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End-Stage Kidney Disease and Kidney Transplantation in HIV-Positive Patients: An Observational Cohort Study

Gathogo, Esther MSc*; Jose, Sophie MSc; Jones, Rachael MRCP; Levy, Jeremy B. FRCP§; Mackie, Nicola E. FRCP§; Booth, John MRCP; Connolly, John FRCP; Johnson, Margaret FRCP; Leen, Clifford FRCP; Williams, Debbie MRCP#; Sabin, Caroline A. PhD; Post, Frank A. MD, PhD, FCP(SA)*,**

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2014 - Volume 67 - Issue 2 - p 177–180
doi: 10.1097/QAI.0000000000000291
Brief Report: Clinical Science
Free

Abstract: End-stage kidney disease (ESKD) is a major complication of HIV infection. We observed a 3.8-fold increase in ESKD prevalence among black patients in the UK CHIC cohort during the 12-year study period. As of 2005, 107 patients had an ESKD diagnosis, 69 of whom (64%) were considered suitable for kidney transplantation (KT) and 34 (32%) had received a KT. Survival was similar for KT recipients and those awaiting KT (85% and 89% at 5 years, respectively; P = 0.53). Our results endorse the use of KT to manage ESKD in HIV-positive patients.

*Department of Renal Sciences, King's College London, London, United Kingdom;

Research Department of Infection and Population Health, University College London, London, United Kingdom;

West London Centre for Sexual Health, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom;

§Imperial College Kidney and Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom;

UCL Centre for Nephrology, Royal Free Hospital NHS Foundation Trust, London, United Kingdom;

Department of Infectious Diseases, The Lothian University Hospitals NHS Trust, Edinburgh, United Kingdom;

#Department of Sexual Health and HIV, Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom; and

**Department of Sexual Health and HIV, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Correspondence to: Frank A. Post, MD, PhD, FCP(SA), Department of Renal Sciences, King's College London, Weston Education Centre (2.53), Cutcombe Road, London SE5 9RJ, United Kingdom (e-mail: frank.post@kcl.ac.uk).

The UK CHIC Study is funded by the Medical Research Council, United Kingdom (grant numbers G0000199, G0600337, and G0900274).

E.G. and S.J. contributed equally. Study design: E.G., S.J., C.A.S., and F.A.P.; provision of clinical care and data: R.J., J.B.L., N.E.M., J.B., J.C., M.J., C.L., D.W., and F.A.P.; data analysis: E.G. and S.J.; writing of the manuscript: E.G., S.J., C.A.S., and F.A.P. All authors provided input into and approved the final version of the manuscript.

R.J. has received honoraria, speaker fees, travel support, and/or research grant funding from Gilead, ViiV Healthcare, BMS, Abbvie, Janssen, and Merck. J.B.L. has received honoraria, speaker fees, and travel support from Gilead, ViiV Healthcare, Abbvie, and Merck. N.E.M. has received honoraria for acting as a consultant for Gilead, MSD, ViiV, and BMS, for speaker bureau services from Gilead and ViiV, for development of educational presentations from ViiV, and travel support from BMS and ViiV. J.B. has received travel support from Shire Pharmaceuticals. C.L. has received honoraria for acting as a consultant for Abbvie, Boehringer Ingelheim, BMS, Gilead, MSD, and ViiV, for speaker bureau services from Gilead and ViiV, research funding from Abbvie, Boehringer Ingelheim, Gilead and Janssen, and travel support from Abbvie, Boehringer Ingelheim, BMS, and Gilead. C.A.S. has received honoraria for advisory board and data safety and monitoring board membership and for the development of educational materials, speaker fees and travel support from Gilead Sciences, ViiV Healthcare, BMS, Abbott Pharmaceuticals, and Janssen-Cilag. F.A.P. has received honoraria, speaker fees, travel support, and/or research grant funding from Gilead, ViiV Healthcare, BMS, Abbvie, Janssen-Cilag, and Merck. The remaining authors have no conflicts of interest to disclose.

Presented at the Conference on Retroviruses and Opportunistic Infections, March 3–6, 2014, Boston, MA (Abstract #800).

Received March 11, 2014

Accepted July 15, 2014

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BACKGROUND

End-stage kidney disease (ESKD) is a major complication of HIV infection, which particularly affects patients of black ethnicity.1–3 The availability and use of combination antiretroviral therapy (cART) has dramatically improved the outcome of HIV-positive patients with ESKD,1 and suppression of HIV replication and immune restoration with cART has made it feasible to perform kidney transplantation (KT) in carefully selected patients with ESKD. Typically, these patients had CD4 cell counts >200 cells per cubic millimeter, undetectable HIV RNA levels, and were free of opportunistic disease, malignancy, and severe vascular or hepatic comorbidities.4,5 Although overall survival of KT patients has been favorable, it remains unclear whether KT affords a survival benefit over dialysis in those who are suitable for transplantation. The objectives of this study were to describe the use of and barriers to KT in HIV-positive patients with ESKD and to compare the survival of patients with ESKD managed with KT and dialysis.

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METHODS

We identified all patients with stage 5 chronic kidney disease (CKD) [estimated glomerular filtration rate (CKD-Epi6) <15 mL·min−1·1.73 m−2 for >3 months] in the United Kingdom Collaborative HIV Cohort (UK CHIC)7 and all HIV-positive patients who had received permanent renal replacement therapy (pRRT, defined as dialysis for >3 months or having received a kidney allograft for the management of ESKD) on local renal databases. The 2 sets of patients were reconciled: UK CHIC patients who had not initiated pRRT or who had exclusively received pRRT before January 01, 2000 or after December 31, 2011, and pRRT patients who did not receive their HIV care at UK CHIC clinics were excluded. The study received approval from the NHS Research Ethics Committee and relevant NHS Research and Development (R&D) Departments.

Suitability for KT was assessed retrospectively for patients who received pRRT from January 2005 onwards. Patients were considered suitable for KT (1) after 6 months of continuously suppressed HIV replication (HIV RNA <50 copies/mL) and (2) absence of medical comorbidities precluding KT. CD4 cell counts were not taken into consideration to determine suitability, as several patients had undergone KT with CD4 cell counts below the recommended threshold of 200 cells per cubic millimeter.

Survival of patients with ESKD was calculated using Kaplan–Meier methods and compared by log-rank test. For patients who were suitable for transplantation, survival was calculated from the date at which patients with ESKD became suitable for KT, which was defined by HIV suppression for at least 6 months, or in patients with sustained viral suppression at the time of pRRT initiation, the date dialysis was started or pre-emptive KT was performed. Follow-up time was divided into time spent on dialysis (pre-KT), and for those who underwent KT, follow-up from the date of the (first) KT (post-KT). The KT population typically contributed follow-up time to both the pre-KT and post-KT cohort. Follow-up was censored at December 31, 2012, or the date of the last clinic visit, whichever occurred earlier. For KT recipients, pre-KT follow-up was censored at the time of KT. Analyses assumed that once patients were eligible for KT, they remained eligible throughout the period of follow-up. Survival was also calculated for patients who were unsuitable for KT. Survival in this cohort was calculated from the date of initiation of pRRT. All analyses were performed in SAS (version 9.3; SAS Institute Inc., Cary, NC) and STATA (version 11.1; StataCorp, College Station, TX).

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RESULTS

Between January 2000 and December 2011, 28,630 patients received HIV care at the participating clinics. The median [interquartile range (IQR)] number of available creatinine measurements was 16 (5–30) and 18 (7–35) for those of black and white/other ethnicity, respectively (P < 0.0001). Median (IQR) follow-up was 6.4 (2.5–11.1) years, during which 1732 individuals (6.0%) died. During the study period, 117 UK CHIC participants received pRRT at the associated renal centers. Of these, 2 patients had not yet contributed data to the latest UK CHIC data set. The commonest renal diagnoses were HIV-associated nephropathy (HIVAN), present in 54 patients (46%), followed by immune complex kidney disease (n = 15), diabetic nephropathy (n = 13), and amyloidosis (n = 6).

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Prevalence and Incidence of ESKD

The clinical characteristics of 115 ESKD cases (0.4%) present in the UK CHIC study data set and the 28,515 patients without ESKD are shown in Table 1. Patients with ESKD were more likely to be female, of black ethnicity, and to have acquired HIV heterosexually. At cohort entry, ESKD cases were older, had lower CD4 cell counts, and markedly worse renal function [median estimated glomerular filtration rate (eGFR), 22 mL·min−1·1.73 m−2]. During the study period, a steady increase in ESKD prevalence was observed among patients of black ethnicity {from 0.44% [95% confidence interval (CI): 0.25 to 0.78] in 2000/2001 to 1.09% (95% CI: 0.85 to 1.41) in 2010/2011, P = 0.008}, whereas the ESKD prevalence among those of white/other ethnicity remained stable [0.09% (95% CI: 0.05 to 0.17) to 0.15% (95% CI: 0.10 to 0.22), P = 0.87]. After adjusting for age, the prevalence of ESKD seemed to increase over time in those of black ethnicity [0.36% (95% CI: 0.18% to 0.65%) 2000/2001 to 1.35% (95% CI: 1.01 to 1.77) 2010/2011] but not in those of other ethnicities [0.09% (95% CI: 0.04 to 0.18) to 0.11% (95% CI: 0.07 to 0.17)]. Reflecting the risk associated with black ethnicity, a 4–5 fold higher ESKD incidence rate [1.14 (95% CI: 0.81 to 1.47) vs. 0.24 (95% CI: 0.16 to 0.32) per 1000 person-years for black vs. white/other patients] was observed in this population. For both patient groups, the incidence of ESKD remained unchanged throughout the study period.

TABLE 1

TABLE 1

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Kidney Transplantation as a Treatment Modality for ESKD

From 2005 onwards, KT was increasingly used to treat ESKD. Before January 2005, 10 patients had died or became lost to follow-up. Of the 107 patients who received pRRT from 2005 onwards, 69 (64%) were considered suitable for KT, 30 (28%) were unsuitable for KT, and the status could not be confirmed for the remaining 8 patients. The reasons for not being suitable for KT were persistent HIV replication (n = 16), prior diagnosis of progressive multifocal leucoencephalopathy (n = 2), or the presence of medical comorbidities [liver, cardiovascular or urological disease, recent history of cancer, or general frailty (n = 10)]. Two patients declined to be considered for KT.

Of those suitable for KT, 34 (49%) had received a kidney allograft by December 2012 (10 from a live donor) after a median of 38.6 months (IQR, 17.1–54.7 months) since being deemed suitable for KT; the median follow-up after KT was 25.2 months (IQR, 12.8–56.9 months). The other 35 patients considered suitable for KT were being worked up for or awaiting KT; they had been followed up for a median of 35.8 months (IQR, 15.0–66.9 months) from the date of becoming suitable for KT. The clinical characteristics of patients awaiting KT (pre-KT) and those who received a KT (post-KT) are displayed in Table 1.

Figure 1 shows survival for the pre-KT and post-KT patients and for those who were unsuitable for KT. Survival pre-KT and post-KT was similar (Kaplan–Meier estimates of 100% and 94% at 1 year and 89% and 85% at 5 years, respectively, P = 0.53). As expected, survival for patients with comorbidities or persistent viremia who were thus ineligible for KT was significantly worse (83% at 1 year and 46% and 5 years, P < 0.0001).

FIGURE 1

FIGURE 1

We reviewed the cART regimens of the 69 patients with ESKD who were suitable for KT (pre-KT or post-KT); 38 (55%) were on a protease inhibitor (PI) and 31 on non-PI (nonnucleoside/nucleotide reverse transcriptase inhibitor, nucleoside/nucleotide reverse transcriptase inhibitor, and/or integrase strand transfer inhibitor) containing cART at the most recent clinic visit. Lamivudine and abacavir were the commonest prescribed nucleoside/nucleotide reverse transcriptase inhibitor (in 74% and 51%, respectively) and darunavir and lopinavir the commonest prescribed PI (in 33% and 18%, respectively). Tenofovir and atazanavir were included in the cART regimen of 11 (16%) and 4 (6%) patients, respectively.

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DISCUSSION

We described the epidemiology of ESKD in the UK CHIC cohort previously.1 Our current analyses demonstrate that the prevalence of ESKD has continued to increase among black patients and that the incidence of ESKD has not declined, despite guidelines recommending earlier HIV diagnosis and more widespread use of cART.8 Since 2005, KT was increasingly used to manage ESKD, with one third of patients having received a kidney allograft and a further one third of patients being prepared for or awaiting KT. Excellent survival rates were observed for patients with ESKD who were suitable for KT.

Although graft survival rates have much improved with currently available antiretroviral and immunosuppressive therapy, there is a considerably higher incidence of acute rejection (31%–48%4,5,9 at 1 year compared with 12%–24% general UK KT populations10,11) that may relate to HIV-associated immune activation and suboptimal exposure to calcineurin inhibitors and other immunosuppressants as a result of complex drug–drug interactions, especially with ritonavir-boosted PI.4,5,9 Although PI-sparing cART regimens may thus be preferable in the setting of KT, less than half of our pre-KT/post-KT patients were managed with such regimens, most commonly as a result of documented HIV resistance. Tenofovir and atazanavir, drugs with nephrotoxic potential that may be best avoided in the setting of KT, were used in relatively few patients.

Our study allowed us to compare the outcomes of HIV-positive patients with ESKD who were awaiting KT with those who had been transplanted. Interestingly, the survival rate on dialysis for patients who were suitable for KT was similar to the survival of the post-KT group. The excellent pre-KT survival rates reflect the relatively young patient population, the relatively short period of follow-up, and most importantly, the exclusion of patients with contraindications to transplantation in whom the survival was significantly curtailed. Viral nonsuppression, typically reflecting poor adherence to cART, was the dominant reason for being unsuitable for KT, although comorbidities that preclude KT may become more common as the HIV population ages.

The strengths of this study include the large HIV patient population, the 12-year study period, and the use of renal databases to enhance case ascertainment and provide information on renal diagnoses and management including KT. Nonetheless, there may have been residual ascertainment bias because of incomplete creatinine data for UK CHIC patients or incomplete recording of HIV-positive diagnoses on renal databases. We excluded patients who received dialysis for less than 3 months; those who died or were lost to follow-up within this period may have had ESKD, and their exclusion may have affected the ESKD incidence and prevalence estimates.

In conclusion, we observed a continued rise in the number of HIV-positive patients with ESKD throughout the 12-year study period. Approximately half of those eligible for KT received a kidney allograft, and our study lends support to the use of KT in HIV-positive patients. Similar 5-year survival rates for transplanted patients and those awaiting KT, however, suggests that KT may only confer long-term survival advantage and that the more imminent benefits of KT are likely to be in terms of quality of life measures, cardiovascular comorbidity, and health economics. This should be addressed in future studies.

The UK CHIC/ESKD study group: Sanjay Bhagani, John Booth, Lucy Campbell, David Chadwick, John Connolly, Esther Gathogo, Lisa Hamzah, Mark Harber, Bruce Hendry, Margaret Johnson, Rachael Jones, Sophie Jose, Ed Kingdon, Emil Kumar, Clifford Leen, Jeremy Levy, Nicola Mackie, Fabiola Martin, Steve McAdoo, Sheila Morris, Frank Post, Michael Rayment, Caroline Sabin, Debbie Williams, Ian Williams.

The UK CHIC Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Chadwick, Valerie Delpech, David Dunn, Martin Fisher, Brian Gazzard (Chair), Richard Gilson, Phillip Hay, Mark Gompels, Teresa Hill, Margaret Johnson, Sophie Jose, Stephen Kegg, Clifford Leen, Nicky Mackie, Mark Nelson, Chloe Orkin, Adrian Palfreeman, Andrew Phillips, Deenan Pillay, Frank Post, Caroline Sabin, Memory Sachikonye, Achim Schwenk, John Walsh.

Central Coordination: UCL Medical School, London (Teresa Hill, Sophie Jose, Andrew Phillips, Caroline Sabin, Alicia Thornton, Susie Huntington), Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Adam Glabay).

Participating Centers: Barts and The London NHS Trust, London (Chloe Orkin, Nigel Garrett, Janet Lynch, James Hand, Carl de Souza), Brighton and Sussex University Hospitals NHS Trust (Martin Fisher, Nicky Perry, Stuart Tilbury, Elaney Youssef, Duncan Churchill), Chelsea and Westminster Hospital NHS Foundation Trust, London (Brian Gazzard, Mark Nelson, Matthew Waxman, David Asboe, Sundhiya Mandalia), Public Health England, London (PHE) (Valerie Delpech), Homerton University Hospital NHS Trust, London (Jane Anderson, Sajid Munshi, Damilola Awosika), King's College Hospital NHS Foundation Trust, London (Frank Post, Hardik Korat, Chris Taylor, Zachary Gleisner, Fowzia Ibrahim, Lucy Campbell), Medical Research Council Clinical Trials Unit (MRC CTU), London (Abdel Babiker, David Dunn, Adam Glabay), Middlesbrough, South Tees Hospitals NHS Foundation Trust (David Chadwick, Kirsty Baillie, Emma Cope, Marie Gibney, Jane Gibson), Mortimer Market Centre, University College London (Richard Gilson, Nataliya Brima, Ian Williams), North Middlesex University Hospital NHS Trust, London (Jonathan Ainsworth, Achim Schwenk, Sheila Miller, Chris Wood), Royal Free Hampstead NHS Trust (Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Grabowska, Clinton Chaloner, Andrew Phillips), Imperial College Healthcare NHS Trust, London (John Walsh, Nicky Mackie, Alan Winston, Jonathan Weber, Farhan Ramzan, Mark Carder), The Lothian University Hospitals NHS Trust, Edinburgh (Clifford Leen, Alan Wilson, Sheila Morris), North Bristol NHS Trust (Mark Gompels, Sue Allan), Leicester, University Hospitals of Leicester NHS Trust (Adrian Palfreeman, Anne Moore, Lynn Fox, Josef Bojanowski, Adam Lewszuk), Woolwich, South London Healthcare NHS Trust (Stephen Kegg, Paul Main, Dr. Mitchell, Dr. Hunter), UK Community Advisory Board (Memory Sachikonye), St. George's Healthcare NHS Trust (Phillip Hay, Mandip Dhillon), York Teaching Hospital NHS Foundation Trust (Fabiola Martin, Sarah Douglas, Sarah Russell-Sharpe).

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Keywords:

HIV; kidney; dialysis; transplantation; end-stage kidney disease

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