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Improving the Clinical Assessment of Renal Function in HIV
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By Stephen Becker, M.D.
Pacific Horizon Medical Group
San Francisco, CA
Becker reported: "...more than 10% of patients in this analysis were found to have renal insufficiency consistent with the National Kidney Foundations's definition of stage 3 chronic kidney disease determined by decreased glomerular filtration rate. Only about 2% would have been identified if serum creatinine alone were used...patients with HIV infection are at risk for renal injury from HIV disease, comorbidities and therapy. The use of a more sensitive marker, like GFR (MDRD, Cockroft-Gault equation), may be warranted for early detection of renail impairment...
...As expected, moderately elevated serum creatinine was unable to identify any women with renal insufficiency. In contrast, 7.4% of women were identified with chronic kidney disease (stage 3+ GFR). Serum creatinine identified more African-Americans than non-African Americans with renal insufficiency but under reported both groups substantially. The most significant difference was observed for the rate of renal impairment in the patients over 50 yrs of age. Serum creatinine only identified a rate of 3.9% compared to the rate of 21.5% with GFR...
...We hypothesized that we would see more renal events in patients with a history of diabetes, hypertension, and past renal disease. Both serum creatinine and GFR identified more events in these at-risk populations. However, GFR identified 8 times more renal impairment in diabetics than serum creatinine and 5 times more in patients with hypertension...
...Finally, we sought to understand the number of clinical renal events predicted by serum creatinine versus GFR (Table 5). 95% of clinical events observed in this analysis population were predicted by a GFR of 59 mL/min/1.73m2 or less. Mild to moderate elevations in serum creatinine only identified 45% of the clinical events. Most clinical events were identified and diagnosed before GFR or serum creatinine reached severe levels (but not all)..."
See Joel gallant's poster abstract at end of this report: "Decline in Renal Function Associated with Tenofovir DF (TDF) Compared to
Nucleoside Reverse Transcriptase Inhibitor (NRTI) Treatment"
Edit note from Jules Levin: these CROI reports raise several questions: (1) what method to evaluate & monitor kidney function should be used in HIV & for patients on tenofovir---serum creatinine, MDRD, Cockroft-Gault equation? It appears that MDRD or Cockroft-Gault is more sensitive evaluation tool in terms of catching at-risk patients, but most doctors/care providers appear to be using Serum Creatinine. (2) should dose adjustment of tenofovir be considered for patients with reduced creatinine clearance, and what dose should be used? (3) perhaps most important, can we avoid irreversible kidney disease & what is the best way to do this? What is the best way to identify patients at-risk for serious kidney disease and what is the best way to prevent it?
BECKER ARTICLE
Assessment of the adequacy of renal function has traditionally relied upon measurement of the serum creatinine. However it has been known that serum creatinine is influenced by several factors including sex, race, age, weight (lean body mass). The use of alternative measures of renal function has been recommended by the National Kidney Foundation for over 10 years. These alternative diagnostic tests use a measure of the glomerular filtration rate, or GFR. Determination of the GFR can be performed by actual measurement of a 24-hour urine collection, or may be calculated by the use of formula derived from the serum creatinine and demographic features. Two such measures, the Cockcroft- Gault equation and the Modified Diet in Renal Disease (MDRD) are very useful approximations of measured GFR. The MDRD has been validated and is recommended by the National Kidney Foundation to quantitate renal impairment. The MDRD utilizes serum creatinine, age, sex and race (Black or not) and is available through many commercial medical laboratories performing routine tests. An age and sex defined normal range is also provided. The use of measures of GFR rather than serum creatinine is particularly important for those with known chronic renal impairment, or those with certain diseases such as diabetes or hypertension, and those using drugs with the potential of causing renal toxicity. HIV has not been routinely considered as a disease that might benefit from a more rigorous assessment of renal function, despite the use of a number of renal toxic agents, and the association of co-morbid diseases such as diabetes, hypertension and viral hepatitis.
Website to calculate cockroft-gault equation for patients:
http://www.clinicalculator.com/english/nephrology/cockroft/cca.htm
MDRD GFR Calculator
http://www.kidney.org/kls/public/gfr_calculator.cfm
At the 12th CROI several presentations addressed this issue. Becker, reporting for the CHORUS investigators evaluated the renal function of more than 1600 patients treated with tenofovir (TDF). Like the NRTI class in general, tenofovir is excreted by the kidneys, but unlike the other NRTIs TDF may be renal toxic. Studies during the clinical development phase of TDF looked very carefully for evidence of renal impairment using the traditional means of assessment, the serum creatinine. In the study reported by Becker, patients beginning TDF and with available baseline and subsequent laboratory data, were evaluated using the standard ACTG toxicity grading system utilizing serum creatinine and the MDRD. Using serum creatinine 1.9% of TDF treated patients developed moderate renal impairment defined as a serum creatinine > 1.5 times the upper limit of normal. When evaluated by use of the equivalent MDRD stage the rate was 13.8%. Serum creatinine was unable to diagnose any cases of moderate renal impairment in women, while using the MDRD the actual rate was 7.4%. Similarly more accurate assessments of renal function were obtained for those over the age of 50 and Blacks. Similar to other studies, predictors of developing renal impairment included prior renal disease, use of concomitant renal toxic drugs, and hypertension. This study was not intended to determine the rate of renal impairment in patients treated with TDF, but rather to evaluate a measure of GFR versus serum creatinine in a cohort of HIV infected patients. Further evaluations from this dataset will include the determination of renal function using GFR for other antiretroviral agents, and stratification by treatment experience, CD4 count, and nadir CD4 count. The take home message from this study is the need to use the more sensitive measure of GFR by MDRD rather than the serum creatinine in HIV drug development, clinical research and routine clinical care.
Two other studies reported on the relationship of HIV and renal disease, and changes of renal function in patients receiving TDF. In an evaluation of individuals from the MACS cohort, Reisler noted that HIV infected patients had a greater reduction in GFR using the MDRD, than matched HIV negative controls. This was true for measures of mild and moderate renal impairment. Reisler could find no relationship with pre-treatment CD4 count or HIV viral load. Patients treated with TDF had lower GFR than those treated with other antiretrovirals. Gallant evaluated approximately 650 patients followed at the Johns Hopkins University, half of whom received TDF and the others non-TDF containing NRTI regimens. Using serum creatinine and the Cockcroft-Gault estimate of GFR these authors noted a greater increase in serum creatinine, and greater decline in GFR in those patients receiving TDF. While these differences were statistically significant, the magnitude of the changes for most had little clinical significance. Gallant found that baseline renal impairment, diabetes and lower CD4 count predicted the development of renal impairment. He cautioned that careful monitoring of renal function is needed in those patients treated with TDF and those at risk for renal disease.
Taken together these studies suggest (1) that HIV itself may be a risk factor for renal disease and (2) the need for more precise measurement of renal function. Following the recommendations of the National Kidney Foundation this measurement should include determination by GFR. Careful and accurate assessment is especially important in those with pre-existing renal disease, those with known risk factors for the development of renal disease, and those receiving renal toxic medications, including tenofovir. These studies do not answer the question of the long term safety of tenofovir, but they do suggest that previous studies of tenofovir that employed serum creatinine, rather than the more sensitive marker of GFR require reanalysis to better estimate the extent of tenofovir toxicity. We can look forward to a more precise analysis of the larger tenofovir studies, as well as ongoing work to define the extent of renal dysfunction in clinical trials, community based cohorts, and to renewed basic science research that should more completely define the mechanism of tenofovir renal toxicity..
POSTER 819 at 12th CROI
Beyond Serum Creatinine: Identification of Renal Insufficiency Using Gglomerular Filtration: Implications for Clinical Research and Care
Stephen Becker*1, R Balu2, and J Fusco2
1Pacific Horizon Med Group, San Francisco, CA, USA and 2GlaxoSmithKline, Research Triangle Park, NC, USA
Background: Recent reports of renal insufficiency associated with the nucleoside reverse transcriptase inhibitors (NRTI) have included elevations in serum creatinine, proximal tubular dysfunction, nephrogenic diabetes insipidus, renal failure, Fanconi-like syndrome, and death. Appropriate methods for identification of patients at risk for severe renal injury are needed for monitoring and clinical dosage modification.
Methods: Using an antiretroviral known to cause renal impairment (tenofovir disproxil fumarate [TDF]), we evaluated the rate of grade 1 and grade 4 renal insufficiency using serum creatinine and a method to more precisely evaluate glomerular filtration. Literature suggests that even minor changes in serum creatinine result in substantial decreases in glomerular filtration. Moreover, serum creatinine is influenced by other factors including age, race, sex, and body mass. According to the National Kidney Foundation, glomerular filtration is the "best overall indicator of the level of kidney function." This is especially true in patients with co-morbid conditions. Multivariable Cox models were fit to consider age, race, study site, sex, route of HIV infection, AIDS, baseline viral load and CD4, baseline renal function, concurrent use of other nephrotoxic drugs, history of renal disease, hypertension, and diabetes as predictors of renal insufficiency in patients treated with TDF.
Results: A total of 1298 patients were initiated first TDF on or after consent to CHORUS. Using a combined endpoint of serum creatinine and clinical events, 22 patients (1.7%) experienced a grade-1 event, 1 patient (< 0.1%) experienced a grade 4 event. Using a combined endpoint of glomerular filtration and clinical events, 128 patients (9.9%) experienced a grade-3 event, 7 patients (< 0.1%) experienced a grade-4 event. Multivariable analysis identified past history of renal disease (hazard ratio = 4.9; 95% CI = 2.7 to 8.8), abnormal baseline glomerular filtration (18.9; 9.2 to 39.1), hypertension (1.6; 1.1 to 2.3), and concurrent use of other nephrotoxic medications (2.7; 1.9 to 3.9) as important predictors of renal insufficiency.
Conclusions: The elevations in serum creatinine observed in CHORUS are consistent with those seen in other populations, observational or otherwise. The proportion of patients with extreme grade 4+ glomerular filtration values is comparable to results seen for grade 4+ serum creatinine in other studies. However, nearly 10% of our patients have renal dysfunction using the grade 3+ glomerular filtration criterion. The National Kidney Foundation defines this level as chronic kidney disease. Glomerular filtration should be considered for the evaluation of renal insufficiency in HIV.
Patients who were prescribed TDF were followed for diagnosis & lab values consistent with renal dysfunction-increase in serum creatinine, decrease in GFR and clinical events indicative of nephrotoxicity.
GFR-glomular filtration rate was calculated using the MDRD formula:
MDRD GFR=(186)*(serum creatinine mg/dl -1.154 )*(age-0.203)*(0.742 if female)*(1.212 if African-American)
Lab events were defined as moderate (ACTG grade 1+) elevations in serum creatinine defined as 1.5 times the upper limit of normal (ULN), severe (ACTG grade3+) elevations in serum creatinine defined as 3X ULN, moderate (NKF stage 3+ chronic kidney disease) decreases in GFR defined as 59 mL/min/1.73m2 or less, and severe (NKF stage 4+ chronic kidney disease) decreases in GFR defined as 29 mL/min/1.73m2 or less.
Clinical events were defined as diagnosis of renal or kidney failure, renail insufficiency, proximal tubular dysfunction, acute tubular necrosis, nephrgenic diabetes, Fanconi's syndrome, hypophosphatemia, acute intestitial nephritis, nephritic syndrome, renal tubular dysfunction, and death due to renal failure. All events were identified while on the regimen of interest or within 7 days after discontinuation.
Table 2: Distribution of Events of Interest During TDF Use
| Analysis population |
| N=1,625 |
| ACTG Grade 1+ serum creatinine >1.5xULN |
31 (1.9%) |
| ACTG Grade 3+ serum creatinine >3xULN |
6 (0.4%) |
| NKF Stage 3+Chronic Kidney Disease |
216 (13.3%) |
| (MDRD GFR <60mL/min/1.73m2) |
| NKF Stage 4+Chronic Kidney Disease |
14 (0.9%) |
| (MDRD GFR <30 mL/min/1.73m2) |
| Clinical renal events |
20 (1.2%) |
The events were further described by demographic characteristics known to effect interpretation of serum creatinine: sex, race and age (Table 3). As expected, moderately elevated serum creatinine was unable to identify any women with renal insufficiency. In contrast, 7.4% of women were identified with chronic kidney disease (stage 3+ GFR). Serum creatinine identified more African-Americans than non-African Americans with renal insufficiency but under reported both groups substantially. The most significant difference was observed for the rate of renal impairment in the patients over 50 yrs of age. Serum creatinine only identified a rate of 3.9% compared to the rate of 21.5% with GFR.
Table 3. Number of Events Stratified by Sex, Race, and Age
| Events |
Sex |
| |
Male |
Female |
| |
N=1489 |
N=136 |
| Grade 1+ serum creatinine |
31 (2.1%) |
0 (0.0%) |
| Grade 3+ serum creatinine |
6 (0.4%) |
0 (0.0%) |
| Stage 3 + GFR |
206 (13.8%) |
10 (7.4%) |
| Stage 4 + GFR |
14 (0.9%) |
0 (0.0%) |
| Events |
Race |
| |
Afr-Am |
Non Afr-Am |
| |
N=208 |
N=1417 |
| Grade 1+ serum creatinine |
10 (4.8%) |
21(1.5%) |
| Grade 3+ serum creatinine |
2 (0.9%) |
4 (0.3%) |
| Stage 3 + GFR |
19 (9.1%) |
197 (13.9%) |
| Stage 4 + GFR |
3 (1.4%) |
11 (0.8%) |
| Events |
Age |
| |
< 51 |
> 50 |
| |
N=1318 |
N=307 |
| Grade 1+ serum creatinine |
19(1.4%) |
12 (3.9%) |
| Grade 3+ serum creatinine |
5 (0.4%) |
1 (0.3%) |
| Stage 3 + GFR |
150 (11.4%) |
66 (21.5%) |
| Stage 4 + GFR |
8 (0.6%) |
6 (1.9%) |
We hypothesized that we would see more renal events in patients with a history of diabetes, hypertension, and past renal disease. Both serum creatinine and GFR identified more events in these at-risk populations. However, GFR identified 8 times more renal impairment in diabetics than serum creatinine and 5 times more in patients with hypertension. This trend continued in patients with a history of renal disease. GFR identified more than twice as many patients with renal impairment as serum creatinine representing more than 50% of all patients at risk.
Table 4. Number of events Stratified by History of Diabetes, Hypertension, and Renal Disease
| Events |
HISTORY OF DIABETES |
| |
Yes |
No |
| |
N=98 |
N=1527 |
| Grade 1+ serum creatinine |
2 (2%) |
29 (1.9%) |
| Grade 3+ serum creatinine |
1 (1%) |
5 (0.3%) |
| Stage 3 + GFR |
17 (17.3%) |
199 (13.0%) |
| Stage 4 + GFR |
1 (1%) |
13 (0.9%) |
| Events |
HISTORY OF HYPERTENSION |
| |
Yes |
No |
| |
N=329 |
N=1296 |
| Grade 1+ serum creatinine |
15 (4.6%) |
16 (1.2%) |
| Grade 3+ serum creatinine |
2 (0.6%) |
4 (0.3%) |
| Stage 3 + GFR |
70 (21.3%) |
146 (11.3%) |
| Stage 4 + GFR |
6 (1.8%) |
8 (0.6%) |
| Events |
HISTORY of Renal disease |
| |
Yes |
No |
| |
N=77 |
N=1548 |
| Grade 1+ serum creatinine |
15 (19.5%) |
16 (1%) |
| Grade 3+ serum creatinine |
3 (3.9%) |
3 (0.2%) |
| Stage 3 + GFR |
41 (53.2%) |
175 (11.3%) |
| Stage 4 + GFR |
8 (10.4%) |
6 (0.4%) |
Finally, we sought to understand the number of clinical renal events predicted by serum creatinine versus GFR (Table 5). 95% of clinical events observed in this analysis population were predicted by a GFR of 59 mL/min/1.73m2 or less. Mild to moderate elevations in serum creatinine only identified 45% of the clinical events. Most clinical events were identified and diagnosed before GFR or serum creatinine reached severe levels.
Table 5. proportion of Renal Clinical Events Predicted by Serum Creatinine Versus GFR
| CLINICAL EVENT |
| |
Yes |
No |
| |
N=20 |
N=1605 |
| Grade 1+ serum creatinine |
9 (45%) |
22 (1.4%) |
| Grade 3+ serum creatinine |
0 (0.0%) |
6 (0.4%) |
| Stage 3 + GFR |
19 (95%) |
197 (12.3%) |
| Stage 4 + GFR |
6 (30%) |
8 (0.5%) |
IMPORTANT PREDICTORS OF RENAL INSUFFICIENCY as Determined by Lab Findings and Clinical Diagnosis (Relative Risks, 95% Confidence Intervals)
| CLINICAL EVENT |
| |
St 3+GFR |
St 4+GFR |
Gr 1+sCR |
Gr 3+sCr |
| |
RR |
RR |
RR |
RR |
| Concurrent Use
Of nephrotoxic meds |
2.7 |
2.4 |
2.9 |
6.1 |
| History of renal dis |
4.5 |
7.5 |
9.9 |
5.5 |
| History of diabetes |
1.1 |
1.3 |
1.0 |
3.5 |
| History of hypertension |
1.6 |
1.9 |
2.6 |
1.0 |
| Abnormal lab values |
19.9 |
4.8 |
12.0 |
28.3 |
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"Decline in Renal Function Associated with Tenofovir DF (TDF) Compared to Nucleoside Reverse Transcriptase Inhibitor (NRTI) Treatment"
Poster N-138, 12th CROI. Joel E. Gallant, Michelle Parish, Jeanne Keruly, Richard Moore
Johns Hopkins University School of Medicine, Baltimore, MD
ABSTRACT
Background: Tenofovir DF (TDF) is a nucleotide analog reverse transcriptase inhibitor used for the treatment of HIV disease. Despite demonstrated renal
safety in several clinical trials, case reports and observational data suggest that it may be associated with nephrotoxicity.
Methods: We analyzed data from a large prospective observational cohort,
comparing all patients who initiated TDF (N=344) or an alternative nucleoside
analog reverse transcriptase inhibitor (NRTI, N=314) after Jan. 1, 2001 and
who had at least two serum creatinines (Cr) drawn within 90 days of initiation.
We assessed change and percentage change in calculated Cr clearance (CLCr)
over the study period for each subject. Baseline CLCr was calculated using the
Cockcroft-Gault equation using the average of the 2 serum Cr measurements
obtained closest to the start of therapy.
Results: TDF recipients had greater increases in Cr and greater absolute and percentage declines in CLCr compared to those in the NRTI group, although
there was no difference in rates of discontinuation coincident with maximum
decline in CLCr. Med. baseline Cr and CLCr were 0.8 mg/dL and 117.5 ml/min,
respectively, with no differences between groups. Median Cr change was +0.15
and +0.10 in the TDF and NRTI groups, respectively (p=0.01). Med. CLCr
change was -13.35 and -7.5 ml/min (p=0.005). The changes were apparent by
90 days of therapy and persisted over the entire year. The percentage change
in CLCr was also associated with longer duration of treatment with TDF or the
NRTI, diabetes, higher baseline Cr, and CD4 count <50 cells/mm3 (p <0.05). In
a multivariate analysis only TDF use and lower CD4 count were associated with
CLCr decline (p<0.05), with a trend toward association with lower baseline CLCr
and diabetes. In this analysis, hypertension, use of LPV/r or any other
concomitant antiretroviral agents, viral load, previous use of adefovir, age, sex, race and HIV transmission risk group were not associated with CLCr decline.
Discussion: Use of TDF is associated with a modest decline in CLCr, especially in patients with baseline renal insufficiency, diabetes, or low CD4 count. While
the differences were statistically significant, they were small in magnitude and
of unclear clinical significance. Patients at risk for renal dysfunction should be carefully monitored when taking TDF, and the dosing interval should be
adjusted when indicated by a reduced creatinine clearance.
RESULTS
⋅ It is now recommended that the dosing interval of TDF be modified in patients with a CLCr <50mL/min. Only 2 subjects, who had a baseline Cr >2.0 mg/dL, received less than 300 mg/day of TDF.
⋅ 19 (5.5%) of TDF- and 21 (6.7%) of NRTI-treated patients discontinued therapy at time of maximum decline in renal function (p>0.05).
Univariate associations: %CLCr change also associated with:
-diabetes (%CLCr change -13) vs. no diabetes (-8) [p<0.04]
-baseline CD4 <50 cells/mm3 (-14) vs. >50 (-8) [p<0.01]
-baseline HIV RNA>20,000 c/ml (-15) vs. >20,000 (-8) [p<0.02]
-initial therapy (-11) vs. subsequent therapy (-8) [p<0.03]
-Not associated: hypertension, age, gender, race, hepatitis C or B, use
of LPV/r or any other specific PI or NNRTI.
Multivariate analysis:
-Overall: only TDF use (p=0.006) and CD4 count <50 cells/mm3 (p<0.001)
were associated with CLCr decline. Trends toward associations with baseline CLCr <50 ml/min and diabetes (p=0.10).
-Patients with baseline CLCr >50 ml/min: Associations unchanged: TDF use (p=0.004), low CD4 count (p<0.001); diabetes (trend, p=0.06)
-Not associated: hypertension, use of LPV/r or other ARVs, HIV RNA, prior use of adefovir, age, sex, race and HIV transmission risk group
CONCLUSIONS
⋅ Over a median treatment duration of 322 days, TDF use was associated with a 4% greater decline in CLCr compared with alternative NRTIs.
⋅ Advanced immunosuppression (CD4<50) was also associated with decline in renal function.
⋅ There were trends toward associations with diabetes and baseline CLCr <50 ml/min.
oRestricting analysis to subjects with baseline CLCr >50, who should receive full-dose TDF, did not change the findings.
⋅ There was no association with age, race, sex, HIV transmission group, HTN, HIV RNA, use of LPV/r or other specific ARV agents, or prior use of adefovir.
o Although statistically significant, the clinical significance of these findings is unclear. The decline in CLCr associated with TDF use was small and was not associated with greater rates of discontinuation.
⋅ The majority of TDF-treated subjects remain on TDF and will continue to be followed.
⋅ Renal function should be assessed prior to starting TDF, and TDF dosing interval should be adjusted in those with impaired renal function as recommended. Renal function should be monitored in TDF-treated patients.
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