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CLINICAL SCIENCE: CONCISE COMMUNICATION

Renal tubular disease in the era of combination antiretroviral therapy

Hamzah, Lisaa; Booth, John W.b; Jose, Sophieb; McAdoo, Stephen P.c; Kumar, Emil A.c; O’Donnell, Patrickd; Hilton, Racheld; Sabin, Carolineb; Williams, Deborah I.e; Jones, Rachaelc; Post, Frank A.a for the HIV/CKD Study

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doi: 10.1097/QAD.0000000000000736
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Abstract

Introduction

HIV infection is an independent risk factor for chronic kidney disease (CKD) [1]. The spectrum of kidney disease in people living with HIV is broad and includes glomerular, tubulo-interstitial and vascular diseases [2–4]. Immunodeficiency is a major risk factor for acute kidney injury (AKI) and CKD in this population [3,5–7]. Antiretroviral therapy (ART) affords protection against CKD, although specific antiretrovirals including tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir (LPV) have been associated with CKD and/or kidney disease progression in observational cohort studies [8–10]. The pathological correlate of these associations remains poorly defined, but is thought to involve AKI, tubulo-interstitial disease and kidney stone formation [11].

Several studies have reported on the renal tubular pathology of HIV-positive patients [12–15]. These studies were variably limited by the small number of cases of renal tubular disease (RTD) [4,14,15], or their restriction to cases of interstitial nephritis [12,13] or TDF-induced RTD [14]. The objectives of the present analyses were to describe the spectrum of RTD in HIV-positive patients, the clinical characteristics at the time of biopsy and the associations with ART.

Methods

We reviewed 265 consecutive renal biopsy reports (2000–2012) of HIV-positive patients attending eight major treatment centres in the United Kingdom, focussing on patients whose native renal biopsies showed predominantly tubular pathology. Clinical information was obtained through case note review and from electronic patient records. The study was approved by the National Health Service Research Ethics Committee.

Three sub-types of RTD were recognized: acute tubular injury (ATI), tubulo-interstitial nephritis (TIN) and interstitial fibrosis and tubular atrophy (IFTA). ATI is characterized by manifestations of tubular cell injury, which may include swelling and detachment of cells from the tubular basement membrane, attenuation of the proximal tubular brush border and thinning of the tubular epithelium with luminal dilatation. ATI is frequently found in conjunction with other histological entities, but was defined in this study by its presence either in isolation or clearly disproportionate to any co-existent tubular or glomerular lesion [16]. TIN was defined by the presence of an appropriate tubulo-interstitial mononuclear cell infiltrate, with or without eosinophils or granuloma formation, and not restricted to zones of chronic tubulo-interstitial damage [17,18]. IFTA was defined by the predominance of interstitial fibrosis and tubular atrophy, with or without associated global glomerulosclerosis, and in the absence of a distinct causative glomerular or tubulo-interstitial lesion (including ATI and TIN) [19]. We excluded patients with tubulo-interstitial pathology (predominantly dilatation, microcyst formation, cellular infiltrates and post-inflammatory scarring) who had HIV-associated nephropathy (HIVAN) or non-collapsing (primary) focal and segmental glomerulosclerosis (FSGS); RTD in these patients was considered not to be a separate renal tubular pathology, but rather a manifestation of the same pathogenic process that resulted in the glomerular disease.

We compared the clinical characteristics, including current or recent (up to 3 months prior to the biopsy) exposure to TDF, ATV, IDV and LPV, of patients with ATI, TIN and IFTA, using Kruskal–Wallis equality-of-populations rank tests, analysis of variance (ANOVA) or Fisher's exact tests, depending on the distributions of the variables. We also analysed the incidence rates of ATI, TIN and IFTA by ART exposure in the United Kingdom Collaborative HIV Cohort (UK CHIC) cohort [20], to provide further comparative data. This analysis was restricted to the 40 patients who received care at one of the six clinics that also participated in the UK CHIC cohort and who received ART at the time of their renal diagnosis. The incidence of ATI, TIN and IFTA was calculated for TDF, ATV and LPV (numerator: number of RTD cases with current or recent exposure to each of these drugs, denominator: total number of person-years that UK CHIC participants at these clinics had been exposed to these drugs) and was compared to the incidence of RTD in ART-treated patients with no exposure to these drugs.

Results

The dominant glomerular diseases in this biopsy series were HIVAN/FSGS (n = 70), immune complex kidney disease (n = 92), diabetic nephropathy (n = 19), and amyloid (n = 11) and secondary FSGS (n = 11) [21]. RTD was present in 60 patients (including 14 cases with concomitant immune complex or diabetic glomerular disease). Of the 60 patients who were diagnosed with RTD, 54 (90%) had clinical information available and were included in the present analyses. The clinical characteristics of patients with ATI (n = 22), TIN (n = 20) and IFTA (n = 12) are shown in Table 1. ATI cases were less likely to be of black ethnicity (10 vs. 42–55%; P = 0.006) and more likely to be on cART (100 vs. 55–67%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54–58%; P < 0.001) at biopsy as compared with TIN or IFTA. In terms of exposure to potentially nephrotoxic ART, 19 (86%) patients with ATI had current/recent exposure to TDF as compared with 36–38% of patients with TIN and IFTA (P < 0.001). The majority of the TDF-associated ATI cases (79%) received TDF together with ritonavir-boosted protease inhibitors (PI/r). Other HIV and renal parameters, including time since HIV diagnosis, current and nadir CD4+ cell count, estimated glomerular filtration rate (eGFR) and the amount of proteinuria, showed considerable overlap.

T1-11
Table 1:
Clinical characteristics of patients with acute tubular injury, tubulo-interstitial nephritis and interstitial fibrosis and tubular atrophy at the time of kidney biopsy.

The renal manifestations of each of the three RTD patterns included proteinuria and eGFR reductions (Table 2). Renal abnormalities manifested acutely in some patients, whereas they were more insidious in onset and of longer duration in others. Proximal tubulopathy/Fanconi syndrome was exclusively observed in patients with ATI.

T2-11
Table 2:
Clinical outcomes.

Six patients with ATI (TDF: 4, TDF + ATV/r: 1) had contributing non-ART causes of renal injury (infection: 4, volume depletion: 1, malignancy/chemotherapy: 1). No cause for the ATI was identified in one patient whose HIV was managed with darunavir/ritonavir and lamivudine. In the remaining 15 patients, TDF (n = 15) and/or ATV/r (n = 4) were considered to be a causative factor of ATI, including one patient who had discontinued TDF 16 months prior to biopsy. Of the 20 TIN cases, 15 patients had non-ART causes identified (infection/antimicrobial chemotherapy: 11, sarcoidosis: 2, malignancy/chemotherapy: 1, co-trimoxazole: 1). In two patients, ART was considered the cause of TIN (ATV/r: 1, IDV: 1), and in 3 patients no cause was identified (no ART exposure: 2, abacavir/lamivudine + efavirenz: 1). The cause of IFTA remained unclear in the majority of patients. Two cases were diagnosed following infection and AKI, one case was associated with lithium exposure, and one case was associated with nephrolithiasis due to ATV/r.

The management of RTD consisted of cART modification (n = 29), immunosuppression (n = 13, predominantly to treat TIN), renal replacement therapy (n = 15) and other supportive measures. The eGFR returned to baseline in 50–77% of patients with RTD. Eight patients progressed to end-stage kidney disease and seven died during follow-up.

To further explore the relationship between ART exposure and RTD, we calculated the RTD incidence rates for TDF, ATV/r and LPV/r [ATI (n = 21), TIN (n = 10), IFTA (n = 9)] in the UK CHIC cohort. The incidence {rate/100 Person Years of Follow Up [95% confidence interval (CI)]} of ATI appeared somewhat higher among those ever (vs. never) exposed to TDF [0.12 (0.06–0.18) vs. 0.06 (0.00–0.13)], ATV/r [0.19 (0.07–0.32) vs. 0.08 (0.03–0.12)] and LPV/r [0.13 (0.07–0.30) vs. 0.08 (0.04–0.14)], although none of the differences was statistically significant. No increased incidence of TIN [TDF: 0.03 (0.00–0.06) vs. 0.10 (0.02–0.17), ATV/r: 0.04 (0.00–0.10) vs. 0.05 (0.02–0.09), LPV/r: 0.07 (0.02–0.18) vs. 0.04 (0.02–0.09)] or IFTA [TDF: 0.03 (0.00–0.07) vs. 0.06 (0.00–0.13), ATV/r: 0.06 (0.00–0.14) vs. 0.04 (0.01–0.07), LPV/r: 0.05 (0.01–0.16) vs. 0.04 (0.02–0.09)] was observed.

Discussion

Renal tubular disease in HIV-positive patients comprised a spectrum that includes ATI, TIN and IFTA with considerable clinical overlap. Consistent with cases in the literature [14,22–24], ATI was associated with exposure to TDF and accompanied by proximal tubulopathy in 23% of the patients. Despite the acute histological appearance, the majority of ATI cases presented with insidious abnormalities of renal function, and less than one-third presented clinically with AKI. The latter may explain why TDF exposure was not associated with AKI in a previous study [5]. In our patients and previous studies, ATI was predominantly observed in patients who received TDF with PI/r. Ritonavir co-administration increases systemic tenofovir exposure by approximately 30% [25] and appears to be a risk factor for the development of proximal tubulopathy [26–28]. Some studies have suggested greater eGFR decline or higher rates of kidney disease progression with ATV/r [10,29] and with LPV/r [9,10]. Our study was not powered to analyse whether the incidence of ATI was higher with TDF + ATV/r or LPV/r as compared with TDF + other PI/r.

Tubulo-interstitial nephritis has been reported with TDF [14,15,30–32], IDV [33,34] and ATV exposure [14,15,31,35–37], and in a single case exposed to high-dose ritonavir [38]. We did not observe an association between TIN and TDF, IDV or ATV. ATV exposure has been associated with crystalluria and kidney stone formation [39–41], and intra-renal crystal deposition may elicit an interstitial inflammatory response [35,37]. Several reported cases in which TDF was linked to TIN received (or had recent exposure to) ATV as part of their ART regimen [14,15,30,31]. While this does not preclude a causal role of TDF, our data suggest that TIN is an infrequent complication of TDF or ATV use; in only one of our patients was ATV considered the causative agent of TIN.

Interstitial fibrosis and tubular atrophy is a well described phenomenon in the kidney transplantation literature. Earlier renal biopsy series of HIV patients did not refer to the presence of IFTA [12] or described that interstitial fibrosis was unremarkable or mild [13]. Herlitz et al.[14] found IFTA to accompany ATI or TIN in 12 of 13 patients, ranging in extent from 5 to 50% (median 10%) of tubulo-interstitial tissue affected, and Schmid et al.[15] reported IFTA in two of three patients with TIN secondary to TDF/ATV. The cause of IFTA was unclear in most of our patients; the ART exposure pattern of patients with IFTA did not suggest an association with ART in general or with specific drugs. In agreement with the previous studies [42–44], reversibility of eGFR decline was observed in patients with ATI who discontinued TDF, whereas the outcomes of TIN and IFTA were less favourable.

We report the spectrum of renal tubular pathology in HIV-positive patients. Our study is limited by the relatively small number of cases of each of the RTD diseases, limited information on proximal tubular function, its retrospective design and the inherent selection bias associated with studying renal biopsy specimens. Although some 40% of the RTD was associated with exposure to TDF, ATV, IDV and LPV, the overall incidence of pathologically-confirmed RTD remains low. TDF, especially when co-administered with a PI/r, appears to be a risk factor for ATI, but not for TIN or IFTA.

Acknowledgements

Members of the HIV/CKD study group: John W. Booth, Stephen P. McAdoo, Sophie Jose, Emil A. Kumar, Tabitha Turner-Stokes, Partha Das, Claire M. Naftalin, Lisa Hamzah, Nadia Khatib, Birgit Engler, Catherine Horsfield, Patrick J. O’Donnell, Deborah I. Williams, Ed Kingdon, John Watson, Jyoti B. Baharani, Margaret Johnson, Bruce M. Hendry, Nick Larbalestier, Rachel Hilton, Jeremy B. Levy, Rachael Jones, Nicola Mackie, Ian Williams, Caroline A. Sabin, John O. Connolly and Frank A. Post.

Study design: L.H., J.W.B., F.A.P.; data collection: J.W.B., S.P.M., E.A.K., T.T.S., P.D., C.M.N., N.K., B.E., R.H., D.I.W., E.K., J.B.L., R.J.; histology review: J.W.B., C.H., P.O’.D.; data analysis: L.H., S.J.; first draft of the manuscript: F.A.P. All authors contributed to the data interpretation, final version of the manuscript and approved the submission.

The UK CHIC study is funded by the Medical Research Council UK (grant numbers G0000199, G0600337, G0900274 and M004236).

Conflicts of interest

Disclosures: L.H. is the recipient of a National Institute for Health Research (NIHR) Doctoral Research Fellowship Award.

J.W.B. has received conference funding from Shire Pharmaceuticals.

R.J. has received funding to attend conferences or educational meetings, honoraria and/or research grants from Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag GlaxoSmithKline/ViiV healthcare and Merck.

C.S. has received funding to attend conferences or educational meetings, honoraria and/or research grants from Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag, GlaxoSmithKline/ViiV Healthcare and Merck.

F.A.P. has received funding to attend conferences or educational meetings, honoraria and/or research grants from Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag, GlaxoSmithKline/ ViiV healthcare and Merck.

S.J., S.Mc.A., P.O’.D., E.A.K., D.W., R.H.: no conflicts.

The views expressed in this manuscript are those of the researchers and not necessarily those of the MRC.

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Keywords:

atazanavir; drug-induced kidney injury; HIV; interstitial; renal tubular disease; tenofovir

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