The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect.

Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20-30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Clinical data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicoureteral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.

The effects of systemic glucose concentration on brain metabolism following repeated brain ischemia.

Since systemic glucose concentration is an important determinant of ischemic brain metabolism in neonates, we sought to determine if the systemic glucose concentration influences brain metabolic alterations following repeated partial ischemia. A group of hyperglycemic piglets (n = 12) were compared to a group of modestly hypoglycemic piglets (n = 12) using in vivo 2H and 31P magnetic resonance spectroscopy to simultaneously measure cerebral blood flow and phosphorylated metabolites before, during and 30 min after two 10-min episodes of ischemia (i.e. Recovery 1 and 2). For both groups, beta-ATP levels at Recovery 1 and 2 were lower than Control (91 +/- 11 and 83 +/- 15% of Control, respectively for both groups combined, P = 0.002 vs Control). Inorganic phosphorus was elevated in hyperglycemic piglets at Recovery 1 and 2 (117 +/- 15 and 118 +/- 10% of Control). In contrast, in modestly hypoglycemic piglets inorganic phosphorus progressively rose from Recovery 1 (131 +/- 24% of Control) to Recovery 2 (149 +/- 37% of Control), and differed from the hyperglycemic group (P = 0.02). These changes did not correlate with post-ischemic cerebral blood flow, cerebral O2 delivery or cerebral glucose delivery. In both groups phosphocreatine and intracellular pH returned to Control values during Recovery 1 and 2. The progressive increase in inorganic phosphorus post-ischemia in hypoglycemic piglets suggests that modest hypoglycemia during and following repeated partial ischemia adversely affects immediate brain metabolic recovery.

Glucose-associated alterations in ischemic brain metabolism of neonatal piglets.

BACKGROUND AND PURPOSE: During global brain ischemia or hypoxia-ischemia in adults, hyperglycemia is deleterious to the brain. In contrast, similar adverse effects have not been found in neonatal animals. This investigation examined neonatal piglets to determine if there were specific alterations of ischemic brain metabolism associated with different systemic glucose concentrations and to potentially clarify the effects of hyperglycemia during ischemia in neonates. METHODS: Two groups of animals (n = 12 in each group) were studied during partial ischemia to compare the effects of hyperglycemia (plasma glucose concentration, 258 +/- 97 mg% [mean +/- SD]) with modest hypoglycemia (plasma glucose concentration, 62 +/- 23 mg%). A broad spectrum of cerebral blood flow reduction was achieved by combining inflation of a cervical pressure cuff with varying degrees of hemorrhagic hypotension. High-energy phosphorylated metabolites, intracellular pH, and cerebral blood flow were simultaneously measured using a magnetic resonance spectroscopic technique. Brain metabolic variables (beta-ATP, inorganic phosphorus, phosphocreatine, intracellular pH) were plotted as a function of blood flow reduction during partial ischemia for each group. RESULTS: During ischemia values of cerebral blood flow were comparably distributed between groups and ranged from 15% to 110% of those of control. At a given reduction of cerebral blood flow, hyperglycemic piglets maintained a higher concentration of beta-ATP (p = 0.011) and had a smaller increase in inorganic phosphorus (p less than 0.001). At cerebral blood flow less than 50% of control, the intracellular pH of piglets with modest hypoglycemia during partial ischemia was never reduced to less than 6.46, whereas intracellular pH fell as low as 5.97 for hyperglycemic animals. CONCLUSIONS: ATP preservation may account for the differing effects of glucose during ischemia in neonates compared with adults, provided that the accentuated brain acidosis is not deleterious to neonatal brain tissue.

Blood flow and metabolism during and after repeated partial brain ischemia in neonatal piglets.

BACKGROUND AND PURPOSE: Our investigation sought to determine whether neonatal brain ischemic vascular and metabolic effects were altered by repeated episodes of ischemia. METHODS: We studied twelve piglets using in vivo magnetic resonance spectroscopy to obtain multiple, simultaneous measurements of cerebral blood flow and phosphorylated metabolites from the same tissue volume. The relationship between cerebral blood flow and energy metabolism was examined over a range of reduced cerebral blood flow (90-10% of control). Three episodes of partial ischemia were studied, each lasting 10 minutes and separated by 45 minutes. RESULTS: During each interval of ischemia, plots of the percent reduction in cerebral blood flow versus the percent change in phosphorylated metabolites (phosphocreatine, inorganic phosphorus) or unit change in intracellular pH did not differ in slope and intercept. The relationship between beta-ATP and cerebral blood flow during repeated ischemia revealed similar slopes, but a lower intercept during the third interval of ischemia (p = 0.029). After ischemia, cerebral blood flow was reduced as a function of the severity of the preceding ischemia. After each interval of ischemia, phosphocreatine and intracellular pH were unchanged from preischemic values. Inorganic phosphorus remained elevated after ischemia (117 +/- 16 and 118 +/- 11% of control, p less than 0.005, following the first and second intervals of ischemia), and beta-ATP was restored to progressively lower values (92 +/- 10 and 83 +/- 11% of control, p less than 0.025). Calculated free ADP decreased after ischemia and correlated with the postischemic level of beta-ATP (r = 0.63, p = 0.001). CONCLUSIONS: These results demonstrate that the relationship between cerebral blood flow and metabolism was reasonably preserved during repeated partial ischemia. However, following ischemia, alterations occurred in both cerebral blood flow and metabolism. These alterations may reflect a relative inhibition of ATP production by metabolic regulators such as ADP on either glycolysis or oxidative phosphorylation or both.