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AIDS:
doi: 10.1097/QAD.0b013e3283320e12
Epidemiology and social: CONCISE COMMUNICATION

Clinical epidemiology of HIV-associated end-stage renal failure in the UK

Bansi, Loveleena; Hughes, Ameliab; Bhagani, Sanjayc; Mackie, Nicola Ed; Leen, Clifforde; Levy, Jeremyb; Edwards, Simona; Connolly, Johnc; Holt, Steve Gf; Hendry, Bruce Mg,h; Sabin, Carolinea; Post, Frank Ag,h; on behalf of the UK CHIC/ESRF study group

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Author Information

aUniversity College London Medical School, UK

bChelsea and Westminster NHS Trust, UK

cRoyal Free NHS Trust, UK

dImperial College Healthcare NHS Trust, London, UK

eThe Lothian University Hospitals NHS Trust, Edinburgh, UK

fBrighton and Sussex University Hospitals NHS Trust, Brighton, UK

gKing's College Hospital, UK

hKing's College London, London, UK.

Received 28 June, 2009

Revised 10 August, 2009

Accepted 19 August, 2009

Correspondence to Dr Frank Post, Department of Renal Sciences, King's College London, Weston Education Centre (rm 3.51), Cutcombe Road, London SE5 9RJ, UK. Tel: +44 207 848 5779/5770; fax: +44 207 848 5769; e-mail: frank.post@kcl.ac.uk

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Abstract

Objective: To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom.

Design: Observational cohort study.

Setting: Seven leading HIV centres and affiliated renal clinics in the United Kingdom.

Participants: A total of 21 951 patients in whom renal function was measured.

Main outcome measure: Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT).

Results: Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998–1999 to 0.92% in 2006–2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year.

Conclusion: The prevalence of HIV/ESRF increased during the HAART era to reach nearly 1% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stem the rising trend of HIV/ESRF.

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Introduction

In the United States, an ‘epidemic’ of HIV-associated end-stage renal failure (HIV/ESRF) has long been recognized among young African–Americans [1]. In a recent study, the risk of HIV/end-stage renal failure (ESRF) was six-fold higher in black patients [2], which reflects the exceptional susceptibility of this population to HIV-associated nephropathy (HIVAN). HIVAN is associated with rapid progression to ESRF and accounts for some 40% of renal pathology in biopsy series of black HIV patients [3,4]. The advent of combination antiretroviral therapy (cART) has been associated with a marked reduction in the incidence of HIVAN and HIV/ESRF among black HIV patients [5,6]. Nonetheless, survival remains poor at a median of 16–20 months from pRRT initiation [7,8].

The epidemiology of HIV/ESRF outside the United States remains less well studied. Reports from France and Spain suggest that 0.54–0.59% of ESRF patients may be infected with HIV [9,10]. In the United Kingdom, HIVAN has been reported to affect approximately 1% of black HIV patients and no patients of nonblack ethnicity [11]. The significant increase in number of black patients diagnosed with HIV in the United Kingdom in the past decade [12] provides the context for a similar rise in HIV/ESRF burden in the United Kingdom as observed in the United States.

The aim of the present study was to define the incidence and prevalence of ESRF in the cART era in a large United Kingdom HIV cohort. In addition, we sought to describe the aetiology of HIV/ESRF, associated risk factors, survival from the time of pRRT initiation, and estimate the HIV prevalence among pRRT recipients in the United Kingdom.

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Methods

Data from the United Kingdom Collaborative HIV Cohort (CHIC) Study and local renal databases were used for this study. The United Kingdom CHIC is an observational cohort of HIV-infected individuals (aged over 16 years) attending some of the largest HIV-clinical centres in the United Kingdom from January 1996 onwards [13]; the dataset used for the current analyses includes information from seven centres (see Acknowledgement). The study protocol was approved by the NHS multicentre research ethics committee (MREC).

Analyses were restricted to patients with at least one serum creatinine value recorded after January 1st 1998; these values were converted to estimated glomerular filtration rates (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation [14]. Patients with stage 5 chronic kidney disease (eGFR < 15 ml/min for >3 months) were identified, reviewed, and included if they had commenced pRRT. Local renal databases were used to provide aetiology of ESRF and details of pRRT. Patient characteristics were described and trends over time from 1998–2007 in the prevalence/incidence of ESRF calculated. Kaplan–Meier methods were used to analyse survival from pRRT initiation up to December 2008. These analyses were stratified by ethnicity (black (black-African, black-Caribbean, and black-other) vs. other) and year of pRRT initiation (1998–2002 vs. 2003–2007). Risk factors associated with ESRF were identified using Cox regression. Finally, we used HIV prevalence data for 2007, standardized for ethnicity [12,15], and data from the Renal Registry [16] to place our findings in the United Kingdom context.

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Results

In 1998–2007, 26 569 patients received HIV care at the study centres, of whom 21 951 (82.6%) had serum creatinine values recorded. In total, 68 (0.31%) had ESRF. Patients with ESRF were more likely to be a woman (29.4 vs. 21.5%), of black ethnicity (64.7 vs. 24.8%), and have lower nadir CD4 cell count (median: 72 vs. 179 cells/μl) compared with those who did not experience ESRF. In patients with ESRF, the median (IQR) CD4 cell count and viral loads at the start of pRRT were 240 (106, 355) cells/μl and 483 (50, 38435) copies/ml respectively. The median (IQR) time from HIV diagnosis to pRRT initiation was 36.5 (0.8, 90.4) months, and pRRT was initiated prior to or within 4 weeks of HIV diagnosis in 19 (27.9%) patients. Thirty-one (45.6%) patients started highly active antiretroviral therapy (HAART) before starting pRRT and 54.4% of patients initiated pRRT after 2002. The most common renal diagnosis was HIVAN, which was present in 36 (52.9%) of all patients and 81.8% of black patients. No patients of nonblack ethnicity were diagnosed with HIVAN.

The overall prevalence of ESRF during the study period was 0.33%. Patients of black ethnicity had a higher overall prevalence of ESRF than patients of nonblack ethnicity (0.83 vs. 0.16%). The prevalence of ESRF increased over time from 0.07% in 1998–1999 to 0.31% in 2006–2007 and again this increase was markedly higher for those of black ethnicity (0.26 to 0.92%) (P for trend = 0.001) than those of nonblack ethnicity (0.03 to 0.11%) (P for trend = 0.07) (Fig. 1a). The incidence [95% confidence interval (CI)] of ESRF was 0.50 (0.38, 0.63)/1000 person-years and significantly higher amongst black patients (1.55 (1.07, 2.03)/1000 person-years) than nonblack patients (0.22 (0.13, 0.31)/1000 person-years).

Fig. 1
Fig. 1
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Five years after starting pRRT, 70.3% of patients were still alive (Kaplan–Meier estimate). There was no significant difference in survival at 5-years amongst patients who started pRRT between 1998 and 2002 (median time under follow-up: 71.4 months) and those who started between 2003 and 2007 (median time under follow-up: 33.7 months) (66.4 vs. 75.5%, P = 0.44). However, patients of black ethnicity had a significantly higher 5-year survival probability than those of nonblack ethnicity (85.2 vs. 43.4%, P = 0.001) (Fig. 1b).

In univariable analyses, patients of black ethnicity had a significantly higher risk of ESRF compared to those of nonblack ethnicity (HR: 5.50 (95% CI: 3.28, 9.21)). Patients with higher current CD4 cell counts (0.82 (0.75, 0.89) per 50 cells higher) and those of MSM exposure group (0.13 (0.07, 0.24) compared to heterosexuals) had a reduced risk of ESRF. After adjusting for potential confounders, black ethnicity was still found to be independently associated with a higher risk of ESRF (6.93 (3.56, 13.48)) and a higher current CD4 cell count was found to be independently associated with a reduced risk of ESRF (0.83 (0.76, 0.95) per 50 cells higher) (Table 1). No association was seen between positive HCV antibody status and ESRF (1.42 (0.50, 4.09)). Although current CD4 cell count was also found to be significantly associated with ESRF in analyses restricted to black patients (0.83 (0.74, 0.94)), no association was found between current viral load or current HAART status and ESRF in this population.

Table 1
Table 1
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Data from the Health Protection Agency [12,15] and Renal Registry [16] were used to estimate the number of HIV/ERSF patients and the prevalence of HIV among pRRT recipients in the United Kingdom. In 2007, 23 195 black patients and 33 361 of other ethnicity received HIV care in the United Kingdom, of whom 4183 (18%) and 8341 (25%), respectively, were included in our analyses. On the basis of the 34 black and 11 other patients with HIV/ESRF in our cohort who were in care on 31 December 2007, we anticipate a total of 231 HIV/ESRF cases and an HIV prevalence of 0.51% among the 45 484 patients who received pRRT in the United Kingdom in December 2007.

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Discussion

In this large HIV cohort, 0.3% of patients had ESRF, and ESRF was associated with black ethnicity and more advanced immunodeficiency. Although the prevalence and incidence of ESRF remained stable from 2000 onwards in nonblack patients, the prevalence of ESRF in black patients increased in each consecutive calendar period to reach nearly 1% in 2006/2007. Black patients diagnosed with ESRF had more advanced kidney disease at HIV diagnosis, experienced more rapid progression to ESRF, and had superior survival after pRRT initiation.

Our study is the first comprehensive cohort analysis of HIV/ESRF outside of the United States. The ESRF incidence rate in black patients in our study (1.55/1000 person years) compares favourably to recent the United States studies, which reported incidence rates of 7.3 and 9.4/1000 person years [2,6]. In addition, survival from RRT initiation in our black patients (97% at 2 years) was markedly better than reported for African–Americans with HIV/ESRF (30–43%) [7,8]. A notable difference between black patients with HIV/ESRF in the United Kingdom and the United States are the low rates of intravenous drug use (IVDU) and hepatitis C co-infection (<10% vs. 60–70%) [6–8]. The virtual absence of IVDU among black Africans in the United Kingdom may have translated in better adherence to cART, improved CD4 cell count recovery, and survival. We observed a low incidence (0.22/1000 person years) of HIV/ESRF among nonblack patients. Survival rates (70 vs. 97% at 2 years) for nonblack patients were relatively poor and contributed to stable prevalence rates throughout the study period. The renal aetiology in nonblack patients was diverse, and it remains unclear whether ESRF can be prevented or delayed by cART in these patients.

Advanced immunodeficiency, as reflected by low nadir CD4 cell count and prior AIDS, was associated with ESRF in our cohort. Prior AIDS was also identified as a risk factor in African–Americans [6]. In multivariate analysis, we found that a higher current CD4 cell count, but not suppression of HIV replication or current/prior cART exposure were associated with reduced risk [11]. Nonetheless, cART may delay the need for dialysis in patients with (early) HIVAN [3,11,17], and should be initiated in an attempt to preserve kidney function [14].

This study has a number of limitations. Patients required a minimum of 3 months follow-up to be included in the analyses. As acute renal failure (ARF) is particularly common in the first 3 months following HIV diagnosis and associated with significant mortality [18], patients with severe ARF who died or who were lost to follow-up within 3 months of their initial presentation and who may have had ESRF were excluded. This may have resulted in slightly lower HIV/ESRF incidence and prevalence rates, and somewhat improved survival estimates. In survival analyses stratified by calendar year of initiating pRRT, those who initiated RRT in later years had limited follow-up time and this may have had some impact on the results. However, given that only five patients initiated pRRT in 2007, we expect this impact to be minimal. Finally, the very low prevalence of ESRF in 1998/9 may reflect a degree of ascertainment bias, possibly as a result of suboptimal links between the United Kingdom CHIC database and electronic biochemistry records. However, extensive searches of local renal databases failed to identify additional HIV/ESRF cases.

In summary, we have shown a stable and low incidence of HIV/ESRF in nonblack patients. By contrast, the prevalence of ESRF among black HIV patients has quadrupled during the cART era. Late HIV diagnosis is a common feature in black patients who develop ESRF in the United Kingdom, and many present too late to benefit from interventions that may prevent progression to ESRF. Favourable survival is likely to result in further increases in the burden of HIV/ESRF and supports the consideration of renal transplantation as pRRT modality. In the United Kingdom setting, earlier HIV diagnosis in black people is likely to be an important strategy to stem the rising trend of HIV/ESRF.

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Acknowledgements

F.A.P. and C.S. designed the study. A.H., S.B., N.M., C.L., J.L., S.E., J.C., S.G.H. and F.A.P. provided data on patients in their HIV or renal cohorts. L.B. performed the analyses with input from F.A.P., B.M.H. and C.S. L.B. and F.A.P. wrote the manuscript with input from all authors. The final version of the manuscript was approved by all authors. The authors wish to acknowledge the contribution of all United Kingdom CHIC/ESRF study group and United Kingdom CHIC members see acknowledgement.

There are no conflicts of interests. Although many members of the group have, at some stage in the past, received funding from a variety of pharmaceutical companies for research, travel grants, speaking engagements or consultancy fees.

The United Kingdom CHIC/ESRF study group: Coordinating study team: Loveleen Bansi, Caroline Sabin, Frank A Post.

Participating Centres: Brighton and Sussex University Hospitals NHS Trust (Steve G Holt, Martin Fisher); Chelsea and Westminster NHS Trust (Amelia Hughes, Jeremy Levy, Rachael Jones); The Lothian University Hospitals NHS Trust (Clifford Leen, Sheila Morris); Imperial College Healthcare NHS Trust (Nicky Mackie); The Mortimer Market Centre (Simon Edwards, Ian Williams); King's College Hospital NHS Foundation Trust (Frank A Post, Lucy J Campbell, Fowzia Ibrahim, Lisa Hamzah, Paul Donohoe, Bruce Hendry); The Royal Free NHS Trust (Sanjay Bhagani, John Connolly, Margaret Johnson, Teresa Hill).

UK CHIC:Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Dunn, Philippa Easterbrook, Martin Fisher, Brian Gazzard (Chair), Richard Gilson, Mark Gompels, Teresa Hill, Margaret Johnson, Clifford Leen, Chloe Orkin, Andrew Phillips, Deenan Pillay, Kholoud Porter, Caroline Sabin, Tariq Sadiq, Achim Schwenk, John Walsh, Valerie Delpech.

Central Co-ordination: Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Adam Glabay, Kholoud Porter); Royal Free NHS Trust and RFUCMS, London (Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin).

Participating Centres: Barts and The London NHS Trust, London (Chloe Orkin, Kevin Jones, Claudio Fassio, James Hand, Carl de Souza); Brighton and Sussex University Hospitals NHS Trust (Martin Fisher, Nicky Perry, Stuart Tilbury, Duncan Churchill); Chelsea and Westminster Hospital NHS Trust, London (Brian Gazzard, Ben Hodgkinson, Sundhiya Mandalia); Health Protection Agency – Centre for Infections London (HPA) (Valerie Delpech); Homerton University Hospital NHS Trust, London (Jane Anderson, Meaghan Kall); King's College Hospital NHS Foundation Trust, London (Philippa Easterbrook, Frank Post, Hardik Korat, Lucy Campbell, Fowzia Ibrahim); Medical Research Council Clinical Trials Unit (MRC CTU), London (Abdel Babiker, David Dunn, Adam Glabay, Kholoud Porter); Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London (Richard Gilson, Emmanuel Mubwandarikwa, Annie Wilkinson, Ian Williams); North Middlesex University Hospital NHS Trust, London (Achim Schwenk); Royal Free NHS Trust and RFUCMS, London (Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Grabowska, Clinton Chaloner, Dewi Ismajani Puradiredja, Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin); St. Mary's Hospital, London (John Walsh, Jonathan Weber, Joceline Cook, Mark Carder); The Lothian University Hospitals NHS Trust, Edinburgh (Clifford Leen, Alan Wilson); North Bristol NHS Trust (Mark Gompels, Debbie Dooley).

Part of this paper was presented at the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, held in Cape Town, South Africa from 19–22 July 2009 (abstract A-155-0098-01488)

Sources of Funding: This work was funded by the Medical Research Council, the United Kingdom (Grants G00001999 and G0600337 to C.S.) and GlaxoSmithKline (Grant COL109793 to FAP). The views expressed in this manuscript are those of the researchers and not necessarily those of the M.R.C.

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Keywords:

dialysis; highly active antiretroviral therapy; HIV; kidney; renal failure

© 2009 Lippincott Williams & Wilkins, Inc.

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