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The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline factors that predict the decline in GFR, or which alter the efficacy of the diet or blood pressure interventions. Univariate analysis identified 18 of 41 investigated baseline factors as significant (P < 0.05) predictors of GFR decline. In multivariate analysis, six factors--greater urine protein excretion, diagnosis of polycystic kidney disease (PKD), lower serum transferrin, higher mean arterial pressure, black race, and lower serum HDL cholesterol--independently predicted a faster decline in GFR. Together with the study interventions, these six factors accounted for 34.5% and 33.9% of the variance between patients in GFR slopes in Studies A and B, respectively, with proteinuria and PKD playing the predominant role. The mean rate of GFR decline was not significantly related to baseline GFR, suggesting an approximately linear mean GFR decline as renal disease progresses. The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions. A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein. None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction.

This study addresses mechanisms of the clinical, encephalopathic uremic illness and its suppression by dialysis. Renoprival rats were treated with peritoneal dialysis (8 exchanges per day, 30 min dwell), or untreated (attrition group), and their EEG's were automatically sampled overnight and subjected to power spectrum analysis as an index of encephalopathy. As in man the background rhythm of the quantified EEG (Q.EEG) in the attrition group slowed with time as extracellular fluid composition became increasingly abnormal; these changes were normalized by therapeutic dialysis (TD) using standard, commercial dialysate. However, Q.EEG slowing was only partially normalized by solute-specific dialysis using "mock uremic dialysate" (M-UD), prepared from laboratory chemicals to equal plasma concentrations in preterminal uremic rats of urea, creatinine, potassium, phosphorus, calcium, magnesium, bicarbonate, sodium, and chloride. When only phosphate was added to TD, the Q.EEG slowed to the same level achieved after M-UD. We conclude that uremic encephalopathy in this model is produced by an unknown neurotoxin and augmented by one or more of the M-UD solutes, phosphate being a likely candidate. To localize the encephalopathic effect, regional brain glucose uptake was estimated in 20 discrete brain areas. Significance of reduced uptake in three areas is discussed.

The disabling, dialysis-responsive symptoms of clinical uremia primarily represent impaired functions of the nervous system. Accordingly, these studies used several quantitative electrophysiologic and cognition-dependent probes of nervous system function: peripheral nerve-conduction velocity, response latency and amplitude; electroencephalographic (EEG) power-spectrum analysis; visual evoked response latency; EEG responses to photic driving; and measures of integrated behavioral performance that stressed sustained and selective attention, reaction time, speed of decision-making, short-term memory, and mental manipulation of symbols. Probes of quanitified central nervous system function consistently revealed impairments that varied directly with the degree of renal failure, that improved following onset of maintenance dialysis, and that improved still further after successful renal transplantation. In contrast, measures of peripheral nerve function were generally unchanged. Neurobehavioral measures that are relevant to uremic symptomatology provide quantitative estimates of the clinically significant, whole-organism biologic effects of renal failure and its several treatments. Applications of such measures in studies of symptomatic states other than uremia are indicated also.

It has been recognized for over 30 years that increased renal dysfunction results in increased slow wave activity in the EEG generally prior to the clinical appearance of disabling, dialysis-responsive encephalopathic symptoms of clinical uremia. This paper describes computerized methods that have been used to quantify this slow wave activity and the results of studies that have employed such computerized techniques. Practical information is furnished to guide those who wish to use these methods in their own research and practice. A survey of the limitations and pitfalls inherent in the various techniques is given. A prospectus outlines possible future directions in the field.