Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation.

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One hundred and fourteen boys with posterior urethral valves were treated between 1966 and 1975. Four died during the first hospital admission, 6 died from renal failure during childhood, 1 died from other causes and 15 were lost to follow-up. Eighty-eight were reviewed 11 to 22 years after diagnosis and the renal outcome of 98 patients is therefore known. Approximately one-third of patients presented under 1 month of age, between 1 month and 1 year, and over 1 year respectively. Bilateral vesicoureteric reflux was observed in one-quarter of the boys, more frequently in those presenting in the first month of life. Half of the patients were treated by primary valve ablation and half underwent temporary upper tract diversion: the outcome was worse for the diverted group. One-third of the boys had a long-term bad outcome for renal function. This outcome was associated with early presentation, bilateral vesicoureteric reflux and day-time urinary incontinence after the age of 5 years. The association of bad outcome with incontinence points to continuing bladder dysfunction as a major determinant of long-term outcome for renal function.

Abstract. The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5' region had significantly more severe disease than the 3' group; median time to ESRD was 53 and 56 yr, respectively (P ϭ 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.

Autosomal recessive polycystic kidney disease causes renal and hepatic dysfunction in childhood. We describe the clinical outcome of 52 children with this diagnosis born between 1950 and 1993. Currently 23 are alive, 24 dead and 5 have been lost to follow-up; 1 has been dialysed and 7 transplanted. Life-table analysis of the patients surviving the 1st month of life revealed an actuarial renal survival of 86% at 1 year and 67% at 15 years. The probability of requiring anti-hypertensive treatment was 39% at 1 year and 60% at 15 years of age. Bleeding from gastro-oesophageal varices occurred in 8 patients at a mean age of 12.5 years, and was preceded by haematological evidence of hypersplenism in 6 of them. The study indicates a relatively good prognosis for patients with this condition who survive the neonatal period and emphasises the importance of early detection and appropriate management of systemic and portal hypertension.

Chantler, C., and Barratt. T. M. (1972). Archives of Disease in Childhood, 47, 613. Estimation of glomerular filtration rate from plasma clearance of 51-chromium edetic acid. The glomerular filtration rate was estimated by a single compartment analysis of the rate of fall of plasma concentration of 5 1-chromium edetic acid after a single intravenous injection. This slope clearance consistently overestimated the simultaneously determined standard urinary clearance, but could be used to predict the latter with an accuracy of ±9% (95% confidence limits).The coefficient of variation of replicate estimates of the slope clearance in the same individual was 3-9 %; thus two estimates of glomerular filtration rate by this technique which differ by 11% have a 95 % probability of reflecting a genuine difference.The method requires an intravenous injection and blood samples at 2 and 4 hours; urine samples are not required. It is simple, safe, and precise, and is applicable to children.The estimation of glomerular filtration rate (GFR) is essential in the management of renal disease, but the inulin clearance is too complex and the endogenous creatinine clearance (Dodge, Travis, and Daeschner, 1967;Doolan, Alpen, and Theil, 1962;Kim et al., 1969) too imprecise for many clinical situations. There has therefore been a revival of interest in the possibility of estimating GFR from the rate of fall of plasma concentration of a substance after a single intravenous injection (slope clearance; C-slope) in spite of theoretical objections (Smith, 1951). The technique is so attractively simple that we have reexamined it using 51chromium edetic acid (51Cr-EDTA) which is not metabolized and is excreted solely by the kidney; its clearance is about 5% less than the simultaneously determined inulin clearance (Chantler et al., 1969; Lavender, Hilton, and Jones, 1969;Stamp, Stacey, and Rose, 1970). Some results of the slope clearance technique have already been published (Chantler et al., 1969) which correlated closely with the urinary clearance measured by the standard clearance techniques (UV/P clearance; C-UV/P). The purpose of this

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