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Keywords:

  • advanced chronic kidney disease;
  • end-stage renal disease;
  • estimated glomerular filtration rate;
  • HIV;
  • kidney

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

Objectives

Knowledge about advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV-positive persons is limited. The aim of this study was to investigate incidence, predictors and outcomes for advanced CKD/ESRD and renal death.

Methods

Advanced CKD was defined as confirmed (two consecutive measurements ≥ 3 months apart) estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 using Cockcroft−Gault, and ESRD as haemodialysis or peritoneal dialysis for ≥ 1 month or renal transplant. Renal death was death with renal disease as the underlying cause, using Coding Causes of Death in HIV (CoDe) methodology. Follow-up was from 1 January 2004 until last eGFR measurement, advanced CKD, ESRD or renal death, whichever occurred first. Poisson regression was used to identify predictors.

Results

Of 9044 individuals included in the study, 58 (0.64%) experienced advanced CKD/ESRD/renal death [incidence rate 1.32/1000 person-years of follow-up (PYFU); 95% confidence interval (CI) 0.98–1.66]; 52% of those who experienced the endpoint had a baseline eGFR ≤ 60 mL/min/1.73 m2 compared with 3% of those who did not. Using Kaplan−Meier methods, at 6 years from baseline, 0.83% (95% CI 0.59–1.07%) were estimated to have experienced the endpoint overall and 11.26% (95% CI 6.75–15.78%) among those with baseline eGFR ≤ 60 mL/min/1.73 m2. Independent predictors of the endpoint included any cardiovascular event [incidence rate ratio (IRR) 2.16; 95% CI 1.24–3.77], lower eGFR (IRR 0.64 per 5 mL/min/1.73 m2; 95% CI 0.59–0.70) and lower CD4 count (IRR 0.77 per doubling; 95% CI 0.62–0.95). One year after experiencing advanced CKD or ESRD, an estimated 19.21% (95% CI 7.84–30.58%) of patients had died, mostly from extra-renal causes.

Conclusions

The incidence of advanced CKD/ESRD/renal death was low and predictors included traditional renal risk factors, HIV-related factors and pre-existing renal impairment. The prognosis following advanced CKD/ESRD was poor. Larger studies should address possible contributions of specific antiretrovirals.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

While the introduction of combination antiretroviral therapy (cART) has reduced the incidence of HIV-associated nephropathy (HIVAN), the resulting improvements in survival may have contributed to an increasing incidence of advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) due to alternative causes [1]. Whereas several studies have identified risk factors for moderate CKD among HIV-positive persons [2, 3], knowledge about risk factors for advanced CKD/ESRD/renal death in the modern cART era is limited.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

The EuroSIDA study is a prospective, observational cohort study of 18 295 HIV-positive persons followed in 108 centres across Europe, Israel and Argentina (details have been presented elsewhere [4]). Baseline is defined as the date of the first creatinine measurement after 1 January 2004, the date on which prospective collection of creatinine data began. Persons with at least three creatinine measurements after baseline and with corresponding body weights measured within 12 months of the creatinine measurements were included in the present study. Creatinine clearance [in this paper referred to as estimated glomerular filtration rate (eGFR)] was calculated, as in previous EuroSIDA analyses, using the Cockcroft − Gault (CG) equation standardized for body surface area [2]. The CG equation was selected based on a similar performance compared with the Modification of Diet in Renal Disease (MDRD) equation among HIV-positive persons [5]. The MDRD and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation were used to test robustness in sensitivity analyses.

Individuals were followed to advanced CKD, ESRD, renal death or last eGFR measurement, whichever occurred first. Advanced CKD was defined as a confirmed (two consecutive measurements ≥ 3 months apart) eGFR ≤ 30 mL/min/1.73 m2. ESRD was defined as haemodialysis or peritoneal dialysis lasting ≥ 1 month, or a kidney transplant (further information at http://www.cphiv.dk). Renal deaths were deaths with renal impairment considered as the underlying cause using Coding Causes of Death in HIV (CoDe) methodology [6]. Persons with baseline eGFR ≤ 30 mL/min/1.73 m2 or ESRD at baseline were excluded.

Statistical methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

Kaplan−Meier estimation was used to determine the proportions progressing in different strata and survival following advanced CKD/ESRD. The advanced CKD/ESRD/renal death incidence was calculated per 1000 person-years of follow-up (PYFU) and Poisson regression was used to identify predictors. Investigated were demographic (including age, gender and ethnicity), HIV-related (mode of transmission, CD4 count and viral load), hepatitis C virus (HCV)/hepatitis B virus (HBV)-related (HCV antibody-positive/HBV surface antigen-positive) and renal risk factors [hypertension (blood pressure > 140/ > 90 mmHg or antihypertensive treatment), diabetes (reported on a case report form or indicated by use of anti-diabetic drugs [2]), smoking and cardiovascular (CV) events (myocardial infarction, stroke or invasive cardiovascular procedures, all reported on a case report form)] [7]. Factors significant for CKD in previous EuroSIDA analyses [2] or in univariate analyses (p < 0.2) were included in multivariate analyses and excluded variables were added in turn to the final multivariate model to determine if their inclusion improved the model fit. All variables were fixed at baseline to avoid adjusting for time-updated variables on the causal pathway.

All statistical analyses were performed using sas version 9.2 (Statistical Analysis Software, Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

Of 12 530 persons with follow-up after 1 January 2004, 9044 (72.2%) were included in the analysis. Excluded persons were more likely to be from Eastern Europe or Argentina compared with other regions, to be injecting drug users (IDUs), and to have a later enrolment date and higher CD4 counts and viral loads at enrolment. Females, non-Caucasians and older persons were less likely to be excluded. Included individuals were primarily Caucasian (87.6%), male (74.7%), and infected with HIV though homosexual contact (42.1%).

During a median follow-up period of 5.0 years [interquartile range (IQR) 3.3–6.9 years], 58 persons (0.64%) experienced advanced CKD/ESRD/renal death. Of these, 31 had advanced CKD, 24 had ESRD and three were renal deaths. The incidence of advanced CKD/ESRD/renal death was 1.32/1000 PYFU [95% confidence interval (CI) 0.98-1.66].

The median baseline eGFR in those with and without advanced CKD/ESRD/renal death was 59 (IQR 45–76) and 98 (IQR 84–113) mL/min/1.73 m2, respectively (p < 0.0001). Of those experiencing the endpoint, 51.7% had a baseline eGFR ≤ 60 mL/min/1.73 m2 compared with 3.2% of those not experiencing the endpoint.

At 6 years after baseline, 0.83% (95% CI 0.59–1.07%) were estimated to have experienced advanced CKD/ESRD/renal death; in those with baseline eGFR ≤ 60 mL/min/1.73 m2 this was 11.26% (95% CI 6.75–15.77%), with much lower proportions in the eGFR 61–90 and > 90 mL/min /1.73 m2 groups (p < 0.0001; log-rank test) (Fig. 1).

figure

Figure 1. Kaplan−Meier plot of progression to advanced chronic kidney disease (CKD)/end-stage renal disease (ESRD)/renal death stratified by baseline estimated glomerular filtration rate (eGFR). CI, confidence interval.

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In adjusted analysis (including prior AIDS, HCV infection, any CV risk, current CD4 count, nadir CD4 count, age and eGFR), persons with any CV risk (diabetes, hypertension or CV event) had, as expected, an increased incidence of advanced CKD/ESRD/renal death [adjusted incidence rate ratio (aIRR) 2.16; 95% CI 1.24–3.77] compared with those without such risks (Fig. 2). Further, those with a higher baseline eGFR had a lower incidence [aIRR 0.64 (95% CI 0.59–0.70) per 5 mL/min/1.73 m2], as did those with a higher baseline CD4 count [aIRR 0.77 (95% CI 0.62–0.98) per doubling]. Higher nadir CD4 count failed to predict risk after adjustment for other factors [aIRR 0.95 (95% CI 0.80–1.11) per doubling]. Older persons had a marginally nonsignificantly increased incidence [aIRR 1.22 (95% CI 0.93–1.59) per 10 years older]. There was inadequate power to investigate effects of exposure to any antiretrovirals (ARVs) or other nephrotoxic drugs, although no strong signals in univariate analyses were observed for cumulative (per year) ARV exposure (all p > 0.2) and models did not converge for multivariate analysis. Results were similar using the MDRD and CKD-EPI equation.

figure

Figure 2. Predictors of advanced chronic kidney disease (CKD)/end-stage renal disease (ESRD)/renal death. *Cardiovascular risk: diabetes, hypertension or prior cardiovascular event (myocardial infarction, stroke or invasive cardiovascular procedure). eGFR, estimated glomerular filtration rate; HCV, hepatitis C virus.

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Of 53 persons with follow-up after having developed advanced CKD/ESRD, 15 (28.3%) died during 100.2 PYFU [median follow-up of 1.7 (IQR 0.4–2.7) years]; the 1-year mortality was estimated to be 19.21% (95% CI 7.84–30.58%), and the overall mortality was 149.7/1000 PYFU (95% CI 83.8–246.9). In those with advanced CKD, mortality was 72.2/1000 PYFU (95% CI 19.7–184.7) and in those with ESRD it was 223.3/1000 PYFU (95% CI 122.6–439.5) (p = 0.036). Of the 15 deaths, three were from unknown causes, three from malignancies, two from renal failure, one from HCV-related liver failure, one from pancreatitis, one from CVD, two from other heart/vascular disease, one from respiratory disease and one from bacterial infection.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

This study documents a low advanced CKD/ESRD/renal death incidence of 1.32 (95% CI 0.98-1.66)/1000 PYFU among HIV-positive individuals of primarily Caucasian origin in the modern cART era.

Incidence and progression

US studies of HIV-positive individuals, predominantly from the pre-cART or early cART era, have reported ESRD incidence rates of up to 3–10 events/1000 PYFU [8-10]. In contrast, recent European HIV studies have reported much lower incidence rates (1.6 and 0.4/1000 PYFU among persons of African and Caucasian descent, respectively) and was similar to the range found in other studies [1, 8]. These differences between US and European studies are probably attributable to differences in both ethnicity and comorbidities and in the observational periods with different cART availabilities [11, 12]. Information on the incidence of advanced CKD in the HIV-positive and general populations is sparse [12].

Moderate CKD currently affects a few per cent of the HIV-positive European population [2, 3], and we estimated that, after 6 years, 11% of these patients would have progressed to advanced CKD/ESRD/renal death. This proportion was much higher (35%) in a US study of HIV-positive persons, but those included were almost exclusively of African descent [13], and possibly genetically predisposed for more rapid progression. In the general population, the estimated incidence of progressing from moderate CKD to ESRD was 2.4 and 6.1/1000 persons/year for European and US patients, respectively [12]. Conversion to projected prevalence after 6 years from the time of developing moderate CKD provides substantially lower percentages (1.4 and 3.7%, respectively) compared with our findings. The ESRD incidence estimates in the general population do, however, vary quite substantially [11, 14], making comparisons somewhat difficult. Even though evidence points to a higher occurrence in HIV-positive persons [10], a case−control analysis matched for all traditional risk factors is probably necessary to reliably answer the question of whether progressed stages of renal disease are more common among HIV-positive persons than in the general population.

Predictors

We found that the advanced CKD/ESRD/renal death incidence was increased among persons with prior CV events compared with persons without, and was similar to the range found in other studies in both HIV-positive and HIV-negative populations [9]. Lower CD4 count was a significant predictor in this study, as in another European study, whereas HIV viral load and prior AIDS events were not significant predictors in either studies [8]. These findings may be explained by either the inclusion of generally well treated patients as opposed to studies carried out in pre- and early cART-era or by our limited statistical power [15].

While numerous studies have identified African descent in general as a major ESRD risk [1, 8-10], the proportion of patients with non-Caucasian descent was too low in our study to assess such trends.

The associations between ESRD, IDU and HCV infection found in a recent study [1] were not confirmed in this analysis. We were, however, limited by using only HCV serology (as HCV RNA was only available for half of the population) and by the low proportion of patients with IDU and HCV infection. In the literature there is now increasing evidence of an association between HCV infection and ESRD [1, 9, 16, 17]

As age is incorporated in the eGFR equation itself, some of this effect is directly captured and may explain the observed borderline nonsignificant results in our study and a US study [18]. Further controlling for baseline eGFR and any CV risk diminished the age effect. In the US study, older age was identified as an ESRD risk factor for persons with normal eGFR, but a protective factor for persons with eGFR impairment, reflecting the competing risks of death among older persons with CKD [18].

Because of the low event rates there was inadequate statistical power to reliably address cumulative effects of individual ARVs, and doing so would lead to a high risk of type II errors. In an exploratory analysis, no significant or strong signals were observed.

Mortality

Renal disease as the underlying cause of death has not been investigated in depth among HIV-positive persons, probably because of both the low occurrence and difficulties associated with collecting quality information [19]. In this study, renal death contributed only three out of the 58 events. In comparison, the D:A:D study has estimated a rate of renal death of 0.16/1000 PYFU [19]. The 1-year mortality after contracting advanced CKD/ESRD in our study was 19.2%, which is lower than in US HIV studies (corresponding rates 50%) [20], but higher than in other European HIV studies [8, 15]. Persons with ESRD had a poorer outcome than persons with advanced CKD, which may explain the better survival compared with US studies focusing only on ESRD. It is unclear why survival was poorer in our study compared with other European studies.

From the current evidence, it is unclear if the prognosis in the mature cART era differs between HIV-positive and HIV-negative populations, and further studies are required [15].

Limitations

There are several limitations of this study. Firstly, competing risks at low eGFR levels may have resulted in the incidence of advanced CKD/ESRD/renal death being underestimated. Secondly, exclusion of a large percentage of the cohort because of limited eGFR data may have introduced selection bias and caused advanced CKD to be under-ascertained compared with ESRD. Further, the ESRD case definition of ≥ 1 month of dialysis may have caused interference of acute renal failure with chronic failure. Neither proteinuria nor other urinary markers were included, as this information has only recently started to be collected within EuroSIDA. Such markers will, with the use of new drugs affecting creatinine secretion (e.g. cobicistat), in the future probably play an important role in the assessment of renal function. Information on the assay used to analyse creatinine was not available, and this may have reduced the accuracy of the CKD-EPI in sensitivity analysis. Finally, our results may not be generalizable to primarily non-Caucasian patients or treatment-limited settings.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

The incidence of advanced CKD/ESRD/renal death was low in this population during a median follow-up of 5.0 years and associated with both traditional and HIV-related factors. Most patients experiencing advanced CKD/ESRD/renal death had pre-existing renal impairment, but some experienced a rapid progression from an initially normal renal function. The prognosis following advanced CKD/ESRD was poor, with almost one-fifth of patients having died 1 year after the diagnosis. Larger studies are required to confirm these findings and to address the potential contributions of specific ARVs.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information

Conflicts of interest

LR and JDL have no conflicts of interest to declare. AM has received consultancy fees/honoraria/speaker's fees from BMS, Pfizer, Merck, Boehringer Ingelhein Pharmaceuticals and Gilead Sciences. OK is currently or was previously a board member at Gilead Sciences and ViiV Healthcare, and has received payment for lectures and/or for development of educational presentations from Abbott, Gilead Sciences and Tibotec. OK has also received travel/accommodation/meeting expenses from Abbott, BMS, Gilead Sciences, Merck and ViiV Healthcare. CP has received payment for lectures from MSD, Abbott and Astyellas and travel expenses from MSD. PR is a board member at BMS, Gilead Sciences and Janssen Pharmaceuticals and was previously a board member at Grupo Ferrer, GSK, Merck & Co and ViiV Healthcare. CP has also received unrestricted independent scientific grants from Gilead Sciences, ViiV Healthcare, Merck & Co, Janssen Pharmaceuticals, BMS, Boehringer Ingelheim Pharmaceuticals and Abbott, consultancy fees/honoraria/speaker's fees and/or payment for development of educational presentations from GSK, BMS and Gilead Sciences, and travel/accommodation/meeting expenses from Janssen Pharmaceuticals and Gilead Sciences. SDW is a board member at BMS and a consultancy fee has been received by his institution from ViiV Healthcare. SDW has also received payment for lectures from Pfizer, and travel/accommodation/meeting expenses from Janssen Pharmaceuticals, GSK, Gilead Sciences, Abbott nv, BMS and ViiV Healthcare. JMG is a board member at BMS, Abbot, Gilead Sciences, MSD, Boehringer Ingelheim Pharmaceuticals, Janssen and Grupo Ferrer and has received grants from Abbot, Gilead Sciences, Boehringer Ingelheim Pharmaceuticals, BMS and Janssen Pharmaceuticals.

Funding

This work was, and the EuroSIDA study is, supported primarily by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), 5th Framework (QLK2-2000-00773), 6th Framework (LSHP-CT-2006-018632) and 7th Framework (FP7/2007–2013, EuroCoord n°260694) programmes. Current support for EuroSIDA also includes unrestricted grants from Gilead, Pfizer and Merck and Co. The participation of centres in Switzerland was supported by The Swiss National Science Foundation (grant number 108787).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Statistical methods
  6. Results
  7. Discussion
  8. Conclusions
  9. Acknowledgements
  10. References
  11. Supporting Information
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hiv12038-sup-0001-appendixs1.pdf27K

Appendix S1. The EuroSIDA Study Group.

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