Mahmoud Loghman-Adham

Aminoaciduria and glycosuria following severe childhood lead poisoning

Abstract. To determine the incidence of renal functional abnormalities after lead poisoning, we evaluated the parameters of renal tubular function in 134 children and young adults, 8–13 years after chelation therapy for severe lead poisoning. There was no evidence of hypertension or reduced kidney function as assessed by serum creatinine (Cr) concentrations. Urinary α-amino nitrogen (Uaan) concentrations were significantly increased compared with 19 healthy age-matched controls. Ninety-four children (70%) had aminoaciduria (Uaan/Cr >0.23). Urinary glucose excretion was also significantly higher than that of 2 historical controls. Thirty-two children (24%) had glycosuria (>125 mg/24 h). Fractional excretion of phosphate was normal in all children. We conclude that a partial Fanconi syndrome can persist up to 13 years after childhood lead poisoning.

Use of phosphonocarboxylic acids as inhibitors of sodium-phosphate cotransport☆

Phosphonocarboxylic acids, initially developed as antiviral agents, are found to be specific inhibitors of phosphate (P(i)) transport across cell membranes. Foscarnet (PFA), the most potent and the most widely used compound, can induce phosphaturia both after parenteral and oral administration. Furthermore, it can inhibit intestinal phosphate absorption when administered orally. PFA absorption and bioavailability are increased in animals on phosphate-restricted diets. PFA also blunts the adaptive increase in intestinal and renal Na(+)-P(i) cotransport which accompanies dietary phosphorus restriction. Finally, PFA is shown to inhibit hydroxyapatite crystal formation and calcium-phosphate precipitation when tested in in vitro systems. These properties, and the low toxicity of PFA, point to potential new applications for PFA and some of its analogs in clinical conditions such as chronic renal insufficiency, where phosphate retention may lead to progression of renal failure and to other serious complications.

Adaptation to changes in dietary phosphorus intake in health and in renal failure

Phosphate (Pi) homeostasis is maintained by the ability of the kidneys to adjust the tubular reabsorption of Pi to changes in the dietary intake of phosphorus. Renal tubular Pi reabsorption increases with the ingestion of a low-phosphorus diet (LPD) and decreases when a high-phosphorus diet (HPD) is consumed. A similar adaptive mechanism is also operative at the intestinal microvillus. The adaptive changes in Pi reabsorption are independent of parathyroid hormone production and are paralleled by similar changes in the Na+-dependent Pi transport at the brush border membrane (BBM). Type II Na+-Pi cotransporters (NaPi-2) are mainly involved in such regulatory mechanisms. Chronic dietary phosphorus restriction leads to increased Na+-Pi cotransport rate, along with increased NaPi-2 protein and mRNA abundance. In acute dietary phosphorus restriction, transport rate and NaPi-2 protein are also increased, but mRNA abundance remains unchanged. A shuttling mechanism involving translocation of cotransporters from intracellular pools to the BBM is involved in the rapid proximal tubular adaptation. The intestinal adaptation to changes in dietary phosphorus are similar to those described for the renal Pi transport, but the molecular structure of the intestinal Na+-Pi cotransporter is not known. When nephron mass is reduced, phosphate homeostasis is maintained through enhanced Pi excretion by residual nephrons. The adaptation to renal mass reduction is mediated by increased parathyroid hormone (PTH) production and by PTH-independent mechanisms, including increased intrarenal dopamine production. The adaptive changes of Pi transport to dietary phosphorus restriction can counteract the effect of dietary phosphorus reduction often prescribed in patients with renal failure. However, because of the reduced filtered load of Pi, the overall impact on serum Pi concentration is minimal.

Spurious hypophosphatemia in a patient with multiple myeloma

We report a patient with multiple myeloma and a prolonged history of hypophosphatemia who had remained asymptomatic. Extensive evaluation for a cause, including the search for a renal tubular disorder, oncogenous osteomalacia, or a parathyroid hormone (PTH)-related protein was unproductive. Renal biopsy showed no evidence of myeloma kidney. Subsequent mixing of the immunoglobulin G (IgG) fraction from the patients serum with normal human serum, confirmed that the observed hypophosphatemia was spurious, resulting from interference of large amounts of an abnormal IgG with a standard automated laboratory assay for phosphate.

kuPasteurella multocida peritonitis in patients undergoing peritoneal dialysis

Abstract. A 12-year-old girl on peritoneal dialysis developed sub-clinical peritonitis due to Pasteurella multocida, following puncture of her dialysis tubing by a domestic cat. Only four other similar cases of P. multocida peritonitis have been reported in adults. This unusual form of peritonitis could be easily prevented by not allowing domestic animals to come into contact with dialysis tubings in patients undergoing peritoneal dialysis.

Use of Phosphonoformic Acid to Induce Phosphaturia in Chronic Renal Failure in Rats

In chronic renal failure (CRF), phosphate (Pi) retention may lead to secondary hyperparathyroidism and progression to end-stage renal disease (ESRD). Dietary phosphorus restriction or phosphate binders can slow progression in experimental CRF. Conversely, diets high in phosphorus can accelerate the progression toward ESRD. Phosphate binders reduce intestinal Pi absorption but have no effect on its renal excretion. Phosphonoformic acid (PFA, foscarnet) is a specific inhibitor of both intestinal and renal brush border Na(+)-Pi cotransport. It causes phosphaturia when administered parenterally or orally to rats. To determine the effect of oral PFA on renal function and on phosphate excretion in renal insufficiency, PFA was administered in drinking water to rats with CRF produced by 5/6th nephrectomy. Blood and 24-h urine collections were performed every 2 weeks for determination of plasma Pi and creatinine concentrations, urinary protein excretion, and urinary creatinine and Pi clearances. PFA, administered for 8 weeks, did not exert any adverse effects on any of the measured parameters. The slopes of the reciprocal of plasma creatinine versus time were not different between control and PFA-treated rats. Although PFA increased Pi excretion over the baseline, it had no persistent effect on plasma Pi concentrations under these experimental conditions.

Mechanisms of heterogeneity of Na+-Pi cotransport in superficial and juxtamedullary renal cortex

To explore the mechanisms of axial heterogeneity of proximal tubular Pi transport, brush border membrane vesicles (BBMV) were prepared from superficial (BBMV-SC) and juxtamedullary (BBMV-JM) cortex of rat kidneys. Na+ gradient-dependent Pi transport was measured after the imposition of an inside-negative electrical potential created by either a K+ gradient ([K+]i greater than [K+]o) or a proton gradient ([H+]i greater than [H+]o) in the presence of ionophores. The initial Na(+)-dependent Pi uptake was higher in BBMV-SC than in BBMV-JM, both in the presence and absence of ionophores. Na(+)-dependent D-glucose uptake remained unchanged. We did not find a significant electrogenic transport component in either BBMV population when the non-specific effect of ionophores on Pi transport was taken into account. The stoichiometry of Na(+)-Pi cotransport was 2:1 in BBMV-SC and BBMV-JM. Phosphonoformic acid (PFA) competitively inhibited Pi transport. The inhibitory constant (Ki) for PFA was lower in BBMV-SC (237 +/- 1.7 microM) than in BBMV-JM (409 +/- 53 microM) (P less than 0.05). Arrhenius plots showed a higher rate of Pi uptake in BBMV-SC compared to BBMV-JM at all temperatures. However, the transition temperatures did not differ. We conclude that axial heterogeneity of Pi transport is not due to differences in electrogenicity or stoichiometry of transport.

Enhanced bioavailability of phosphonoformic acid by dietary phosphorus restriction

Phosphonoformic acid (PFA, foscarnet) is a potent inhibitor of Na(+)-P(i) cotransport in intestinal and renal brush border membranes (BBM). We have studied the effect of dietary phosphorus restriction on intestinal PFA absorption and bioavailability. Rats were placed on low (0.04% P(i), LPD) or normal (0.95% P(i), NPD) phosphorus diets for 5 days, followed by administration of an oral bolus of [14C]PFA (100 mg/kg). Of the oral PFA dose, 60 +/- 4% was absorbed in LPD rats, compared with 43 +/- 3% in NPD rats (P < 0.05, N = 5). This was associated with higher plasma PFA concentrations in LPD compared with NPD rats (44.2 +/- 2.0 and 17.9 +/- 4.3 micrograms/mL, respectively). [14C]PFA uptake, determined in intestinal BBM vesicles (BBMV), was Na+ gradient (Na+out > Na+in) dependent. Dietary phosphorus restriction resulted in a 39.8% increase in the initial (1 min) Na(+)-dependent [14C]PFA uptake by intestinal BBMV. We conclude that PFA absorption is enhanced by dietary phosphorus restriction.