Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is a dominantly inherited condition characterized by young-onset hyperuricemia, gout, and renal disease. The etiologic genes are unknown, although a locus on chromosome 16 has been identified in some kindreds. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with dominant inheritance of a variety of disorders of renal development, particularly renal cystic disease and early onset diabetes; hyperuricemia has been reported in some kindreds. METHODS: To assess a possible role for the HNF-1beta gene in some FJHN kindreds we sequenced the HNF-1beta gene in subjects from three unrelated FJHN families with atypical features of renal cysts or abnormalities of renal development. We also compared serum urate levels in subjects with HNF-1beta mutations with populations of controls, type 2 diabetic subjects, and subjects with mild chronic renal failure without HNF-1beta mutations. RESULTS: A splice-site mutation in intron 2, designated IVS2+1G>T, showed complete co-segregation with FJHN in one family with diabetes. Serum urate levels were significantly higher in the HNF-1beta subjects compared with the normal control subjects (384 micromol/L vs. 264 micromol/L, P = 0.002) and the type 2 diabetic subjects (397 micromol/L vs. 271 micromol/L, P = 0.01). Comparison of serum urate levels in the HNF-1beta subjects with gender-matched subjects with renal impairment of other causes did not reach significance (402 micromol/L vs. 352 micromol/L, P = 0.2). CONCLUSION: Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.     

Enlarged nephrons and severe nondiabetic nephropathy in hepatocyte nuclear factor-1beta (HNF-1beta) mutation carriers

BACKGROUND: Mutations in hepatocyte nuclear factor-1beta (HNF-1beta) lead to a syndrome with diabetes and urogenital malformations [maturity onset of diabetes of the young, type 5 (MODY5)]. The aim of this study was to perform a clinicopathologic investigation of the renal disease in members of a Norwegian family with the HNF-1beta mutation R137-K161del. METHODS: The study was based on long-term clinical observations of five mutation carriers, combined with renal biopsies from four of these. The biopsies were examined by light microscopy, immunohistochemistry, and transmission electron microscopy. The diameter of the glomerulus, proximal and distal tubules, in addition to thickness of the glomerular basement membrane (GBM), were measured in light microscopic slides and transmission electron micrographs. The results were compared with biopsies from adult patients with diabetic glomerulopathy, glomerulonephritis, and/or benign nephrosclerosis, and children with minimal-change glomerulopathy or glomerulonephritis, respectively. RESULTS: Clinically, there was a wide intrafamilial variation from stable or slightly increasing serum creatinine to progressive renal failure and end-stage renal disease (ESRD). In all cases, the kidney disease was diagnosed prior to diabetes. Hypertrophy of the proximal and distal tubules as well as enlarged glomeruli were found in three of four mutation carriers. Essentially normal nephrons were found in the 10-year-old boy. The thickness of the GBM was considered near normal in all mutation carriers. Oligomeganephronia was found in one patient. CONCLUSION: Histopathologic and morphometric studies of kidney biopsies from four carriers of an HNF-1beta mutation revealed enlarged glomeruli and tubular structures. Long-term clinical follow-up demonstrated that the renal disease developed prior to and independently of diabetes. Finally, there is a wide phenotypic variation of the renal disease caused by HNF-1beta mutations.     

Evolving concepts in human renal dysplasia

Human renal dysplasia is a collection of disorders in which kidneys begin to form but then fail to differentiate into normal nephrons and collecting ducts. Dysplasia is the principal cause of childhood end-stage renal failure. Two main theories have been considered in its pathogenesis: A primary failure of ureteric bud activity and a disruption produced by fetal urinary flow impairment. Recent studies have documented deregulation of gene expression in human dysplasia, correlating with perturbed cell turnover and maturation. Mutations of nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which renal dysplasia can feature, including Fraser, renal cysts and diabetes, and Kallmann syndromes. Here, it is possible to begin to understand the normal nephrogenic function of the wild-type proteins and understand how mutations might cause aberrant organogenesis.     

Pkd1 inactivation induced in adulthood produces focal cystic disease

Autosomal dominant polycystic kidney disease, the most common monogenetic disorder, is characterized by gradual replacement of normal renal parenchyma by fluid-filled cysts. Mutations in either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease. Pkd1(-/-) or Pkd2(-/-) mice develop rapid renal cystic disease and exhibit embryonic lethality; this supports the "two-hit" hypothesis, which proposes that a germline mutation in PKD1 (or PKD2) followed by a second somatic mutation later in life is responsible for the phenotype. Here, for investigation of the loss of Pkd1 at specific times of development, an inducible Pkd1-knockout mouse model was generated. Inactivation of Pkd1 in 5-wk-old mice resulted in formation of only focal renal cysts 6 to 9 wk later but in a severe polycystic phenotype nearly 1 yr later. Cysts derived from either collecting tubules or distal tubules but not from proximal tubules, which correlated with sites of Cre-mediated recombination. Inactivation of Pkd1 in 1-wk-old mice, however, resulted in massive cyst disease 6 wk later, despite a similar pattern of Cre-mediated recombination between 1- and 5-wk-old kidneys. Moreover, a germline heterozygous Pkd1 mutation facilitated cyst formation when a somatic Pkd1 mutation was induced. A marked increase in proliferating cell nuclear antigen expression was observed in cyst-lining epithelia and in normal-looking tubules adjacent to but not in those distant from cysts. These data suggest that Pkd1 inactivation is not sufficient to initiate the cell proliferation necessary for cyst formation; a paracrine mechanism may account for focal cell proliferation and regional disease progression. We propose that an additional genetic or nongenetic "third hit" may be required for rapid development of cysts in polycystic kidney disease.     

The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria

Hepatocyte nuclear factor-1alpha (HNF-1alpha) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1alpha homozygous knockout mice exhibit a renal Fanconi syndrome with glucosuria and generalized aminoaciduria in addition to diabetes. We investigated glucosuria and aminoaciduria in patients with HNF-1alpha mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1alpha mutations, age-matched nondiabetic control subjects, and age-matched type 1 diabetic patients, type 2 diabetic patients, and patients with diabetes and chronic renal failure. The HNF-1alpha patients had glucosuria at lower glycemic control (as shown by HbA1c) than type 1 and type 2 diabetic patients, consistent with a lower renal glucose threshold. The HNF-1alpha patients had a generalized aminoaciduria with elevated levels of 14 of 16 amino acids and an increased mean Z score for all amino acids compared with control subjects (0.66 vs. 0.00; P < 0.0005). Generalized aminoaciduria was also present in type 1 diabetic (Z score, 0.80; P < 0.0001), type 2 diabetic (Z score, 0.71; P < 0.0002), and chronic renal failure (Z score, 0.65; P < 0.01) patients. Aminoaciduria was not associated with microalbuminuria or proteinuria but was associated with glucosuria (1.00 glucosuria vs. 0.19 no glucosuria; P = 0.002). In type 1 diabetic patients, urine samples taken on the same day showed significantly more aminoaciduria when glucosuria was present compared with when it was absent (P < 0.01). In conclusion, HNF-1alpha mutation carriers have a mutation-specific defect of proximal tubular glucose transport, resulting in increased glucosuria. In contrast, the generalized aminoaciduria seen in patients with HNF-1alpha mutations is a general feature of patients with diabetes and glucosuria. Glucose may depolarize and dissipate the electrical gradient of the sodium-dependent amino acid transporters in the proximal renal tubule, causing a reduction in amino acid resorption.     

Glomerulocystic kidney disease in a family.

BACKGROUND: Glomerulocystic kidney disease (GCKD) is a rare renal disorder, the identity of which has long been discussed. GCKD can occur in a familial form with autosomal dominant transmission. The presence of GCKD in families affected with autosomal dominant polycystic kidney disease (ADPKD) has lent support to the hypothesis that GCKD may be an early manifestation of ADPKD. In families with hypoplastic forms of GCKD, the HNF-1beta gene has recently been identified. METHODS: Three members of a family were evaluated: a girl (case 1) and her brother (case 2), who were aged 11 and 12 years, respectively, at the beginning of the study, and, subsequently, the girl's son, when he was 4 years old (case 3). They all had mild renal insufficiency. Clinical, morphological and genetic evaluations were performed on 11 members of the family. RESULTS: Case 1. A mild reduction in renal length with modest dysmorphology of renal calyces and hyperechogenic parenchyma were present when the patient was 11 years old. At the age of 29 some small renal cysts were identified, which remained unchanged over the next 8 years. Renal dysfunction remained stable. Case 2. A slight reduction in size of a hyperechogenic kidney was found. Cysts were seen at the age of 38. Renal dysfunction remained unchanged. Case 3. Kidneys were of normal size. Small cysts were found at the age of 9 years. In cases 1 and 2, histopathology was highly consistent with GCKD. In none of the cases associated pathological conditions could be identified. Haplotype reconstruction allowed the exclusion of PKD1 and PKD2 genes. No mutation of the HNF-1beta gene was found. CONCLUSIONS: The morphological data from the three cases are suggestive of GCKD. The involvement of PKD1, PKD2 and HNF-1beta gene mutations was excluded.     

Optimal timing of prenatal treatment of obstructive uropathy in the fetal lamb

Purpose: It was still unclear how urinary tract obstruction alters normal nephrogenesis and leads to renal dysplasia. The authors created an obstructive uropathy model in fetal lambs and reviewed the pathology of the obstructed kidney to determine the optimal timing for decompression of the obstruction.Methods: Obstructive uropathy was created in fetal lambs at 60 days’ gestation by ligating the urethra and urachus. They were delivered 20 to 31 days later by cesarian section. The kidneys were processed for histologic examination.Results: Thirty-four 60-day lambs were operated on. Dysplastic changes were noted in 25 fetuses, and 24 fetuses had cysts in the nephrogenic zone. The cystic components in multicystic dysplastic kidneys (MCDK) are mainly in the proximal tubules.Conclusions: In utero urinary tract obstruction causes reduction of numbers of functioning nephrons and produces cysts in the nephrogenic zone and in the deeper cortex. These cysts and dilated proximal tubules suppress new nephron formation. Twenty days after obstruction, there were early features of dysplasia, but the nephrogenic zones still were present. Early shunting may salvage renal function.     

Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort

The hepatocyte nuclear factor-1beta encoded by the TCF2 gene plays a role for the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for the maturity-onset diabetes of the young type 5 associated with renal manifestations. Several observations have suggested that TCF2 mutations may be involved in restricted renal phenotypes. Eighty children (median age at diagnosis 0.2 yr) with renal cysts, hyperechogenicity, hypoplasia, or single kidneys were studied. Quantitative multiplex PCR amplification of short fluorescence fragments for the search of large genomic rearrangements and sequencing for the detection of point mutations were performed. TCF2 anomalies were detected in one third of patients (25 of 80). The main alteration was the complete deletion of the TCF2 gene detected in 16 patients. Family screening revealed de novo TCF2 anomalies in nine of 17 probands with a high prevalence of deletions (seven of nine). TCF2 anomalies were associated with bilateral renal anomalies (P < 0.001) and bilateral cortical cysts (P < 0.001). However, abnormal renal function, detected in 40% of patients, was independent of the TCF2 genotype. No difference in renal function or severity of renal morphologic lesions was observed between patients with a TCF2 deletion and those with point mutations. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. These findings have important implications in the diagnosis of patients with renal dysplasia with cysts and their follow-up.     

Phylogenetic, ontogenetic, and pathological aspects of the urine-concentrating mechanism

The urine-concentrating mechanism is one of the most fundamental functions of avian and mammalian kidneys. This particular function of the kidneys developed as a system to accumulate NaCl in birds and as a system to accumulate NaCl and urea in mammals. Based on phylogenetic evidence, the mammalian urine-concentrating mechanism may have evolved as a modification of the renal medulla's NaCl accumulating system that is observed in birds. This qualitative conversion of the urine-concentrating mechanism in the mammalian inner medulla of the kidneys may occur during the neonatal period. Human kidneys have several suboptimal features caused by the neonatal conversion of the urine-concentrating mechanism. The urine-concentrating mechanism is composed of various functional molecules, including water channels, solute transporters, and vasopressin receptors. Abnormalities in water channels aquaporin (AQP)1 and AQP2, as well as in the vasopressin receptor V2R, are known to cause nephrogenic diabetes insipidus. An analysis of the pathological mechanism involved in nephrogenic diabetes insipidus suggests that molecular chaperones may improve the intracellular trafficking of AQP2 and V2R, and, in the near future, such chaperones may become a new clinical tool for treating nephrogenic diabetes insipidus.     

ADAM19 expression in human nephrogenesis and renal disease: associations with clinical and structural deterioration

ADAM19, an enzyme from the ADAM (a disintegrin and metalloproteinase) family, is involved in various cell-cell and cell-matrix interactions. It can cleave epidermal growth factor (EGF)-like growth factors, such as heparin-binding (HB)-EGF and neuregulin (NRG), from the cell membrane. ADAM-mediated EGF receptor activation is crucial in the development of renal pathology. Based on these data, we studied ADAM19 in human nephrogenesis and renal disease. We collected 20 fetal kidneys and 56 biopsies from patients with various renal diseases. The unaffected part of kidneys from eight patients with renal cell carcinoma served as control. RNA in situ hybridization revealed widespread ADAM19 mRNA expression in the nephrogenic zone of human fetal kidneys. Normal human kidneys showed constitutive ADAM19 expression in distal tubules and endothelial cells, whereas proximal tubules were negative. In renal disease, ADAM19 was de novo expressed in proximal tubules and glomerular mesangium and upregulated in distal tubules and endothelial cells. ADAM19 colocalized with tubular and interstitial NRG, however, not with HB-EGF. Independent of renal disorder, mesangial ADAM19 expression was associated with glomerular damage as assessed by mesangial matrix expansion, focal glomerulosclerosis, and glomerular macrophage influx (all P<0.001). ADAM19 in proximal tubules and in peritubular capillaries was associated with interstitial fibrosis (P<0.05). Finally, increasing tubular ADAM19 was associated with declining renal function (P<0.05). The abundant ADAM19 expression during nephrogenesis points to a role in growth promotion and regulation. The high ADAM19 expression in renal disease suggests involvement in profibrotic and proinflammatory processes leading to renal deterioration.     

Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys

Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1beta that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between -2 and +2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.