Wieneke M. Michels

Performance of the Cockcroft-Gault, MDRD, and New CKD-EPI Formulas in Relation to GFR, Age, and Body Size

BACKGROUND AND OBJECTIVES We compared the estimations of Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to a gold standard GFR measurement using (125)I-iothalamate, within strata of GFR, gender, age, body weight, and body mass index (BMI). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For people who previously underwent a GFR measurement, bias, precision, and accuracies between measured and estimated kidney functions were calculated within strata of the variables. The relation between the absolute bias and the variables was tested with linear regression analysis. RESULTS Overall (n = 271, 44% male, mean measured GFR 72.6 ml/min per 1.73 m(2) [SD 30.4 ml/min per 1.73 m(2)]), mean bias was smallest for MDRD (P < 0.01). CKD-EPI had highest accuracy (P < 0.01 compared with Cockcroft-Gault), which did not differ from MDRD (P = 0.14). The absolute bias of all formulas was related to age. For MDRD and CKD-EPI, absolute bias was also related to the GFR; for Cockcroft-Gault, it was related to body weight and BMI as well. In all extreme subgroups, MDRD and CKD-EPI provided highest accuracies. CONCLUSIONS The absolute bias of all formulas is influenced by age; CKD-EPI and MDRD are also influenced by GFR. Cockcroft-Gault is additionally influenced by body weight and BMI. In general, CKD-EPI gives the best estimation of GFR, although its accuracy is close to that of the MDRD.

The MDRD formula does not reflect GFR in ESRD patients

BACKGROUND The Modification of Diet in Renal Disease (MDRD) equation is widely used for the estimation of glomerular filtration rate (GFR) from plasma creatinine. It has been well validated in patients with various degrees of impaired kidney function, but not in patients with end-stage renal disease (ESRD). Plasma creatinine is determined by GFR and muscle mass. Importance of the latter may increase at low GFR. Our aim was to firstly compare estimated GFR (eGFR by MDRD equation) with measured GFR (mGFR, mean of creatinine and urea clearance) just before the start of dialysis. Secondly, the relationship of eGFR and mGFR with mortality and muscle mass was analysed. METHODS ESRD patients with 24-h urine collections and a plasma sample available at the start of dialysis [n = 569, 61% male, mean (standard deviation) age 58 (15) years] were selected from the Netherlands Cooperative Study on the Adequacy of Dialysis. Incident dialysis patients were followed until death, transplantation or end of study. RESULTS mGFR was 6.0 (2.6) and eGFR was 6.8 (2.4) mL/min/1.73 m(2). Although eGFR overestimated mGFR with only 0.8 mL/min/1.73 m(2), limits of agreement ranged from - 4.1 to + 5.6 mL/min/1.73 m(2). The highest eGFR values were associated with the highest mortality rates [adjusted hazard ratio 1.4 (1.0, 1.9)]. eGFR but not mGFR was associated with muscle mass (P = 0.001). CONCLUSIONS These data imply that estimation of GFR by equations using plasma creatinine in the denominator cannot be used for this purpose in patients with ESRD because the effect of GFR on plasma creatinine is overruled by that of muscle mass.

Intravenous Iron Exposure and Mortality in Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding. RESULTS Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of >150-350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or >350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with >0-150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infection-related mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of >1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and >2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46). CONCLUSIONS Among patients on incident dialysis, receipt of ≤ 1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of >1050 mg in 3 months or >2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses.

Decline in Residual Renal Function in Automated Compared with Continuous Ambulatory Peritoneal Dialysis

BACKGROUND AND OBJECTIVES We compared the decline of RRF in patients starting dialysis on APD with those starting on CAPD, because a faster decline on APD has been suggested. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS NECOSAD patients starting dialysis on APD or CAPD with RRF at baseline were included and followed for 3 years. Residual GFR (rGFR) was the mean of urea and creatinine clearances. Differences in yearly decline of rGFR were estimated in analyses with linear repeated measures models, whereas the risk of complete loss of RRF was estimated by calculating hazard ratios (HRs) for APD compared with CAPD. As-treated (AT) and intention-to-treat (ITT) designs were used. All of the analyses were adjusted for age, gender, comorbidity, and primary kidney disease and stratified according to follow-up and mean baseline GFR. RESULTS The 505 CAPD and 78 APD patients had no major baseline differences. No differences were found in the analyses on yearly decline of rGFR. APD patients did have a higher risk of losing RRF in the first year (ITT crude HR 2.43 [confidence interval 95%, 1.48 to 4.00], adjusted 2.66 [1.60 to 4.44]; AT crude 1.89 [1.04 to 3.45], adjusted 2.15 [1.16 to 3.98]). The higher risk of losing all RRF was most pronounced in patients with the highest rGFR at baseline (ITT; crude 3.91 [1.54 to 9.94], adjusted 1.85 to 14.17). CONCLUSIONS The risk of losing RRF is higher for patients starting dialysis on APD compared with those starting on CAPD, especially in the first year.

Estimating residual kidney function in dialysis patients without urine collection

Residual kidney function contributes substantially to solute clearance in dialysis patients but cannot be assessed without urine collection. We used serum filtration markers to develop dialysis-specific equations to estimate urinary urea clearance without the need for urine collection. In our development cohort, we measured 24-hour urine clearances under close supervision in 44 patients and validated these equations in 826 patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. For the development and validation cohorts, median urinary urea clearance was 2.6 and 2.4 ml/min, respectively. During the 24-hour visit in the development cohort, serum β-trace protein concentrations remained in steady state but concentrations of all other markers increased. In the validation cohort, bias (median measured minus estimated clearance) was low for all equations. Precision was significantly better for β-trace protein and β2-microglobulin equations and the accuracy was significantly greater for β-trace protein, β2-microglobulin, and cystatin C equations, compared with the urea plus creatinine equation. Area under the receiver operator characteristic curve for detecting measured urinary urea clearance by equation-estimated urinary urea clearance (both 2 ml/min or more) were 0.821, 0.850, and 0.796 for β-trace protein, β2-microglobulin, and cystatin C equations, respectively; significantly greater than the 0.663 for the urea plus creatinine equation. Thus, residual renal function can be estimated in dialysis patients without urine collections.

Comparative Effectiveness of Early Versus Conventional Timing of Dialysis Initiation in Advanced CKD

BACKGROUND Previous observational studies examining outcomes associated with the timing of dialysis therapy initiation in the United States have often been limited by lead time and survivor bias. STUDY DESIGN Retrospective cohort study comparing the effectiveness of early versus later (conventional) dialysis therapy initiation in advanced chronic kidney disease (CKD). The analysis used inverse probability weighting to account for an individuals contribution to different exposure groups over time in a pooled logistic regression model. Patients contributed risk to both exposure categories (early and later initiation) until there was a clear treatment strategy (ie, dialysis therapy was initiated early or estimated glomerular filtration rate [eGFR] decreased to <10mL/min/1.73m(2)). SETTING & PARTICIPANTS Patients with CKD who had at least one face-to-face outpatient encounter with a Cleveland Clinic health care provider as of January 1, 2005, and at least 3 eGFRs in the range of 20-30mL/min/1.73m(2) measured at least 180 days apart. PREDICTORS Timing of dialysis therapy initiation as determined using model-based interpolation of eGFR trajectories over time. Timing was defined as early (interpolated eGFR at dialysis therapy initiation≥10mL/min/1.73m(2)) or later (eGFR < 10mL/min/1.73m(2)) and was time-varying. OUTCOMES Death from any cause occurring from the time that eGFR was equal to 20mL/min/1.73m(2) through September 15, 2009. RESULTS The study population consisted of 652 patients meeting inclusion criteria. Most (71.3%) of the study population did not initiate dialysis therapy during follow-up. Patients who did not initiate dialysis therapy (n=465) were older, more likely to be white, and had more favorable laboratory profiles than those who started dialysis therapy. Overall, 146 initiated dialysis early and 80 had eGFRs decrease to <10mL/min/1.73m(2). Many participants (n=426) were censored prior to attaining a clear treatment strategy and were considered undeclared. There was no statistically significant survival difference for the early compared with later initiation strategy (OR, 0.85; 95% CI, 0.65-1.11). LIMITATIONS Interpolated eGFR, moderate sample size, and likely unmeasured confounders. CONCLUSIONS In patients with advanced CKD, timing of dialysis therapy initiation was not associated with mortality when accounting for lead time bias and survivor bias.

Effect of intravenous iron use on hospitalizations in patients undergoing hemodialysis: a comparative effectiveness analysis from the DEcIDE-ESRD study

BACKGROUND Intravenous iron use in hemodialysis patients has greatly increased over the last decade, despite limited studies on the safety of iron. METHODS We studied the association of receipt of intravenous iron with hospitalizations in an incident cohort of hemodialysis patients. We examined 9544 patients from Dialysis Clinic, Inc. (DCI). We ascertained intravenous iron use from DCI electronic medical record and USRDS data files, and hospitalizations through Medicare claims. We examined the association between iron exposure accumulated over 1-, 3- or 6-month time windows and incident hospitalizations in the follow-up period using marginal structural models accounting for time-dependent confounders. We performed sensitivity analyses including recurrent events models for multiple hospitalizations and models for combined outcome of hospitalization and death. RESULTS There were 22 347 hospitalizations during a median follow-up of 23 months. Higher cumulative dose of intravenous iron was not associated with all-cause, cardiovascular or infectious hospitalizations [HR 0.97 (95% CI: 0.77-1.22) for all-cause hospitalizations comparing >2100 mg versus 0-900 mg of iron over 6 months]. Findings were similar in models examining the risk of hospitalizations in 1- and 3-month windows [HR 0.88 (95% CI: 0.79-0.99) and HR 0.88 (95% CI: 0.74-1.03), respectively] or the risk of combined outcome of hospitalization and death in the 6-month window [HR 0.98 (95% CI: 0.78-1.23)]. CONCLUSIONS Higher cumulative dose of intravenous iron may not be associated with increased risk of hospitalizations in hemodialysis patients. While clinical trials are needed, employing higher iron doses to reduce erythropoiesis-stimulating agents does not appear to increase morbidity in routine clinical care.

Peritoneal Membrane Failure in Peritoneal Dialysis Patients

A review is given of the conditions associated with peritoneal membrane failure, and the possible causes. Ultrafiltration failure is the most important manifestation. It is mostly associated with high transport rates of low molecular weight solutes suggesting the presence of a large vascular surface area. Enlargement of the peritoneal surface area can be functional (effective surface area: more perfused microvessels) or anatomic (more microvessels). The former is likely to be present in some patients in the beginning of peritoneal dialysis, and also during peritonitis. The latter can develop in long-term peritoneal dialysis.

Glomerular filtration rate measurements by 125I-iothalamate should be corrected for inaccurate urine collections with 131I-hippuran.

BACKGROUND Measuring GFR using exogenous markers without a bladder catheter, errors can be easily made due to incomplete urine collection. The aim was to quantify agreement for 125I-iothalamate GFR measurements with and without a correction for inaccurate urine collection using 131I-hippuran. METHODS The last available GFR measurement of adult patients was included. GFR was measured in two subsequent clearance periods with 125I-iothalamate by the standard method with correction for inaccurate urine collections using 131I-hippuran. The uncorrected and corrected GFR measurements were compared within and between the time periods for each individual patient. To study the agreement between both methods, intraclass correlation coefficients (ICC) were calculated and Bland-Altman plots, with accompanying accuracies and precisions, were used. Cohens kappa was calculated to analyze the agreement of both methods for classifying patients according to the stages of chronic kidney disease (CKD). RESULTS For the 332 stable included patients, the mean GFR of the uncorrected measurements was 77.8 ml/min (34.7) and the mean GFR of the corrected measurements was 81.0 ml/min (34.9). The ICC was 0.80 for the uncorrected measurements with an accuracy of 7.3 ml/min and a precision of 21.7 ml/min. For the corrected GFR measurements the ICC was 0.98, with an accuracy of 2.1 ml/min and a precision of 6.5 ml/min. Comparison between the methods showed an ICC of 0.95, an accuracy of 3.2 and a precision of 11.0. In total, 86% of the patients were classified similarly into CKD stages with both methods, overall Cohens kappa was 0.81. CONCLUSION Agreement was better for GFR measurements corrected for inaccurate urine collections. Therefore, GFR measurements with 125I-iothalamate should be corrected for inaccurate urine collections using 131I-hippuran. Without such correction the GFR is easily underestimated which may lead to overtreatment.

QUALITY OF LIFE IN AUTOMATED AND CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

♦ Objective: Despite a lack of strong evidence, automated peritoneal dialysis (APD) is often prescribed on account of an expected better quality of life (QoL) than that expected with continuous ambulatory peritoneal dialysis (CAPD). Our aim was to analyze differences in QoL in patients starting dialysis on APD or on CAPD with a follow-up of 3 years. ♦ Methods: Adult patients in the prospective NECOSAD cohort who started dialysis on APD or CAPD were included 3 months after the start of dialysis. The Medical Outcomes Survey Short Form 36 [SF-36 (Medical Outcomes Trust and QualityMetric, Lincoln, RI, USA)] and Kidney Disease and Quality of Life Short Form [KDQOL-SF (KDQOL Working Group, Santa Monica, CA, USA)] questionnaires were used to measure QoL. Differences in QoL over time were calculated using linear mixed models. Patients were followed until transplantation, death, or a first switch to any other dialysis modality. ♦ Results: The clinical and social characteristics of the 64 APD and 486 CAPD patients were slightly different at baseline. In the crude analysis, the pattern of the mental summary score differed between the modalities (p = 0.03, adjusted p = 0.06), because of a different pattern for role function emotional (p = 0.03, adjusted p = 0.05). The pattern of the physical summary score was not different between the groups. Scores on dialysis staff encouragement had a different pattern over time (p = 0.01), because of an inequality in scores 3 months after the start of dialysis, which disappeared after 18 months on dialysis. Over time, patients on APD scored higher on sexual function. After adjustment for age, sex, glomerular filtration rate, comorbidity, and primary kidney disease, that difference disappeared. This study showed no major differences in QoL on the KDQOL-SF and the SF-36 between the two modalities.