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15th Conference on Retroviruses and Opportunistic Infections

Boston, Massachusetts / February 3-6, 2008

Several recently completed studies, many of which evaluated relatively large patient populations, have confirmed that HIV and its treatments increase the risk of renal disease. Although there is concern that the complications generated by renal disease will be more fully realized as greater numbers of HIV-infected patients enter the age ranges where renal impairment is prevalent, the best opportunity to avoid complications may be in prevention. Based on new data, prevention may include preserving immune function, judicious use of tenofovir (TDF) or other drugs associated renal with dysfunction, and routinely screening patients for renal dysfunction.

Copenhagen Study Focus

“Deterioration of renal function among HIV-positive patients is recognized to be caused by traditional renal risk factors, HIV itself, and exposure to ARTs,” stated Dr. Ole Kirk, Copenhagen HIV Program, University of Copenhagen, Denmark. Senior author of a study that observed renal function in relation to immunodeficiency in 5526 patients, he reported that evidence of renal dysfunction was observed in approximately 5% of patients over three years of follow-up but that higher CD4+ cell counts mitigated risk.

The prospective Copenhagen study was specifically designed to identify the incidence of renal dysfunction, the rate of deterioration over a three-year study period, and the risk factors associated with renal impairment. Renal function in all patients was evaluated with estimated glomerular filtration rate (eGFR), calculated by Cockcroft-Gault equation, at baseline and on at least four subsequent occasions. Deterioration in renal function was defined as two consecutive eGFR measurements of £60 mL/min/1.73 m2 or a confirmed 25% decline in eGFR since the last measurement. Most of the patients included in the study were on ART and 75% had a viral load of <500 HIV RNA copies/mL. Median age of the study population was 43 and median CD4+ cell count was 453 cells/mL.

The incidence of renal dysfunction was 2.4%, while another 3.2% of the population had a 25% decline in eGFR over the course of follow-up. When known or suspected risk factors for renal impairment were evaluated, an elevated CD4+ cell count was associated with a reduced risk of renal dysfunction so that any twofold increase in CD4+ cell count was associated with a 31% reduction in risk (hazard ratio [HR] 0.69 (95% CI, 0.55-0.87; P=0.0034). A prior AIDS diagnosis was associated with a 75% increase in risk (HR 1.75 [95% CI, 1.10-2.79; P=0.0002]). Other independent risk factors predicting renal dysfunction included a low eGFR at baseline, a previous cardiovascular event and elevated HIV RNA levels.

“The data confirm that immunodeficiency does contribute significantly to the risk of renal impairment in HIV- infected patients. This has been suggested but not well demonstrated in previous studies,” Dr. Kirk maintained.

The Role of Treatment

In another study, a retrospective analysis was conducted to evaluate change in renal function in patients taking TDF within a HAART regimen. Previous studies have associated TDF with increased risk of renal dysfunction, but there have been inconsistent estimates of the relative risk. In this study, 1742 HIV-infected patients taking TDF as part of HAART and 623 HIV-infected patients not taking TDF were evaluated over a median follow-up of 2.7 years. The groups did differ in several baseline characteristics with a potential influence on renal function, but these did not consistently weigh in favour of one group relative to the other. Specifically, although fewer TDF patients were previously naive to ART, they had higher CD4+ cell counts. TDF patients did have a higher prevalence of diabetes, but all other characteristics, including serum creatinine, phosphorus, HCO3, urinalysis and viral load were similar.

“The risk of a 50% or greater decrease in GFR was increased by 76% [HR 1.76, 95% CI, 1.10-2.82; P=0.02] in TDF patients relative to individuals not receiving TDF,” reported Dr. Michael Horberg, Kaiser Permanente, Oakland, California. Employing data generated by the Kaiser Permanente database, Dr. Horberg also reported that TDF patients had a 90% higher risk of >2.0 mg/dL (>176.8 µmol/L) increase in serum creatinine (HR 1.9, 95% CI 1.0-3.29; P=0.05).

Other Risk Factors

The patients were also compared for relative risk of Fanconi syndrome, which was defined as having at least three of five criteria over a 30-day period: increased serum creatinine by 50% or by ³0.5 mg/dL (³44.2 µmol/L) or serum creatinine >1.5 mg/dL (>132.6 µmol/L), phosphorus <2.7 mg/dL (<0.87 mmol/L), proteinuria, glycosuria with normal serum glucose or HCO3 <23 mEq/L (<23 mmol/L). By this definition, the risk of Fanconi syndrome was increased almost threefold in patients being treated with TDF relative to those who were not (HR 2.91, 95% CI 1.80-4.71; P<0.001).

“Proteinuria, elevated serum creatinine, and HCO3 were the criteria for the Fanconi syndrome most frequently met by the TDF patients. When we compared the proportion of patients with less than three criteria, the rates were 16% for TDF vs. 28% (P<0.001) for those not taking TDF,” Dr. Horberg reported. While regimen discontinuation was more frequent on TDF (39% vs. 32%; P<0.001), Dr. Horberg observed that efficacy did not appear to be an issue. Rather, TDF patients were substantially more likely than those not taking TDF to have a viral load <75 HIV RNA copies/mL at the time of discontinuation (P=0.002).

“TDF is highly efficacious, but it is associated with a statistically significant decrease in renal function, including Fanconi syndrome as we defined it,” Dr. Horberg observed. “Close monitoring of renal function and the components of Fanconi syndrome among patients taking TDF is warranted.”

However, not all patients appear to be at the same risk for renal dysfunction. In addition to the risk factors identified in the Copenhagen cohort, an evaluation of patients treated at Johns Hopkins University, Baltimore, Maryland, found that African-Americans had almost double the risk (HR 1.9, 95% CI 1.2-2.8) as Caucasians for chronic kidney disease (CKD). In this study, data were analyzed from 3332 African-Americans and 927 Caucasian patients in an HIV cohort that has generated 18,778 person-years of follow-up between 1990 and 2004. Over this period, 284 patients or 7% of the cohort developed CKD and 100 (2%) developed end-stage renal disease (ESRD). African-Americans were more likely to have proteinuria and to progress to ESRD.

“The reason for the racial disparity in the rates of CKD are unclear, but follow-up indicated that African-Americans had a more aggressive course with faster progression to ESRD than Caucasians even after controlling for HIV disease,” reported Dr. Gregory Lucas, Associate Professor, Division of Infectious Diseases, Johns Hopkins University.

These results demonstrate that the risk of renal dysfunction is not evenly distributed among HIV patients and may be exacerbated by relative immune deficiency and comorbidities. While data from both the Copenhagen and Kaiser Permanente cohorts indicate that there are characteristics that may help guide clinicians in identifying patients at high risk of renal dysfunction, these data also indicate that renal dysfunction can occur in the absence of risk factors. Overall, these findings support routine monitoring of renal function in an HIV population. Early detection may permit changes in therapy to reduce progression and end-stage complications.

Summary

Renal dysfunction is a common clinical problem in HIV- infected individuals, which can pose a significant threat of life-threatening complications in individuals whose infection remains well controlled. Like cardiovascular and hepatic diseases, which are also a potential threat to long-term survival in HIV patients responsive to ART, new data suggest that HIV patients should be routinely monitored for renal function. Strategies for reducing the risk of renal impairment are particularly important for those with an elevated baseline risk.