotte Maxeke Johannesburg academic hospital, and the transplant center at Wits Donald Gordon Medical Centre (WDGMC).

The patients' demographic and clinical information was recorded on a database created on the Redcap electronic data capture system. Patients were then divided according to their HIV status into an HIV-uninfected and an HIV-infected group for the analysis of their epidemiological and immunological risk characteristics. Patient blood results were obtained from the NHLS's Labtrak Viewer, as well as the SANBS.

All patients on the transplant list between November 2016 and October 2017 were included. Exclusion criteria included patients who were younger than 18 years and patients with no recorded HIV testing from the date of listing.

Data analysis was carried out by using Stata software (StataCorp. 2017) licensed to the University of the Witwatersrand, Johannesburg. Baseline descriptive statistics were calculated, including means with standard deviations and median values with interquartile ranges (IQRs) for nonparametric data. Comparison of continuous variables was conducted by using a student t-test for parametric variables and a Mann–Whitney U test for data, which were not normally distributed. Comparison of categorical variables was undertaken by using a two-tailed Chi-squared test. A p-value of less than .05 was considered statistically significant.

Results

A total of 248 patients were analyzed during the study period. A total of 215 patients had documented nonreactive HIV serology, and 33 patients were HIV-infected. There were no significant differences in the age at listing between the HIV-infected (M = 39, IQR 29–47) and HIV-uninfected groups (M = 39, IQR 33–46). The median age at the time of analysis for the HIV-infected and HIV-uninfected groups was 41 years (IQR 36–47) and 42 years (IQR 36–47), respectively. The epidemiological features of these patients are demonstrated in Table 2. The majority of the patients were referred from the two major academic centers in our region. The remaining 35% were from peri-urban secondary and tertiary level hospitals.

Table 2.

Characteristics of Patients on the Renal Waiting List

Variable	HIV-negative (n = 215)	HIV-positive (n = 33)	p
Gender, n (%)
Male	112 (52.1)	14 (42.4)	.3
Female	103 (47.9)	19 (57.6)
Ethnicity, n (%)
Black	184 (85.6)	32 (97.0)	.28
White	18 (8.4)	0 (0.0)
Indian	4 (1.9)	0 (0.0)
Coloured	9 (4.2)	1 (3.0)
Age at listing, median (IQR)
Years	39 (33–46)	39 (29–47)	.99
Age at analysis, median (IQR)
Years	42 (30–50)	41 (36–47)	.72
Blood group, n (%)
A	50 (23.3)	12 (36.3)	.23
B	56 (26.1)	5 (15.2)
AB	5 (2.3)	0 (0.0)
O	104 (48.4)	16 (48.5)
CD4 count, mean (SD)
Cells/ul	N/A	474 (±261)	N/A
Hepatitis B surface antigen, n (%)
Positive	2 (1)	0 (0)	N/A
Referring hospital, n (%)
Academic institution	140 (65)	18 (55)	.23
Tertiary and secondary level hospital	75 (35)	15 (45)
Previous renal transplant, n (%)
Yes	32 (15.0)	1 (3.0)	.07
Cause of renal failure
Diabetes mellitus	2	0
Lupus nephritis	8	5
ADPCKD	0	1
Sepsis	1	0
Antiphospholipid syndrome	1	0
HIVAN	0	6
Hypertension	69	10
Pre-eclampsia	1	0
Reflux nephropathy	123	0
Glomerulonephritis	5	0
IgA nephropathy	2	0
Unknown	123	13

ADPCKD, autosomal dominant polycystic kidney disease; HIVAN, HIV-associated nephropathy; IQR, interquartile range; N/A, not applicable; SD, standard deviation.

The cause of the CKD was not stated for the majority of the study population (57%). Where stated, hypertension was the most common underlying cause described for end-stage renal failure in both the HIV-infected and HIV-uninfected groups (32.1% and 30.3%, respectively) although in the majority of these cases, no formal biopsy had been conducted. The second most common diagnosis in HIV-infected patients was HIVAN (18.1%) (Table 2).

Immunological risk stratification in the Johannesburg transplant program utilizes PRA values. We compared the PRA values of all of the tested individuals to assess whether HIV-infected patients are at higher immunological risk. This study considered the PRA levels assessed at the South African National Blood Service and at the immunohaematology laboratory at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). PRA Class 1 and 2 values were compared for both HIV-infected and HIV-uninfected groups for samples tested at the NHLS and at SANBS. There were no significant differences in the PRA Class 1 values of HIV-infected when compared with HIV-uninfected patients in both the NHLS (median values 2% and 1% respectively, p = .5) and the SANBS testing (median values 45% and 40.5%, p = .3). Similarly, no significant differences could be demonstrated in the PRA Class 2 PRA values of both groups (median values calculated at the NHLS of 6% and 7%, p = .7 and 1% for both populations at SANBS, p = .4). Only one HIV-infected patient received a kidney transplant during the study period.

Discussion

This study aimed at establishing the characteristics of HIV-infected patients currently on the renal transplant waiting list in the Johannesburg transplantation program and at assessing the immunological risk of these patients for adverse outcomes in the peri-transplantation period.

The number of HIV-infected patients listed over the study period was lower than expected (13%), despite the overall high prevalence of HIV in the study population and the prevalence of ESRD in the HIV-infected South African population.²⁶ The reasons for this discrepancy may include the recent inclusion of HIV-infected individuals onto the program.

This study failed to show any significant differences in age or pretransplantation immunological risk characteristics between the HIV-infected and HIV-uninfected groups, including the median time spent on the transplant waiting list. The HIV-infected patients were more likely to be female and black, although this did not reach statistical significance. Contrary to expectations, antibody levels were not significantly different irrespective of whether these were assessed by luminex methodology or serologically. This suggests that, for immunological risk stratification purposes by PRA levels, HIV-infected and HIV-uninfected patients could be considered equivalent. All of the patients evaluated were on ART and were aviraemic. This may have mitigated the effect of the virus on the development of nonspecific antibodies. Recent studies suggest that the PRA values are influenced by the duration of viral suppression and are lower in patients who are aviraemic for 2 years.²⁷

The median age of the HIV-infected patients and HIV-uninfected patients on the waiting list was not significantly different either at the time of listing or at the time of analysis. Although this analysis was cross-sectional, this suggests that HIV-infected patients are not disadvantaged in waiting times.

The causes for renal failure in these patients were not generally noted at the time of transplantation (46%). The most common cause in both HIV-infected and HIV-uninfected patients was essential hypertension. Eighteen percent of the HIV-infected patients had biopsy-confirmed HIVAN.

This study had a number of limitations. This was a cross-sectional study focusing on the state patient population only. No HIV-infected patients were transplanted over the study period and data were collected retrospectively, so outcomes could not be recorded. The number of HIV-infected individuals in the program was small, which may have influenced the data spread and, in some cases, information regarding the underlying cause of renal failure was not completed. Longitudinal data for both CD4⁺ T cell count and viral load were not collected.

The study does, however, provide reassurance about the immunological risk characteristics of patients with HIV infection awaiting renal transplantation and highlights the potential of this therapy for definitive management of ESRD in HIV-infected individuals.

Footnotes

Acknowledgments

The authors are grateful to Sinesha Moodley and Dineo Chavani for providing access to patient records, Dr. Deidre Kruger for assistance with protocol optimization, and Dr. Maemu Gededzha and Mr. Nakampe Mampeule for laboratory assistance.

Author Contributions

B.S.N. designed and collected data, conducted statistical analysis, and wrote the article. E.S.M. designed and collected data, conducted statistical analysis, and provided critical review. A.S. collected data and provided critical review.

Author Disclosure Statement

No competing financial interests exist.

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