Familial glomerulopathy with proximal tubular dysfunction: a new syndrome?

Two female siblings with nephrotic syndrome and proximal tubular dysfunction are described. One, aged 15 months, presented with steroid-resistant nephrotic syndrome and was found to have partial Fanconi syndrome and hypothyroidism. At the age of 21 months her renal function started deteriorating rapidly and she died of septicaemia 5 months later. The second sibling, aged 3 years, had steroid-resistant nephrotic syndrome with proximal renal tubular acidosis and hyperaminoaciduria. The renal biopsies in both showed unusual changes in glomerular basement membrane along with IgM and C3 deposition. It is suggested that these siblings may be suffering from a hitherto undescribed clinico-pathological entity.     

Renal handling of uric acid under cyclosporin A treatment

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567±156 mol/l) compared with the AZA group (378±98), the CRF group (415±119) and the N group (290±68). Mean uric acid clearances in each group measured 3.9±2.8 ml/min per 1.73 m² (CyA), 5.6±3.4 (AZA), 4.0±2.2 (CRF) and 8.4±3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53±0.15 mol/ml in the CyA group (P<0.01) compared with 0.34±0.08, 0.29±0.15 and 0.27±0.07 mol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.     

New applications of total parathyroidectomy and autotransplantation: Use in proximal renal tubular dysfunction

Total parathyroidectomy with autotransplantation is frequently used in the treatment of hyperparathyroidism associated with renal osteodystrophy because of the high incidence of recurrent disease following subtotal resection. A similar argument has been made to support the application of this technique to cases of recurrent or persistent hyperparathyroidism and to familial polyendocrine syndromes with parathyroid hyperplasia. We have recently had occasion to apply this approach in a new clinical setting of metabolic bone disease. Three patients with congenital hypophosphatemic rickets and 1 with pseudohypoparathyroidism were treated with total parathyroidectomy and autotransplant into the forearm. All 4 had developed secondary hyperparathyroidism with hypercalcemia while being treated with 1,25(OH) ₂ D ₃ (with or without inorganic phosphate). Each had a history of previous vitamin D intoxication. Reduction of parathyroid mass permitted effective treatment of severe bone disease in each case. Two patients developed graft-dependent hypercalcemia which required resection of graft tissue from the forearm under local anesthesia. Both have shown a further recurrence. Total parathyroidectomy and autotransplantation may be useful in the management of selected patients with metabolic bone disease due to familial hyophosphatemic rickets or pseudohypoparathyroidism.

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Resumen La paratiroidectomía total con autotransplante es un procedimiento frecuentemente asociado con osteodistrofia renal debido a la elevada incidencia de hiperparatiroidismo recurrente cuando sólo se realiza resección subtotal. Una argumentación similar se usa en apoyo de la aplicación de este procedimiento en casos de hiperparatiroidismo recurrente o persistente y de síndromes poliendocrinos familiares con hiperplasia paratiroidea. Recientemente tuvimos oportunidad de utilizar este enfoque en una nueva condición clínica de enfermedad ósea metabólica. Tres pacientes con raquitismo hipofosfatémico congénito y uno con pseudohipoparatiroidismo fueron tratados con paratiroidectomía y autotransplante en el antebrazo. Todos los cuatro habían desarrollado hiperparatiroidismo secundario con hipercalcemia en el curso de tratamiento con 1,25 (OH)₂D₃ (con o sin fosfato inorgánico). Cada uno tenía historia de intoxicación previa con vitamina D. La reducción de la masa paratiroidea hizo posible la realización de tratamiento efectivo de la severa enfermedad ósea en cada caso. Dos pacientes desarrollaron hipercalcemia transplante-dependiente, lo cual exigió la resección del tejido transplantado al antebrazo bajo anestesia local. Ambos han exhibido una nueva recurrencia. La paratiroidectomía total con autotransplante puede ser útil en el manejo de pacientes seleccionados que sufren de enfermedad ósea metabólica debida a raquitismo hipofosfatémico familiar o pseudohipoparatiroidismo.

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Résumé La parathyroïdectomie totale suivie d'autotransplantation est souvent employée pour traiter l'hyperthyroïdisme associé avec une ostéodystrophie rénale en raison de la fréquence de la récidive après parathyroïdectomie subtotale. Il en est de même en présence d'hyperparathyroïdisme persistant ou récidivant et des syndromes endocriniens familiaux s'accompagnant d'hyperplasie hyperthyroïdienne. Ce choix thérapeutique a été appliqué récemment à une nouvelle entité clinique répondant à une affection osseuse métabolique. Trois malades qui présentaient un rachitisme congénital avec hypophosphatase et un sujet qui était atteint de pseudo-hypoparathyroïdisme ont été traités par parathyroïdectomie totale avec autotransplantation au niveau de l'avant-bras. Tous les quatre avaient développé un hyperparathyroïdisme secondaire avec hypercalcémie alors qu'ils recevaient du 1,25 OH₂D₃ (avec ou sans phosphate inorganique). Chacun présentait des antécédents d'intoxication par la vitamine D. La réduction de la masse parathyroïdienne donna lieu à un traitement efficace de tous les cas. Deux malades cependant accusèrent une hypercalcémie liée à la présence du greffon autotransplanté, hypercalcémie qui fut traitée par l'ablation de celui-ci sous anesthésie locale. En conclusion, la parathyroïdectomie totale avec autotransplantation peut être utile pour traiter certains malades qui présentent une maladie osseuse métabolique due à un rachitisme familial avec hypophosphatasémie ou un pseudo-hypoparathyroïdisme.

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Supported by a grant (RR125) from the National Institutes of Health and by the Pediatric and Adult Clinical Research Centers of the Yale-New Haven Hospital.     

Effect of valsartan on renal handling of uric acid in healthy subjects

OBJECTIVE: To evaluate the effect of valsartan on renal handling of uric acid in healthy subjects. METHODS: A randomized, single-blind, placebo-controlled clinical trial was performed in twelve healthy volunteers. Six received a morning dose of valsartan 80 mg orally during 14 to 21 days and the other six received placebo. Before and after valsartan or placebo, clearance, fractional excretion and excretion uric acid rates were calculated. Presecretory reabsorption, tubular secretion and postsecretory reabsorption of uric acid were assessed by pharmacological tests using pyrazinamide or probenecid. RESULTS: There were no differences in clearance, fractional excretion and excretion uric acid rates with valsartan and placebo. Valsartan did not affect presecretory reabsorption (p = 0.92), tubular secretion (p = 0.62) or postsecretory reabsorption (p = 0.52) of uric acid. CONCLUSION: Valsartan did not significantly affect renal handling of uric acid in healthy subjects.     

Proximal tubular handling of phosphate: A molecular perspective

Members of the SLC34 gene family of solute carriers encode for three Na+-dependent phosphate (P i) cotransporter proteins, two of which (NaPi-IIa/SLC34A1 and NaPi-IIc/SLC34A3) control renal reabsorption of P i in the proximal tubule of mammals, whereas NaPi-IIb/SCLC34A2 mediates P i transport in organs other than the kidney. The P i transport mechanism has been extensively studied in heterologous expression systems and structure-function studies have begun to reveal the intricacies of the transport cycle at the molecular level using techniques such as cysteine scanning mutagenesis, and voltage clamp fluorometry. Moreover, sequence differences between the three types of cotransporters have been exploited to obtain information about the molecular determinants of hormonal sensitivity and electrogenicity. Renal handling of P i is regulated by hormonal and non-hormonal factors. Changes in urinary excretion of P i are almost invariably mirrored by changes in the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Therefore, understanding the mechanisms that control the apical expression of NaPi-IIa and NaPi-IIc as well as their functional properties is critical to understanding how an organism achieves P i homeostasis.     

Effect of cyclosporine on the renal tubular amino acid handling after kidney transplantation

The renal tubular handling of free amino acids was studied 5-6 weeks after successful renal transplantation (tx) in 20 children treated with CsA and in 10 children treated with azathioprine (Aza). The results were compared with those of 34 control children. The amino-acid clearance studies were performed in combination with short-term inulin clearance. The CsA group revealed a mean inulin clearance of 49 +/- 16.8 ml/min/1.73 m2, the Aza group of 76.9 +/- 18.2, and the controls of 114 +/- 15.6. The plasma amino-acid concentrations were not different between CsA- and Aza-treated groups; however, most of the essential amino acids were lower in transplanted children than in controls. The decrease was correlated with the GFR. The amino-acid-clearance rates were statistically not different between both transplanted groups, but lower values than in controls were found for alanine, glycine, histidine, lysine, and phenylalanine, and significantly higher values for methionine. The fractional clearance rates of most amino acids were significantly elevated in transplanted children compared to controls. In CsA-treated patients, the fractional clearance rates of arginine, glycine, and serine were higher than in Aza-treated patients. No influence of CsA blood levels or rejection episodes on the amino-acid handling were detectable. We conclude that CsA has no specific influence on the renal handling of amino acids. Most disturbances observed depend on the graft function or may be caused by injuries to the graft following the tx procedure.     

Maturation of proximal tubular acidification

Neonatal juxtamedullary proximal convoluted tubules (PCTs) transport bicarbonate at one-third the rate of adult rabbit PCTs. The lower rate of bicarbonate transport could be due to a greater permeability of the neonatal PCT to bicarbonate or to a lower rate of active bicarbonate transport. This review discusses potential factors which could result in a lower rate of bicarbonate transport by the neonatal PCT. In isolated perfused PCT, bicarbonate permeability is lower in neonatal than adult PCT, and thus it does not account for the lower rate of bicarbonate transport in neonatal PCT. In the adult PCT, apical proton secretion occurs via the Na⁺/H⁺ antiporter and H⁺-ATPase; basolateral bicarbonate exit occurs via the Na(HCO₃)₃ symporter. The activity of transporters can be ascertained by measuring intracellular pH with the fluorescent dye BCECF. Apical Na⁺/H⁺ antiporter, apical H⁺-ATPase and basolateral Na(HCO₃)₃ symporter activity are all significantly lower in neonatal PCT. The factors which stimulate PCT maturation are unknown, however glucocorticoids have been postulated to play an important role in this process. Administration of dexamethasone to pregnant does results in higher rates of PCT volume absorption, bicarbonate transport, Na⁺/H⁺ antiporter and Na(HCO₃)₃ symporter activities than in PCT from vehicle-treated controls. Thus, the lower rate of neonatal PCT bicarbonate transport is due to lower activities of the apical Na⁺/H⁺ antiporter, apical H⁺-ATPase and basolateral Na(HCO₃)₃ symporter. Glucocorticoids may be an important factor in the maturation of PCT acidification.     

Cyclosporine inhibits renal uric acid transport in renal transplants not in children treated for nephrotic syndrome

Children with various grades of renal insufficiency (CON group) maintained uric acid excretion over a range of glomerular filtration rate (GFR) from 27 to 160 ml/min*1.73m2 despite a decreased filtered load which was paralleled by glomerular filtration of uric acid. This was achieved by a compensatory decrease of net uric acid reabsorption (TUA) and an increasing fractional excretion of uric acid (FEUA) with decreasing GFR. Although there was a decreased GFR in the group of children after transplantation (NTx group) there was no difference in TUA and FEUA between the NTx group and the CON group. Uric acid transport was not affected in children treated with Cyclosporine (CyA) for nephrotic syndrome (NEPH group) compared to the CON group. Decreased fractional phosphate reabsorption in the NTx group suggests proximal tubule damage associated with disturbed uric acid handling. Under conditions of water diuresis hyperuricemia seen in NTx may result from an indirect effect of renal ischemic damage due to the transplantation procedure causing disturbance of proximal tubular uric acid (active) secretion/reabsorption.     

Renal tubular dysfunction in epileptic children on valproic acid therapy

To investigate the effects of valproic acid (VPA) on renal tubular function, we examined 15 ambulatory children with epilepsy who received VPA for at least 6 months. None of the patients had mental retardation. Fourteen age- and sex-matched children were used as a control group. No statistically significant differences were found between patients and control subjects with respect to blood urea nitrogen (BUN), creatinine (Cr), uric acid, creatinine clearance (C_cr), tubular reabsorption of phosphorus (TRP), urinary Ca:creatinine ratio, urinary pH and mean urinary β₂-microglobulin concentrations (P>0.05). Protein and glucose in patient urine samples were negative. Urine microscopic examinations and amino acid chromatographies of patients were also normal. However, significant differences were found between patient and control groups with respect to mean urinary N-acetyl-beta-d-glucosamine:creatinine ratio (NAG:Cr) and mean urinary malondialdehyde:creatinine (MDA:Cr) ratio (P<0.05). In conclusion, ambulatory children with epilepsy taking VPA therapy may develop proximal renal tubular dysfunction. Although this finding is clini-cally insignificant, it should be kept in mind during VPA therapy. Received: 11 November 1999 / Revised: 21 September 2000 / Accepted: 26 October 2000     

Upregulation of prolactin receptor in proximal tubular cells was induced in cardiac dysfunction model mice

Background

In order to clarify the interaction between cardiac dysfunction and sodium homeostasis in the kidney, we used a murine model of cardiac dysfunction and investigated the effect on sodium transporters in renal tubular cells.

Methods

Cardiac function was deteriorated by abdominal aortic banding, and the gene expression of sodium transporters in the kidneys was evaluated by real-time RT-PCR and compared with that in the kidneys of control mice.

Results

Gene expression of all three variants of the murine prolactin receptor was enhanced by aortic banding. Upregulated prolactin receptor was distributed in the proximal tubular cells of the pars recta in the deep inner cortex and the outer stripe of the outer medulla. Prolactin has been reported to be a natriuretic hormone that inhibits proximal tubular Na⁺/K⁺-ATPase activity, resulting in reduced sodium reabsorption and the acceleration of natriuresis. Inhibition of endogenous prolactin secretion by bromocriptine administration decreased the urine sodium excretion in both aortic banding and control mice. On the other hand, excess exogenous prolactin administration enhanced urine potassium excretion in aortic banding mice. Furthermore, a high-sodium diet accelerated urinary sodium excretion, which was also significantly decreased by inhibition of endogenous prolactin secretion in aortic banding mice.

Conclusion

We reported that the prolactin receptor was upregulated by aortic banding treatment. Prolactin-prolactin receptor interaction in the proximal tubular cells of the pars recta should involve a different mechanism of kaliuresis other than inhibition of Na⁺/K⁺-ATPase.     

Evaluation of renal handling of uric acid in essential hypertension: hyperuricemia related to decreased urate secretion.

The tubular transport of urate was studied in 40 hypertensive patients and in 20 normal subjects by means of pyrazinamide and benzbromarone tests. There was a marked decrease in urate excretion per nephron in hyperuricemic patients with essential hypertension. Serum uric acid correlated inversely with fractional excretion of urate (r = -0.7450, p less than 0.001). Presecretory and postsecretory reabsorption of urate did not significantly differ between hypertensive patients with high uric acid levels and control subjects. Urate secretion was significantly reduced in hypertensive patients and in those with hyperuricemia showed a twofold decrease. Serum uric acid correlated inversely with tubular secretion of urate (r = -0.7091, p less than 0.001) in hypertensive patients. These findings indicate that impaired tubular secretion of urate is a potential mechanism of hyperuricemia in essential hypertension.