Xuelei Wang

Performance of the Modification of Diet in Renal Disease and Cockcroft-Gault Equations in the Estimation of GFR in Health and in Chronic Kidney Disease

The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

Uric Acid and Long-term Outcomes in CKD

BACKGROUND Hyperuricemia is prevalent in patients with chronic kidney disease (CKD); however, data are limited about the relationship of uric acid levels with long-term outcomes in this patient population. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N = 840) conducted from 1989 to 1993 to examine the effects of strict blood pressure control and dietary protein restriction on progression of stages 3 to 4 CKD. This analysis included 838 patients. PREDICTOR Uric acid level. OUTCOMES & MEASUREMENTS The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular disease (CVD) mortality, and kidney failure. RESULTS Mean age was 52 +/- 12 (SD) years, glomerular filtration rate was 33 +/- 12 mL/min/1.73 m(2), and uric acid level was 7.63 +/- 1.66 mg/dL. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) died of CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.07 to 2.32), a trend toward CVD mortality (HR, 1.47; 95% CI, 0.90 to 2.39), and no association with kidney failure (HR, 1.20; 95% CI, 0.95 to 1.51) compared with the lowest tertile. In continuous analyses, a 1-mg/dL greater uric acid level was associated with 17% increased risk of all-cause mortality (HR, 1.17; 95% CI, 1.05 to 1.30) and 16% increased risk of CVD mortality (HR, 1.16; 95% CI, 1.01 to 1.33), but was not associated with kidney failure (HR, 1.02; 95% CI, 0.97 to 1.07). LIMITATIONS Primary analyses were based on a single measurement of uric acid. Results are generalizable primarily to relatively young white patients with predominantly nondiabetic CKD. CONCLUSIONS In patients with stages 3 to 4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality, but not kidney failure.

Adiponectin and Mortality in Patients with Chronic Kidney Disease

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular filtration rate (GFR) rate was 33 +/- 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean +/- SD adiponectin was 12.8 +/- 8.0 mug/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-mug/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Longitudinal progression trajectory of GFR among patients with CKD.

BACKGROUND The traditional paradigm of glomerular filtration rate (GFR) progression in patients with chronic kidney disease (CKD) is a steady nearly linear decline over time. We describe individual GFR progression trajectories over 12 years of follow-up in participants in the African American Study of Kidney Disease and Hypertension (AASK). STUDY DESIGN Longitudinal observational study. SETTING & PARTICIPANTS 846 AASK patients with at least 3 years of follow-up and 8 GFR estimates. MEASUREMENTS Longitudinal GFR estimates from creatinine-based equations. PREDICTORS Patient demographic and clinical features. OUTCOMES Probability of a nonlinear trajectory and probability of a period of nonprogression calculated for each patient from a Bayesian model of individual estimated GFR (eGFR) trajectories. RESULTS 352 (41.6%) patients showed a > 0.9 probability of having either a nonlinear trajectory or a prolonged nonprogression period; in 559 (66.1%), the probability was > 0.5. Baseline eGFR > 40 mL/min/1.73 m2 and urine protein-creatinine ratio < 0.22 g/g were associated with a higher likelihood of a nonprogression period. 74 patients (8.7%) had both a substantial period of stable or increasing eGFR and a substantial period of rapid eGFR decrease. LIMITATIONS Clinical trial population; absence of direct GFR measurements. CONCLUSIONS In contrast to the traditional paradigm of steady GFR progression over time, many patients with CKD have a nonlinear GFR trajectory or a prolonged period of nonprogression. These findings highlight the possibility that stable kidney disease progression can accelerate and, conversely, provide hope that CKD need not be relentlessly progressive. These results should encourage researchers to identify time-dependent factors associated with periods of nonprogression and other desirable trajectories.

Cystatin C as a risk factor for outcomes in chronic kidney disease.

Context Does cystatin C, glomerular filtration rate (GFR), or creatinine better predict mortality? Contribution This study examined long-term outcomes of 825 adults with nondiabetic chronic kidney disease who had participated in 2 trials of protein restriction in the early 1990s. Higher cystatin C and creatinine levels and lower GFR at baseline were all associated with an increased risk for kidney failure and for all-cause and cardiovascular mortality. Associations between cystatin C and cardiovascular mortality seemed slightly stronger than those between GFR or creatinine and cardiovascular mortality. Implication Cystatin C levels seem to be at least as strongly associated with mortality as either GFR or creatinine concentration in adults with nondiabetic chronic kidney disease. The Editors Mild to moderate reductions in kidney function are associated with a marked increase in the risk for cardiovascular disease (CVD) (14). Assessing the degree of kidney function is now recognized as an important component of risk stratification for CVD morbidity and mortality. Cystatin C is a novel measure of kidney function (5, 6) that seems to be less sensitive than creatinine to factors other than glomerular filtration rate (GFR), particularly muscle mass (7). Thus, the serum cystatin C level may be a better marker of kidney function than the serum creatinine concentration, especially in elderly persons and in the setting of mild kidney dysfunction (8, 9). Cystatin C is easily measured in serum, making it a practical alternative to measured GFR, which is too cumbersome for clinical practice. Studies in elderly persons suggest that the cystatin C level has a stronger association with CVD events than do creatinine concentration and GFR estimated from serum creatinine (1012). No study has compared cystatin C and serum creatinine as risk factors for outcomes in persons with established chronic kidney disease (CKD). Furthermore, no study has compared outcomes on the basis of cystatin C level versus measured GFR, the gold standard for measurement of kidney function. We examined the associations of cystatin C level, creatinine concentration, and measured GFR with all-cause and CVD mortality and kidney failure in patients with CKD stages 3 to 4. Methods Study Sample The Modification of Diet in Renal Disease (MDRD) Study, conducted from 1989 to 1993, was a randomized, controlled trial of the effect of dietary protein restriction and blood pressure control on the progression of kidney disease (13). In brief, 840 patients with predominantly nondiabetic kidney disease and reduced GFR were included in the MDRD Study. Key inclusion criteria were age 18 to 70 years and a serum creatinine concentration of 106.08 to 618.81 mol/L (1.2 to 7.0 mg/dL) in women and 123.76 to 618.81 mol/L (1.4 to 7.0 mg/dL) in men. Glomerular filtration rate was measured at screening and again after a 3-month baseline period, during which patients were instructed about the study procedures, dietary protein intake, and control of blood pressure. We use the term screening GFR to refer to the first baseline GFR for screening and the term 3-month baseline GFR to refer to the GFR measured at the end of the 3-month baseline period. The range of screening GFR (10 to 65 mL/min per 1.73 m2) was less restrictive than the range for 3-month baseline GFR (13 to 55 mL/min per 1.73 m2). Patients were eligible for study A if their 3-month baseline GFR was 25 to 55 mL/min per 1.73 m2 and for study B if it was 13 to 24 mL/min per 1.73 m2. Patients in studies A and B were combined for the current analyses. Because the measured GFR ranged from 13 to 55 mL/min per 1.73 m2, with 6% of the cohort having a GFR less than 15 mL/min per 1.73 m2, the study sample consists predominantly of patients with stage 3 or 4 CKD, as defined by the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (14). Baseline Measurement of Kidney Function Glomerular filtration rate was measured by using iothalamate clearance (15). After subcutaneous injection of 125I-iothalamate, investigators collected 4 consecutive urine and 5 serum samples after an equilibration period of 1 hour. Measurements of serum and urine radioactivity were performed at the central MDRD Study laboratory. Glomerular filtration rate was calculated as the time-weighted averages of urine excretion rates and the serum concentration of the marker over the collection periods and was adjusted for body surface area. Estimated GFR was calculated from baseline serum creatinine concentration by using the 4-variable MDRD Study equation: 186.3(serum creatinine concentration1.154)(age0.203)1.212 (if black)0.742 (if female) (16). Serum creatinine was measured at baseline at the Cleveland Clinic Foundation, Cleveland, Ohio, by using the kinetic alkaline picrate assay on a Beckman Astra CX3 (Beckman, Fullerton, California). Cystatin C was measured in frozen samples collected at baseline from 825 participants of the MDRD Study. Samples were assayed for cystatin C by using a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring, Deerfield, Illinois). Measurement of a quality control specimen was included in each analytic run. Calculation of the SD and the coefficient of variation demonstrated an interrun precision for the assay of 5.6% (mean cystatin C level, 1.62 mg/L [SD, 0.09]; n= 14). Outcomes We assessed 4 outcomes: all-cause mortality, CVD mortality, kidney failure (the need for renal replacement therapy with dialysis or transplantation), and a composite outcome of kidney failure and all-cause mortality. We ascertained survival status and cause of death from the National Death Index and ascribed deaths to CVD if the primary cause of death was International Classification of Diseases, Ninth Revision, codes 390 to 459 or if kidney disease was listed as the primary cause of death and CVD was the secondary cause. We defined survival time as the time from randomization to death or end of follow-up (31 December 2000). We obtained kidney failure outcomes from the U.S. Renal Data System. The institutional review boards of The Cleveland Clinic, Cleveland, Ohio, and TuftsNew England Medical Center, Boston, Massachusetts, approved the data collection procedures. Statistical Analysis We compared baseline characteristics of the study sample across quartiles of serum cystatin C values and calculated P values for linear trend. We also compared baseline characteristics across quartiles of estimated GFR (Appendix Table). Because serum cystatin C and creatinine vary as the inverse of GFR, we used the inverse of serum cystatin C (1/cystatin C) and creatinine (1/creatinine) to facilitate direct comparison with GFR. Pearson correlations were used to examine univariate associations among the 3 measures of kidney function. We calculated incidence rates for all-cause mortality, CVD mortality, and kidney failure by quartiles of each baseline measure of kidney function: 1/creatinine, GFR, estimated GFR, and 1/cystatin C. Appendix Table. Baseline Characteristics, by Quartile of Estimated Glomerular Filtration Rate* We compared the association of the baseline measures of kidney function with outcomes by using unadjusted and adjusted Cox proportional hazards models. Covariates specified a priori in the adjusted models were age, race, sex, smoking, history of diabetes and CVD, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and log-transformed proteinuria. Models for kidney failure and the composite outcome were adjusted for cause of kidney disease in addition to the previously listed covariates. The models for the mortality outcomes included patients with kidney failure and were censored only at death or the end of follow-up. The models for kidney failure and the composite outcome were censored at kidney failure, death, or the end of follow-up. We repeated the adjusted Cox models for each of the 4 outcomes after additional adjustment for log-transformed C-reactive protein (CRP) level. We entered the measures of kidney function as continuous variables (1/creatinine, GFR, and 1/cystatin) and calculated the hazard ratios and 95% CIs per 1-SD change in each measure to allow a standardized comparison across measures with the same scale. We tested for nonlinearity by examining the functional form of the relationship of all-cause mortality risk and CVD mortality risk versus each marker of kidney function as a continuous variable while controlling for the covariates by fitting a cubic smoothing spline. We tested proportional hazards assumptions by using log(log) survival plots and plots of Schoenfeld residuals versus survival time. We used S-Plus, version 6.2 (Insightful Corp., Seattle, Washington), and SPSS, version 14.0 (SPSS, Chicago, Illinois), to perform the statistical analyses. Additional Analyses We repeated the adjusted Cox models for each outcome by using 2 additional measures of kidney function. First, we used estimated GFR because measuring GFR is impractical in clinical practice and research settings and, hence, GFR estimated from the serum creatinine concentration is often used as a surrogate measure. Second, to reduce variability in GFR measurements, we used the average of 2 baseline iothalamate GFR measurements performed 3 months apart. Sensitivity Analyses Transformation of cystatin C and serum creatinine values may make the expressions of their effects relative to SDs less comparable than if no transformation had been performed. To address this issue, we repeated the unadjusted Cox models with hazard ratios comparing the 80th to the 20th percentile of decreasing kidney function. Because entry criteria into the MDRD Study were based on GFR values, the range of GFR, but not of cystatin C or creatinine, is artificially restricted by study design. To address this limitation, we performed 2 sets of sensitivity analyses. First, because study entry was based o

Assessing Glomerular Filtration Rate by Estimation Equations in Kidney Transplant Recipients

Surveillance of glomerular filtration rate (GFR) is crucial in the management of kidney transplant recipients. With especial emphasis on serum creatinine (SCr) calibration assay, we assessed the performance of estimation equations as compared to iothalamate GFR (iGFR) in 209 patients using the modification of diet in renal disease (MDRD), Nankivell and Cockcroft‐Gault methods. Fifty‐five percent of patients were treated with a calcineurin inhibitor (CNI) and all were taken trimethroprim‐sulfametoxazole at the time of SCr measurement. The mean iGFR was 44 ± 26 mL/min/1.73 m2. The MDRD equation showed a median difference of 0.9 mL/min/1.73 m2 with 53% of estimated GFR within 20% of iGFR. Median differences were 7.5 and 7.0 mL/min/1.73 m2 for Nankivell and Cockcroft‐Gault formulas, respectively. The accuracy of the Nankivell and Cockcroft‐Gault formulas was such that only 38% and 37% of estimations, respectively, fell within 20% of iGFR. The performance of all equations was not uniform throughout the whole range of GFR, with some deterioration at the extremes of GFR levels. In addition, good performance of the MDRD equation was seen in subjects taking CNI. In conclusion, the overall performance of the MDRD equation was superior to the Nankivell and Cockcroft‐Gault formulas in renal transplant recipients including subjects treated with CNI.

Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease

BACKGROUND C-Reactive protein (CRP) level is elevated in kidney failure and may be related to malnutrition and cardiovascular disease (CVD). Data are limited regarding relationships between CRP levels and glomerular filtration rate (GFR), nutritional indices, and CVD in patients with earlier stages of kidney disease. METHODS CRP was assayed from samples from the Modification of Diet in Renal Disease (MDRD) Study (n = 801). CRP distributions were compared between the MDRD Study and National Health and Nutrition Examination Survey (NHANES; 1999 to 2000). Associations between CRP level and GFR, nutritional indices, serum albumin levels, and CVD risk factors were examined in the MDRD Study. RESULTS Geometric means of CRP, adjusted for age and sex, were similar in NHANES (0.23 mg/dL) and the MDRD Study (0.22 mg/dL). In the MDRD Study, CRP level was related directly to measures of body fat and CVD risk factors, inversely with serum albumin level and energy intake, and unrelated to GFR. In multivariable analysis adjusting for other determinants of serum albumin level, high CRP level (>0.6 mg/dL) was associated with a 0.07-g/dL (0.7-g/L; 95% confidence interval [CI], 0.03 to 0.12) lower mean serum albumin level. After adjusting for traditional CVD risk factors, the odds of CVD were 1.73 (95% CI, 1.07 to 2.78) times greater in subjects with a high CRP level. CONCLUSION GFR level does not appear to influence CRP level in the earlier stages of chronic kidney disease. CRP levels are independently associated with serum albumin level and CVD prevalence. Inflammation may be involved in the pathophysiological state of malnutrition and CVD in the earlier stages of predominantly nondiabetic kidney disease.

Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans

BACKGROUND Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. METHODS Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. RESULTS During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). CONCLUSION Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.

Effect of a Very Low-Protein Diet on Outcomes: Long-term Follow-up of the Modification of Diet in Renal Disease (MDRD) Study

BACKGROUND The long-term effect of a very low-protein diet on the progression of kidney disease is unknown. We examined the effect of a very low-protein diet on the development of kidney failure and death during long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. STUDY DESIGN Long-term follow-up of study B of the MDRD Study (1989-1993). SETTING & PARTICIPANTS The MDRD Study examined the effects of dietary protein restriction and blood pressure control on progression of kidney disease. This analysis includes 255 trial participants with predominantly stage 4 nondiabetic chronic kidney disease. INTERVENTION A low-protein diet (0.58 g/kg/d) versus a very low-protein diet (0.28 g/kg/d) supplemented with a mixture of essential keto acids and amino acids (0.28 g/kg/d). OUTCOMES Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality until December 31, 2000. RESULTS Kidney failure developed in 227 (89%) participants, 79 (30.9%) died, and 244 (95.7%) reached the composite outcome of either kidney failure or death. Median duration of follow-up until kidney failure, death, or administrative censoring was 3.2 years, and median time to death was 10.6 years. In the low-protein group, 117 (90.7%) participants developed kidney failure, 30 (23.3%) died, and 124 (96.1%) reached the composite outcome. In the very low-protein group, 110 (87.3%) participants developed kidney failure, 49 (38.9%) died, and 120 (95.2%) reached the composite outcome. After adjustment for a priori-specified covariates, hazard ratios were 0.83 (95% confidence interval, 0.62 to 1.12) for kidney failure, 1.92 (95% confidence interval, 1.15 to 3.20) for death, and 0.89 (95% confidence interval, 0.67 to 1.18) for the composite outcome in the very low-protein diet group compared with the low-protein diet group. LIMITATIONS Lack of dietary protein measurements during follow-up. CONCLUSION In long-term follow-up of the MDRD Study, assignment to a very low-protein diet did not delay progression to kidney failure, but appeared to increase the risk of death.