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 (). 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.
Characteristics of the Manhattan HIV Brain Bank Cohort
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 –. 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 (). 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.
Other renal pathology identified in MHBB kidney tissue donors
Dominant renal pathology in 89 MHBB kidney tissue donors
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 (). 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.
Characteristics of MHBB kidney tissue donors with specific renal diagnoses
Findings consistent with HIVAN were observed in 12 African-Americans and 3 nonblack participants of Hispanic ethnicity, all with advanced HIV disease (). 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 (). 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 (). There was also a single case of diffuse endocapillary proliferative and exudative glomerulonephritis, suggestive of acute post-infectious glomerulonephritis.
Other diagnoses included diabetic nephropathy (), chronic pyelonephritis, and interstitial nephritis (). One case of chronic interstitial nephritis had numerous intratubular crystals consistent with indinavir nephrotoxicity (). There were 3 cases of parenchymal mycoses, all occurring in patients with disseminated fungal infection (), and a single case of advanced renal amyloid was observed in a patient with systemic amyloidosis (). 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 (). 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.