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With prolonged survival and aging of the HIV-infected population in the era of antiretroviral therapy, biopsy series have found a broad spectrum of HIV-related and co-morbid kidney disease in these patients. Our study describes the variety of renal pathology found in a prospective cohort of antiretroviral-experienced patients (the Manhattan HIV Brain Bank) who had consented to postmortem organ donation. Nearly one-third of 89 kidney tissue donors had chronic kidney disease, and evidence of some renal pathology was found in 75. The most common diagnoses were arterionephrosclerosis, HIV-associated nephropathy and glomerulonephritis. Other diagnoses included pyelonephritis, interstitial nephritis, diabetic nephropathy, fungal infection and amyloidosis. Excluding 2 instances of acute tubular necrosis, slightly over one-third of the cases would have been predicted using current diagnostic criteria for chronic kidney disease. Based on semi-quantitative analysis of stored specimens, pre-mortem microalbuminuria testing could have identified an additional 12 cases. Future studies are needed to evaluate the cost-effectiveness of more sensitive methods for defining chronic kidney disease, in order to identify HIV-infected patients with early kidney disease who may benefit from antiretroviral therapy and other interventions known to delay disease progression and prevent complications.
Kidney disease was first described as a complication of the acquired immunodeficiency syndrome (AIDS) in 1984, when physicians in New York City described a unique form of collapsing focal segmental glomerulosclerosis (FSGS) in African-Americans and Haitian immigrants with AIDS.1 This kidney disease, now known as HIV-associated nephropathy (HIVAN), occurred almost exclusively in blacks with advanced AIDS and quickly became a leading cause of end-stage renal disease (ESRD) among African-Americans.2 Although the incidence of new ESRD cases attributed to HIVAN reached a plateau following the introduction of combination antiretroviral therapy, the prevalence of HIV-related ESRD continues to increase,2 at least in the United States.3
With prolonged survival and aging of the HIV-infected population in the United States and Western Europe, the spectrum of kidney disease in patients with HIV also reflects the growing burden of comorbid diabetes and hypertension.4,5 Kidney biopsy series have demonstrated an increasing number of HIV-related and comorbid diagnoses in antiretroviral-treated patients,4,6 although patients who have undergone clinically indicated kidney biopsy may not be representative of all patients with HIV and kidney disease. A recent biopsy study demonstrated early HIVAN in six South African patients with microalbuminuria, who would not have undergone kidney biopsy as part of standard clinical care.7 In an earlier autopsy series, FSGS was identified in 3 of 40 Brazilian patients without overt glomerular disease.8 Recognition of early, subclinical kidney disease may allow the initiation of antiretroviral therapy and other interventions to prevent or delay progression to ESRD.9
Autopsy series provide a unique window into the spectrum of renal pathology in HIV-infected patients who are unselected for the presence of overt kidney disease. The majority of published autopsy series included patients who died before the introduction of combination antiretroviral therapy,10–19 or in resource-limited settings.20,21 Several previous studies have focused on the specific diagnosis of HIVAN,12,18 whereas others have described the involvement of multiple organ systems and have provided only superficial descriptions of renal pathology.10,22 With few exceptions,17 autopsy series have also been limited by incomplete or absent data on premortem kidney function. The Manhattan HIV Brain Bank (MHBB) was established in 1998 to investigate AIDS-related neuropathology and comorbid conditions in the era of antiretroviral therapy.23 MHBB subjects are selected for the presence of advanced HIV disease, and consent to postmortem organ donation and to the prospective collection of clinical and laboratory data. This study describes the prevalence of kidney pathology in a well-characterized cohort of antiretroviral-experienced AIDS patients, using clinical data and autopsy specimens from the MHBB.
At the time of this analysis, the MHBB cohort included 244 active or deceased subjects, including 89 who had donated kidney tissue at the time of rapid autopsy (Table 1). More than one-third of MHBB participants were at least 50 years of age, and nearly three-quarters were men. Consistent with the epidemiology of the local HIV epidemic, half of the MHBB subjects were African-American and nearly one-third were Hispanic. Kidney tissue donors were similar to the overall MHBB cohort with respect to demographic characteristics. Clinical characteristics were reflective of the MHBB inclusion criteria, which were designed to identify patients with advanced HIV disease. Compared to the overall MHBB cohort, deceased kidney tissue donors had more advanced HIV disease. At the most recent study visit, nearly 75% of the kidney tissue donors had a CD4 cell count <200 cells per mm3, and HIV RNA was suppressed below 400 copies per ml in only 30%. Nearly half of the kidney tissue donors were coinfected with hepatitis C, and 13% with hepatitis B. Although all MHBB subjects were antiretroviral treatment-experienced, only 57% of kidney tissue donors were receiving combination antiretroviral therapy at the study visit most proximate to death. History of exposure to indinavir was similar in kidney tissue donors and nondonors (43 versus 45%, P = 0.8). Previous or current use of tenofovir was less common among kidney tissue donors (22 versus 49%, P<0.0001), 45% of whom expired before its approval in late 2001.
At least one serum creatinine value was available for 87 of the 89 kidney tissue donors, including 34 (39%) with an estimated glomerular filtration rate (GFR) <60 ml/min per 1.73 m2. A total of 21 kidney tissue donors with a GFR <60 ml/min per 1.73 m2 had one or more confirmatory results separated by at least 3 months, establishing the diagnosis of chronic kidney disease (CKD) according to National Kidney Foundation (NKF) and Infectious Disease Society of America guidelines.9,24 One subject without confirmatory GFR estimates had a documented diagnosis of advanced CKD, bringing the total number of kidney tissue donors with stage 3 or higher CKD to 22 (24.7%). GFR estimates were obtained a median of 75 days before death in deceased subjects, most often during a routine study visit. In all subjects whose final serum creatinine result was obtained within 3 months of death, the diagnosis was confirmed using earlier results.
At least one urinalysis result was available for 79 kidney tissue donors. After excluding specimens with evidence of urinary tract infection, 16 kidney tissue donors had at least one urinary protein of 100 mg/100 ml or greater. A total of 10 of these subjects had one or more confirmatory results separated by at least 3 months, indicating chronic kidney damage.9,24 Four of these subjects also met GFR criteria for the diagnosis of stage 3 or greater CKD, whereas six kidney tissue donors with normal or mildly reduced GFR met criteria for stages 1 and 2 CKD according to NKF and Infectious Disease Society of America guidelines.9,24
Overall, 27 of 85 (31.8%) MHBB kidney tissue donors with available data met current diagnostic criteria for CKD based on the presence of proteinuria and/or an eGFR <60 ml/min/1.73 m2 for at least 3 months.9,24 The prevalence of CKD among deceased kidney tissue donors was slightly higher than that observed among active participants and deceased participants without available kidney tissue (32 versus 20%, P = 0.05). In the overall cohort, clinical evidence of CKD was associated with older age, black race (OR 1.92, 95% CI 1.04–3.54), and female gender (OR 2.34, 95% CI 1.26–4.36). In this cohort of antiretroviral-experienced patients with advanced HIV/AIDS, disease-specific characteristics such as CD4 cell count, HIV RNA, and hepatitis coinfection were not associated with clinically evident CKD.
The spectrum of renal pathology is illustrated in Figures 1–3. Among the 89 subjects with kidney tissue available for blinded review, 75 subjects (84%) had some evidence of renal pathology. There were five subjects with mild isolated arteriosclerosis and no other renal pathology, and only nine subjects with no pathologic diagnosis (Table 2). Among the 75 participants with renal pathology, nonspecific and focal changes including cortical scars, glomerulosclerosis, or interstitial fibrosis were observed in 15. There were no significant differences in demographics or HIV disease characteristics between kidney tissue donors with and without renal pathology. Clinically evident CKD was only observed in the setting of renal pathology, with no cases of CKD among participants with isolated arteriosclerosis or with no pathologic diagnosis.
Arterionephrosclerosis was one of the most common specific diagnoses, observed in 15 subjects. The diagnosis of arterionephrosclerosis was only associated with a history of hypertension in four participants (Table 3). Among the participants without documented hypertension, two subjects with arterionephrosclerosis were over the age of 50 years, and two were engaged in active cocaine use as documented by urine toxicology.
Findings consistent with HIVAN were observed in 12 African-Americans and 3 nonblack participants of Hispanic ethnicity, all with advanced HIV disease (Figure 1). Among the 15 subjects with HIVAN, 3 displayed collapsing glomerulopathy and microcysts, 2 had collapsing glomerulopathy without microcysts, and 8 had FSGS with microcysts but lacking collapsing features. Two end-stage kidneys with segmental glomerulosclerosis and focal tubular microcysts were considered to represent advanced HIVAN. Only 4 of the subjects with HIVAN were on antiretroviral therapy at the time of death, and none had a suppressed plasma HIV viral load. The CD4 cell count was below 200 cells per mm3 in 13 of the 15 subjects with HIVAN, and below 50 cells per mm3 in 7 subjects. Five of the subjects with HIVAN had already reached ESRD at the time of death, and 5 others had GFR <60 ml/min per 1.73 m2. Among the subjects with HIVAN who had not reached ESRD, urinary protein of greater than 300 mg/100 ml was documented on at least one urinalysis in 7 of 9 subjects with available data. Four participants with mild HIVAN had no premortem evidence of CKD.
Another common diagnosis was membranoproliferative pattern of glomerulonephritis (MPGN), which was observed in 7 cases, including 3 associated with hepatitis C coinfection (Figure 2). In one patient without hepatitis C coinfection, the MPGN pattern may represent a chronic glomerular thrombotic microangiopathy. A second patient with membranoproliferative features had many glomerular and arteriolar fibrin thrombi consistent with acute and subacute thrombotic microangiopathy (Figure 2b). There was also a single case of diffuse endocapillary proliferative and exudative glomerulonephritis, suggestive of acute post-infectious glomerulonephritis.
Other diagnoses included diabetic nephropathy (Figure 3a), chronic pyelonephritis, and interstitial nephritis (Figure 3b and c). One case of chronic interstitial nephritis had numerous intratubular crystals consistent with indinavir nephrotoxicity (Figure 3c). There were 3 cases of parenchymal mycoses, all occurring in patients with disseminated fungal infection (Figure 3d and e), and a single case of advanced renal amyloid was observed in a patient with systemic amyloidosis (Figure 3f). Two subjects with isolated premortem acute tubular necrosis died from overwhelming infection, and one met criteria for CKD based on preexisting hepatorenal syndrome in the setting of hepatitis B and C coinfection. In addition to the two end-stage kidneys with segmental glomerulosclerosis and focal tubular microcysts suggestive of advanced HIVAN, there was a third case of end-stage kidney of uncertain etiology.
The presence of renal pathology was poorly correlated with premortem evidence of overt CKD. Excluding the two cases of pre-terminal acute tubular necrosis, only 27 of the 73 cases (37%) with renal pathology would have been predicted based on current diagnostic criteria for CKD (Table 2). In six cases with renal pathology and no clinical evidence of CKD, there were no urinalysis (n = 5) or serum creatinine (n = 1) results available within the year before death. The most common sub-clinical diagnoses were isolated arterionephrosclerosis or non-specific pathologic findings. In 5 cases of chronic pyelonephritis and all 3 cases of parenchymal fungal infection, there was no clinical evidence of CKD, with no proteinuria or pyuria identified in 6 subjects with available urine microscopy results. Among the 5 cases of interstitial nephritis, one subject had overt CKD, one subject had pyuria, and three subjects had no clinical evidence of overt renal involvement, including one subject with no available urinalysis results.
Although sub-clinical glomerular disease was less common, there were 4 cases of mild HIVAN, 4 cases of glomerulonephritis, and 1 case of diabetic nephropathy that would not have been predicted using the NKF definition of CKD. On further review of these cases, two participants with HIVAN and one with MPGN had 300 mg/100 ml of protein on the urinalysis most proximate to death, but failed to meet criteria for CKD because there were no prior confirmatory results. A third participant with mild HIVAN and another participant with MPGN had only 30 mg/100 ml of protein on prior urinalyses, and the fourth subject with HIVAN had no urinalysis results available within the year before death. One subject with probable post-infectious glomerulonephritis had hematuria and pyuria, but no proteinuria, and the subject with silent diabetic nephropathy had a single urinalysis with 100 mg/100 ml of protein more than 3 years earlier, with all subsequent measurements below 30 mg/100 ml.
Stored urine specimens were available for semiquantitative microalbuminuria testing in 30 additional participants with renal pathology who did not meet clinical criteria for CKD, including 5 subjects with sub-clinical glomerular disease. Microalbuminuria testing was positive in the stored urine specimen most proximate to death from 12 participants who would not have been identified using standard diagnostic criteria for CKD. Serial urine specimens were available for 7 of the 12 subjects, five of whom had persistent microalbuminuria. Among participants with subclinical glomerular disease, microalbuminuria testing was positive in the specimen most proximate to death in 2 of the 5 subjects with stored specimens, including one participant with diabetic nephropathy and one with HIVAN. As mentioned previously, three other subjects with HIVAN had at least one prior urinalysis demonstrating proteinuria, but did not meet the NKF definition for CKD. Microalbuminuria testing was negative in stored specimens from three subjects with glomerulonephritis.
In this well-characterized prospective cohort of antiretroviral treatment-experienced patients with advanced HIV/AIDS, we observed a high prevalence of both clinically evident CKD and subclinical renal pathology. Among 89 kidney tissue donors, postmortem histopathologic examination identified 46 cases of subclinical renal pathology that would not have been predicted using current diagnostic criteria for CKD. The prevalence of clinical CKD was increased among African-Americans and women, consistent with previous studies demonstrating an association between HIV-related kidney disease and black race5,25,26 and female gender.25 In contrast to some previous studies, HIV-related factors including HIV viral load, CD4 cell count, and Hepatitis C coinfection were not associated with clinical CKD or with the presence of renal pathology in this cohort with advanced HIV/AIDS,5,27 although the histologic diagnosis of HIVAN was associated with detectable HIV RNA.
Consistent with recent biopsy series in patients with HIV infection, HIVAN and glomerulonephritis were two of the most frequent diagnoses in the current study.4,6,7 The spectrum of renal pathology also included a number of diagnoses that are not commonly encountered in biopsy series, in part because they are less likely to present with clinical indications for kidney biopsy. Parenchymal infections, including chronic pyelonephritis and mycoses, have been observed in previous autopsy series, particularly among patients with advanced AIDS or in resource-limited settings.13,17,20,21
The finding of subclinical glomerular disease in a small number of subjects is also consistent with previous studies, which have identified early FSGS in HIV-infected patients without overt kidney disease.7,8 Retrospective analysis of stored specimens from 5 subjects with subclinical glomerular disease revealed microalbuminuria in 2 cases, including one case of mild HIVAN. Overall, microalbuminuria was detected in 12 subjects with renal pathology who did not meet standard clinical criteria for CKD.
Although this study offers a rare opportunity to describe the prevalence and spectrum of renal pathology in a cohort of antiretroviral-experienced patients unselected for the presence of overt kidney disease, a number of important limitations must be acknowledged. Autopsy series are inherently limited by the potential for postmortem tissue autolysis. The current study focused on chronic glomerular, interstitial, and vascular pathology, which are less sensitive to postmortem alterations. In addition, the prospective design of the MHBB facilitates rapid postmortem examination and harvesting of tissue, thereby minimizing autolytic changes. The design of this study was also limited by the lack of immunofluorescence and electron microscopic analysis, which might have refined the diagnosis in cases of glomerulonephritis. On the other hand, the evaluation of over 100 glomeruli per case and the large sampling of medullary parenchyma including pelvic urothelium had the advantage of providing a broad sampling of both cortex and medulla that is not attainable by needle biopsy. This was particularly helpful to diagnose early forms of HIVAN affecting a small percentage of glomeruli and relatively focal tubulointerstitial processes. In particular the presence of pelvic urothelium made it possible to specifically diagnose chronic pyelonephritis, as distinct from other forms of interstitial nephritis.
Autopsy series are also susceptible to inherent selection bias, and MHBB subjects who have succumbed to AIDS may not be representative of all persons living with HIV in the era of antiretroviral therapy. MHBB subjects were selected for the presence of advanced HIV disease at the time of enrollment, and the results of this study may not be generalizable to patients with well-controlled HIV infection. In fact, the prevalence of clinically evident CKD observed in MHBB kidney tissue donors was higher than that recently reported in other urban HIV populations with a broader range of HIV disease severity.5,25 Clinical evidence of CKD was more common among deceased MHBB participants, consistent with the observed association between CKD and increased mortality in the general population28,29 and in patients with HIV.30 Half of the subjects with subclinical renal pathology had nonspecific changes or renal parenchymal infection on postmortem examination. Although these diagnoses may not cause classic CKD, it is unknown whether this type of underlying kidney injury could predispose patients with HIV/AIDS to acute kidney injury in the setting of recurrent sepsis or exposure to nephrotoxic medications. Microalbuminuria testing was performed on the stored urine specimen most proximate to death. Although a single microalbuminuria measurement is inadequate for screening purposes,31 the results are likely to be more reproducible in the setting of underlying renal pathology, and 5 of 7 subjects with serial urine specimens available for analysis had persistent microalbuminuria.
This study demonstrates a high prevalence of clinical CKD and renal pathology in a cohort of antiretroviral-experienced patients with advanced HIV/AIDS. More than half of the observed renal pathology would not have been predicted based on current clinical criteria for CKD, although microalbuminuria screening may have identified additional cases. Recognition of subclinical kidney disease may allow targeted interventions to prevent or delay the progression of kidney disease and to avoid complications such as medication nephrotoxicity and acute kidney injury. Future studies should evaluate the cost-effectiveness of microalbuminuria screening and the use of more sensitive criteria or more frequent screening for CKD to identify HIV-infected patients with early kidney disease, who may benefit from the initiation of antiretroviral therapy or other interventions such as ACE inhibitors or angiotensin receptor blockers.9
The MHBB was established in 1998 to investigate AIDS-related neuropathology, neurocognitive deficits, and comorbid conditions in the era of antiretroviral therapy. The study design and eligibility criteria have been described previously.23 Briefly, HIV-positive patients are eligible for enrollment in the MHBB if they have advanced HIV disease, as indicated by a prespecified AIDS-defining condition or a CD4 cell count persistently ≤50 cells per mm3, or if they are at risk for imminent mortality in the clinical judgment of the treating physician. Following enrollment, participants who respond to effective antiretroviral therapy with improvement in these clinical parameters may remain in the MHBB cohort. MHBB subjects consent to postmortem organ donation, and to the collection of clinical and laboratory data through patient interview and medical record review. All subjects provide written informed consent, and the MHBB has been approved by the Institutional Review Boards at all enrolling sites. This study was approved by the Program for the Protection of Human Subjects of the Mount Sinai School of Medicine.
Basic demographic, clinical, and laboratory data were analyzed for all active and deceased subjects to describe the prevalence of clinically evident kidney disease in the cohort. The most recent serum creatinine values for each subject were used to estimate GFR using the four-variable Modification of Diet in Renal Disease equation.9 Proteinuria was defined as the presence of 100 mg/100 ml or greater protein on quantitative urinalysis, excluding specimens with evidence of active infection (leukocyte count >10 cells per high power field). CKD was defined according to the NKF and Infectious Disease Society of America guidelines as a GFR <60 ml/min per 1.73 m2 and/or the presence of proteinuria, confirmed on two or more measurements separated by at least 3 months.9,24 Hepatitis B coinfection was defined by surface antigenemia or the detection of viral DNA. Hepatitis C coinfection was defined by the detection of hepatitis C antibody or viral RNA; in cases where both hepatitis C antibody and RNA results were available, RNA results were used to determine hepatitis C status. Because the sensitivity of HIV-1 RNA testing has evolved during the study period, HIV viral load was considered suppressed for all values below 400 copies per ml. For kidney tissue donors, additional data on comorbid conditions (documented diagnosis of diabetes mellitus or hypertension based on the clinical judgment of the treating physician) and cause of death were abstracted from the study chart, and evidence of active cocaine or opiate use was determined by urine toxicology results.
Pathologic analysis was limited to light microscopy. Hematoxylin and eosin and Periodic Acid-Schiff (PAS)-stained slides were prepared from a large wedge of cortex and medulla that had been fixed promptly in formalin at the time of autopsy. Sections (3 μm) were reviewed by a single-blinded pathologist (VD’A), focusing on glomerular, tubulointerstitial, and vascular pathology, whereas discounting autolytic changes. On average, over 100 glomeruli were sampled per section. HIVAN was defined as FSGS with either focal collapsing features or tubular microcysts. To fulfill the definition of collapse, glomeruli had to demonstrate wrinkling and collapse of the glomerular basement membranes with overlying podocyte hypertrophy and hyperplasia. Arteriosclerosis was defined as narrowing of intrarenal arteries of any caliber by intimal sclerosis. Mild arteriosclerosis was graded as intimal thickening involving ≤25% of the luminal diameter. Arterionephrosclerosis consisted of arteriosclerosis accompanied by focal global glomerulosclerosis and focal tubular atrophy and interstitial fibrosis in a patchy, vascular distribution, often producing subcapsular scars. Chronic pyelonephritis was defined as chronic pyelitis with interstitial nephritis affecting cortex and medulla. The membranoproliferative pattern was defined as extensive mesangial interposition and duplication of glomerular basement membranes. End-stage kidney was reserved for those cases with >90% global glomerulosclerosis and tubular atrophy and interstitial fibrosis affecting >90% of the renal parenchyma.
Stored urine specimens from subjects with subclinical renal pathology were analyzed for the presence of microalbuminuria by semiquantitative dipstick (Bayer Diagnostics, Elkhart, Indiana). Persistent microalbuminuria was defined as a positive result in at least two of three consecutive specimens. Comparisons between subjects with and without available tissue and those with and without evidence of CKD or renal pathology were performed by χ2 or Fisher’s exact test for dichotomous variables and by t-tests or Wilcoxon’s rank-sum for continuous variables.
We thank the patients, staff, and investigators of the Manhattan HIV Brain Bank. Portions of this work were presented at American Society of Nephrology Renal Week, November 2008. This work was supported by NIH grants R24MH59724, P01DK56492-05, and K23DK077568, and by the Clinical Research Center of the Mount Sinai School of Medicine (MO1-RR-00071).
All the authors declared no competing interest.