Search

Background: Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. Objective: To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Design: Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Setting: Research studies and clinical populations ('studies') with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. Participants: 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16032 participants in NHANES. Measurements: GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. Results: In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 [m.sup.2]), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 [m.sup.2]), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 [m.sup.2] (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 [m.sup.2], and the prevalence of chronic kidney disease was 11.5% (95% Cl, 10.6% to 12.4%) versus 13.1% (Cl, 12.1% to 14.0%). Limitation: The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. Conclusion: The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.

Background: No study has compared cystatin C level, serum creatinine concentration, and estimated glomerular filtration rate (GFR) as risk factors for outcomes in chronic kidney disease (CKD), and none has compared measured GFR with CKD in any population. Objective: To compare cystatin C level with serum creatinine concentration and iothalamate GFR as risk factors for death and kidney failure. Design: Observational study using serum cystatin C assayed from baseline samples of the Modification of Diet in Renal Disease Study (1989-1993). Setting: 15 clinical centers in the United States that participated in the Modification of Diet in Renal Disease Study. Participants: 825 trial participants with stage 3 or 4 nondiabetic CKD who had measurements of serum cystatin C. Measurements: All-cause mortality, cardiovascular (CVD) mortality, and kidney failure until December 2000. Results: Mean cystatin C level, creatinine concentration, and GFR were 2.2 mg/L (SD, 0.7), 212.16 [micro]mol/L (SD, 88.4) (2.4 mg/dL [SD, 1.0]), and 33 mL/min per 1.73 [m.sup.2] (SD, 12), respectively. Median follow-up was 10 years. Twenty-five percent of patients (n = 203) died of any cause, 15% (n = 123) died of CVD, and 66% (n = 548) reached kidney failure. In multivariate-adjusted models, 1-SD decreases in 1/creatinine, GFR, and 1/cystatin C were associated with increased risks for all-cause mortality of 1.27 (95% Cl, 1.06 to 1.49), 1.27 (Cl, 1.08 to 1.49), and 1.41 (Cl, 1.18 to 1.67), respectively. For CVD mortality, the increased risks were 1.32 (Cl, 1.05 to 1.64), 1.28 (Cl, 1.04 to 1.59), and 1.64 (Cl, 1.28 to 2.08), respectively. For kidney failure, the increased risks were 2.81 (Cl, 2.48 to 3.18), 2.41 (Cl, 2.15 to 2.70), and 2.36 (Cl, 2.10 to 2.66), respectively. Limitation: The Modification of Diet in Renal Disease Study cohort may not be representative of all patients with nondiabetic CKD because participants were more likely to reach kidney failure than death in follow-up. Conclusion: The association of cystatin C level with all-cause and CVD mortality was as strong as or perhaps stronger than that of iothalamate GFR with these outcomes in stage 3 or 4 CKD.

Background: Glomerular filtration rate (GFR) estimates facilitate detection of chronic kidney disease but require calibration of the serum creatinine assay to the laboratory that developed the equation. The 4-variable equation from the Modification of Diet in Renal Disease (MDRD) Study has been reexpressed for use with a standardized assay. Objective: To describe the performance of the revised 4-variable MDRD Study equation and compare it with the performance of the 6-variable MDRD Study and Cockcroft-Gault equations. Design: Comparison of estimated and measured GFR. Setting: 15 clinical centers participating in a randomized, controlled trial. Patients: 1628 patients with chronic kidney disease participating in the MDRD Study. Measurements: Serum creatinine levels were calibrated to an assay traceable to isotope-dilution mass spectrometry. Glomerular filtration rate was measured as urinary clearance of [sup.125]I-iothalamate. Results: Mean measured GFR was 39.8 mL/min per 1.73 [m.sup.2] (SD, 21.2). Accuracy and precision of the revised 4-variable equation were similar to those of the original 6-variable equation and better than in the Cockcroft-Gault equation, even when the latter was corrected for bias, with 90%, 91%, 60%, and 83% of estimates within 30% of measured GFR, respectively. Differences between measured and estimated GFR were greater for all equations when the estimated GFR was 60 mL/min per 1.73 [m.sup.2] or greater. Limitations: The MDRD Study included few patients with a GFR greater than 90 mL/min per 1.73 [m.sup.2]. Equations were not compared in a separate study sample. Conclusions: The 4-variable MDRD Study equation provides reasonably accurate GFR estimates in patients with chronic kidney disease and a measured GFR of less than 90 mL/min per 1.73 [m.sup.2]. By using the reexpressed MDRD Study equation with the standardized serum creatinine assay, clinical laboratories can report more accurate GFR estimates.

Background: The influence of type of dialysis on survival of patients with end-stage renal disease (ESRD) is controversial. Objective: To compare risk for death among patients with ESRD who receive peritoneal dialysis or hemodialysis. Design: Prospective cohort study. Setting: 81 dialysis clinics in 19 U.S. states. Patients: 1041 patients starting dialysis (274 patients receiving peritoneal dialysis and 767 patients receiving hemodialysis) at baseline. Measurements: Patients were followed for up to 7 years and censored at transplantation or loss to follow-up. Cox proportional hazards regression stratified by clinic was used to compare the risk for death with peritoneal dialysis versus hemodialysis. Results: Twenty-five percent of patients undergoing peritoneal dialysis and 5% of hemodialysis patients switched type of dialysis. After adjustment, the risk for death did not differ between patients undergoing peritoneal dialysis and those undergoing hemodialysis during the first year (relative hazard, 1.39 [95% CI, 0.64 to 3.06]), but the risk became significantly higher among those undergoing peritoneal dialysis in the second year (relative hazard, 2.34 [Cl, 1.19 to 4.59]). After stratification, the survival rate was no different for patients who had the highest propensity of being initially treated with peritoneal dialysis. Results were consistent with adjustment based on a propensity score model and in sensitivity analyses that used as-treated models and models in which switches in type of dialysis were treated as treatment failures. Results were similar but stronger in analyses that were restricted to patients who were treated only in clinics offering both types of dialysis. Limitations: Patients were not randomly assigned to their initial type of dialysis. Also, more patients undergoing peritoneal dialysis than hemodialysis switched type of dialysis over time, and the reason for switching was often a consequence of the technique. Conclusions: The risk for death in patients with ESRD undergoing dialysis depends on dialysis type. Further studies are needed to evaluate a possible survival benefit of a timely change from peritoneal dialysis to hemodialysis.

Background: Hypertension is a risk factor for progression of chronic kidney disease. The optimal blood pressure to slow progression is unknown. Objective: To evaluate the effects of a low target blood pressure on kidney failure and all-cause mortality. Design: Long-term follow-up of the Modification of Diet in Renal Disease Study, a randomized, controlled trial conducted from 1989 to 1993. Setting: 15 outpatient nephrology practices. Participants: 840 persons with predominantly nondiabetic kidney disease and a glomerular filtration rate of 13 to 55 mL/min per 1.73 [m.sup.2]. Intervention: A low target blood pressure (mean arterial pressure < 92 mm Hg) or a usual target blood pressure (mean arterial pressure < 107 mm Hg). Measurements: After the randomized trial was completed, kidney failure (defined as initiation of dialysis or kidney transplantation) and a composite outcome of kidney failure or all-cause mortality were ascertained through 31 December 2000. Results: Kidney failure occurred in 554 participants (66%), and the composite outcome occurred in 624 participants (74%). After Cox proportional hazards modeling and intention-to-treat analysis, the adjusted hazard ratios were 0.68 (95% CI, 0.57 to 0.82; P < 0.001) for kidney failure and 0.77 (CI, 0.65 to 0.91; P = 0.0024) for the composite outcome in the low target blood pressure group compared with the usual target blood pressure group. Evidence was insufficient to conclude that the benefit of a low target blood pressure differed according to the cause of kidney disease, baseline glomerular filtration rate, or degree of proteinuria. Limitations: The exact mechanism underlying the benefit of a low target blood pressure is unknown. Conclusions: Assignment to a low target blood pressure slowed the progression of nondiabetic kidney disease in patients with a moderately to severely decreased glomerular filtration rate.

Background: Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and urine protein excretion and slow the progression of chronic kidney disease. Purpose: To determine the levels of blood pressure and urine protein excretion associated with the lowest risk for progression of chronic kidney disease during antihypertensive therapy with and without ACE inhibitors. Data Sources: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens with or without ACE inhibitors for patients with predominantly nondiabetic kidney disease. Study Selection: MEDLINE database search for English-language studies published between 1977 and 1999. Data Extraction: Data on 1860 nondiabetic patients were pooled in a patient-level meta-analysis. Progression of kidney disease was defined as a doubling of baseline serum creatinine level or onset of kidney failure. Multivariable regression analysis was performed to asses the association of systolic and diastolic blood pressure and urine protein excretion with kidney disease progression at 22 610 patient visits. Data Synthesis: Mean duration of follow-up was 2.2 years. Kidney disease progression was documented in 311 patients. Systolic blood pressure of 110 to 129 mm Hg and urine protein excretion less than 2.0 g/d were associated with the lowest risk for kidney disease progression. Angiotensin-converting enzyme inhibitors remained beneficial after adjustment for blood pressure and urine protein excretion (relative risk, 0.67 [95% CI, 0.53 to 0.84]). The increased risk for kidney progression at higher systolic blood pressure levels was greater in patients with urine protein excretion greater than 1.0 g/d (P < 0.006). Conclusion: Although reverse causation cannot be excluded with certainty, a systolic blood pressure goal between 110 and 129 mm Hg may be beneficial in patients with urine protein excretion greater than 1.0 g/d. Systolic blood pressure less than 110 mm Hg may be associated with a higher risk for kidney disease progression.

Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Outcomes of chronic kidney disease include not only kidney failure but also complications of decreased kidney function and cardiovascular disease. Current evidence suggests that some of these adverse outcomes can be prevented or delayed by early detection and treatment. Unfortunately, chronic kidney disease is underdiagnosed and undertreated, in part as a result of lack of agreement on a definition and classification of its stages of progression. Recent clinical practice guidelines by the National Kidney Foundation 1) define chronic kidney disease and classify its stages, regardless of underlying cause, 2) evaluate laboratory measurements for the clinical assessment of kidney disease, 3) associate the level of kidney function with complications of chronic kidney disease, and 4) stratify the risk for loss of kidney function and development of cardiovascular disease. The guidelines were developed by using an approach based on the procedure outlined by the Agency for Healthcare Research and Quality. This paper presents the definition and five-stage classification system of chronic kidney disease and summarizes the major recommendations on early detection in adults. Recommendations include identifying persons at increased risk (those with diabetes, those with hypertension, those with a family history of chronic kidney disease, those older than 60 years of age, or those with U.S. racial or ethnic minority status), detecting kidney damage by measuring the albumin-creatinine ratio in untimed ('spot') urine specimens, and estimating the glomerular filtration rate from serum creatinine measurements by using prediction equations. Because of the high prevalence of early stages of chronic kidney disease in the general population (approximately 11% of adults), this information is particularly important for general internists and specialists.

Background: Care for chronic renal failure involves management of complications and preparation for possible dialysis. Patients often are not evaluated by nephrologists in a timely manner. Objective: To identify factors associated with a late evaluation by a nephrologist and to assess whether late evaluation is associated with worse survival once patients develop end-stage renal disease (ESRD). Design: National prospective cohort study. Setting: 81 dialysis facilities throughout the United States. Patients: 828 patients with new-onset ESRD. Measurements: Time from first evaluation by a nephrologist to initiation of dialysis, classified as late (12 months); rate of death, from initiation of dialysis to an average of 2.2 years of follow-up; and demographic, clinical, and laboratory characteristics. Results: After adjustment for potential confounders, late evaluation was more common among black men than white men (44.8% vs. 24.5%; P Conclusions: Late evaluation of patients with chronic renal failure by a nephrologist is associated with greater burden and severity of comorbid disease, black ethnicity, lack of health insurance, and shorter duration of survival.

Background: Chronic renal insufficiency leads to muscle wasting, which may be exacerbated by low-protein diets prescribed to delay disease progression. Resistance training increases protein utilization and muscle mass. Objective: To determine the efficacy of resistance training in improving protein utilization and muscle mass in patients with chronic renal insufficiency treated with a low-protein diet. Design: Randomized, controlled trial. Setting: Tufts University, Boston, Massachusetts. Patients: 26 older patients with moderate renal insufficiency (17 men, 9 women) who had achieved stabilization on a low-protein diet. Intervention: During a run-in period of 2 to 8 weeks, patients were instructed and their adherence to the low-protein diet (0.6 g/kg of body weight per day) was evaluated. They were randomly assigned to a low-protein diet plus resistance training (n=14) or a low-protein diet alone (n=12) for 12 weeks. Measurements: Total body potassium, mid-thigh muscle area, type I and II muscle-fiber cross-sectional area, and protein turnover. Results: Mean protein intake was 0.64 +/- 0.07 g/kg per day after stabilization. Total body potassium and type I and II muscle-fiber cross-sectional areas increased in patients who performed resistance training by a mean (+/-SD) of 4% +/- 8%, 24% +/- 31%, and 22% +/- 29%, respectively, compared with those who did not. Leucine oxidation and serum prealbumin levels also improved significantly. Patients assigned to resistance training maintained body weight compared with those who were not. Improvement in muscle strength was significantly greater with resistance training (32% +/- 14%) than without (-13% +/- 20%) (P Conclusion: By improving muscle mass, nutritional status, and function, resistance training seems to be effective against the catabolism of a low-protein diet and uremia in patients with renal failure.

Purpose: To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. Data Sources: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. Study Selection: Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. Data Extraction: Data on 1860 nondiabetic patients were analyzed. Data Synthesis: Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P=0.03 and P=0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. Conclusion: Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.

Background: The effect of angiotensin-converting enzyme (ACE) inhibitors in slowing the decline in renal function in nondiabetic renal disease varies among studies. Purpose: To use meta-analysis to assess the effect of ACE inhibitors on the development of end-stage renal disease caused by factors other than diabetes. Data Sources: The English-language medical literature, identified by a MEDLINE search, and unpublished studies. Study Selection: All randomized studies that compared ACE inhibitors with other antihypertensive agents and had at least 1 year of planned follow-up were selected. Studies of diabetic renal disease and renal transplants were excluded. A total of 1594 patients in 10 studies was included. Data Extraction: Data on end-stage renal disease, death, drop out, and blood pressure were extracted. Study investigators confirmed results and provided additional data. Data Synthesis: Among 806 patients receiving ACE inhibitors, 52 (6.4%) developed end-stage renal disease and 17 (2.1%) died; in the 788 controls, the respective values were 72 (9.1%) and 12 (1.5%). The pooled relative risks were 0.70 (95% Cl, 0.51 to 0.97) for end-stage renal disease and 1.24 (Cl, 0.55 to 2.83) for death; the studies were not significantly heterogeneous. The decreases in weighted mean systolic and diastolic blood pressures during follow-up were 4.9 and 1.2 mm Hg greater, respectively, in the patients who received ACE inhibitors. Conclusions: Angiotensin-converting enzyme inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage nondiabetic renal disease, and they do not increase mortality. it could not be determined whether this beneficial effect is due to the greater decline in blood pressure or to other effects of ACE inhibition. This paper is also available at http://www.acponline.org., Fewer patients with non-diabetic kidney disease taking angiotensin-converting enzyme (ACE) inhibitors appear to develop life-threatening kidney complications compared to those taking other medications to lower blood pressure. Of 1,594 patients in 10 studies, 6.4% taking ACE inhibitors and 9.1% taking other medications developed kidney failure. Two percent of those taking ACE inhibitors and 1.5% of those taking other medications died. Patients taking ACE inhibitors had greater decreases in blood pressure than those taking other medications.

Background: Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restriction is beneficial. Purpose: To use meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the recently completed Modification of Diet in Renal Disease Study. Data Sources: The English-language medical literature published from January 1966 through December 1994 was searched for studies examining the effect of low-protein diets in humans with chronic renal disease. A total of 1413 patients in five studies of nondiabetic renal disease (mean length of follow-up, 18 to 36 months) and 108 patients in five studies of type I diabetes mellitus (mean length of follow-up, 9 to 35 months) were included. Study Selection: Randomized, controlled studies were selected for nondiabetic renal disease; randomized, controlled studies or time-controlled studies with nonrandomized crossover design were selected for diabetic nephropathy. Data Extraction: Data in tables, figures, or text were independently extracted by two of the authors. Data Synthesis: The relative risk for progression of renal disease in patients receiving a low-protein diet compared with patients receiving a usual-protein diet was calculated by using a random-effects model. in five studies of nondiabetic renal disease, a low-protein diet significantly reduced the risk for renal failure or death (relative risk, 0.67 [95% Cl, 0.50 to 0.89]). In five studies of insulin-dependent diabetes mellitus, a low-protein diet significantly slowed the increase in urinary albumin level or the decline in glomerular filtration rate or creatinine clearance (relative risk, 0.56 [Cl, 0.40 to 0.77]). Tests for heterogeneity showed no significant differences in relative risk among studies of either diabetic or nondiabetic renal disease. No significant differences were seen between diet groups in pooled mean arterial blood pressure (diabetic and nondiabetic patients) or glycosylated hemoglobin level (diabetic patients only). Conclusion: Dietary protein restriction effectively slows the progression of both diabetic and nondiabetic renal diseases., Restricting protein intake may delay the progression of chronic kidney disease. Researchers performed a search of the medical literature from 1966 to 1994 to find studies on the association between low-protein diets and chronic kidney disease. Five studies comprising 1,413 patients with nondiabetic kidney disease and five studies comprising 108 patients with diabetic kidney disease were identified. Restricting protein intake through diet was found to significantly delay the progression of kidney disease in both diabetic and nondiabetic patients. Low-protein diets were associated with reduced risks of kidney failure and of death. The suggested daily protein intake for a low-protein diet is 0.6 grams per kilogram of body weight. Patients must receive protein that can be used by the body and that contains enough calories.

Computer programs are needed to allow physicians to easily combine data from different clinical trials, a technique called meta-analysis. A group of researchers published two papers on the use of antilymphocyte antibodies to prevent graft rejection in kidney transplant recipients. One paper analyzed group data from clinical trials and the other analyzed individual patient data provided by physicians. Individual-patient meta-analysis revealed several facts about the treatment that had not been detected by the group-data meta-analysis. However, individual-patient meta-analysis is complicated and expensive, and needs to be simplified.