Julia B. Lewis

A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation

The glomerular filtration rate (GFR) is traditionally considered the best overall index of renal function in health and disease (1). Because GFR is difficult to measure in clinical practice, most clinicians estimate the GFR from the serum creatinine concentration. However, the accuracy of this estimate is limited because the serum creatinine concentration is affected by factors other than creatinine filtration (2, 3). To circumvent these limitations, several formulas have been developed to estimate creatinine clearance from serum creatinine concentration, age, sex, and body size (4-12). Despite more recent studies that have related serum creatinine concentration to GFR (13-24), no formula is more widely used to predict creatinine clearance than that proposed by Cockcroft and Gault (4). This formula is used to detect the onset of renal insufficiency, to adjust the dose of drugs excreted by the kidney, and to evaluate the effectiveness of therapy for progressive renal disease. More recently, it has been used to document eligibility for reimbursement from the Medicare End Stage Renal Disease Program (25) and for accrual of points for patients on the waiting list for cadaveric renal transplantation (26). Major clinical decisions in general medicine, geriatrics, and oncology (as well as nephrology) are made by using the Cockcroft-Gault formula and other formulas to predict the level of renal function. Therefore, these formulas must predict GFR as accurately as possible. The Modification of Diet in Renal Disease (MDRD) Study, a multicenter, controlled trial, evaluated the effect of dietary protein restriction and strict blood pressure control on the progression of renal disease (27-30). During the baseline period, GFR, serum creatinine, and several variables that affect the relation between them were measured in patients with chronic renal disease. The purpose of our study was to develop an equation from MDRD Study data that could improve the prediction of GFR from serum creatinine concentration. Methods Baseline Cohort and Measurement Methods in the Modification of Diet in Renal Disease Study The overall study design and methods of recruitment for the MDRD Study have been described elsewhere (31, 32). A total of 1785 patients entered the baseline period. Of these patients, 1628 (91%) also underwent measurement of GFR and the other variables described below; these patients constitute the study group for these analyses. Glomerular filtration rate was measured as the renal clearance of 125I-iothalamate (33, 34). Creatinine clearance was computed from creatinine excretion in a 24-hour urine collection and a single measurement of serum creatinine. Serum and urine creatinine were measured by using a kinetic alkaline picrate assay with a normal range in serum of 62 to 124 mol/L (0.7 to 1.4 mg/dL) (35). Glomerular filtration rate and creatinine clearance were expressed per 1.73 m2 of body surface area by multiplying measured values by 1.73/body surface area (36). The serum and urine specimens were also used for other measurements, including serum albumin (bromcresol green method [35]), serum urea nitrogen (urease method [35]), and urine urea nitrogen (urease method [35]). Protein intake (g/d) was estimated as 6.25 [UUN (g/d) + 0.031 (g/kg per day) SBW (kg)], where UUN is urine urea nitrogen, SBW is standard body weight, and 0.031 g/kg per day is a constant reflecting the rate of excretion of nitrogen in compounds other than urine urea (37, 38). The diagnosis of diabetes and the cause of renal disease were assigned on the basis of chart review at the clinical center (39). Statistical Analysis Descriptive Statistics The relation of renal function measurements to other baseline characteristics was assessed by using contingency tables, t-tests, analysis of variance, and linear regression, as appropriate. Nonparametric tests (Wilcoxon rank-sum tests and Kruskal-Wallis tests) gave consistent results. A P value less than 0.01 was considered statistically significant. Multivariable Analysis of Glomerular Filtration Rate We used stepwise multiple regression to determine a set of variables that jointly predicted GFR. The stepwise regression models were developed by using a training sample consisting of a random sample of 1070 of the 1628 patients. We found that the variability of the difference between the observed and predicted GFR values was greater for higher GFR values. This increase was eliminated by performing multiple regressions on log-transformed data. To facilitate clinical interpretation, the results were re-expressed in terms of the original units. Consequently, the prediction equation is a multiplicative model; regression coefficients refer to the change in geometric mean GFR associated with unit changes in the independent variable. Predicted GFR is expressed in mL/min per 1.73 m2. The following variables were considered for possible inclusion in the regression model: weight, height, sex, ethnicity, age, diagnosis of diabetes, serum creatinine concentration, serum urea nitrogen level, serum albumin level, serum phosphorus level, serum calcium level, mean arterial pressure, urine creatinine level, urine urea nitrogen level, urine protein level, and urine phosphorus level. The cause of renal disease was not included because in clinical practice, the cause may be unknown or clinicians may not use the same classification method as the investigators in the MDRD Study. A P value less than 0.001 was used as the criterion for entry of a variable into the model. Because of the difficulty in collecting complete 24-hour urine samples in clinical practice, an additional stepwise regression was performed to develop a prediction model that did not include urine biochemistry variables. Finally, because of the interest in developing a prediction equation to assess eligibility for Medicare reimbursement and listing for cadaveric renal transplantation, we repeated the analysis restricting the population to the subgroup of patients with higher serum creatinine concentrations (>221 mol/L [2.5 mg/dL]; n=509 in the training sample). Methods for Comparing Equations To Predict Glomerular Filtration Rate We first developed coefficients for each prediction equation (including the selection of the predictor variables for the stepwise regressions) using the data from the training sample to predict log GFR. Each prediction equation also included a multiplicative constant to account for any consistent bias in the application of that equation in the MDRD Study Group. This was particularly important for equations that are intended to estimate creatinine clearance, which is known to be higher than GFR. The regression coefficients determined in the training sample were then applied to obtain predicted GFRs in a separate validation sample consisting of the remaining 558 patients (172 patients with serum creatinine concentration>221 mol/L [2.5 mg/dL]). These predicted GFR values were compared with the actual GFRs in the validation sample to evaluate the performance of each prediction equation. In this way, separate data sets were used to construct the equations and assess their accuracy after removal of systematic bias. For each equation, we computed overall R 2 (percentage of variability in log GFR explained by the regression model) and the 50th, 75th, and 90th percentiles of the distribution of the percentage absolute difference between measured and predicted GFRs in the validation sample. The 50th percentiles indicate the typical size of the errors in prediction of GFR, and the 75th and 90th percentiles assess the sizes of the larger errors that occurred for each model. Development of Final Prediction Equations To improve the accuracy of the final MDRD Study prediction equations, the regression coefficients derived from the training sample were updated on the basis of data from all 1628 patients. As a result, the standard errors of the regression coefficients in the final MDRD Study prediction equations are slightly smaller than those derived from the training sample; thus, the accuracy of the final prediction equations may be slightly better (by about 0.1% to 0.2%) than their accuracy as assessed in the validation sample. Results Demographic and Clinical Characteristics The mean age ( SD) of the cohort was 50.6 12.7 years. Sixty percent of patients were male, 88% were white, and 6% were diabetic. Causes of renal disease were glomerular disease (32%), polycystic kidney disease (22%), tubulointerstitial disease (7%), and other or unknown renal diseases (40%). Mean protein intake was 0.99 0.24 g/kg of body weight per day and mean arterial pressure was 99.4 12.2 mm Hg. Mean weight was 79.6 16.8 kg, body surface area was 1.91 0.23 m2, serum urea nitrogen concentration was 11.4 5.7 mmol/L [32 16 mg/dL], and serum albumin concentration was 40.0 4.0 g/L [4.0 0.4 g/dL], respectively. Glomerular Filtration Rate, Creatinine Clearance, and Serum Creatinine Concentration Renal function measurements for the study group and for various subgroups are shown in Table 1. Mean GFR for the population was 0.38 mL s 2 m 2 (39.8 mL/min per 1.73 m2), with lower values in patients with lower protein intake, white patients compared with black patients, and older patients ( 55 years) compared with younger patients (P<0.01). The mean value of creatinine clearance was 0.81 mL s 2 m 2 (48.6 mL/min per 1.73 m2) and was lower in older patients and patients with lower protein intake (P 0.01). The mean serum creatinine concentration was 203 mol/L (2.3 mg/dL) and was higher in men, patients with lower protein intake, and patients with higher mean arterial pressure (P 0.01). Figure 1 shows the well-known reciprocal relation of serum creatinine concentration to GFR for subgroups based on sex and ethnicity. At any given GFR, the serum creatinine concentration is significantly higher in men than in women and in black persons than in white persons (P<0.001). Table 1. Association of Renal Fu

Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. METHODS We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. RESULTS The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. CONCLUSIONS Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

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.)

Comparative Performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study Equations for Estimating GFR Levels Above 60 mL/min/1.73 m2

BACKGROUND The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)>or=60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics. STUDY DESIGN Test of diagnostic accuracy. SETTING & PARTICIPANTS Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index. INDEX TESTS eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine. REFERENCE TEST Measured GFR using urinary or plasma clearance of exogenous filtration markers. RESULTS Mean measured GFR was 68+/-36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR>or=90 mL/min/1.73 m2. LIMITATIONS Limited number of elderly people and racial and ethnic minorities with measured GFR. CONCLUSIONS The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR>or=60 mL/min/1.73 m2 can be reported using the CKD-EPI equation.

Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy

Context Previously published results of this randomized, double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy. Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine. Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks. Cautions The trial had limited power to detect important differences between groups in mortality or strokes, and most patients received several antihypertensive agents. The Editors Patients with diabetes have an increased risk for cardiovascular complications and death (1). Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes (2-5) or were done exclusively in patients with diabetes (6-8). The meta-analysis of these studies (9), the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation (HOPE) study (2), and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial (5) demonstrated that angiotensin-converting enzyme (ACE) inhibitors (2, 9) and angiotensin-receptor blockers (5) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events. These studies randomly assigned few patients with renal involvement and overt proteinuria. Overt proteinuria occurred in fewer than 20% of the 470 patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (6), and only 11% of the 1195 patients in the LIFE trial (5). The Captopril Prevention Project (CAPP) (3) and the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) (4) did not state the number of patients with diabetes and overt proteinuria. There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) (7), and patients with dipstick-positive albuminuria were excluded from the HOPE trial (2). Since proteinuria is an independent risk factor for cardiovascular disease (10, 11), the data obtained in the aforementioned trials cannot be extrapolated to patients with type 2 diabetes and overt nephropathy. Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy (12, 13) without a change in all-cause mortality. Apart from studies in heart failure, few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers. We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial (IDNT) (12) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents. Methods Patients The IDNT was a randomized, double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy. The protocol of this study has been published (12, 14). Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy, as evidenced by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater, serum creatinine level of 89 mol/L (1.0 mg/dL) to 266 mol/L (3.0 mg/dL) in women or of 106 mol/L (1.2 mg/dL) to 266 mol/L (3.0 mg/dL) in men, and baseline seated blood pressure greater than 135/85 mm Hg. The institutional review boards of each center approved the protocol. All patients gave written informed consent. Treatment and Randomization Patients were randomly assigned centrally by computer to receive treatment with irbesartan, 300 mg/d (Avapro, Bristol-Myers Squibb, Princeton, New Jersey); amlodipine, 10 mg/d (Norvasc, Pfizer, New York); or matched placebo. To minimize any center effect, randomization was blocked by center. All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors, angiotensin II receptor blocking agents, or calcium-channel blockers. For the analysis of cardiovascular end points, patients were followed to initiation of treatment for end-stage renal failure (dialysis or renal transplantation), reaching a serum creatinine level of 530.4 mol/L (6.0 mg/dL) or higher, death, or administrative censoring in December 2000. Outcomes We prospectively established cardiovascular outcomes, defined in the Appendix Table. Appendix Table. Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb, Princeton, New Jersey, by trained, blinded clinical research associates to identify potential cardiovascular events. Investigators used study forms to report and characterize all cardiovascular outcomes. For all potential events, records, including laboratory values, electrocardiograms, and radiographic reports were obtained for clarification. Since myocardial infarctions may go unrecognized, a central electrocardiogram reading center was established at Brigham and Womens Hospital, Boston, Massachusetts, where two cardiologists reviewed every electrocardiogram. Electrocardiography was performed at baseline, 6 months, 12 months, and annually thereafter. A total of 5698 electrocardiograms were reviewed at the center. When a new Q-wave infarction was found, the cardiologists asked whether a clinical myocardial infarction was reported. Even when myocardial infarctions were not clinically reported, these Q-wave infarctions were adjudicated as myocardial infarctions. Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events, defined in the Appendix Table. The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee (Appendix). If the committee member agreed with the judgment of the center investigator, their combined judgment was accepted. If the center investigator and the committee member differed, the case material was reviewed by the membership of the committee, whose decision was accepted. Deaths were adjudicated by a Mortality Committee (Appendix). Each death was reviewed by two members of the committee and presented to the membership, whose decision was accepted as final. Statistical Analysis For graphical presentation (Figure) and overall testing for statistically significant differences among the three treatment groups, time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test (15). We used proportional hazards modeling to determine hazard ratios. For the cardiovascular death outcome, which could occur only once, we used the standard proportional hazards model (16), with treatment assignment as the only independent covariate. For other cardiovascular outcomes, which could occur more than once, we used the AndersonGill formulation of the proportional hazards model (17), in which patients are considered at risk for the first event from randomization to the first event, at risk for the second event from the day following the first event to the second event, and so forth, permitting use of all the data. In accordance with the method of Lee and colleagues (18), we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient. We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event. Therefore, both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses. The time-dependent covariate was statistically significant in each case, confirming the above assumption. There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent eventsand inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significances. Figure. Time to first cardiovascular composite event as a function of treatment assignment. P Data management and computations were done by using SAS software for Windows, version 8 (SAS Institute, Inc., Cary, North Carolina), or S-Plus for Windows, version 6.0 (Insightful Corp., Seattle, Washington). Statistical tests were two sided. A P value of 0.05 or less, unadjusted for the multiple comparisons, was considered statistically significant. Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to submit the manuscript for publication. Results The baseline characteristics of the three groups are shown in Table 1. A flow diagram of the study is shown in the Appendix Figure. Table 1. Baseline Characteristics Appendix Figure. Flow diagram for the Irbesartan Diabetic Nephropathy Trial. Clinical Management During the study, the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group, 141/77 mm Hg in the amlodipine group, and 144/80 mm Hg in the placebo group. Blood pressure in the two active treatment groups did not differ; values in both groups were statistically significantly lower than in the placebo group (P = 0.001). The distribution of nonstudy drugs used to achieve the target blood pressure was similar i

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Comparison of Drug Dosing Recommendations Based on Measured GFR and Kidney Function Estimating Equations

BACKGROUND Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation. STUDY DESIGN Diagnostic test study. SETTINGS & PARTICIPANTS Pooled data set for 5,504 participants from 6 research studies and 4 clinical populations with measured glomerular filtration rate (GFR). INDEX TEST Estimated kidney function using the MDRD Study and CG equations incorporating actual (CG) or ideal body weight (CG(IBW)) and standardized serum creatinine concentrations. REFERENCE TEST Measured GFR assessed by using iodine-125-iothalamate urinary clearance. OUTCOME Concordance of assigned kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies and recommended dosages of 15 medications cleared by the kidneys. RESULTS Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P < 0.001) and 66% for the CG(IBW) equation (P < 0.001). Concordance between the MDRD Study equation and CG and CG(IBW) equations was 78% and 75%, respectively (P < 0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P < 0.001) and 82% for the CG(IBW) equation (P < 0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CG(IBW) equations and MDRD Study equation were 89% and 88%, respectively (P < 0.05). LIMITATIONS Results based on simulation rather than pharmacokinetic studies. Outcome was drug dosage recommendations, rather than observed drug efficacy and safety. CONCLUSIONS The MDRD Study equation can also be used for pharmacokinetic studies and drug dosage adjustments. As more accurate GFR-estimating equations are developed, they should be used for these purposes.

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.

Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

WAGR Syndrome: A Clinical Review of 54 Cases

WAGR syndrome is a rare genetic disorder characterized by a de novo deletion of 11p13 and is clinically associated with Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation (W-A-G-R). Although the genotypic defects in WAGR syndrome have been well established, the large variety of phenotypic manifestations of the syndrome has never been reported. We report on 54 cases of WAGR syndrome to demonstrate both the classical clinical signs and nonclassical manifestations found in a large population of individuals with this disorder. An understanding of WAGR syndrome and its clinical findings can provide important insight regarding the functions of the involved genetic region. Recommendations for diagnosis, evaluation, and surveillance of patients with WAGR syndrome are also presented.