Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma.

AIM: To study the radiological characteristics of renal masses in individuals with tuberous sclerosis complex (TSC) using serial CT, and to examine how renal cell carcinoma (RCC) may be differentiated from indeterminate cysts or masses. METHODS: This was a retrospective study of 12 cases of TSC in which dedicated renal CT followed after US had demonstrated cystic or sonographically unusual renal masses. The CT density of all masses was measured and the masses categorized as simple cysts, complex cysts, angiomyolipomas or indeterminate solid masses. Subjects were maintained on regular follow-up with repeat CT or MRI and interval renal US. Indeterminate masses that showed rapid growth were considered suspicious for renal cell carcinoma and biopsy or nephrectomy followed. RESULTS: Comparative data were available for a median of 4 years. In each case the renal masses were multiple and bilateral; mean mass diameter was 3.6 cm. Among a total of 206 masses, 18 were simple cysts and 3 were complex cysts. Of the complex cysts, 1 proved to be an angiomyolipoma on histology and the other 2 showed no growth. Of the solid masses, 133 were typical angiomyolipomas (AMLs) and 52 were indeterminate. On follow-up, only 3 indeterminate masses showed rapid growth (>0.5 cm/year), of which only 1 proved to be an RCC on biopsy. The other 2 were minimal-fat AMLs, and the remainder of the masses showed no or slow growth. CONCLUSION: Many renal masses associated with TSC are radiologically indeterminate. A growth threshold of >0.5 cm/year identified the only RCC in this study (0.5% of all masses). Yearly radiological follow-up of indeterminate renal masses is recommended for individuals with TSC.

T594M mutation of the beta-subunit of the epithelial sodium channel in Ghanaian populations from Kumasi and London and a possible association with hypertension.

We have tested 186 individuals from Ghana, 95 indigenous and 91 who have settled in the United Kingdom, for the presence of the T594M mutation in the beta-subunit of the epithelial sodium channel, which is associated with hypertension in black populations. The group living in Ghana had a mean age of 27 years and were normotensive, but had an increased frequency of the T allele compared to the London-based population. If this is reflected in larger studies, and the link with hypertension is maintained in the Ghanaian population, this mutation could be a significant cause of hypertension in Ghana.

Location of mutations within the PKD2 gene influences clinical outcome.

BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed clinical information was collected for PKD2 families in which the underlying mutation had been identified. Logistic regression analysis was employed to assess the influence of age and sex on hypertension, hematuria, renal calculi, and urinary tract infections, and a clinical phenotype score was computed. Patients were then grouped according to the relative location of their mutation within the cDNA sequence, and differences in the mean phenotypic score between groups were tested for statistical significance by means of a multiple pairwise t-test. RESULTS: While phenotypic scores for each mutational group revealed a considerable degree of intragroup variability, the variability in phenotypic scores was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observation of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. CONCLUSION: The identification of groups of mutations in the PKD2 gene, which differ significantly with respect to clinical outcome, is to our knowledge the first description of a genotype/phenotype correlation in autosomal dominant polycystic kidney disease. It also provides evidence against complete loss of function of the mutant PKD2 gene product.

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease.

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

Novel mutations in the duplicated region of the polycystic kidney disease 1 (PKD1) gene provides supporting evidence for gene conversion.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human single-gene disorders, and is the most common inherited form of cystic kidney disease. It is estimated that approximately 85% of ADPKD is due to mutations in the PKD1 gene, which is located on chromosome 16p13.3. Mutation analysis in this gene is difficult, because more than two-thirds of reiterated several times at 16p13.1. In this study, mutation screening in 90 ADPKD patients was carried out on exons in the duplicated region of the PKD1 gene (23-34), using genomic long-range PCR followed by nested PCR and single-strand conformation polymorphism (SSCP), and finally cycle sequencing. Two nonconservative missense mutations were detected in exons 25 and 31, and two conservative mutations were found in exons 24 and 29. A novel splicing mutation, which is expected to cause skipping of exon 30, was detected in one case. Moreover, six intronic variants, three silent variants, and one polymorphic variant were detected in this study. Comparison between some of these changes and published sequences from the homologous genes on 16p13.1, revealed supporting evidence for the gene conversion theory as a mechanism responsible for some of the mutations in the PKD1 gene. Factors likely to facilitate gene conversion in this region of the PKD1 gene are discussed.

Hypertension and renal failure in Kumasi, Ghana.

Hypertension is common in West Africa and likely to become more common as urbanisation increases. There are at present few facilities for the detection and management of hypertension so the influence it has on overall morbidity and mortality in the population is not clear. The objectives of the study were to assess: (a) renal disease and blood pressure related admissions and deaths among acute medical admissions to Komfo Anokye Teaching Hospital, Kumasi, during an 8-month period; and (b) the burden of renal disease among out-patient hypertensives at the same hospital. Ward admission books were examined in the four acute medical wards to ascertain admission diagnosis and cause of death (two 4-month periods in 1995 and 1996). Clinical assessment (blood pressure, plasma creatinine, proteinuria) was also made of 448 consecutive out-patient hypertensives seen between March 1995 and April 1996. Five hundred and ninety-three (17.9%) of 3317 acute medical admissions were ascribable to a cardiovascular cause (hypertension, heart failure, stroke); 171 (28.8%) of these died. One hundred and sixty-six (5.0%) had renal disease of whom 45 (27.1%) died, usually of end-stage renal disease. Among the 448 hypertensive out-patients, 30.2% (110 out of 365) had a plasma creatinine >140 micromol/l (48 > or = 400 micromol/l) and 25.5% (96 out of 376) had proteinuria. Eighty-nine of the 448 had a diastolic blood pressure > or =115 mm Hg; in this group 38 (42.7%) had a plasma creatinine of >140 micromol/l (and 18 or 20.2% > or =400 micromol/l). In conclusion, cardiovascular and renal disease are important contributors to morbidity and mortality among acute medical admissions to a large city hospital in Ghana. Among out-patient hypertensives renal disease is an important complication, especially in those with the more severe hypertension.

Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.

BACKGROUND: Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2. METHODS: Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at-event data. Differences in the prevalence of complications were assessed by logistic regression. FINDINGS: Median age at death or onset of end-stage renal disease was 53.0 years (95% CI 51.2-54.8) in individuals with PKD1, 69.1 years (66.9-71.3) in those with PKD2, and 78.0 years (73.8-82.2) in controls. Women with PKD2 had a significantly longer median survival than men (71.0 [67.4-74.8] vs 67.3 [64.9-69.7] years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74.0 [67.2-80.8] vs 54.3 [52.7-55.9] years). PKD2 patients were less likely to have hypertension (odds ratio 0.25 [95% CI 0.15-0.42]), a history of urinary-tract infection (0.50 [0.31-0.83]), or haematuria (0.59 [0.35-0.98]). INTERPRETATION: Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.

Novel mutations in the 3 region of the polycystic kidney disease 1 (PKD1) gene.

Mutation screening in 90 unrelated ADPKD1 patients was carried out on some of the exons in the single copy area (37, 38, 39, 44, 45) using genomic PCR and SSCP. Four novel mutations were found: a 15 bp in-frame deletion in exon 39 [nt11449 (del 15)], a 2 bp deletion in exon 44 [nt12252 (del 2)], a G insertion in exon 44 [nt12290 (Ins G)], and a GTT in-frame deletion in exon 45 [nt12601 (del 3)].

Association between atrial natriuretic peptide and cyclic GMP in hypertension and in chronic renal failure.

This study has examined the association between circulating atrial natriuretic peptide (ANP), plasma cyclic GMP and urinary cyclic GMP in relation to hypertension and reduced renal function in 30 normotensives, in 30 patients with essential hypertension and in 22 patients with stable dialysis-independent chronic renal failure (CRF). Plasma ANP was significantly raised (about two-three-fold) in the CRF group compared with the hypertensive and normal groups; plasma cyclic GMP was also significantly raised in the CRF group (median group values: 4.6, 5.8 and 11.0 pmol/ml, respectively, for the normal, hypertensive and CRF groups). There were no significant differences in urinary cyclic GMP between the normotensives and hypertensives but urinary cyclic GMP was significantly reduced in the patients with CRF (median group values: 407.1, 450.9 and 247.8 pmol/min for the normal, hypertensive and CRF groups, respectively, P < 0.001). In the subjects with CRF, the clearance of cyclic GMP was reduced in proportion to the clearance of creatinine, but there was no significant difference in the fractional excretion of cyclic GMP (median group values: 78.1% in the normal group, 78.9% in the hypertensive group and 70.2% in the CRF group). In all groups, there was no association between circulating ANP and urinary cyclic GMP: By contrast, there was a positive association between plasma ANP and plasma cyclic GMP (r = 0.39 P < 0.001) that was independent of blood pressure or renal function. These results demonstrate that while a substantial amount of urinary cyclic GMP originates from the glomerular filtrate, to some extent, raised plasma ANP also contributes to the circulating levels of cyclic GMP. However, plasma cyclic GMP cannot be taken as a direct substitute for plasma ANP.

Apparent normalisation of fetal renal size in autosomal dominant polycystic kidney disease (PKD1).

We present a family with adult onset autosomal dominant polycystic kidney disease (ADPKD) in two generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23 and 34 weeks of gestation. Surprisingly, the newborn renal scan showed normal sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in one kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs. The observed normalisation of fetal renal ultrasound appearances at birth has not previously been described in fetuses presenting with PKD1.

Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease.

We describe four prenatal diagnoses in a family with autosomal dominant polycystic kidney disease. Two pregnancies were terminated following the detection of enlarged echogenic fetal kidneys with cysts. Histopathological examination confirmed the diagnosis of polycystic kidney disease. Linkage to PKD1 was obtained by the analysis of DNA from relatives in three generations and from paraffin blocks and formalin fixed fetal tissues. Prenatal DNA analysis in subsequent pregnancies identified one unaffected fetus and one fetus carrying the high risk PKD1 allelle. Information on survival and subsequent outcome of PKD cases presenting in utero was requested by this family before prenatal testing was performed. Of 83 reported cases of ADPKD presenting in utero (excluding termination of pregnancy) or in the first few months of life, 43% died before 1 year. Longitudinal follow up of 24 children in two studies showed that 67% of survivors developed hypertension, of whom three had end stage renal failure at a mean age of 3 years.

Polycystin expression during embryonic development of human kidney in adult tissues and ADPKD tissue.

Normal renal tissue, ranging from 8 weeks' gestation to full term to adult, was probed with polyclonal antibodies raised to peptide epitopes within the translated PKD1 gene sequence. Three antibodies were studied, all of which gave similar results. Renal tissue from patients with autosomal dominant polycystic kidney disease (ADPKD) and samples from normal adult liver, heart, brain, skeletal muscle and lymph node were also studied. Tissue staining demonstrated that the pattern of polycystin expression changed with gestational age in normal kidney. Whereas the precursors to the renal excretory unit were stained at 12 weeks, and the proximal and distal convoluted tubules stained to differing degrees throughout development, the glomeruli were poorly stained until full term and also in the adult. Extrarenal tissue stained in both adult and juvenile samples, with the exception of lymph node, which remained unstained. The intensity of polycystin staining increased in ADPKD renal tissue. The widespread distribution of polycystin was consistent with the systemic nature of ADPKD and the role of epithelial cells in the disease.

Genetic analysis of 20 families with autosomal dominant adult polycystic kidney disease from South West Thames Region.

Twenty families with autosomal dominant polycystic kidney disease from S. W. Thames Region were analysed using markers for chromosome 16p13.3, the site of the common mutation (PKD1). Six families gave a negative lod-score for 3'HVR, the most informative distal marker. This could be explained in four cases by recombination events. Of the two families where this was not an explanation, one, of Italian origin, was unequivocally unlinked for all markers, and the other was more likely to be non-PKD1 than linked to 16p13.3. The Italian family was ascertained through the Blood Pressure Unit, and the other via the Genetic Clinic. No members of either family had ever attended a renal clinic. The remaining 18 families either came via renal clinics, or had at least one member attending such a centre.

Original articles: increased platelet volume in patients with adult polycystic kidney disease.

Platelet volume is a measure of platelet function. An increased platelet volume is found in acute vascular syndromes and may have a causative role and predict outcome. Patients with autosomal dominant polycystic kidney disease (APKD) are at increased risk of developing, and dying from, premature vascular disease. We hypothesized that platelet volume might be altered in patients with APKD. Platelet volume was measured in 16 normotensive APKD patients with normal renal function and 16 normal volunteers pair-matched for age, gender, race and body mass index. Mean platelet volume was increased by 0.4 fl (95% confidence limits 0.1 to 0.9, 2P=0.017) in patients with APKD as compared with normal subjects: median 8.4 fl (0.7) versus 8.0 fl (0.3) respectively. In contrast, platelet count was lower by 63 × 10(9)/1 (-5 to -108, 2P = 0.031): 225 (40) × 10(9)/1 versus 280 (35) × 10(9)/1 while the platelet mass was not different, -0.36 ml/l (-0.81 to 0.02, 2P=0.070): 1.82 (0.30) ml/l versus 2.28 (0.38) ml/l. Platelet volume and count were inversely correlated across the two groups, r(s)= -0.342 (2P=0.055). Serum levels of erythropoietin, a hormone that contributes to the regulation of thrombopoeisis, were not different between the APKD patients and normal controls, 35 U/1 (-71 to 120, 2P=0.42): 107 U/I (53) versus 84 U/I (57). Although erythropoietin did not correlate with platelet volume, R., = -0.185 (2P =0.36), it was positively associated with platelet count, R., = 0.465 (2P=0.029) and platelet mass, r(s) = 0.466 (2P= 0.028). Since an increased platelet volume is associated with platelet hyperactivity, the increased platelet volume in APKD may be a marker, or even contribute to the development, of premature vascular disease and sudden cardiac death in patients with APKD.