Frequent Hemodialysis Network (FHN) randomized trials: study design.

Observational studies suggest improvements with frequent hemodialysis (HD), but its true efficacy and safety remain uncertain. The Frequent Hemodialysis Network Trials Group is conducting two multicenter randomized trials of 250 subjects each, comparing conventional three times weekly HD with (1) in-center daily HD and (2) home nocturnal HD. Daily HD will be delivered for 1.5-2.75 h, 6 days/week, with target eK(t)/V(n) > or = 0.9/session, whereas nocturnal HD will be delivered for > or = 6 h, 6 nights/week, with target stdK(t)/V of > or = 4.0/week. Subjects will be followed for 1 year. The composite of mortality with the 12-month change in (i) left ventricular mass index (LVMI) by magnetic resonance imaging, and (ii) SF-36 RAND Physical Health Composite (PHC) are specified as co-primary outcomes. The seven main secondary outcomes are between group comparisons of: change in LVMI, change in PHC, change in Beck Depression Inventory score, change in Trail Making Test B score, change in pre-HD serum albumin, change in pre-HD serum phosphorus, and rates of non-access hospitalization or death. Changes in blood pressure and erythropoiesis will also be assessed. Safety outcomes will focus on vascular access complications and burden of treatment. Data will be obtained on the cost of delivering frequent HD compared to conventional HD. Efforts will be made to reduce bias, including blinding assessment of subjective outcomes. Because no large-scale randomized trials of frequent HD have been previously conducted, the first year has been designated a Vanguard Phase, during which feasibility of randomization, ability to deliver the interventions, and adherence will be evaluated.

Design and statistical issues of the hemodialysis (HEMO) study.

The Hemodialysis Study is a multicenter clinical trial of hemodialysis prescriptions for patients with end stage renal disease. Participants from over 65 dialysis facilities associated with 15 clinical centers in the United States are randomized in a 2 x 2 factorial design to dialysis prescriptions targeted to a standard dose or a high dose, and to either low or high flux membranes. The primary outcome variable is mortality; major secondary outcomes are defined based on hospitalizations due to cardiovascular or infectious complications, and on the decline of serum albumin. The Outcome Committee, consisting of study investigators, uses a blinded review system to classify causes of death and hospitalizations related to the major secondary outcomes. The dialysis dose intervention is directed by the Data Coordinating Center using urea kinetic modeling programs that analyze results from dialysis treatments to monitor adherence to the study targets, adjust suggested dialysis prescriptions, and assist in trouble-shooting problems with the delivery of dialysis. The study design has adequate power to detect reductions in mortality rate equal to 25% of the projected baseline mortality rate for both of the interventions.

Kidneys of the killerwhale and significance of reniculism.

BACKGROUND: The kidneys of all Cetacea are composed of many small relatively independent kidneys (renicules) containing considerable interrenicular tissue. Although reniculism is not entirely confined to the Cetacea, it is desirable to consider the possible advantage of reniculism to mammals of gigantic size. The kidneys of the killerwhale, Orcinus orca, are compared from this standpoint to the kidneys of diverse mammals. METHODS: The specific renal parenchymal mass, glomerular counts, glomerular size, and specific glomerular mass of the killerwhale are measured and compared quantitatively (statistically) with similar data from numerous diverse mammals. Simultaneously, a method is described for enumerating the renicules of a cetacean kidney. RESULTS: Specific parenchymal mass of a killerwhale adult's two kidneys (0.33%) is close to the expected value for mammals of its adult body mass (2,087 kg). The diameter of the adult's glomerular capsules (153 microm) is strikingly less than that expected from its body mass (regression equation and graph for mammals in general). However, the number of glomeruli per kidney (approximately 100 x 10[6]) is markedly greater than that for mammals of its body mass (regression equation and graph for mammals in general) and is the first such count for a cetacean. The total glomerular mass relative to parenchymal renal mass of the O. orca infant and adult is, nevertheless, 5.5% and 6.0%, respectively, and is thus close to the general mammalian value of approximately 5%. CONCLUSIONS: Organization of a cetacean kidney into numerous renicules does not increase specific renal parenchymal mass or specific glomerular mass. The apparent advantage of numerous independent renicules is the limit that is afforded for length of tubules in the necessarily large kidneys of gigantic mammals.

Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study.

The safety of dietary protein and phosphorous restriction was evaluated in the Modification of Diet in Renal Disease (MDRD) Study. In Study A, 585 patients with a glomerular filtration rate (GFR) of 25 to 55 ml/min/1.73 m2 were randomly assigned to a usual-protein diet (1.3 g/kg/day) or a low-protein diet (0.58 g/kg/day). In Study B, 255 patients with a GFR of 13 to 24 ml/min/1.73 m2 were randomly assigned to the low-protein diet or a very-low-protein diet (0.28 g/kg/day), supplemented with a ketoacid-amino acid mixture (0.28 g/kg/day). The low-protein and very-low-protein diets were also low in phosphorus. Mean duration of follow-up was 2.2 years in both studies. Protein and energy intakes were lower in the low-protein and very-low-protein diet groups than in the usual-protein group. Two patients in Study B reached a "stop point" for malnutrition. There was no difference between randomized groups in the rates of death, first hospitalizations, or other "stop points" in either study. Mean values for various indices of nutritional status remained within the normal range during follow-up in each diet group. However, there were small but significant changes from baseline in some nutritional indices, and differences between the randomized groups in some of these changes. In the low-protein and very-low-protein diet groups, serum albumin rose, while serum transferrin, body wt, percent body fat, arm muscle area and urine creatinine excretion declined. Combining patients in both diet groups in each study, a lower achieved protein intake (from food and supplement) was not correlated with a higher rate of death, hospitalization or stop points, or with a progressive decline in any of the indices of nutritional status after controlling for baseline nutritional status and follow-up energy intake. These analyses suggest that the low-protein and very-low-protein diets used in the MDRD Study are safe for periods of two to three years. Nonetheless, both protein and energy intake declined and there were small but significant declines in various indices of nutritional status. These declines are of concern because of the adverse effect of protein calorie malnutrition in patients with end-stage renal disease. Physicians who prescribe low-protein diets must carefully monitor patients' protein and energy intake and nutritional status.

Cross-sectional study of quality of life and symptoms in chronic renal disease patients: the Modification of Diet in Renal Disease Study.

The purposes of this study were to measure health-related quality of life in the Modification of Diet in Renal Disease clinical trial; correlate quality of life measures with demographic, medical, and laboratory variables; and compare quality of life in various chronic diseases. The 1,284 patients enrolled in the baseline period of the Modification of Diet in Renal Disease study who completed at least one measurement of quality of life or symptoms served as the subjects of this study. The Quality of Well-Being (QWB) scale, which was a general health-related quality of life index, the Symptom Checklist-90R (SCL-90R), which provided a global measure of mental health, and the Patient Symptom Form, which assessed the frequency of symptoms specific to this population, were used as measurements. The mean +/- SD QWB score was 0.74 +/- 0.09. Using multivariate analysis, there was a significant negative correlation between the overall QWB score and age and female gender, and a significant positive correlation between the QWB and level of education, income, and glomerular filtration rate (GFR). For the SCL-90R subscores, the mean normalized Global Symptom Index was 49.7 +/- 9.6, the Positive Symptom Total was 47.9 +/- 10.4, and the mean Positive Symptom Distress Index was 51.3 +/- 12.6. Using multivariate analysis, significant inverse relationships were seen between each of the SCL-90R subscores and income, serum albumin level, and GFR. The most commonly reported medical symptoms in this cohort included tiring easily, weakness, lack of pep or energy, difficulty sleeping, and abdominal bloating or gas. Symptoms in which the severity index score had a negative correlation with GFR included tiring easily, weakness, lack of pep and energy, muscle cramps, easy bruising or bleeding, bad taste in mouth, and hiccoughs. In conclusions, patients with moderate to advanced renal insufficiency have a reduced quality of life and an increased frequency and severity of both symptoms and psychological distress, with the magnitude of these changes negatively correlated with GFR.

Data quality assurance, monitoring, and reporting.

In conclusion, the quality assurance and monitoring program is an integral and continuing part of study operations. A system must be devised and implemented by the coordinating center investigators, with the endorsement of the study leadership and support of the field site and resource center personnel. Proactive mechanisms for promoting high-quality data acquisition and reporting must be implemented. Data quality monitoring must address the entire process by which the data are gathered, transmitted, stored, and analyzed. Data quality should be monitored continually, with summary reports prepared and distributed to the study leadership. Appropriate training and certification enhance data quality, and site visits allow data collection and storage processes to be observed directly. The quality assurance and monitoring system must be documented. It should be flexible enough so that new means of quality assurance or monitoring can be added when necessary during the course of the study. At the completion of the study, quality monitoring results should be summarized in a final report regarding the level of quality achieved by the study investigators and personnel. Finally, for a quality assurance and monitoring program to be successful, the coordinating center investigators and personnel must provide prompt feedback and suggestions for corrective action whenever a data quality problem is discovered. This need can be met only when the coordinating center staff understand data quality goals and are up to date with all phases of data management and reporting. Delays in initiating any stage of data management and quality monitoring may result in uncorrectable data problems. Thus, knowledgeable and efficient coordinating center personnel are essential to achieving good data quality studywide.

Recruitment experience in the full-scale phase of the Modification of Diet in Renal Disease Study.

The Modification of Diet in Renal Disease (MDRD) Study is a randomized, multicenter clinical trial testing the effects of three different levels of dietary protein and phosphorus intake and two levels of blood pressure control on the rate of loss of kidney function in persons with various chronic kidney diseases. During a 27-month recruitment period, 2507 persons who had objective evidence of impaired kidney function were screened at 15 centers. Eight hundred and forty men and women aged 18-70 with a glomerular filtration rate between 13 and 55 ml/min/1.73 m2 were randomized. Medical record review was the primary means of identifying study participants at the beginning of recruitment. Later, use of mass media was instrumental in alerting both the public and the medical community of the need for MDRD Study participants. Overall, the most important sources of randomized participants were referral by personal physician (45.4%) and relative/friend (5.6%), and self-referral after hearing about the trial from newspapers (23.9%) and television (5.2%). Review of medical records from defined patient populations was the source of 22.3% of the randomized study participants. A total of 9.4% of the randomized participants called a toll-free (800) telephone number before contacting the centers.

Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group.

The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 x 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.

Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. Modification of Diet in Renal Disease (MDRD) Study Group.

Many clinical studies of the effects of low-protein and low-phosphorus diets on the course of chronic renal disease have used the rate of decline in renal function to assess the rate of progression. In this report, data from the feasibility phase of the Modification of Diet in Renal Disease Study were used to analyze methods used in other studies. The focus is particularly on the effects of duration of follow-up and of regression to the mean. The findings are summarized as follows. (1) During the mean follow-up period of 14.1 months, rates of decline in glomerular filtration rate, creatinine clearance, and the reciprocal of the serum creatinine concentration were highly variable among individuals, and mean rates of decline were slow. (2) Precision of estimates of individual rates of decline in renal function were relatively low and improved with increasing duration of follow-up. (3) Correlations between rates of decline in creatinine clearance and the reciprocal of the serum creatinine concentration with glomerular filtration rate in individuals were significant but weak and became stronger with increasing duration of follow-up. (4) After entry into the study, mean rate of decline in the reciprocal of the serum creatinine concentration became less negative. The change predicted simply from regression to the mean was 68.4% of the observed change.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group.

The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized, controlled trial to determine acceptance, safety, and efficacy of low protein and phosphorus diets in patients with progressive renal disease. During the feasibility phase, 96 patients aged 18 to 75 years, with previously declining reciprocal serum creatinine concentration (1/PCr) and current glomerular filtration rate (GFR) from 7.5 to 80 ml/min/1.73 m2, were randomly assigned four study diets. After randomization, 91 patients were followed for a mean duration of 14.1 months. GFR, 1/PCr and creatinine clearance (CCr) were measured every three months. In an earlier report, we demonstrated relatively weak correlations of rates of change in GFR and 1/PCr during the feasibility phase; the proportion of variability in 1/PCr slopes that was explained by variability in GFR slopes (r2) was only 0.49 to 0.55. In this study, we examined the relationship of GFR and 1/PCr to other determinants of the serum creatinine concentration, including filtration (GFCr), secretion (TSCr), and total renal excretion (UCrV) of creatinine. Our results show that these parameters varied widely among individuals and changed over time. These findings may explain, in part, the relatively weak correlations. These results strengthen our previous suggestion that the rate of change in 1/PCr may not be an accurate index of the rate of change in GFR and raise questions about the validity of conclusions from other studies in which the efficacy of dietary modification in retarding the progression of renal disease was based principally on measurements of 1/PCr.

A proposed method to evaluate brain stem auditory evoked potential amplitude: pilot study.

The distribution and variability of brain stem auditory evoked potentials (BAEP) were studied in 30 guinea pigs under controlled conditions. Coefficient of variation showed amplitude variables to have a greater intersubject variability than latency variables. However, amplitude variables were not found to be normally distributed. Therefore, evaluation of amplitude variables using statistics which assume that the underlying data are normally distributed can be misleading. One must either transform the data so they fit a normal distribution or use statistical methods that do not depend on a normal distribution. A nonparametric analysis study on amplitude variables in humans in recommended to update its clinical applicability.

Cancer of the esophagus. The Cleveland Clinic experience.

The therapy and survival rates of patients with esophageal carcinoma at the Cleveland Clinic over the 12-year period 1969-1980 are reviewed. Data on 238 patients were analyzed. Seventy-one per cent of the patients underwent surgery, with esophagogastrectomy being performed in half of these. One or more early postoperative complications occurred in 72.6% of these patients. Most of these complications were pulmonary and related to the patients' chronic obstructive pulmonary disease. The mortality rate for esophagogastrectomy at the Cleveland Clinic has decreased over the past 15 years to 7.1%. The 5-year survival rate after "curative" esophagogastrectomy was 15.4% with a mean survival time of 34.4 months. Invasion of the tumor through or beyond the serosa in this group of patients was associated with an increased relative risk of death of 3.3 compared to those with lesser degrees of invasion. The cell type, degree of differentiation, stage of disease, and presence of tumor at the lines of resection were all prognostically significant for all patients.