Protein substitute dosage in PKU: how much do young patients need? Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Neuropsychological studies on adolescents with phenylketonuria returned to phenylalanine-restricted diets. The Resource Mothers Study of Maternal Phenylketonuria: preliminary findings. Protein-restricted diets in chronic renal failure: a four year follow-up shows limited indications. Transitory hyperphenylalaninaemia in children with continuously treated phenylketonuria. Pentoxifylline reduces proteinuria in insulin-dependent and non insulin-dependent diabetic patients. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial.
The optimal dose of protein substitute has not been determined in children with phenylketonuria (PKU).
                To determine if a lower dose of protein substitute could achieve the same or better degree of blood phenylalanine control when compared to the dosage recommended by the UK MRC.(1)
                In a six week randomised, crossover study, two doses of protein substitute (Protocol A: 2 g/kg/day of protein equivalent; Protocol B: 1.2 g/kg/day protein equivalent) were compared in 25 children with well controlled PKU aged 2-10 years (median 6 years). Each dose of protein substitute was taken for 14 days, with a 14 day washout period in between. Twice daily blood samples (fasting pre-breakfast and evening, at standard times) for plasma phenylalanine were taken on day 8-14 of each protocol. The median usual dose of protein substitute was 2.2 g/kg/day (range 1.5-3.1 g/kg/day).
                When compared with control values, median plasma phenylalanine on the low dose of protein substitute increased at pre-breakfast by 301 mumol/l (95% CI 215 to 386) and in the evening by 337 micromol/l (95% CI 248 to 431). On the high dose of protein substitute, plasma phenylalanine concentrations remained unchanged when compared to control values. However, wide variability was seen between subjects.
                A higher dosage of protein substitute appeared to contribute to lower blood phenylalanine concentrations in PKU, but it did have a variable and individual impact and may have been influenced by the carbohydrate (+/- fat) content of the protein substitute. To test the efficacy of tyrosine supplementation, as an adjunct to dietary treatment, on neuropsychological test performance in individuals with phenylketonuria.
                A randomised controlled trial of tyrosine supplementation using a double blind crossover procedure with three four week phases.
                The Hospital for Sick Children, Toronto.
                21 individuals with phenylketonuria (ages 6 to 28 years, mean 11.3).
                Participants were given 100 mg/kg body weight/d of L-tyrosine or L-alanine (placebo).
                At baseline, performance on several of the neuropsychological test measures was correlated with tyrosine levels. Dietary supplements of tyrosine increased plasma tyrosine concentrations; however, no change in test performance was found across the tyrosine and placebo phases of the study.
                Tyrosine supplementation of this type does not appear to alter neuropsychological performance in individuals with phenylketonuria. Nine adolescents with phenylketonuria (PKU), who had been on unrestricted diets for 2 to 11 years, underwent serial neuropsychological testing over two consecutive 4- to 5-week periods during which each was maintained on a low-phe diet supplemented in a triple-blind fashion either with L-phe (high phe) or L-alanine (low phe). Assignment to the initial condition was done randomly, and the alternate condition was substituted at the end of the first 4- to 5-week period. In 6 of 7 subjects with PKU, baseline median choice reaction times (RTs) were slower than those of controls matched for age, sex, handedness, and Full-Scale IQ (WISC-R). A highly significant improvement occurred during the low-phe phases of the study. Results suggest that adolescents with PKU on unrestricted diets have a neuropsychological deficit that is out of proportion to their overall intellectual handicap. Moreover, this deficit appears to be at least partly reversible by return to dietary phe restriction despite years of hyperphenylalaninemia. Women with phenylketonuria (PKU) must follow a strict low-phenylalanine diet during pregnancy in order to protect the fetus from the deleterious effects of high maternal blood phenylalanine. The Resource Mothers Study of Maternal PKU was undertaken to determine whether a home visitation programme was effective in helping women with PKU attain blood phenylalanine control earlier during pregnancy. Resource Mothers were trained to provide social support and practical assistance to women with PKU during pregnancy. Eight metabolic clinics in the United States participated in the study. Women with PKU who were planning pregnancy or already pregnant were enrolled in the study and were treated with a low-phenylalanine diet aimed at controlling blood phenylalanine to 120-360 micromol/L. They were randomly assigned to receive the services of a Resource Mother (RM group) or to a control group. Fifty women were enrolled, and accounted for 44 pregnancies which resulted in 28 live births, and 6 spontaneous abortions. Ten women are currently pregnant and another 6 have not become pregnant. Fifty-six percent of enrolled women began the diet prior to becoming pregnant. Fifty-three percent of women in the Resource Mother group were in metabolic control by 10 weeks gestation as compared to 39% in the control group. In addition, women who began diet after pregnancy and had a Resource Mother attained metabolic control earlier (mean gestational age of 22.4 weeks in the RM group vs 29.8 weeks in the control group). There was no difference in birth measurement z -scores of offspring born to women in the RM group compared to controls. All but 4 women rated themselves as feeling worse about the diet at the end of pregnancy than at the beginning, and few women in either group remained on diet after delivery. Several retrospective and prospective studies confirmed the beneficial effect of dietary protein restriction (DPR) on the downhill course of renal function in chronic kidney disease. The long-term results of this therapeutic modality may be different than the short-term effects. In our nephrology outpatient department, a prospective randomized trial has been in progress since April, 1982. In 1984, we reported a general beneficial effect of our diet after two years of follow-up. Two hundred and forty-eight patients with initial creatinine clearances between 10 and 60 ml/min entered the trial. Patients were stratified for sex, age and degree of renal insufficiency. One hundred and twenty-nine patients were randomly assigned to a DPR-group (0.4 to 0.6 g/kg/day); 118 patients to a control group. Patients on DPR visited the dietitian every three months during the first 24 months of the study; thereafter, as with the controls, the dietitian visits were only for specific needs. Urea excretion decreased significantly in DPR patients as a sign of good compliance and stayed at that level, even without frequent visits to the dietitian. Biochemical parameters showed no signs of malnutrition. Amino acid profiles were related to the degree of renal failure. The diet appeared to have a selective effect on the progression rate of renal failure: only patients with primary glomerular disease responded to the diet. Furthermore, there were striking intersex differences. Males showed a more rapid decline towards end-stage renal failure, but responded in a positive way to the diet, whereas female patients did not benefit from the dietary manipulation at all.(ABSTRACT TRUNCATED AT 250 WORDS) Cognitive and behavioral effects of temporarily challenging the CNS with elevated levels of phenylalanine in treated phenylketonuria (PKU) were investigated in a triple-blind, cross-over study. A high phenylalanine supplement was given over 3 months to sixteen 10- to 16-year-old early and continuously treated children with classical PKU. We used the WISC and Rivermead tests to measure cognitive function and the Rutter Scales to assess disordered behavior. Parents and children guessed at the condition imposed. The Group x Phase interaction for phenylalanine level was statistically significant, but this pattern was not mirrored in the psychological test data, and guessing was random. Results suggest that intellectual ability, memory, and conduct are not affected by medium-term hyperphenylalaninaemia in PKU after 10 or more years of treatment. Pentoxifylline is a drug with hemorheological actions used in the management of microcirculatory abnormalities, such as those usually seen in diabetic patients. The drug has been successfully used in improving peripheral and central circulation, as well as proteinuria of long-term diabetes. With the hypothesis that pentoxifylline reduces proteinuria in patients with IDDM and NIDDM, with a wide range of urinary protein excretion, 86 diabetic patients were studied. Forty-one patients with IDDM were stratified in 2 subgroups: one of 18 patients with microalbuminuria, and the other of 23 patients with overt proteinuria. In the same way, 45 patients with NIDDM were divided in 2 subgroups: one of 23 patients with microalbuminuria, and the other of 22 patients with proteinuria. Patients in each subgroup were randomized to receive either placebo or pentoxifylline 1,200 mg/d, during 4 months, using a double blind design. At the beginning of the study and after treatment, 24-hour urinary albumin excretion was measured by nephelometry in each patient.(ABSTRACT TRUNCATED AT 250 WORDS) There is no generally accepted treatment for primary focal segmental glomerulosclerosis (FSGS). Steroids alone and steroids plus cyclophosphamide can be expected to induce a remission of the proteinuria in only 27% of patients. Probably the majority of FSGS patients will reach ESRD over the extended course of their disease. In addition to the work presented in this study, there have been many reports of the potential effectiveness of cyclosporine (CSA) on reducing the proteinuria of FSGS. This study was undertaken to test the efficacy and safety of a 6-month course of CSA in a double-blinded, prospectively randomized, placebo-controlled trial in children with corticosteroid-resistant FSGS. The potential inhibitory effect of hypercholesterolemia on the proteinuria-reducing actions of CSA was also assessed. Twenty-five patients with FSGS were randomized to receive either placebo or CSA for 6 months. Twelve of the 12 patients that received CSA experienced a diminution of their proteinuria as opposed to only two of the 12 placebo-treated patients. Proteinuria was significantly reduced from 151.7 +/- 162.4 mg/kg per 24 h at Week 0 to 36.9 +/- 42.3 at the end of the study in the group that received CSA (P < 0.05). There was no significant change in the proteinuria of the patients in the placebo group. A significant correlation between the percentage change of proteinuria over the 6 months of the study and the prestudy serum cholesterol levels (r = 0.79, P < 0.05) was seen in the CSA group. A partial correlation analysis controlling for the effects of serum cholesterol uncovered a significant relationship between average CSA level and proteinuria change (r = -0.76, P < 0.05). The fractional decline in GFR over the course of the study was not significantly different between the CSA and placebo-treated groups. In conclusion, CSA reduces proteinuria, increases serum albumin levels, and can be expected, therefore, to reduce the symptoms of nephrotic syndrome. Hypercholesterolemia antagonizes this effect of CSA. Protein restriction delays the progression of non-diabetic and type 1 diabetic renal disorders. This study assessed whether protein restriction delays the onset or early progression of renal disorders in type 2 diabetes.
                Randomized controlled trial. Outcomes were albuminuria (mg/24 h) and, as an estimate of the glomerular filtration rate, cimetidine-influenced creatinine clearance.
                Primary care.
                Patients with type 2 diabetes and microalbuminuria or at least detectable albuminuria, or a diabetes duration >5 y.
                The experimental group received dietary counselling on protein restriction (n=63); a control group (n=68) received the usual dietary advice. The duration of intervention and follow-up was 28+/-7 months.
                After 6 months, protein intake differed only by 0.08 g/kg/day between the study groups. Subsequently, this difference decreased and eventually disappeared. An initial effect of protein restriction on albuminuria in favor of the experimental group was not sustained, and the glomerular filtration rate decreased in the experimental group at a 1.6+/-2.2 ml/min/1.73 m(2) y lower rate than in the control group (P=0.5). Comparison of patients in the experimental group with a decrease in protein intake of at least 0.20 g/kg/day, with controls with no decrease, indicated a similarly small and insignificant effect on glomerular filtration rate.
                It is concluded that, in the longer term prevention or delay of renal damage in patients with type 2 diabetes, protein restriction is neither feasible nor efficacious.
No conclusions could be drawn about the short- or long-term use of protein substitute in phenylketonuria due to the lack of adequate or analysable trial data. Additional data and randomised controlled trials are needed to investigate the use of protein substitute in phenylketonuria. Until further evidence is available, current practice in the use of protein substitute should continue to be monitored with care.