Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330).

We present a family with autosomal-dominant inheritance of renal insufficiency caused by renal hypoplasia in six individuals. In all affected individuals, signs of optic disk dysplasia were detected, but most patients were asymptomatic. A heterozygous missense mutation in the PAX2 gene causing a Gly75 to Ser substitution was present in all affected individuals. A second, unrelated patient presented with ocular complaints related to optic disk dysplasia, and had a history of vesico-ureteral reflux. A heterozygous hexanucleotide duplication in the PAX2 gene was detected leading to the duplication of GluThr at positions 74 and 75. The mutations in these two families are the first mutations in the PAX2 gene that do not lead to a truncated protein. Mechanistically, these mutations are expected to result in abnormal folding of the PAX2 protein. These observations further expand the spectrum of clinical features associated with PAX2 mutations, and suggest that a distinct genetic disorder can be identified in patients with renal dysplasia through a careful eye examination. As the ocular manifestations in this syndrome are variable anomalies of retinal and optic disk dysplasia, we prefer the term "papillo-renal syndrome".

Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis.

AIMS: The purpose of this study was to investigate the pharmacokinetics of a single oral dose of lamivudine administered to subjects with renal impairment and to determine whether lamivudine was dialysable in subjects with severe renal impairment undergoing haemodialysis. METHODS: Twenty-nine subjects were enrolled, nine with normal renal function (creatinine clearance (CL(CR)) 82-117 ml min(-1)), eight with moderately impaired renal function (CL(CR) 25-49 ml min(-1)), six with severe impairment (CL(CR) 13-19 ml min(-1)) and six with severe impairment who were also receiving haemodialysis. After an overnight fast, nondialysis subjects received a single oral dose of lamivudine. Subjects on haemodialysis were given two doses on separate occasions (intra and interdialysis). Blood was obtained before lamivudine administration and at regular intervals to 48 h post dose. Timed urine collections were performed for subjects able to produce urine. Pharmacokinetic parameters were calculated by using standard non compartmental techniques. RESULTS: Decreasing renal function was associated with reduced lamivudine clearance in a proportional and apparently linear relationship. Lamivudine was well dialysed with an extraction ratio in the order of 50%. However, because lamivudine has a large volume of distribution (approximately 100 1), a haemodialysis session of 4 h did not affect overall exposure to a clinically significant degree in most subjects. CONCLUSIONS: Impaired renal function does require lamivudine dose modification according to the degree of impairment, but no further modification of dose is required for subjects undergoing regular haemodialysis.

High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure.

Recently, well performing diagnostic criteria for analgesic nephropathy in end-stage renal failure (ESRF) patients were defined by the demonstration of a bilateral decrease in renal volume combined with either bumpy contours or papillary calcifications. In this study, the diagnostic value of computed tomography (CT) scan was compared to the previously used renal imaging techniques (sonography and conventional tomography). In a first study, a cohort of 40 analgesic abusers (defined as daily use of analgesic mixtures during at least 5 years) and 40 controls, all ESRF patients without a clear renal diagnosis, were investigated with sonography, tomography and CT scan without injection of iodinated contrast material, to search for the imaging signs of analgesic nephropathy. Using CT scan, sonography and tomography, renal size could be evaluated with comparable results while CT scan was superior in the detection of papillary calcifications (sensitivity 87%, specificity 97%). In a second controlled study of 53 analgesic abusers with a serum creatinine between 1.5 to 4 mg/dl in the absence of a clear renal diagnosis, a CT scan was performed and scored for the presence of decreased renal volume, bumpy contours and papillary calcifications. It was found that the renal image of analgesic nephropathy on CT scan in an early stage of renal failure is comparable with the observations made in ESRF patients. Particularly the demonstration of papillary calcifications showed a high sensitivity of 92% with a specificity of 100% for the early diagnosis of analgesic nephropathy.