Baseline Characteristics in the Modification of Diet in Renal Disease Study1

Transcription

1 Correction Because of a printing system failure at the publishers, the version of the article 0Baseline Characteristics in the Modification of Diet in Renal Disease Study (J Am Soc Nephrol 1993;3: ) did not incorporate the author s corrections to the proofs. The corrected article appears here in its entirety. Baseline Characteristics in the Modification of Diet in Renal Disease Study1 The MDRD Study Group (Prepared by Tom Greene,2 Jacques J. Bourgoignie, Violet Habwe, John W. Kusek, Linda G. Snetselaar, J. Michael Soucie, Monica E. Yamamoto) 1. Greene, The Cleveland Clinic Foundation, Cleveland, OH J.J, Bourgoignie, University of Miami School of Medicine, Miami, FL V. Habwe, George Washington University, Washington, DC J.W. Kusek, National Institutes of Health, Bethesda, MD L.G. Snetselaar, University of Iowa Hospitals and Clinics, Ames, IA J.M. Soucie, Emory University, Atlanta, GA ME. Yamamoto, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA (J. Am. Soc. Nephrol. 1993; 4: ) ABSTRACT The Modification of Diet in Renal Disease Study is randomized, multicenter, clinical trial designed to determine the effects of three levels of dietary control of protein and phosphorus and two levels of blood pressure control on the rate of decline of kidney function among persons with chronic renal disease. Study participants were assigned to one of two studies, Study A or, depending on their GFR just before randomization. Within each study, participants were randomly allocated to one of two levels of blood pressure control and to one of two I ReceIved January 12, Accepted March 23, Correspondence to Dr. T. 6reene, Department of Biostatistlcs and Epidemlol ogy. Cleveland Clinic Foundation EuclId Avenue, Cleveland. OH / /0 Journal of the American Society of Nephrolo9y Copyright C 1993 by the American Society of Nephrology dietary interventions according to separate 2 x 2 factorial designs. A total of 840 men and women aged 18 to 70 were randomized. This report summarizes the demographic, biochemical, and clinical characteristics of the randomized participants at the time of entry into the trial, overviews the protocol and purposes of the baseline period before randomization, and evaluates the balance among the treatment intervention groups within Studies A and B at the time of randomization. Major indicators of renal function were found to be well balanced among the treatment groups. Selected baseline characteristics of participants in the Modification of Diet in Renal Disease Study are compared with those of other renal clinical trials and with those of new cases of treated ESRD reported in the United States Renal Data System. Key Words: Protein, blood pressure, GFR, clinical trial, kidney disease T he Modification of Diet in Renal Disease (MDRD) Study is a randomized, multicenter, clinical trial sponsored by the National Institutes of Health and the Health Care Financing Administration. The study was initially designed to determine whether dietary protein and phosphorus control could slow the progression of chronic renal disease, thereby delaying the need for dialysis or kidney transplantation. Results from an 1 8-month pilot study, completed in 1988, indicated that a reduction of dietary intake of protein and phosphorus was feasible in a large-scale, mubticenter, clinical trial and verified the accuracy of procedures for the measurement of GFR to assess change in renal function (1-3). In addition, mean rates of decline in GFR were found to be significantly greater among study participants with higher mean blood pressure (1 ). On the basis of this latter obscrvation, the protocol for the full-scale study included Journal of the American Society of Nephrology I 221

2 MDPD aseline Characteristics a second intervention to control blood pressure at one of two separate levels. Recruitment for the full-scale trial was begun in January and was completed inaugust The purpose of this report is to summarize the demographic, biochemical, and clinical characteristics of the randomized MDRD Study participants at the time of entry into baseline, to overview the protocol and purposes of the baseline period before randomization, and to describe the balance between the diet and blood pressure treatment intervention groups at the time of randomization. Future reports will provide more detailed analyses of the association between renal function and other factors at entry into baseline and will examine the effects of dietary interventions during baseline on short-term changes in GFR and other measures of renal function. METHODS Study Design Between January 1989 and March 1991, 2,507 persons with objective evidence of impaired kidney function were screened at 1 5 clinical centers for entry into the MDRD Study (4). After a baseline period, 585 of these potential study participants with GFR between 25 and 55 ml/min m2 and with estimated dietary protein intakes of at least 0.9 g/ kg.day were assigned to Study A, and 255 persons with GFR between 13 and 24 ml/min m2 were assigned to. Individuals assigned to Studies A and B were randomly allocated to one of two levels of blood pressure control and to one of two levels of protein and phosphorus intake according to separate 2 x 2 factorial designs. Study A participants were randomized to either a moderate (Diet M) protein and phosphorus eating pattern with follow-up targeted intakes of 1.30 g/kg.day and 16 to 20 mg/kg.day, respectively, or to a low (Diet L) protein and phosphorus eating pattern with targeted intakes of g/ kg.day and 5 to 10 mg/kg.day, respectively. The targeted intakes arc expressed relative to kilograms of standard body weight (5). Individuals in were randomized to Diet L or to a very low protein and phosphorus diet (Diet K) with targeted intakes of 0.28 g/kg.day and 4 to 9 mg/kg.day supplemented with a mixture of ketoacid analogs of essential amino acids (Ross Laboratories, Columbus, OH). In both studies, participants were also randomized to either a moderate or a low blood pressure goal defined by mean arterial blood pressure (MAP = two-thirds diastolic + one-third systolic blood pressure). The followup target MAP for participants assigned to the modcrate goal was 1 07 mm Hg for participants aged 60 yr or younger and mm Hg for participants over 6 1. The target MAP levels of the low MAP goal were s92 and 98 mm Hg for participants with age 60 or 6 1 yr. respectively. Within each clinical center, Study A participants were stratified into four groups before randomization defined by the rate of progression of renal disease before entry into the study and by average MAP during baseline. The progression of renal disease before entry into the study and by average MAP during baseline. The progression strata were defined by a slope of reciprocal serum creatininc concentration > dl/mg.month or unknown (nonprogressor) or a slope (progressor). High- and bow-map strata were defined in accordance with the MAP goals for the moderate blood pressure intervention during follow-up. participants were stratified before randomization only into the highand low-map groups as defined above. The primary outcome variable by which the treatment factors will be compared is the follow-up rate of change in GFR. On the basis of estimates of between- and withinparticipant variability from the MDRD pilot study, the original sample size targets for Studies A and B were 604 and 1 96 participants, respectively (6). During the course of follow-up, the between-participant variability of the rate of change in GFR was found to be higher in and slightly lower in Study A than was the case in the pilot study. Because the sample size required to achieve the desired level of power to detect a diet or MAP treatment effect depends heavily on the between-person variance in the rate of change in GFR (6), the target sample sizes were subsequently reduced to 550 participants in Study A and increased to 250 in. As noted above, 585 and 255 participants were actually randomized in Studies A and B, respectively. The numbers of patients allocated to the specific diet and blood pressure interventions are given in Table 1. The Baseline Period The primary objectives of the baseline period were to determine the level of kidney function for study TABLE I. Sample sizes of diet and blood pressure treatment groups Dietary Protein Group StudyA (GFR ml/ (GFR ml/ mm 1.73 m2) min#{149} 1.73 m2) (N= 585) (N 255) Moderate MAP Low MAP Moderate MAP Low MAP DietM DietL DietK Volume 4 #{149}Number

3 Greene et al eligibility, to instruct participants about study procedures, to prescribe and assess compliance to antihypertensive medications as well as to specified 1evcbs of dietary protein and phosphorus, and to assess compliance to the clinic visit schedule. Four clinic visits were scheduled at 1 -month intervals during baseline (labeled BO, Bi, B2, and B3 in this report), along with one additional visit (labeled BOA) for dietary assessment and counseling 2 wk after the initial baseline visit. The clinic visit schedule was adhered to as rigorously as possible, and participants were excluded from randomization at B3 if visits were not held within specified windows. The maximum allowable time between the initial baseline visit (BO) and the final baseline visit (B3) was 5 months; the median time between these visits for randomized participants was 98 days. Potential study participants found ineligible during baseline could restart baseline evaluation if eligibility criteria were satisfied at a later time. The 840 randomized participants included 69 who restarted baseline. For participants who restarted baseline, only measurements obtained during their final baseline period are summarized in this report. Urinary urea nitrogen was measured from 24-h urine samples each month during baseline to estimate protein intake (7). At their B1 baseline visit, participants were given dietary protein goals on the basis of their BO GFR and usual protein intake. Participants with BO GFR in the Study A range (i.e., 25 ml/min m2) were prescribed protein intakes between 0.90 and 1.30 g/kg.day. For participants with BO GFR 24 ml/min m2, the protein prescription was consistent with the participant s usual intake, so long as the usual intake exceeded 0.60 g/ kg.day, but was set at 0.60 g/kg.day otherwise. To be eligible for randomization, baseline participants were required to accept their baseline protein intake prescription and to demonstrate the ability to keep intake records and to come in to scheduled visits. Throughout baseline, antihypertensive regimens were adjusted to achieve the same MAP goals as the follow-up period for the moderate-map treatment group. There was no lower limit set for MAP. Antihypertensive regimens were based on a stepped-care approach defined in the Report of the Joint National Committee (8). This approach includes both nonpharmacobogic and pharmacologic therapy. Any antihypertensivc medications could be used, but angiotensmn-converting enzyme (ACE) inhibitors and calcium channel blockers (with or without diuretics) were encouraged as agents of first choice in order to limit variability in antihypertensive regimens (9). Of the 2,507 potential participants who were screened, 1,795 satisfied the entrance criteria (9), which included ( 1 ) age of 1 8 to 70 yr, (2) serum creatinine level within 1 yr of screening of 1.4 to 7.0 mg/dl for men and 1.2 to 7.0 mg/dl for women; (3) MAP s125 mm Hg; (4) not a kidney transplant reciplent; (5) urinary protein excretion 10 g/day; and (6) not taking insulin. Nine-hundred forty-three of the persons who met the screening eligibility criteria and entered baseline were excluded before randomization. A complete list of eligibility and exclusion cr1- teria has been published elsewhere (6). The frequencies of the reasons for exclusion or dropout arc provided in a separate report (4). Demographics and Renal Diagnosis Demographic information summarized in this report was obtained by interviews with the patients at the BO visit. Hypertensive status was also assessed by study physicians at this visit and was subsequently finalized after further review of the medical records of participants who were prescribed antihypertensive drugs during baseline. Renal diagnoses were assigned on the basis of data obtained at the Bi visit from examinations of medical records and review of historical information availabbe from the patients. The diagnoses were classified into 10 categories: ( 1 ) glomerular diseases; (2) polycystic kidney disease; (3) hypertensive nephrosclerosis; (4) tububointerstitial diseases; (5) urinary tract diseases; (6) absence of one kidney; (7) diabetic nephropathy; (8) hereditary nephritis; (9) other or unknown with a urinary protein level of 1 to 3 g/day; (10) other or unknown with a urinary protein level of < 1 g/day. The categories of gbomerular diseases, hypertensive nephrosclcrosis, and tububointerstitial diseases were restricted to participants in whom the diagnoses were confirmed by biopsy or considered established by other objective evidence by the investigator. With the exception of pobycystic kidney disease, the remaining diagnosis categories (5 to 8 above) included participants with both established and presumptive diagnoses. Laboratory Measurements Table 2 gives the schedule for the primary measurements during baseline. Study participants provided a 24-h urine sample at each monthly visit (visits BO, Bi, B2, and B3). Blood was collected at visits BO and B3 under fasting conditions before sc [ 25ljsodium iothalamate injection. Urine and serum samples were analyzed at the Central Biochemistry Laboratory (Department of Biochemistry, Cleveland Clinic Foundation, Cleveland, OH) by standard methods. At visits BO and B3, serum concentrations of clectrobytes, glucose, total calcium, organic phosphorus, iron, magnesium, urea nitrogen, creatinine, albumin, transferrmn, total cholesterol, high-density lipopro- Journal of the American Society of Nephrology 1223

4 MDRD aseline Characteristics TABLE 2. Schedule of baseline visit measurements Visit Baseline 0 Baseline OA Baseline I Baseline 2 Baseline 3 Blood Pressure 3-day Food Record Blood Pressure Blood Pressure Blood Pressure Weight and Other Anthro- Weight and Other Weight Weight and Other Weight pometry Anthropometry Anthropometry 24-h Urine 24-h Urine 24-h Urine 24-h Urine Blood Lab Tests EKG Blood Lab Tests lothalamate GFR lothalamate GFR Medical History Plasma Amino Acids Physical Exam 3-Day Food Record tein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol were measured. At visit B3, additional serum samples were analyzed for HDL2, HDL3, apolipoprotein Al, apolipoprotcin B, bibirubin, uric acid, lactic dehydrogenase, glutamic oxaboacetic transaminase, and whole blood for hemogbobin A1C. Additional hematologic measurements, including white blood cell count, hemoglobin, and hematocrit values were performed locally at each center at baseline visits BO and B3. GFR was measured at baseline visits BO and B3 with the renal clearance of [ 25lliothalamate after its sc injection without cpinephrinc (1). The Central GFR Laboratory (Department of Hypertension and Nephrology, Cleveland Clinic Foundation) received urine and serum samples from the clinical centers for counting [ 25ljiothalamatc. GFR was calculated as the ratio of time-weighted averages of urine excretion rates of the lothalamate marker and the serum concentrations of the marker over three to four consecutive collection periods. The Central Amino Acid Laboratory (Department of Pediatrics, University of Iowa, Iowa City, IA) anabyzed amino acid and abloisolcucinc concentrations in plasma samples prepared at the B3 visit. An electrocardiogram (EKG) was done at the B2 visit and was read by the Central EKG Laboratory (Department of Cardiology, The Cleveland Clinic Foundation). The EKG readings were based on a consensus reached by two cardiologists. Assessments of Dietary Intake Three-day food records returned at the BOA visit were used to assess initial baseline dietary intakes of MDRD participants. Patient food report training at the initial BO visit included a 24-h recall interview to demonstrate needed food detail. Training in food intake report completion included specifics for weights and measures. Participants were also supplied with a battery-operated, portable, platform scale and set of measuring cups and spoons. The scale could provide weights in ounces and grams and had a built-in tare capability. Completed food records were reviewed with the patient by a dietitian trained and certified in food data documentation by the MDRD Nutrition Coordinating Center (NCC) at the University of Pittsburgh. Food quantity verification was done with food models, cups, plates, bowls, dimensional representations, and rulers. A comparable trained and certified dietitian checked the records for completeness and clarity before the data were transmitted to the MDRD Nutrition Coordinating Center for processing. Data were coded and entered by trained dietary data entry specialists and analyzed with a food and nutrient database specially tailored for the MDRD Study (1 0). This database included food composition information from the U.S. Department of Agriculture s (USDA) Nutrient Databases for Standard Reference (1 1), the Individual Food Intake Surveys (12), the Primary Nutrient Data Set for USDA Nationwide Food Consumption Surveys (13), fish items from USDA Handbook 8-1 5, and brand-name manufactured items, nutrient supplements, and bowprotein products. A second 3-day food record was collected from MDRD participants at their B3 visit. This information was used to verify the patients adherence to their baseline protein intake prescription. Anthropometric Measurements Several body measurements were completed to assess nutritional status in the MDRD Study population. Measuring technique and equipment were standardized by methods used in the Third National 1224 Volume 4. Number

5 Greene et al Health and Nutrition Examination Survey (NHANES- 3). These measures included stature, weight, skinfolds (triceps and subscapular), and midarm circumferences. Additional measures included elbow breadths and biceps skinfolds; these procedures were standardized to techniques recommended by the Anthropometry Standardization Consensus Conference (1987). Bicondylar Vernier calipers (Seratex Co., Carlstadt, NJ) were used for elbow breadths; a stadiometer was used for heights; Holtain skinfold calipers (Seratex Co.) were used for skinfold thicknesses; double-beam balances were used for weights; and steel tapes were used for circumferences. Dietitians were trained, certified, and recertified yearly in anthropometric techniques and were required to provide monthly quality control measures. Measurement of Blood Pressure All of the participants entering baseline had a MAP : 1 25 mm Hg. Arterial blood pressure for all of the visits was measured with a standardized Hawksbcy random zero sphygmomanometer (Hawkslcy & Sons Limited, Sussex, England) by the technique adopted from the Joint National Committee report (8). Statistical Analyses Standard descriptive statistics (e.g., relative frequency distributions, means, medians, etc.) were used to summarize the univariate distributions of demographic and clinical variables of the randomized participants at entry to baseline. Differences between Studies A and B were tested by 2 tests for qualitative variables and two-sample unpoobed t tests for continuous variables. The Wilcoxon rank sum test was used in place of the two-sample t test for highly skewed variables. Unless specified otherwise, a two-sided significance level of 5% (denoted as a 0.05) was used in all tests comparing the two studies. Formal hypothesis tests were used to identify vanabbes with the greatest imbalance among the four treatment intervention groups in Studies A and B and were interpreted with the awareness that the randomization procedure used should assure that approximately 5% of the variables considered would exhibit significant imbalances based on a significance level of 5%. Imbalances in continuous variables were tested by analysis of variance with the randomization strata included as covaniates. x2 tests were used to examine balance between the treatment groups for qualitative variables. When one or more expected cell frequencies were less than 5, exact conditional P values were obtained with the software package StatXact (1 4). All other analyses were conducted with the statistical package SAS (15). RESULTS Characteristics of MDRD Participants at Entry Into Baseline Demographic Characteristics. The distributions of selected demographic characteristics are summarized for randomized participants in Table 3. The majority of both Study A and participants were men. The age distributions were similar in the two studies. The ages of Study A participants were not significantly related to gender, with mean ages of and yr for men and women, respectively. In, there was a small but statistically significant (P < 0.02) difference in mean age between men (52. 1 yr) and women (48.3 yr). Approximately 85% of the study participants were white for both study groups. However, a higher percentage of black participants (P = 0.05) were enrolled in Study A (9. 1 %) compared with (5. 1 %). The majority of study participants were married, had at least 1 3 yr of education, were currently employed full time, and were current nonsmokers. The vast majority of participants in both studies were hypertensive as determined by a review of the medical history. Measurable edema was identified in 9.2% of Study A participants and in 12.2% of participants. Marital status, education category, smoking status, or hypertensive status did not differ significantly between Studies A and B. The two most frequent renal diagnoses, making up almost 50% of the diagnoses for both study groups, were glomerular disease and pobycystic kidney disease (PKD). If the two Other or Unknown categories are excluded, the distribution of remaining renal diagnoses was not significantly different between the study groups. Among the participants with diagnoses of Other or Unknown, the proportion with mean baseline urine protein 1 g/day was significantly higher among participants (P < ). Laboratory Values. The initial baseline iothalamate GFR, hematology, and blood and urine chemistry results are presented in Table 4 for participants randomized to Study A and. All values were obtained at baseline visit BO unless samples were only collected at baseline visit B3 as indicated. participants with GFR less than 25 ml/ mm m2 had lower serum hematocrit, hemoglobin, sodium, total CO2, calcium, albumin, lactic dehydrogenase, glutamic oxaboacetic transaminase, bilirubin, iron, transferrmn and higher potassium, chboride, creatinine, urea nitrogen, phosphorus and magnesium values than participants of Study A. Participants of also had more proteinunia and excreted bess sodium, potassium, phosphorus, creatmine, and urea nitrogen per 24-h period than those with higher GFR levels. urine protein excretion cxceeded 3 g/day in 50 of 57 1 and 40 of 243 participants in Studies A and B, respectively. Journal of the American Society of Nephrology I 225

6 MDRD aseline Characteristics TABLE 3. Demographic characteristics of randomized participants at entry into baseline Study A Variable (N= 585) (N 255) Race White Black Hispanic Other Gender (Male) Age (yr) < Marital Status (Married) Education :s9 yr yr 13 yr Current Employment Status#{176} Full time Part time Retired or none Annual lncomeb ($) < ,500-24,999 25,000-49, Current Smokers#{176} Hypertensive Renal Diagnosis Glomerular diseases PKD Hypertensive nephrosclerosls Tubulointerstitlal diseases Urinary tract diseases Absence of one kidney (without other known cause) Diabetic nephropathy (nonlnsplln dependent) Hereditary nephritis Other or unknown with nonnephrotlc protelnuria Other or unknown without protelnurla 0 Study A, N = 584;. N = 255. b Study A, N = 580;. N = 245. N % N % Initial baseline lipid and lipoprotein serum concentrations and baseline plasma concentrations of total essential amino acids and essential to nonessential amino acid ratios for Studies A and B are presented in Table 5. Neither total serum cholesterol nor its LDL or HDL components differed significantly between the two studies. The mean concentration of essential amino acids was significantly higher among Study A participants. EKG Results. The EKG results from the B2 visit indicated atrial fibrillation in 0 of 549 (0%) Study A participants and in 3 of 239 (1.3% participants. Evidence of previous myocardiab infarction was detected in 3.6 and 1.3% of Study A and Study B participants, respectively. Left ventricular hypertrophy was indicated in 3. 1 and 5.4% of Study A and participants, respectively. Dietary Assessments and Anthropometry. Base line intakes of protein, phosphorus, and calories from 3-day food records returned at the BOA visit are presented in Table 6. Daily intakes are expressed per kilogram body weight. Mean reported daily protein intakes were significantly higher in Study A than in (1. 1 versus 0.9 g/kg.day). Study A participants also had higher average reported intakes of phosphorus (16.7 versus 14.8 mg/kg.day) and total calories (26.9 versus 25.2 kcal/kg.day). Anthropometric measures are also presented in Table 6. Study groups showed significant differences by frame size and body weight, with Study A participants being slightly larger on average. The mean body mass index was also significantly higher in Study A than in (27.6 versus 26.0). I Blood Pressure and Antihypertensive Medica tlons During Baseline. At the initial baseline visit, % of Study A participants and 86% of participants were prescribed antihypertensive mcdi cations. Among hypertensive participants, these percentages increased to 93 and 96% in Studies A and B, respectively. The percentages of Study A participants using major classes of antihypertensive mcdications were as follows: f3-blockers, 30%; calcium channel blockers, 25%; ACE inhibitors, 36%; diuretics, 38%; and other antihypertensive agents, 17%. Among participants, the corresponding percentages were: /3-blockers, 37%; calcium channel blockers, 27%; ACE inhibitors, 35%; diuretics, 46%; and other antihypertensive agents, 22%. Multiple drug classes were often used in combination, so the above percentages add up to more than 100%. The mean number of distinct antihypertensive drugs used was significantly higher among participants (1.72) than among Study A participants (1.50). During the course of baseline, there were small but statistically significant increases in the prescription of antihypertensive medications in both studies; by the B3 visit, the mean numbers of distinct antihypertensive drugs prescribed to participants in Studies A and B increased to 1.56 and 1.78, respectively. This increase in the number of distinct antihypertensive drugs was associated with a small increase in the use of ACE inhibitors, with 40% of Study A participants 1226 Volume 4 #{149}Number 5 #{149}1993

7 - Greene et al TABLE 4. lnitial baseline GFR, hematology, blood, and urine chemistry values for participants randomized in Studies A and B#{176} N Mean SD Median 10th Percentile 90th Percentile GFR GFR (ml/min m2) Study Ab StudyB GFR (mi/mm) StudyAb StudyB Hematology Hematocrit (%) Study Ab StudyB Hemoglobin (g/di) StudyAb StudyB WBC (x I 03/cm3) Study A StudyB Blood Chemistry Sodium (meq/l) StudyAb StudyB Potassium (meg/i) Study Ab StudyB Chloride (meg/i) StudyAb StudyB Total CO2 (meg/i) Study Ab StudyB Creatinine (mg/di) StudyAb Urea nitrogen (mg/di) Study Ab StudyB Uric acid (mg/di)c Study A StudyB Calcium (mg/di) Study Ab StudyB Phosphorus (mg/di) Study Ab StudyB Magnesium (mg/dl) StudyAb StudyB Glucose (mg/di) StudyA StudyB Albumin (g/di) Study Ab Journal of the American Society of Nephrology 1227

8 MDRD aseline Characteristics TABLE 4. Continued N Mean SD Median 10th Percentile 90th Percentile LDH (lu/i)c Study Ad GOT (lu/i)c Study Ad Bilirubin (mg/di)c Study Ad Iron (g/dl) Study Ab Transferrin (mg/di) Study Ab Urine Chemistry Sodium (meg/day) Study Ab Potassium (meg/day) Study Ad Phosphorus (mg/day) Study Ab Creatinine (mg/day) Study Ab Creatinine clearance (mi/ mm m2) Study Ab Protein (g/day) Study Ad Urea nitrogen (g/day) Study Ab Estimated protein intake (g/ kg. day) Study Ab WBC. white blood cell count; GOT. glutamic oxaloacetic transaminase; LDL. lactic dehydrogenase. b Studies A and B means significantly different at a 0.05; two-sample t test. C Obtained at B3 visit. d Studies A and B significantly different at a 0.05; Wilcoxon rank-sum test. and 38% of participants prescribed ACE inhibitors by the B3 visit. Table 7 shows the average MAP and systolic and diastolic blood pressures of randomized participants according to age and study group. At the BO visit, the MAP and systolic and diastolic blood pressures did not differ significantly between Study A and participants. Among Study A participants, MAP and systolic and diastolic blood pressures all exhibited small but statistically significant decreases between the BO and the B3 visits. The trend towards a reduction in blood pressure was less evident among Study B participants, particularly in the age 60 and under group, and the changes between BO and B3 were not 1228 Volume 4 Number 5 #{149}1993

9 Greene et al TABLE 5. Initial baseline lipid and amino acid data N Mean SD. Median 10th. Percentile 90th Percentile Serum Lipids (mg/di) Total Serum Cholesterol StudyA StudyB HDL Serum Cholesterol StudyA StudyB idi Serum Cholesterol StudyA StudyB HDL2#{176} StudyA HDL3#{176} StudyA StudyB Apolipoprotemn A 1#{176} StudyAb StudyB Apolipoprotein B#{176} StudyA StudyB Triglycerides StudyA StudyB Plasma Amino Acids#{176} Essential (SM) StudyAb StudyB Total Essential to total Nonessential StudyAb StudyB a Obtained at B3 visit. b Studies A and B means significantly different at a 0.05; two-sample t test. statistically significant for any of the three blood pressure parameters. Balance of Diet and Blood Pressure treatment Groups Before Randomization None of the demographic variables described in Table 5 (including renal diagnosis) differed significantly at the a = 0.05 level among the four randomized groups in either Study A or. Means of selected continuous variables are presented in Tables 8 and 9 by diet and blood pressure group for Study A and, respectively. In order to evaluate balance among the treatment groups at the time of randomization, the final baseline measurements are used. In Study A, there is a statistically significant imbalance for weight. In, imbabances are present for serum total and LDL cholesterol, urine creatinine, and urine sodium. All other continuous variables considered in Tables 4 through 7 as well as age did not exhibit significant differences among the four subgroups of participants randomized in Study A or the four subgroups of participants randomized in. The same set of imbalances was indicated regardless of whether the randomization strata were controlled for in the statistical analysis. Table 1 0 gives the mean changes from the initial BO visit to the B3 visit in indicators of progression of renal disease, estimated protein intake, and MAP. None of the mean changes differed significantly among the diet and blood pressure intervention groups in either Study A or. Overall, the declines in mean GFR of 0.65 ml/min m2 in Journal of the American Society of Nephrology 1229

10 MDRD aseline Characteristics TABLE 6. Initial baseline dietary intake from three-day diaries and anthropometry measurements N Mean SD Median 10th Percentile 90th Percentile Dietary Intake (3-Day Diaries)0 Avg. protein (g/kg. day) StudyAb StudyB Avg. phosphorus (mg/kg. day) StudyAb StudyB Avg. calories (kcal/kg.day) Study Ab StudyB Anthropometry Height (cm) StudyA StudyB Elbow width (cm) StudyAb StudyB Body weight (kg) StudyAb Body mass index (kg/m2) Study Ab StudyB Standard body weight (kg) StudyA Body surface area (m2) StudyAb StudyB Obtained at BOA visit. b Studies A and B means significantly different at a = 0.05; two-sample i test. TABLE 7. Blood pressure during baseline Systolic (mean) Diastolic (mean) MAP (mean) MAP (std) Study A Ageooyr BO andunder B Ageolyr BO andover B Ageooyr BO andunder B Ageolyr BO andover B N because participants were defined to have lower B3 GFR than Study A participants, leading to a statistical tendency for more patients with larger declines in GFR between BO and B3 to be included in than In Study A. In each of the two studies, 58 continuous variables (including derived variables) and 9 categorical demographic variables were formally tested for significant imbalance. Thus, a total of (58 + 9) x 2 = 134 tests were conducted, and the 5 nominally significant imbalances reported above represent 5 of 134 (3.7%) of all of the tests conducted. This proportion is consistent with the fraction of nominally significant results expected by chance at the 5% level of significance. Study A and 1.70 ml/min m2 in were both statistically significant. The greater rate of dedine in is due in part to the statistical phenomenon of regression to the mean (16). This is DISCUSSION The MDRD Study is the largest randomized clinical trial designed to evaluate the effects of dietary protein and phosphorus and blood pressure control on 1230 Volume 4 - Number 5 #{149}1993

11 Greene et al TABLE 8. Means of selected continuous variables in Study A by diet and blood pressure groups immediately before randomization (B3 visit)0 BP Goal Die ti Die tm Moderate low Moderate low GFR (mi/mm m2) (mi/mm) MAP Body Mass Index (kg/m2) Weight(kg)b Hematocrit (%) Hemoglobin (g/di) WBC (x103/cm3) Serum Albumin (g/di) Creatinine (mg/di) Sodium(mEq/i) Phosphorus (mg/di) Transferrmn(mg/dl) Urea nitrogen (mg/di) SerumTotalCholesterol idi cholesterol Plasma Essential Amino Acids (EAA) (NM) EAA/NEAA Urine Creatinine (g/day) Phosphorus (mg/day) Potassium (meg/day) Protein (g/day) Creatinine clearance (mi/mm m2) Sodium (meg/day) Urea nitrogen (g/day) Estimated Protein Intake (g/kg day) N ( ) ( ) ( ) ( ) a BP. blood pressure; WBC. white blood cell count; NEAA. nonessential amino acids. b Means are significantly different at a the rate of progression of chronic renal insufficiency. The study participants are primarily middle class and well educated, with 65% having at least 1 yr of education beyond high school. Over 85% of the participants have hypertension in addition to chronic renal insufficiency. The baseline period provided measurements of renal function, nutritional intake, and other vanabbes before the initiation of the follow-up treatment. The 3-month baseline phase of the MDRD Study provided study participants with valuable training in following a prescribed protein and phosphorus dietary regimen and in keeping 3-day diet diaries. It provided the study physicians an opportunity to adjust blood pressure control before randomization. The five baseline visits provided the opportunity to exclude, before randomization, participants who would not keep diet records, who missed visits, or who were otherwise noncompliant. Participants were also exposed during baseline to all of the assessment procedures to be used during the study, including two GFR measurements and four 24-h urine sample collections. Thus, having gained firsthand experience of the requirements of the study, participants were better abbe to decide whether to provide informed consent to be randomized. These practices increased the likelihood that the 840 participants who were eventually randomized would have good compliance to the dietary and blood pressure interventions duning follow-up and would not drop out before the end of the study. At entry to baseline, Study A participants with Journal of the American Society of Nephrology 1231

12 MDRD aseline Characteristics TABLE 9. Means of selected contin before randomization (B3 visit)0 uous variables in Stud y B by die t and bi ood press ure gro ups immediately BP Goal Diet K Diet I Moderate low Moderate Low GFR (mi/mm m2) (mi/mm) MAP Body Mass Index (kg/m2) Weight(kg) Hematocrit (%) Hemoglobin (g/dl) I WBC (x103/cm3) Serum Albumin (g/di) Creatmnine (mg/di) Sodlum(mEg/i) Phosphorus (mg/dl) Transferrin (mg/di) Urea Nitrogen (mg/di) Serum total cholesterol (mg/di)b LD1 Cholesterol (mg/di)#{176} Plasma Essential Amino ACld$(EAA)(iM) EAA/NEAA Urine Creatinine (g/day)b Phosphorus (mg/day) Potassium (meg/day) Protein (g/day) Creatinine clearance (mi/mm m2) Sodium (meg/day)#{176} Urea nitrogen (g/day) Estimated Protein Intake (g/kg day) N (59-61) (64-65) (56-62) (63-67) 0 BP. blood pressure; NEAA. nonessential amino acids. b Means are significantly different at a = moderate renal insufficiency (GFR, 25 to 55 ml/min m2) were heavier and had higher dietary intakes (adjusted for body weight) of protein, phosphorus, and total calories than participants (GFR, 15 to 24 ml/min m2) with more advanced renal failure. Blood pressure levels did not differ significantby between the two studies. However, Study A participants were prescribed fewer antihypertensive drugs than patients, suggesting that the absence of a significant difference in blood pressure may have resulted from good control of hypertension rather than an equivalence of hypertensive disease between the two groups. As expected, participants with more extensive renal diseas had greater proteinuria, higher serum creatinine and urine nitnogen levels, and lower hematocnit and serum total CO2 values than Study A participants. At randomization, measures of renal function, estimated protein intake, and blood pressure were well balanced among the four treatment intervention groups in both Studies A and B. Among 67 demographic, biochemical, and clinical variables considered in this report, five small but statistically significant imbalances among the treatment groups were identified in the two studies. This represents 3.7% of all of the tests for imbalance that were conducted and is slightly less than the proportion of significant results that would be expected by chance alone (5% based on a significance level of 0.05). The implications of the limited imbalances that did occur for I 232 Volume 4 Number

13 Greene et al TABLE 10. Mean changes in selected variables during baseline0 MAP Goal Diet I Diet M Diet K Moderate Mean (SD) low Mean (SD) Moderate low Mean (SD) Mean (SD) Moderate Mean (SD) low Mean (SD) Study A GFR (mi/mm m2) GFR (mi/mm) 100 x Inverse Serum Creatinine (100 x di/mg) Estimated Protein Intake(g/kg. day) MAP (mm Hg) GFR (mi/mm m2) GFR (mi/mm) 100 x Inverse Serum Creatinine (100 x di/mg) Estimated Protein Intake (g/kg. day) MAP (mm Hg) (5.2) (5.6) (7.3) (0.2) (1 1.2) (3.3) (3.5) (4.8) (0.3) (12.8) (5.8) (6.4) (6.1) (0.3) (9.9) (2.8) (3.1) (3.6) (0.2) -2.64(12.3) (5.2) (5.5) (5.9) (6.4) (5.3) (6.0) (0.2) (0.2) (10.2) (13.1) (2.9) (3.1) (4.4) (0.2) (11.0) (3.4) (3.8) (4.6) (0.2) (10.1) 0 The mean baseline changes did not differ significantly among the four Studies A and. diet-blood pressure groups for any of the specified variables in both analyses of follow-up outcome variables depend on the relationships between the baseline measurements and the specific outcomes (1 7) and will be evaluated as analyses involving follow-up data are conducted. The presentation of baseline data provides a basis for comparing the characteristics of study participants with those of participants in related clinical trials and for evaluating the generalizability of study results to reference populations of interest. Unfortunately, the majority of studies that have investigated the relationship between a low-protein diet and the progression of chronic kidney disease have provided only minimal information about the baseline characteristics of study participants. Nonetheless, some limited comparisons can be made. Although many studies have investigated the potential role of dietary restriction on delaying the need for kidney replacement therapy, few were randomized clinical trials. A recent meta-analysis, restricted to six randomized trials selected among 46 studies performed since 1 975, supported the effectiveness of a low-protein, low-phosphorus diet in delaying the onset of end-stage renal failure (18). Such an anabysis, however, contains a number of methodological limitations (1 9), and the validity of this meta-analysis is particularly questionable because: ( 1 ) two of the six studies selected arc not published; and (2) the analysis included the short-term but not the longterm results of a large Dutch study (N = 228 patients) in which a general beneficial effect of restricted diets on renal function (measured as changes in serum creatinine) was apparent after 1 8 months but was subsequently reported to be limited to male patients with primary glomerular disease after 36 months of follow-up (20-22). In addition to the Dutch study, two other important randomized clinical trials have been reported in nondiabetic patients. In Australia, an 1 8-month study of 64 adult patients with advanced renal disease (mean serum creatinine, 7.3 mg/dl) indicated that protein and phosphorus restriction significantly slowed the progression of chronic renal disease (23). In that study, renal function was measured by the plasma clearance of [51CnIEDTA. The Northern Italian Cooperative Study monitored 456 patients for up to 2 yr using endogenous creatinine clearance to assess renal function (24,25). That study provided little support for the hypothesis that protein and phosphorus restriction retarded the progression of chronic renal insufficiency. Table 1 1 compares selected baseline demographic and clinical data between these three clinical trials and the MDRD Study. All studies involved adults of both sexes. Patients with a variety of renal diseases were recruited in all studies by the use of relatively similar selection criteria. Patients with systemic illnesses, including autoimmune diseases, active malignant disorders or infections, or insulin-dependent diabetes mellitus, and those receiving drugs that might alter the natural history of their renal disease were excluded. Glomerubar disorders were predomi- Journal of the American Society of Nephrology 1233

14 MDRD aseline Characteristics TABLE I I. Baseline demographic and clinical data of randomized clinical trials Holland#{176} (20) Australia (23) Italy (24) MDRD Study A No.ofPatients Age (yr) (Mean) b Male(%) MAP (mm Hg) (Mean) NAC Protein Intake (g/kg. day) NAC NAC NAC I.Od 0.9d Renal Function Serum creatinine (mg/di) NAC (Mean) Creatinine clearance (mi/ NAC mm m2) (Mean) GFR (mi/mm) (Mean) NAC 14.4 NAC Types of Nephropathies (%) Glomerular disease PKD Decreased renal mass NAC NAC Tubulointerstitial disease Nephrosclerosis I I NAC Urological disease NAC Others or unknown Two groups defined by baseline creatinine clearance > or < 30 ml/min. I.73 m2. b Median. C NA. not available or not applicable. 0 Estimated from urea nitrogen appearance.. Plasma clearance of (61Cr)EDTA. f Urinary clearance of (1261)iothalamate. 9 Includes hereditary nephropathies. type II diabetics. and others. nant in all studies (approximately one-fourth of the participants in the MDRD Study). The MDRD Study contained a greater proportion of patients with PKD (1 of 4 patients) but a smaller proportion of patients with tububointerstitiab disease (1 of 22 patients) than did the other studies. The latter stems from the more frequent identification of analgesic nephropathy in Europe and Australia than in the United States and from the restriction of this diagnosis to participants in whom the diagnosis was verified by biopsy or other objective data in the MDRD Study. Participants in the MDRD Study had a slightly higher mean age and had better blood pressure control at the initiation of the trial. Baseline dietary intakes were not reported in previous studies of diet and renal disease progression. MDRD Study A participants mean baseline dietary intakes of each of the three dietary components given in Table 6 are nearly identical to those of a national sample of U.S. healthy adults examined in the Second National health and Nutritional Examination Survey ( ) (NHANES-2) (26,27). As expected, the mean protein, phosphorus, and total caloric intakes of patients (0.9 g/kg.day, 14.8 g/kg.day, and 25.2 kcal/kg.day, respectively) are slightly lower than the corresponding averages in NHANES-2 (1.05 g/kg.day of protein, 16.9 mg/kg.day of phosphorus, and 26.7 kcab/kg.day of calories). MDRD Study participants body mass indexes, a measure of body fatness. are slightly higher than those of the NHANES-2 adults, whose body mass indexes averaged However, it is possible that U.S. adults may have become heavier on average in the decade since the NHANES-2 survey. The availability of the U.S. Renal Data System (USRDS) (28). a national database of treated ESRD patients, provides the opportunity to compare selected characteristics of the MDRD Study cohort, a group of prc-esrd patients, with those characteristics found among new (incidence) cases of treated ESRD. It is important to note, however, that the MDRD Study inclusion criteria substantially influenced certain characteristics of the randomized study participants. In particular, the age range was restricted, persons requiring insulin were excluded, and only patients with mild to moderate impairment of kidney function (GFR between 1 3 and 55 ml/min m2) were included. Thus, inferences made by the MDRD Study do not directly apply to persons older than 70 or to insulin-dependent diabetics. Other studies have examined the effect of restricting dietary protein or the treatment of high blood pres Volume 4 #{149}Number

15 Greene et al sure with ACE inhibitors on the progression of renal disease (29,30) in diabetic patients. A majority of the participants in the MDRD Study are men (60.5%), which is a slightly greater percentage than in the general population of patients starting ESRD therapy in 1988 (54.4%). The mean ages of yr for Study A and 50.5 yr for participants are somewhat lower than the mean age of 56.6 yr for incident ESRD patients in The slightly younger age of MDRD Study participants compared with USRDS patients is not surprising because neither Study A non participants had yet reached ESRD (mean GFR at study entry was 39.3 ml/min m2 for Study A and 20.2 ml/min m2 for ) and the upper age limit for study entry was 70 yr (in 1988, 14.2% of the new ESRD patients were age 75 and oven). The greater proportion of white participants in the MDRD Study (85%) compared with incident cases of ESRD from to 1989 (68.7%) may be rebated to a number of factors including recruitment techniques used (a majority of study participants were referred by their physicians), a higher proportion of African-Americans who dropped out or were excluded from the study during baseline compared with white participants (7 1 versus 50%), and no specific requirement for the recruitment of minorities. There are also dissimilarities between the renal diagnoses for MDRD Study participants compared with those for ESRD patients in the USRDS. As noted previously, persons taking insulin were excluded from the MDRD Study; however, diabetic nephropathy is the most common cause of ESRD (32.2% of new cases in 1986 to 1988). Although gbomerubar disease is the most common diagnosis in the MDRD Study, this diagnosis was noted among only 13.8% of the new ESRD patients in 1987 to Of particubar interest was the fact that approximately one fourth of the MDRD Study participants have a diagnosis of PKD; only 3.6% of the new cases of ESRD for the period from to had this diagnosis. The high proportion of patients with PKD in the MDRD Study could be attributed to recruitment techniques, which included notices in PKD patient newsletters and presentations by study physicians and dietitians at local meetings of these patients. The lower percentage of MDRD Study participants with hypertensive nephnosclerosis (6.5%) compared with cases identified in the USRDS for to 1988 (27.9%) may be due, in part, to underrecruitment of African-Americans, because there is a high prevalence of ESRD associated with hypertension in this segment of the U.S. population. In addition, in the MDRD study, the renal diagnosis classification of hypertensive nephroscbcnosis excluded participants with presumptive diagnoses. As noted recently by Williams and Schbuchter (31), the nonrandom nature of participants in clinical trials may influence the gencralizability of study results. The above discussion of differences between the randomized MDRD participants and the ERSD population, as well as the high rate of exclusions during baseline, indicates that the characteristics of the randomized MDRD participants also differ in certain respects from those of the general pre-esrd population. If the effects of the MDRD diet and blood pressure interventions arc similar among the different renal disease etiologies and/or other demographic and clinical subgroups, then overall estimates of the effects of the diet and blood pressure interventions should be broadly applicable throughout the pne- ESRD population (with the exception of subgroups such as type I diabetics, who were excluded from the MDRD study). If, on the other hand, the diet and blood pressure interventions have different effects for certain chronic renal diseases and/or demographic subgroups, then it is necessary to evaluate these interventions separately for these subgroups. The MDRD Study will provide useful data for evabuating the effect of the interventions for specific subgroups with large numbers of participants such as those defined by gender on by renal diagnoses of PKD. In addition to the implications regarding generalizability and the balance of the treatment intervention groups discussed in this article, the detailed characterization of the MDRD Study participants during baseline will provide many additional insights about renal disease beyond the context of this trial. Cross-sectional analyses of the study participants at entry to baseline will provide a comprehensive representation of the associations among factors related to renal disease, including the class of renal disease, measures of kidney function (GFR, creatinine clearance), and other clinical, demographic, and biochemistry variables. With its large number of participants and intensive clinical and dietary supervision, the MDRD Study can be expected to substantially affect future approaches to the treatment of participants with renal disease. ACKNOWLEDGMENTS This study is supported by the National Institute of Diabetes. Digestive and Kidney Diseases and the Health Care Financing Administration. A complete list of participants in the MDRD study is provided in a separate publication (4). REFERENCES 1. Modification of Diet in Renal Disease Study Group. The Modification of Diet in Renal Disease Study: Design, methods, and results from the feasibility study. Am J Kidney Dis 1992;2O Perrone PD, Stemman TI, Beck GJ, Skibinski CI, Royal HD, Lawlor M, Hunsicker LG, and the Modification of Diet in Renal Disease Study. Utility of radioisotopic filtration markers in Journal of the American Society of Nephrology I 235

16 MDRD aseline Characteristics chronic renal insufficiency. Simultaneous companison of 25I-iothalamate, 6Yb-DTPA, 99mTc DTPA, and inulin. Am J Kidney Dis 1990;16: Modification of Diet in Renal Disease (MDRD) Study Group (Prepared by Levey AS, Gassman JJ, Hall PM, Walker WG). Assessing the progression of renal disease in clinical studies: Effects of duration of follow-up and regression to the mean. J Am Soc Nephrol ; 1: The Modification of Diet in Renal Disease Study Group (Prepared by Kusek JW, Coyne T, DeVelasco A, Finlay A, Gassman J, Kiefer 5, Powers 5, Steinman T). Recruitment experience in the full-scale phase of the Modification of Diet in Renal Disease Study. Controlled Clin Trials, 1993, in jress. 5. Metropolitan Life Insurance Company. Metropolitan Height and Weight Tables, Stat Bull 1983;64: The Modification of Diet in Renal Disease Study Group (Prepared by Beck GJ, Berg RI, Coggms CH, Gassman JJ, Hunsicker LG, Schluchter MD, Williams GW). 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Controlled low protein diets in chronic renal insufficiency. BMJ 1992; 304: Kassirer JP. Clinical trials and meta-analysis. What do they do for us? N Engl J Med 1992; 327: Rosman JB, Donker AJ, Meijer 5, Sluiter WJ, Piers-Becht TP, Van der Hem GK. Two years experience with protein restriction in chronic renal failure. Contrib Nephrol 1986;53: Rosman JB, Langer K, Brandz M, et at. Protein restricted diet in chronic renal failure: A four year follow-up shows limited indications. Kidney Int 1989;36:S96-S Ihle BU, Becker G, Whitworth JA, Chariwood PA, Kincaid-Smith PS. The effect of protein restriction on the progression of renal insufficiency. N Engl J Med 1989;321: Locatelli F. Dietary compliance in patients with chronic renal failure: Experience in a Northern Italy trial. Contnib Nephrol 1 99O;8 1 : Locatelli F, Alberti D, Graziani G, et at. Prospective, randomized, multicenter trial of effect of protein restriction on progression of chronic renal insufficiency. Lancet ;337: Carroll MD. Dietary intake source data: U.S Data from the Second National Health and Nutrition Examination Survey. Series 1 1, No. 23 1, DHHS Publication No. (PHS) Hyattsville, MD: U.S. Dept. of Health and Human Services, Public Health Service, National Center for Health Statistics; National Center for Health Statistics. Anthropometnic Reference Data and Prevalence of Overweight U.S Data from the 5ccond National Health and Nutrition Examination Survey. Series 1 1, No. 238, DHHS Publication No. (PHS) Hyattsville, MD: U.S. Depart. of Health and Human Services, Public Health Service, National Center for Health Statistics; U.S. Renal Data System. USRDS 1991 Annual Data report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Zeller XR, Whittaker E, Sullvan L, Raskin P. Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin dependent diabetes mellitus. N Engl J Med 1991;324: Bain1, Rohde R, Hunsicker L, McGill J, Kobrin 5, LeWiS E.: A controlled clinical trial of angiotensin converting enzyme inhibition in type I diabetic nephropathy: Study design and patient characteristics. J Am Soc Nephroi 1992;3:S Williams GW, Schluchter MD. Statistical Considerations for Assessing the Influence of Therapy on Progression of Chronic Renal Failure. In: Mitch WE, Stein JH, Eds: The Progressive Nature of Renal Disease. Contemporary Issues in Nephrology. Vol. 26, 2nd Ed. New York: Churchill Livingstone; 1 992; Volume 4. Number