Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis.

The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. Frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position +5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of Frasier syndrome.

[Long-term prognosis of childhood IgA nephropathy in adult life]. / Pronóstico en la vida adulta de la nefropatía IgA diagnosticada en la edad pediátrica.

BACKGROUND: To evaluate long-term prognosis in a group of children with IgA nephropathy and to analyse which clinical factors were associated with progression to chronic renal failure in adulthood. PATIENTS AND METHOD: Retrospective study. 58 young adults with IgA nephropathy diagnosed at 10.6(SD 2.9) years old and studied after a follow-up of 11.8 (SD 2.9) years. RESULTS: Relapses of macroscopic hematuria and proteinuria were the most frequent symptoms at onset (75.9%). In 25.9% of patients high plasmatic IgA levels were also detected. Most cases had grade I (44.8%)or grade II (44.8%) histological lesions at diagnosis. At the last control, clinical remision was observed in 21 patients (36.2%) and 50% of the whole group remained with abnormal urine. 8 patients(13.8%) reached terminal renal failure. Mean renal survival (defined as glomerular filtration rate above 50 ml/min/1.73 m2)was 100, 93.3 and 81.1% at 5, 10 and 15 years of evolution, respectively. CONCLUSIONS: About 14% of children with IgA nephropathy had long-term renal bad prognosis. Hypertension at onset, plasma creatinine elevation and proteinuria during adolescence were significant risk factors associated with chronic renal failure during adulthood. Minimal lesions at IgA nephropathy diagnosis in children did not exclude long-term poor prognosis.

Renal tubular acidosis.

The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3-), the excretion of hydrogen ions, or both. On clinical and pathophysiological grounds, RTA can be separated into three main types: distal RTA (type 1), proximal RTA (type 2) and hyperkalaemic RTA (type 4). Some patients present combined types of proximal and distal RTA or of hyperkalaemic and distal RTA. Diagnosis of RTA should be suspected when a patient presents a normal plasma anion gap, and hyperchloraemic metabolic acidosis. A normal plasma anion gap (Na(+)-[Cl- + HCO3-] = 8-16 mEq/l) reflects loss of HCO3- from the extracellular fluid via the gastro-intestinal tract or the kidney, dilution of extracellular buffer or administration of hydrochloric acid (HCl) or its precursors. Distinction of RTA from other disorders is greatly facilitated by the study of the urine anion gap (Na+ + K+ - Cl-). This index estimates the urinary concentration of ammonium in a patient with hyperchloraemic metabolic acidosis. A negative urine anion gap (Cl- much greater than Na+ + K+) suggests the presence of gastro-intestinal or renal loss of HCO3-, while a positive urine anion gap (Cl- less than Na+ + K+) is indicative of a distal acidification defect. Determination of plasma potassium, of urine pH at low plasma HCO3- concentration, and of urine PCO2 and fractional excretion of HCO3- at normal plasma HCO3- concentration permits the differentiation between the various types of RTA.

Renal tubular hyperkalaemia in childhood.

Potassium output from the body is regulated by renal excretion, which takes place predominantly in the late distal and cortical collecting tubules. The accepted model for potassium secretion implies the accumulation of potassium into the cell by the activity of basolateral Na-K-ATPase and its exit through voltage-dependent conductive channels. The factors regulating renal potassium secretion are potassium intake, distal urinary flow, systemic acid-base equilibrium, aldosterone, antidiuretic hormone and, probably, epinephrine. Renal handling of potassium is best studied by the response to the acute administration of furosemide. This loop diuretic not only increases sodium and chloride excretion but also enhances potassium and hydrogen ion excretion and stimulates the renin-aldosterone axis. The term "renal tubular hyperkalaemia" refers to a tubular dysfunction where the hyperkalaemia is disproportionate to any reduction in glomerular filtration rate (GFR) and not due primarily or solely to aldosterone deficiency or to drugs impairing either mineralocorticoid action or tubular transport. The syndromes of renal tubular hyperkalaemia mainly observed in childhood are "chloride shunt" syndrome, hyporeninaemic hypoaldosteronism and primary or secondary pseudohypoaldosteronism. Differential diagnosis between these conditions is easily made if attention is paid to the level of GFR, presence of sodium wasting, activity of the renin-aldosterone axis and renal response to acute administration of furosemide.

Pathophysiology of the renal acidification defect present in the syndrome of familial hypomagnesaemia-hypercalciuria.

A distal acidification defect is frequently observed in the syndrome of familial hypomagnesaemia-hypercalciuria and hence this condition can be confused with primary distal renal tubular acidosis (RTA). This study demonstrates that in four unrelated patients with familial hypomagnesaemia-hypercalciuria the acidification defect is functionally different from that present in primary distal RTA. All patients exhibited hypomagnesaemia, hypermagnesuria, hypercalciuria, hyposthenuria, nephrocalcinosis and slight reduction of glomerular filtration rate (GFR). A moderate degree of metabolic acidosis was also present and basal data showed an inappropriately high urine pH (5.7-5.9) and a positive urine anion gap (Na + K-Cl = 11-28 mmol/l). Stimulation of distal acidification induced a fall in urine pH (4.7-5.6), but ammonium excretion remained low despite factoring by GFR (26-46 mumol/min per 1.73 m2, 35-54 mumol/100 ml GF). The urine to blood PCO2 gradient also remained low after sodium bicarbonate loading (1.3-17.7 mmHg). These results are best explained by both defective ammonia transfer to the deep nephron and impaired hydrogen ion secretion at the level of the medullary collecting duct, and probably are secondary effects of the medullary interstitial nephropathy.

Salt-losing nephropathy associated with inappropriate secretion of atrial natriuretic peptide--a new clinical syndrome.

A state of normokalemic renal sodium wasting associated with an apparently inappropriate secretion of atrial natriuretic peptide (ANP) has not been previously recognized. We here report an 11-year-old boy who presented with a chronic "salt-losing" nephropathy manifested by normonatremic or mildly hyponatremic extracellular fluid volume depletion, hypodipsia, absence of salt appetite, normokalemic metabolic alkalosis, hyper-reninemic hyperaldosteronism, hypertrophy of the juxtaglomerular apparatus, and highly conserved capacities for concentrating diluting the urine. Plasma ANP values were paradoxically elevated (between 10 and 47 fmol/ml), despite the coexistence of intravascular volume depletion and increased plasma levels of renin and aldosterone. Although the patient had some clinical similarities to Bartter's syndrome, fractional sodium chloride (NaCl) reabsorption during hypotonic saline diuresis was normal and no clinical amelioration was observed while on indomethacin therapy. Neither a tumor nor cardiac or cerebral abnormalities, which could be responsible for the increased ANP secretion, were detected. These clinical, biochemical, and histological features have not been previously described together and may represent a new clinical syndrome. The pathophysiology of this entity remains unknown, but an attractive, although unproven, hypothesis is that the renal defect in NaCl reabsorption in this patient could be related to an inappropriate and unregulated secretion of ANP.

[Alterations of renal function in pyelonephritis (author's transl)]. / Alteraciones de la función renal en las pielonefritis

Renal function was investigated in a group of ten patients aged two months to eleven years, with chronic or recurrent urinary tract infection caused by different malformations of the urinary tract. The following tests were performed: endogenous creatinine clearance, maximal urinary concentrating ability, urinary acidification, maximal urinary diluting ability, free water clearance, index of fractional distal sodium delivery and index of distal tubular reabsorption of sodium. It is concluded that the follow-up of glomerular function by means of creatinine clearance and of tubular function by means of maximal concentrating ability consitute the most sensible way to detect renal functional impairment in children with chronic or recurrent pyelonephritis.

Oral phosphate-loading test for the assessment of distal urinary acidification in children.

Neutral phosphate infusion results in an elevated urinary minus blood PCO2 gradient (U-B PCO2), providing that the urinary pH is close to the pK (6.8) of the phosphate buffer system. The present investigation was designed to evaluate whether an oral phosphate load could achieve similar results in children. 18 normal children, aged 3-13 years, were studied. Following the oral phosphate load, the urinary phosphate concentration increased to 44.8 +/- 4.7 mmol/l (mean +/- SEM), and U-B PCO2 reached 68.8 +/- 7.0 mm Hg, with a urinary pH of 6.87 +/- 0.07. With a urinary phosphate concentration above 20 mmol/l, all children reached a U-B PCO2 above 40 mm Hg. 4 children with primary distal renal tubular acidosis were also studied. All exhibited a U-B PCO2 below 20 mm Hg despite values of urinary phosphate concentration at or above 20 mmol/l, indicating the presence of a true secretory defect in distal hydrogen ion secretion. The present study demonstrates that an oral phosphate load is as effective as a phosphate infusion in elevating the urinary PCO2 and, therefore, could have a wide application in the pathophysiologic evaluation of renal tubular acidosis.

Bartter's syndrome presenting with features resembling renal tubular acidosis. Improvement of renal tubular defects by indomethacin.

A 2-year-old girl presenting with features of both Bartter's syndrome and renal tubular acidosis was investigated. Hypokalemia, increased plasma renin activity in the absence of hypertension, insensitivity to the pressor effects of angiotensin and a histological picture of juxtaglomerular hyperplasia were characteristic of Bartter's syndrome, but an unusual finding was the presence of metabolic acidosis instead of alkalosis. Functional studies revealed a proximal tubular defect in sodium and bicarbonate reabsorption and a distal defect in sodium reabsorption, urinary acidification and concentrating mechanism. Indomethacin administration was followed by an excellent clinical response and improvement of most functional abnormalities. The defect in distal sodium reabsorption was, however, not corrected by prostaglandin inhibition, and could represent the primary event leading to potassium wasting and secondary hypersecretion of prostaglandins.

Renal handling of water and sodium in children with proximal and distal renal tabular acidosis.

Renal sodium wasting has been observed in both proximal and distal renal tubular acidosis (RTA), although few studies have been reported indicating the tubular localization of such a defect. The use of clearance methodology during hypotonic saline diuresis may give an indirect estimate of proximal tubular reabsorption of sodium, sodium reabsorption at the diluting segments and proportion of sodium load reabsorbed distally. This study was carried out in 17 normal children, in 9 children with proximal RTA, associated in all but one with the Fanconi syndrome, and in 5 children with primary distal RTA. Patients with proximal RTA presented mainly an impaired reabsorption of sodium in the proximal tubule, which was in great part but not completely compensated by an absolute increase in distal sodium reabsorption. Patients with distal RTA showed normal reabsorption of sodium in the proximal tubule but they were unable to reabsorb completely the load of sodium escaping proximal reabsorption due to a defect of sodium reabsorption in the distal diluting segments. These results indicate that the classification of RTA in proximal and distal types is also valid according to the differences found in the tubular handling of water and sodium.

Pathophysiology of primary distal renal tubular acidosis.

Functional indices of distal acidification were assessed in five unrelated children with primary distal renal tubular acidosis. All patients were unable to lower urinary pH below 6.0 both during ammonium chloride-induced acidosis or after acute i.v. administration of furosemide. In these patients the urine minus blood Pco2 gradient failed to increase normally during acute sodium bicarbonate loading (mean +/- SEM: 5.8 +/- 2.0 mmHg), or after neutral phosphate administration (13 +/- 2.7 mmHg), despite adequate urinary concentrations or bicarbonate (72.2 +/- 14.6 mmol/L) and phosphate (25 +/- 2.3 mmol/L), respectively. They also failed to decrease urine pH below 5.5 with sodium sulfate (7.17 +/- 0.08), but urinary potassium excretion increased significantly. These results strongly suggest that the mechanism responsible for defective distal acidification is a failure of hydrogen ion secretion ("secretory' defect) and not an inability to establish a steep hydrogen ion gradient, as it was formerly believed.

Transtubular potassium concentration gradient: a useful test to estimate renal aldosterone bio-activity in infants and children.

The present investigation was designed to validate the usefulness of transtubular potassium (K) concentration gradient (TTKG) as an indicator of aldosterone bio-activity in infants and children. TTKG was calculated by the formula: [K]urine: (urine/plasma)osmolality/[K]venous blood. We compared this index with fractional K excretion (FEK) and urine K concentration to urine sodium (Na) concentration ratio (UK/UNa) in 473 normal children aged 1 month-15 years. Values of TTKG followed a non-gaussian distribution (median, 6.3; 3rd centile, 4.1; 97th centile, 13.4). TTKG in infants (n = 108; median, 7.8) was significantly higher than in children (n = 365; median, 6.0). TTKG correlated directly with FEK and UK/UNa. Indices of K excretion were also assessed in 13 patients with hypo- and pseudohypoaldosteronism. TTKG values varied between 1.6 and 4.1 and were all below the 3rd percentile established for the age of the subject. We conclude that calculation of TTKG is an easy and sensitive method for the evaluation of mineralocorticoid action in distal and collecting tubules.

Hypomagnesaemia of hereditary renal origin.

Cases of hypomagnesaemia of hereditary renal origin represent at least three different congenital disorders of tubular reabsorption of magnesium (Mg). Isolated familial hypomagnesaemia has been reported in a heterogeneous group of patients and an autosomal dominant pattern of inheritance has often been found to be present. Familial hypokalaemia-hypomagnesaemia, inherited as an autosomal recessive trait, has been reported in 17 patients and we now describe 3 additional cases. Hypomagnesaemia is accompanied by hypokalaemia, metabolic alkalosis, hypocalciuria and moderate sodium chloride wasting. Titration of renal Mg reabsorption indicates the presence of a low threshold but a normal Tm. The inherited defect is probably situated at the level of the distal convoluted tubule and mimics the therapeutic effect of thiazides. This condition is frequently confused with Bartter's syndrome. Familial hypomagnesaemia-hypercalciuria, also inherited as an autosomal recessive trait, has been reported in at least 15 patients and we now add 3 new cases. Hypomagnesaemia is always accompanied by hypercalciuria and nephrocalcinosis. Ocular abnormalities such as myopia and horizontal nystagmus are often present. Hypermagnesiuria is of a greater degree than that observed in the previous entity and reflects a low Tm of Mg reabsorption. The defect must be situated at the level of the ascending limb of the loop of Henle and affects the transport of both calcium and Mg but not of sodium and chloride. This condition has not been clearly separated from hereditary distal renal tubular acidosis in the literature.

"Chloride-shunt" syndrome: an overlooked cause of renal hypercalciuria.

The case of a 7-year-old boy with the normotensive form of "chloride-shunt" syndrome is described. An unusual feature was the clinical presentation with lithiasis, caused by marked hypercalciuria of renal origin. The present studies were carried out to investigate the nature of the renal tubular defect. Indices for proximal and distal sodium chloride reabsorption were increased during hypotonic saline diuresis. Baseline sodium chloride excretion was low but increased above the range of control values after acute furosemide administration. Baseline potassium excretion was low, was not modified by the infusion of sodium chloride and increased significantly during infusions of sodium sulphate or sodium bicarbonate. Calcium excretion remained unchanged during sodium chloride, sodium sulphate or sodium bicarbonate infusions, but increased after furosemide administration. Nasal insufflation of 1-desamino-8-D-arginine-vasopressin induced both an increase in potassium excretion and a decrease in calcium and magnesium excretion. Plasma atrial natriuretic peptide was increased and was not significantly modified by infusion of hypertonic saline or acute administration of furosemide. These findings indicate that the primary renal abnormality appears to be an enhanced tubular reabsorption of sodium chloride, apparently present in the proximal tubule and the ascending loop of Henle. The associated presence of hypercalciuria also suggests a transport defect in the distal tubule. Decreased potassium excretion probably depends on a voltage-shunting defect in the cortical collecting tubule, which can be reversed by increasing the delivery of non-reabsorbable anions or by enhancing the conductance of the luminal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal potassium excretion is reduced in children with idiopathic hypercalciuria.

Increased luminal calcium decreases potassium secretion in microperfused rat distal tubule. To determine if such an effect is also present in vivo, we evaluated renal potassium excretion in 49 children with idiopathic hypercalciuria (urinary excretion of Ca = 5.5 +/- 1.3 mg/kg/day) and in 214 age-matched control children (urinary excretion of Ca = 1.9 +/- 0.3 mg/kg/day). In comparison to controls, hypercalciuric children had significantly increased levels of sodium excretion (fractional excretion of Na = 0.7 +/- 0.3 vs. 0.6 +/- 0.3%, respectively; p less than 0.001) and decreased levels of fractional potassium excretion (7.2 +/- 2.9 vs. 9.2 +/- 3.4%, respectively; p less than 0.001) and of the transtubular potassium concentration gradient (4.2 +/- 1.5 vs. 5.9 +/- 1.5, respectively; p less than 0.001). All indices of potassium excretion correlated significantly and inversely with urinary calcium excretion (p less than 0.001). After an oral calcium load, performed in 30 hypercalciuric children, the increased rates of urinary calcium excretion were accompanied by increased rates of urinary sodium excretion and by a significant decrease in the transtubular potassium concentration gradient. These results support the hypothesis that increased luminal calcium concentration also inhibits renal potassium secretion in man.

Acute and chronic effects of cisplatin therapy on renal magnesium homeostasis.

Although the acute renal toxicity of cisplatin has been well documented, long-term follow-up studies in cisplatin-treated children are scanty. We have evaluated the incidence and characteristics of both acute and chronic nephrotoxicity in 22 children (median age 8 years) treated with cisplatin as part of different chemotherapeutic protocols. All patients exhibited a significant and progressive decrease in plasma magnesium (Mg) values soon after cisplatin administration. Magnesiuria also increased immediately after therapy. Hypomagnesemia (plasma Mg < 1.4 mg/dl) occurred in 10 patients and it was dose-dependent. Minimal and mean cumulated doses inducing hypomagnesemia were 300 and 500 mg/m2, respectively. In 18 children we followed renal function prospectively for a mean time of 2.3 years after arrest of cisplatin therapy. Chronic hypomagnesemia and moderate elevation of plasma creatinine were observed in 6 children, hypocalciuria in 5 children, and hypokalemia in 1 child. Presence of hypomagnesemia was unrelated to the total dose received or the time elapsed since cisplatin therapy. Renal function studies, performed in the 6 children with chronic hypomagnesemia, revealed different degrees of impairment in Mg reabsorption. The functional characteristics of chronic cisplatin nephrotoxicity found in the present series-contrary to prior reports-are not comparable to those present in the inherited Gitelman's syndrome.

Renal magnesium handling in infants and children.

Renal handling of magnesium (Mg) has been incompletely studied during infancy and childhood due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg. In the present investigation this methodology has been used to assess Mg homeostasis in 45 healthy infants, aged 1 to 12 months, and in 63 healthy children, aged 1 to 15 years. When compared to children, infants had significantly higher plasma values (mean +/- SD) for both total (0.76 +/- 0.08 versus 0.70 +/- 0.06 mmol l-1; p < 0.001) and ultrafilterable Mg (0.51 +/- 0.07 versus 0.49 +/- 0.04 mmol l-1; p < 0.05). No significant correlations were present between values of plasma Mg and plasma concentrations of calcium, creatinine, total protein or albumin. The ratio Umg/Ucr, calculated in the second morning urine (median, 3rd-97th centiles), was also significantly higher during infancy (0.023, 0.009-0.07 versus 0.015, 0.006-0.04; p < 0.001). On the contrary, fractional excretion of Mg (median, 3rd-97th centiles) was identical in both age groups and did not correlate significantly with age (infants: 3.2, 1.0-7.8%, children 3.4, 1.6-8.1%; p = NS). During a Mg infusion, carried out in six children, we could establish an approximative value for renal Mg threshold (plasma ultrafilterable Mg = 0.50 mmol l-1) close to that found in adults. These results indicate that no functional immaturity is present during infancy for renal tubular reabsorption of Mg and that the high Umg/Ucr ratio observed in this age group is a phenomenon not dependent on a higher urinary Mg excretion but probably related to a lower urinary creatinine excretion per unit of lean body mass.