Christine A. White

Estimating Glomerular Filtration Rate in Kidney Transplantation: A Comparison between Serum Creatinine and Cystatin C–Based Methods

Accurate measurement of GFR is critical for the evaluation of new therapies and the care of renal transplant recipients. Although not accurate in renal transplantation, GFR is often estimated using creatinine-based equations. Cystatin C is a marker of GFR that seems to be more accurate than creatinine. Equations to predict GFR based on the serum cystatin C concentration have been developed, but their accuracy in transplantation is unknown. GFR was estimated using four equations (Filler, Le Bricon, Larsson, and Hoek) that are based on serum cystatin C and seven equations that are based on serum creatinine in 117 adult renal transplant recipients. GFR was measured using radiolabeled diethylenetriaminepentaacetic acid (99mTc-DTPA), and the bias, precision, and accuracy of each equation were determined. The mean (99m)Tc-DTPA GFR was 58 +/- 23 ml/min per 1.73 m(2). The cystatin C-based equations of Filler and Le Bricon had the lowest bias (-1.7 and -3.8 ml/min per 1.73 m2), greatest precision (11.4 and 11.8 ml/min per 1.73 m2), and highest accuracy (87 and 89% within 30% of measured GFR, respectively). The cystatin C equations remained accurate even when the measured GFR was >60 ml/min per 1.73 m2. The creatinine-based equations were not as accurate, with only 53 to 80% of estimates within 30% of measured GFR. Cystatin C-based equations are more accurate at predicting GFR in renal transplant recipients than traditional creatinine-based equations. Further prospective studies with repetitive measurement of cystatin C are needed to determine whether cystatin C-based estimates of GFR will be sufficiently accurate to monitor long-term allograft function.

Performance of creatinine-based estimates of GFR in kidney transplant recipients: a systematic review

BACKGROUND Glomerular filtration rate (GFR) commonly is estimated in kidney transplantation by using creatinine-based estimation equations. The performance of these equations in kidney transplant recipients is unclear, with conflicting results between studies. STUDY DESIGN Systematic review. SETTING & POPULATION Stable adult kidney transplant recipients more than 6 months posttransplantation. SELECTION CRITERIA Reporting of or ability to calculate from available data the GFR estimation equation bias (mean difference between measured GFR and estimated GFR) and percent accuracy (percentage of GFR estimates within 10%, 20%, or 30% of measured GFR). INDEX TESTS Creatinine-based GFR estimation equations (Cockcroft-Gault, 6-variable Modification of Diet in Renal Disease [MDRD] Study, 4-variable MDRD Study, and Nankivell). REFERENCE TESTS GFR determination using plasma or renal clearance of inulin, radioisotopes, or nonradiographic contrast. RESULTS The search yielded 23 studies. For the 4-variable MDRD Study equation, bias ranged from -11.4 to +9.2 mL/min/1.73 m(2) (0.15 mL/s/1.73 m(2)). Only 76% of estimates were within 30% of measured GFR. For the Cockcroft-Gault equation, bias ranged from -4.0 to +16 mL/min/1.73 m(2) and 73% of estimates were within 30% of measured GFR. For the Nankivell equation, bias ranged from -1.4 mL/min to 36.3 mL/min with a 30% accuracy of only 68%. LIMITATIONS This review is limited by the inability to pool bias data, lack of calibration of serum creatinine in the majority of studies, and inclusion of nonindependent observations in many studies. CONCLUSIONS Differences in patient populations, baseline GFRs of the study group, reference standard GFR used, and creatinine assay calibration likely account for the heterogeneity in results. These factors need to be considered by investigators and clinicians when interpreting estimates of GFR in kidney transplant recipients.

Estimating Glomerular Filtration Rate in Kidney Transplantation: Is the New Chronic Kidney Disease Epidemiology Collaboration Equation Any Better?

BACKGROUND The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed to address the systematic underestimation of the glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) Study equation in patients with a relatively well-preserved kidney function. The performance of the new equation for kidney transplant recipients (KTRs) is unknown. METHODS We used the plasma clearance of (99m)Tc-diethylenetriamine pentaacetic acid to measure the GFR in a cohort of 207 stable KTRs and estimated the GFR with the new CKD-EPI equation. RESULTS The mean bias for the CKD-EPI equation of -4.5 mL x min(-1) x (1.73 m(2))(-1) was lower than that of the 4-variable MDRD Study equation; however, the 2 equations showed similar variation of individual biases around the mean or median bias, so that only modest improvement was seen in the overall percentage of GFR estimates within 30% of the measured GFR (84% vs 77% for the CKD-EPI vs MDRD Study equations, respectively). In the cohort with a GFR >60 mL x min(-1) x (1.73 m(2))(-1) (n = 98), the CKD-EPI bias was much less than that of the MDRD Study equation [-7.4 mL x min(-1) x (1.73 m(2))(-1) vs -14.3 mL x min(-1) x (1.73 m(2))(-1)], and an accuracy of + or - 30% was seen for 89% of GFR estimates, compared with 77% with the MDRD Study equation. The variation of the individual biases around the mean bias remained substantial [SD = 13.7 mL x min(-1) x (1.73 m(2))(-1)]. CONCLUSIONS The CKD-EPI equation shows improved estimation ability, and we recommend that it replace the MDRD Study equation as the currently preferred creatinine-based estimating equation for KTRs. The precision of GFR estimates obtained with the CKD-EPI equation remains suboptimal, however, and we recommend that research on other markers of GFR, such as cystatin C and beta-trace protein, be pursued.

Estimating GFR using serum beta trace protein: accuracy and validation in kidney transplant and pediatric populations

The limitations of estimates of glomerular filtration rate (GFR) based only on serum creatinine measurements have spurred an interest in more sensitive markers of GFR. Beta-trace protein (BTP), a low-molecular-weight glycoprotein freely filtered through the glomerular basement membrane and with minimal non-renal elimination, may be such a marker. We have recently derived two GFR estimation equations based on BTP. To validate these equations, we measured BTP and the plasma clearance of (99)mTc-DTPA in 92 adult kidney transplant recipients and 54 pediatric patients with impaired kidney function. GFR was estimated using the serum creatinine-based Modification of Diet in Renal Disease (MDRD) Study equation for adults, the Schwartz and updated Schwartz equations in children, and 4 novel BTP-derived equations (our 2 equations and 2 proposed by Poge). In adults, our BTP-based equations had low median bias and high accuracy such that 89-90% of estimates were within 30% of measured GFR. In children, the median bias of our 2 equations was low and accuracy was high such that 78-83% of estimates were within 30% of measured GFR. These results were an improvement compared to the MDRD and Schwartz equations, both of which had high median bias and reduced accuracy. The updated Schwartz equation also performed well.

Effect of Clinical Variables and Immunosuppression on Serum Cystatin C and Beta-Trace Protein in Kidney Transplant Recipients

BACKGROUND Cystatin C and beta-trace protein (BTP) are low-molecular-weight proteins that have generated interest as alternative endogenous markers of glomerular filtration rate (GFR). Studies examining the effect of demographic, biometric, clinical, and biochemical variables on cystatin C levels have yielded conflicting results, perhaps because of the reliance on inferior methods of GFR determination. The aim of this study is to examine the independent effect of various clinical parameters on serum concentrations of creatinine, cystatin C, and BTP in kidney transplant recipients. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 207 kidney transplant recipients with stable kidney function. PREDICTORS GFR, age, race, sex, body mass index, albumin level, proteinuria, smoking status, prednisone, and calcineurin inhibitor and mycophenolate mofetil use. OUTCOMES & MEASUREMENTS Multiple linear regression analysis was used to examine the relationship between predictor variables and cystatin C, BTP, and creatinine levels. GFR was measured by using technetium 99m-radiolabeled diethylenetriaminepentaacetic acid clearance. RESULTS After adjusting for GFR, cystatin C and BTP levels were significantly lower in women compared with men. Greater albumin concentration was associated with significantly lower cystatin C and BTP concentrations. There was a statistically significant, but clinically small, association between body mass index and cystatin C level, but no association between the other demographic variables or medications analyzed. LIMITATIONS Predominantly white population; results may not be applicable to other racial groups. CONCLUSION Important nonrenal factors can influence BTP and cystatin C concentrations and need to be considered when interpreting BTP and cystatin C values in kidney transplant patients.

Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial

BACKGROUND Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria. METHODS In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m(2) or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m(2)). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473. FINDINGS Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio [HR] 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m(2) (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02). INTERPRETATION Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population. FUNDING Canadian Institutes of Health Research.

Trimethoprim, creatinine and creatinine-based equations.

Co-trimoxazole is a frequently prescribed antibiotic worldwide. It is composed of both trimethoprim and sulfamethoxazol (Sfx) and is used in the treatment and prophylaxis of urinary tract and Pneumocystis jirovecii infections. The Sfx component appears to be nephrotoxic at high doses or doses inappropriately adjusted for glomerular filtration rate (GFR). The trimethoprim component, even at recommended doses, inhibits tubular creatinine secretion, leading to a rapid but ultimately reversible increase in serum creatinine independent of any changes in GFR. This translates into a falsely low estimated GFR when creatinine-based equations are used. This review focuses on evidence of the differential effects of trimethoprim and Sfx on serum creatinine concentrations and GFR and their relevance to clinical practice, with particular attention to kidney transplantation.

Accuracy of cystatin C-based estimates of glomerular filtration rate in kidney transplant recipients: a systematic review

BACKGROUND As with creatinine, cystatin C can be incorporated into a formula to estimate the glomerular filtration rate (GFR). The overall performance of cystatin C-based equations in kidney transplantation is unclear with conflicting results between studies. METHODS Systematic review of adult kidney transplant recipients. Studies that reported mean bias (mean difference between the measured and estimated GFRs) or accuracy of the cystatin C-based GFR estimation equation (e.g. percentage of estimates within 30% of the measured GFR) against the measured GFR using renal or plasma clearance of contrast agents, radioisotopes or inulin were included. RESULTS The search identified 10 studies that examined 14 different cystatin C-based estimating equations (n = 5 equations evaluated in more than one study). The Le Bricon equation had the best performance with a bias that ranged from -6.4 to +2.8 mL/min/1.73 m(2); 85% (95% CI, 82-88) of estimates were within 30% of the measured GFR. For the other equations, 66-82% of estimates were within 30% of the measured GFR. For the modification of diet in renal disease (MDRD) equation, 68% (95% CI, 65-72) of estimates were within 30% of the measured GFR. CONCLUSIONS The cystatin C-based Le Bricon equation was the most accurate, and most of the cystatin C-based equations showed improvements in 30% and 50% accuracy compared with the creatinine-based MDRD equation. Cystatin C-based equations may offer an advantage over the MDRD equation in kidney transplant recipients. Estimating equations re-expressed with standardized cystatin C have been developed and their accuracy needs to be tested in the kidney transplant population.

Use of Kidney Function End Points in Kidney Transplant Trials: A Systematic Review

BACKGROUND Clinical trials in kidney transplantation are beginning to include markers of kidney function as end points now that traditional outcomes, such as acute rejection, become increasingly rare events. The frequency and type of kidney function end points used are unknown. STUDY DESIGN Systematic review. SETTING & POPULATION Randomized controlled trials in adult kidney transplant recipients reported in 5 major general medical journals and 5 major subspecialty journals in nephrology and transplantation between January 2003 and November 2008. SELECTION CRITERIA Inclusion of at least one kidney function end point at least 1 month posttransplant. RESULTS 133 (79%) of 169 randomized trials identified used a kidney function end point. Of these, 37 (28%) used one or more measures of kidney function as the primary end point, and 81 (61%), as a secondary end point. For the primary end point, 21 (57%) trials used a creatinine-based estimated glomerular filtration rate (eGFR), 18 (49%) used serum creatinine level, and 7 (19%) used measured GFR. Overall, eGFR was an end point in 81 (61%) trials, and measured GFR, in 12 (9%) trials. LIMITATIONS This review is limited by the poor quality of the included trials, with many not defining either primary or secondary end points. CONCLUSIONS Measures of kidney function are used commonly as surrogate end points in kidney transplant trials, with eGFR becoming more frequently used over time. Further data are needed to properly validate these surrogate end points and fully understand their limitations when designing and interpreting randomized trials.

The Estimation, Measurement, and Relevance of the Glomerular Filtration Rate in Stage 5 Chronic Kidney Disease

The glomerular filtration rate (GFR) is considered the best index of overall kidney function. The level of GFR is used in patients with chronic kidney disease (CKD) to classify them into CKD stages. Stage 5 CKD encompasses patients with a GFR below 15 ml/minute/1.73 m2 and those requiring chronic dialysis. Preservation of GFR, even at its very low level, is of great importance in both dialysis and non‐dialysis stage 5 CKD patients. Residual GFR is considered in the prescription of both hemodialysis and peritoneal dialysis and interventions to preserve residual GFR are an active area of clinical research. The application of traditional methods of estimating and measuring GFR can be problematic in this patient population. This review will focus on the methods available to quantify GFR in stage 5 CKD and their use in both clinical and research settings.