Phosphate binders for control of phosphate retention in chronic renal failure.

In patients with chronic renal insufficiency, phosphate retention is a major factor in the development of secondary hyperparathyroidism, renal osteodystrophy, and soft tissue calcification, and may contribute to progression of renal failure. Prevention of phosphate retention with dietary and pharmacological means, along with the administration of calcitriol, may prevent or reverse secondary hyperparathyroidism. With more-advanced renal failure, phosphate binders become necessary to maintain phosphate balance and to prevent hyperphosphatemia. Because of toxicity, aluminum-containing phosphate binders are no longer used. Currently, calcium-containing phosphate binders, such as calcium carbonate and calcium acetate, are the most widely prescribed. Although calcium salts eliminate the problems associated with aluminum toxicity, they often result in transient hypercalcemia, requiring discontinuation of calcitriol and the use of low-calcium dialysate. Several new non- aluminum- and non-calcium-containing phosphate binders are currently at various stages of development, and may provide an alternative to the currently used binders. It is unlikely, however, that the newer compounds will completely replace calcium salts, since mild hypercalcemia may be necessary in chronic renal failure patients to suppress parathyroid hormone production. Other areas of investigation must include the development of drugs to inhibit soft tissue and renal calcifications, and to enhance urinary phosphate excretion.

Evaluating proteinuria in children.

Proteinuria is a common laboratory finding in children. It can be identified as either a transient or a persistent finding and can represent a benign condition or a serious disease. A rapid but qualitative assessment of proteinuria can be made using dipstick or sulfosalicylic acid methods. More precise quantitation is obtained by measuring protein excretion in 24-hour urine samples or by calculating the protein/creatinine ratio in random urine samples. Orthostatic proteinuria is a benign condition characterized by the presence of protein in urine samples collected in the upright position during the day and its absence in samples collected in the supine position. Persistent proteinuria and proteinuria associated with hematuria or other signs of renal disease carry a more severe prognosis. The latter conditions require referral to a pediatric nephrologist for further evaluation, which may include renal biopsy.

Increased reabsorptive capacity after ureteral obstruction reduces the ability of glucose to inhibit phosphate reabsorption in rat kidney.

BACKGROUND: Proximal tubular reabsorption of glucose (G), phosphate (Pi) and amino acids is energized by the transmembrane Na+ gradient, which explains why decreased concentration of one solute can enhance the transport of another. Accordingly, we postulated that the consistent increase in Pi reabsorption seen in the post-obstructed kidney (POK) could be caused, in part, by the low filtered load of glucose and reversed by glucose loading. METHODS: Renal function was examined before and after i.v. glucose loading in POKs (after release of 24 h of unilateral ureteral obstruction) and control kidneys (CK) of 10 adult rats. Brush-border membrane vesicle (BBMV) transports of Pi and glucose were assessed in POKs and CKs. RESULTS: In POKs GFR, urine flow and Na+ excretion were significantly reduced and tubular reabsorption of both Pi (T(P)/GFR) and glucose (TG/GFR) were significantly increased: T(P)/GFR, 2.0 +/- 0.2 vs 1.36 +/- 0.1; TmG/GFR, 23.4 +/- 1.7 vs 18.9 +/- 1.1 mmol/l. Glucose loading inhibited T(P)/GFR only in the CK. Initial Na+ gradient-dependent uptakes of D-glucose and Pi were similar in BBMVs from POK and CK. CONCLUSIONS: The increases in T(P)/GFR and TG/GFR seen in the POK do not result from decreased glucose delivery or from alterations in BBM Pi and glucose transporters. The reduced ability of glucose to inhibit Pi reabsorption in the POK results primarily from a generalized increase in proximal tubular reabsorption of Na+ and cotransported Pi and glucose. A specific rise in distal Pi transport capacity may be an additional adaptive response to the low filtered load of Pi in the POK. In addition, absent distal glucose reabsorption may further facilitate Pi reclamation at these sites.

Aminoaciduria and glycosuria following severe childhood lead poisoning.

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 alpha-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.

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 patient's 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.

Renal effects of environmental and occupational lead exposure.

Environmental and industrial lead exposures continue to pose major public health problems in children and in adults. Acute exposure to high concentrations of lead can result in proximal tubular damage with characteristic histologic features and manifested by glycosuria and aminoaciduria. Chronic occupational exposure to lead, or consumption of illicit alcohol adulterated with lead, has also been linked to a high incidence of renal dysfunction, which is characterized by glomerular and tubulointerstitial changes resulting in chronic renal failure, hypertension, hyperuricemia, and gout. A high incidence of nephropathy was reported during the early part of this century from Queensland, Australia, in persons with a history of childhood lead poisoning. No such sequela has been found in studies of three cohorts of lead-poisoned children from the United States. Studies in individuals with low-level lead exposure have shown a correlation between blood lead levels and serum creatinine or creatinine clearance. Chronic low-level exposure to lead is also associated with increased urinary excretion of low molecular weight proteins and lysosomal enzymes. The relationship between renal dysfunction detected by these sensitive tests and the future development of chronic renal disease remains uncertain. Epidemiologic studies have shown an association between blood lead levels and blood pressure, and hypertension is a cardinal feature of lead nephropathy. Evidence for increased body lead burden is a prerequisite for the diagnosis of lead nephropathy. Blood lead levels are a poor indicator of body lead burden and reflect recent exposure. The EDTA lead mobilization test has been used extensively in the past to assess body lead burden. It is now replaced by the less invasive in vivo X-ray fluorescence for determination of bone lead content.

A conditionally immortalized cell line from murine proximal tubule.

We have developed a conditionally immortalized murine cell line with proximal tubule characteristics (tsMPT) and a background suitable for genetic manipulations. tsMPT was derived from the F1 progeny of crosses between: [1] a transgenic mouse harboring a gamma-interferon (IFN-gamma)-inducible, temperature sensitive SV40 large T antigen gene (tsA58) and [2] mice of the 129/SvEv strain, the background from which most embryonic stem (ES) cells are derived. Under permissive conditions (33 degrees C and in the presence of IFN-gamma), tsMPT cells grow rapidly as monolayers with a doubling time of 23 hours; the large T antigen can be detected by immunocytochemistry and by Western blotting. When transferred to non-permissive conditions (39 degrees C, without IFN-gamma), the cells undergo differentiation coinciding with the disappearance of the large T antigen. By electron microscopy, tsMPT cells are polarized and show microvilli at their apical surface. tsMPT cells express brush border enzymes gamma-glutamyl transpeptidase and carbonic anhydrase IV. They possess Na(+)-dependent transport systems for Pi, D-glucose and L-proline as well as an amiloride-insensitive Na(+)-H+ exchanger. Intracellular cAMP generation is stimulated by parathyroid hormone but not by arginine vasopressin. Angiotensinogen mRNA and protein are present in tsMPT with markedly higher levels at non-permissive conditions. tsMPT cells should be a useful model for investigation of the functional features of the proximal tubule epithelium in relation to cellular differentiation.

Pasteurella multocida peritonitis in patients undergoing peritoneal dialysis.

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.

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.

Acute renal failure in idiopathic nephrotic syndrome.

Acute renal failure (ARF) associated with idiopathic nephrotic syndrome has been reported in adults with advanced age but is a rare event in children. We have reviewed the literature on this subject and report an additional pediatric case. The pathogenetic mechanisms which may lead to ARF during the course of idiopathic nephrotic syndrome are reviewed with a brief discussion of the role of angiotensin II and angiotensin converting enzyme inhibition in this setting. Although no consensus has emerged for the prevention and treatment of ARF in patients with nephrotic syndrome, a combination of salt-poor albumin and diuretics to reduce interstitial edema may be beneficial as a preventive measure. Once acute tubular necrosis is diagnosed, dialysis may be indicated. In the majority of reports the prognosis for recovery of renal function has been good even in patients in whom long-term dialysis was required.

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.

Acute renal failure with hyperuricemia as initial presentation of leukemia in children.

PURPOSE: We report on two children who presented with hyperuricemia and acute renal failure (admission uric acid levels 57.4 and 59.2 mg/dl). RESULTS: Both were subsequently diagnosed to have acute lymphoblastic leukemia, despite normal initial complete blood counts and peripheral smear. Neither patient had nephromegaly on renal ultrasound. CONCLUSIONS: Hyperuricemia and acute renal failure, particularly if recurrent, may be an early presentation of childhood leukemia and should lead to a bone marrow aspirate/biopsy.

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.

Characterization of Na(+)-phosphate cotransporters in renal cortical endosomes.

To determine the role of membrane recycling in proximal tubular P(i) transport, we studied the transport functions of simultaneously prepared rat renal cortical endosomal vesicles (EV) and brush-border membrane vesicles (BBMV). Initial P(i) uptake was Na+ gradient-dependent in both vesicles. Kinetic studies showed a lower apparent maximal rate (Vmax) for P(i) uptake in EV compared with BBMV (446 +/- 69 vs. 1493 +/- 117 pmol.mg protein-1 x 15 s-1, respectively; n = 4, P < 0.05), with no difference in the apparent Michaelis constant (Km). Endosomal Na(+)-P(i) cotransport was inhibited by phosphate analogues, phosphonoformic acid and arsenate, but not by the anion-exchange inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Na(+)-P(i) cotransport was electroneutral in both vesicles, with a stoichiometry of 2 for BBMV and 1 for EV. The nonpermeant sulfhydryl reagent, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), produced a marked inhibition of Na(+)-P(i) cotransport in EV but not in BBMV, suggesting accessible sulfhydryl groups, an "inside-out" orientation in EV, and "right-side-out" orientation in BBMV. The EV and the BBMV differed significantly in their phospholipid composition and lipid fluidity. The Na(+)-P(i) cotransporter protein (NaPi-2) abundance, determined by Western blots, was five times lower in EV than in BBMV (0.25 +/- 0.05 vs. 1.36 +/- 0.20 arbitrary units). Renal cortical endosomes contain Na(+)-P(i) cotransporters, albeit at a lower density, suggesting involvement of membrane recycling in the regulation of proximal tubular P(i) 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.

Phosphonoformic acid blunts adaptive response of renal and intestinal Pi transport.

Parenteral administration of phosphonoformic acid (PFA) results in phosphaturia, but the effects of oral PFA on Pi handling are not known. To assess this effect, PFA was administered in drinking water for 5 days to rats stabilized on normal (NPD) or low (LPD) phosphorus diets. In renal brush-border membrane vesicles (BBMV), kinetic studies showed a higher apparent Vmax for Pi in rats on LPD compared with rats on NPD (1,840 +/- 274 vs. 1,111 +/- 192 pmol.mg-1.5 s-1, respectively, P < 0.05, n = 5). In LPD rats, PFA reduced the apparent Vmax for Pi to 1,047 +/- 191 pmol.mg-1.5 s-1 (P < 0.05, n = 5) with no change in the apparent Km. Similarly, there was a higher apparent Vmax for Pi in intestinal BBMV from rats on LPD compared with rats on NPD. In LPD rats, PFA reduced the apparent Vmax for Pi with no change in the apparent Km. Oral PFA had no effect on the kinetics of Pi transport in renal or intestinal BBMV from rats on NPD. Pi-protectable [14C]PFA binding was lower in renal BBMV from PFA-treated LPD rats, but membrane fluidity was not different. Orally administered PFA can blunt the adaptive response of the renal and intestinal BBM to an LPD. The downregulation of Na(+)-Pi cotransport is mediated through a reduction in the number of Na(+)-Pi cotransporters.

Role of phosphate retention in the progression of renal failure.

Dietary phosphorus restriction can prevent the progression of renal failure in subtotally nephrectomized rats or in rats with nephrotoxic serum nephritis, independent of protein and caloric intake. Conversely, diets high in phosphorus content result in a more rapid deterioration of renal function. The results are less compelling in indicating that phosphorus restriction can slow the progression of renal failure in the clinical setting. The toxicity of phosphate appears to be related to induction of calcium phosphate precipitation, resulting in tubulointerstitial disease. Most studies of prevention of renal calcification have addressed a single pathway in the development of nephrocalcinosis. These include inhibitors of calcium phosphate precipitation, calcium channel blockers, or an inhibitor of PTH secretion. All of these studies have shown a beneficial effect in preserving renal function. It is possible that a combination of these agents, started early in the course of CRF, may have an additive effect in preventing the progression to ESRD. The discussion of other factors associated with progression of renal failure is beyond the scope of this review. It is obvious that dietary protein restriction, treatment of systemic and intraglomerular hypertension and lipid abnormalities, and prevention of iron overload, all play roles in the preservation of renal function in CRF.

Renal and intestinal Pi transport adaptation to low phosphorus diet in uremic rats.

The normal response of the kidney and intestine to a low-phosphorus diet (LPD) is an increased rate of Na(+)-dependent Pi transport by their brush border membranes (BBM). Dietary phosphorus restriction is used to reduce Pi accumulation in chronic renal failure. It is not known, however, if the uremic state alters the adaptive responses to an LPD. The adaptive response of the renal and intestinal BBM vesicles (BBMV) to LPD in acutely uremic (NX) and sham-operated (SH) control rats placed on a normal diet or an LPD was studied. In renal BBMV, the initial Na+ gradient-dependent Pi transport was lower in NX than in SH rats. Na(+)-independent uptake was unchanged. Thyroparathyroidectomy did not reverse the reduced Pi transport in NX rats. Kinetic studies showed a reduction of the apparent Vmax for Pi in BBMV from NX compared with SH rats (738 +/- 69 and 1,078 +/- 90 pmol/5 s.mg for NX and SH rats, respectively; P < 0.05; N = 5) with no change in the apparent Km. In intestinal BBMV, the initial Na+ gradient-dependent Pi transport was not different between SH and NX rats. There was also no difference in Pi transport kinetics between SH and NX rats. The adaptive response to an LPD persisted in renal and intestinal BBMV from NX rats and was comparable to that observed in SH rats: +54% for SH versus +48% for NX rats in kidney BBMV and +70.2% for SH versus +71.8% for NX rats in intestinal BBMV.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of P(i) transport in opossum kidney cells by hyposmotic media.

Exposure of various cells to hyposmotic media (Hypo) results in a rapid inhibition of both receptor-mediated and fluid-phase endocytosis. We used this maneuver to investigate the role of endocytosis in regulation of Pi transport in opossum kidney (OK) cells. Following exposure to Hypo, Na(+)-dependent Pi uptake increased rapidly, reaching a maximum within 5 min, and remained elevated up to 30 min. This was associated with a simultaneous reduction of horseradish peroxidase uptake. Kinetic studies showed increased apparent Vmax for Pi (9.38 +/- 0.93 vs. 13.08 +/- 1.04 nmol.mg-1.5 min-1 for control and Hypo, respectively; P < 0.05, n = 6) with no change in apparent Km. The effect was specific for Pi with no change in the Na(+)-dependent or -independent uptake of L-proline, L-glutamine, or methyl-alpha-D-glucopyranoside. Stimulation of Pi transport persisted when control and Hypo had identical ionic compositions. Stimulation of Pi transport was rapidly reversed when cells were returned to an isosmotic medium. Preincubation with Hypo at 4 degrees C had no effect on Pi transport. Addition of cycloheximide or actinomycin D did not prevent the increased Pi uptake after exposure to Hypo. The effect also persisted after protein kinase C downregulation. Stimulation of Pi transport by Hypo is consistent with reduced endocytic retrieval of Na(+)-Pi cotransporters from brush-border membrane (BBM), resulting in an increase in their number on the BBM.