Iron management in end-stage renal disease.

One of the important components of successful anemia therapy in patients with end-stage renal disease (ESRD) treated with recombinant human erythropoietin is the maintenance of adequate available iron. To accomplish this task, iron status must be serially monitored and supplemental iron administered as required. Among nonuremic subjects, the body's iron supply is tightly conserved, and iron deficiency usually develops only when chronic blood loss occurs. In patients with ESRD, iron deficiency occurs more frequently, because of increased external losses of iron, decreased availability of the body's storage of iron, and perhaps a deficit in intestinal iron absorption. Detecting iron deficiency in these patients can be difficult because of the inaccuracy of available diagnostic tests. The goals of iron therapy in ESRD include the prevention of iron deficiency by chronically supplementing iron, and the prompt treatment of overt iron deficiency. Oral iron supplements are inexpensive and safe, but poor patient compliance and reduced intestinal absorption may limit their effectiveness. Intravenous iron supplements have a greater efficacy then oral iron, which must be weighed against the small risk of allergic reactions. We present strategies for using the various diagnostic tests and treatment modalities to effectively manage iron supply for predialysis, hemodialysis, and peritoneal dialysis patients.

Vitamin E ameliorates renal injury in an experimental model of immunoglobulin A nephropathy.

IgA nephropathy is one of the most common forms of glomerular disease. Nearly 25% of affected patients progress to end-stage renal disease over a 20-25-y follow-up period. IgA-containing immune complexes stimulate oxygen-free radical production by mesangial cells in vitro. The excessive oxidant stress may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal disease in an experimental model of incipient IgA nephropathy with mild kidney inflammation. IgA nephropathy was induced in male Lewis rats by oral immunization with 0.1% bovine gamma-globulin (BGG)-containing drinking water for 8 wk. At the completion of this period, animals received BGG, 1 mg/dose i.v., on three successive days. Experimental rats (n = 10) received a specially formulated diet containing 100 IU of vitamin E/kg of chow, whereas control animals (n = 10) were fed chow containing 30 IU of vitamin/kg of chow. The BGG immunization regimen induced mesangial IgA deposition in all rats. Vitamin E supplementation resulted in a nearly 5-fold increase in the serum vitamin E concentration. Vitamin E-treated rats gained more weight and had a lower incidence of hematuria, 20% versus 80% (p < 0.03). Moreover, proteinuria was decreased by 50%, and reduced renal plasma flow was restored to normal, compared with untreated rats with IgA nephropathy. Glomerular hypertrophy occurred in animals with IgA nephropathy, but less so in those receiving vitamin E supplementation. Renal cortical malondialdehyde content was reduced from 1.55 +/- 0.10 to 1.22 +/- 0.09 nmol/mg of protein (p < 0.01) in rats fed the vitamin E-enriched diet. Finally, renal transforming growth factor-beta 1 gene expression was reduced by 34% in rats with IgA nephropathy receiving vitamin E treatment (p < 0.05). We conclude that experimental IgA nephropathy is associated with increased renal oxidant injury. Dietary treatment with the antioxidant agent, vitamin E, attenuated renal functional and structural changes in this experimental glomerulopathy. These studies support the importance of clinical trials for the evaluation of the efficacy of antioxidant therapy in patients with IgA nephropathy.

Taurine ameliorates chronic streptozocin-induced diabetic nephropathy in rats.

We examined the effect of two endogenous antioxidant agents, taurine and vitamin E, on renal function in experimental diabetes. Male Sprague-Dawley rats, rendered diabetic with streptozocin (STZ), were assigned to one of the following groups: 1) untreated; 2) insulin treatment with 6 U Ultralente insulin/day in two doses; 3) taurine supplementation by 1% taurine in drinking water; and 4) vitamin E supplementation at 100 IU vitamin E/kg chow. Animals were kept for 52 wk. The survival rate was similar (70-90%) in all groups except vitamin E-treated animals, of which 84% died by 6 mo. At 52 wk, glomerular filtration rate was elevated in untreated and taurine-treated STZ rats compared with normal or insulin-treated diabetic rats. Taurine supplementation reduced total proteinuria and albuminuria by nearly 50%. This treatment also prevented glomerular hypertrophy, preserved immunohistochemical staining for type IV collagen in glomeruli, and diminished glomerulosclerosis and tubulointerstitial fibrosis in diabetic animals. The changes in renal function and structure in taurine-treated diabetic rats were associated with normalization of renal cortical malondialdehyde content, lowering of serum free Fe2+ concentration, and decreased formation of the advanced glycooxidation products, pentosidine, and fluorescence in skin collagen. Administration of the vitamin E-enriched diet exacerbated the nephropathy in STZ-diabetic rats. In addition, vitamin E supplementation increased serum free Fe2+ concentration, enhanced renal lipid peroxidation, and accelerated the accumulation of advanced glycosylation end products (AGEs) in skin collagen. We conclude that administration of taurine, but not vitamin E, to rats with STZ-diabetes ameliorates diabetic nephropathy. The beneficial effect of taurine is related to reduced renal oxidant injury with decreased lipid peroxidation and less accumulation of AGEs within the kidney.

Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.

We have compared the efficacy of oral to intravenous iron for the chronic maintenance of iron stores in hemodialysis patients. Fifty-two hemodialysis patients with initial serum ferritin greater than 100 ng/mL and transferrin saturation greater than 15% were randomly assigned to one of two groups: those receiving oral iron therapy (n = 32) and those receiving intravenous iron dextran (100 mg twice weekly) (n = 20). At study completion (4 months), the mean hematocrit was significantly higher in the intravenous group than in the oral iron group (34.4% +/- 0.7% v 31.8% +/- 0.4%, respectively; P < 0.05), the final mean recombinant human erythropoietin dose was 46% lower in the intravenous iron group than in the oral group (4,050 +/- 634 U/treatment v 7,563 +/- 378 U/treatment; P < 0.05), and the mean serum ferritin was significantly higher in the intravenous group than in the oral iron group (753.9 +/- 30.2 ng/mL v 157.3 +/- 15.4 ng/mL, respectively; P < 0.05). We have found that administering iron intravenously instead of orally for chronic maintenance iron supplementation in hemodialysis patients resulted in improved erythropoiesis. We hypothesize that most hemodialysis patients have inadequate iron stores for optimal erythropoiesis when currently recommended levels of ferritin and transferrin saturation are used to guide therapy, and that the chronic use of intravenous iron could reduce recombinant human erythropoietin requirements by maximizing iron stores. The improvement in erythropoiesis was accompanied, however, by an increase in iron indices to levels that could be indicative of tissue iron overload. Future studies must be performed to determine whether lower doses of intravenous iron dextran would improve erythropoiesis without causing potential organ iron overload.

Dietary vitamin E supplementation ameliorates renal injury in chronic puromycin aminonucleoside nephropathy.

Chronic puromycin aminonucleoside nephropathy (PAN) is an experimental analog of focal segmental glomerulosclerosis. Progressive renal damage in this model is partly mediated by excessive production of oxidant species. Whether dietary supplementation with vitamin E, an endogenous lipophilic antioxidant, ameliorates the severity of chronic PAN was tested. PAN was induced by seven serial injections of the glomerular epithelial cell toxin puromycin aminonucleoside, 2 mg/100 g body wt per dose, over a 12-wk period. Experimental animals (N = 8) received vitamin E-enriched chow (100 IU/kg), whereas control PAN rats (N = 10) were fed standard rodent diet containing vitamin E (30 IU/kg of chow). The administration of vitamin E had no effect on somatic growth or blood pressure; however, rats with PAN fed the vitamin E-enriched diet had an increased hematocrit. In addition, the experimental diet resulted in a 50% reduction in urinary total protein and albumin excretion and stabilization of the serum albumin, cholesterol, and triglyceride concentrations (P < 0.01). The inulin clearance was 69% higher in the vitamin E-supplemented animals (P < 0.001). Tubular function, namely, phosphate reabsorption and beta 2-microglobulin excretion, was improved in rats with chronic PAN treated with the vitamin E-enriched diet. There was a significant decrease in glomerulosclerosis and glomerular planar area, and tubulointerstitial scarring was diminished in vitamin E-treated animals with chronic PAN (P < 0.01). These beneficial effects on renal structure and function were associated with reduced malondialdehyde content in the kidney and liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of time of day of dialysis shift on serum biochemical parameters in patients on chronic hemodialysis.

It is unknown whether predialysis serum biochemical parameters may differ among chronic hemodialysis patients depending on the shift during which they are dialyzed. We studied 115 patients on chronic hemodialysis in our institution for 3 consecutive months and compared clinical and biochemical parameters based on the shift during which they were dialyzed. Predialysis serum potassium was found to be progressively higher for patients dialyzed on later as compared with earlier dialysis shifts, and phosphate was significantly higher for patients dialyzed during the evening shift as well. Regression analysis suggested that higher of potassium and phosphate levels were related to the time of day these sessions and not to patient age, amount of dialysis given or diet. By contrast, serum albumin, creatinine, sodium, and chloride levels were found to differ depending on dialysis shift, though these differences appeared to be accounted for by patient age. We concluded that the time of day of the beginning of the dialysis shift appears to mildly influence the levels of serum predialysis biochemical parameters which are important in monitoring patients on chronic hemodialysis, in particular potassium and phosphate. Further insight into the mechanism of this observed effect might improve our ability to interpret and treat derangements of these serum biochemical parameters in patients on chronic hemodialysis.

Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.

OBJECTIVE: To study tubular urate transport in Alzheimer's disease (AD) and measure sodium and lithium transport rates in rats exposed to AD plasma. DESIGN: Cross-sectional study in three comparison groups. SETTING: Referral private institution involving outpatient and hospitalized patients. PATIENTS: AD, multi-infarct dementia (MID) and non-demented controls (C) were selected and evaluated by a geriatrician and a psychiatrist according to availability and willingness to participate in the study. Demented patients had brain imaging, categorized according to NINCDS-DSM III criteria, and had Mini-mental status examination (MMSE) scores determined. INTERVENTIONS: Injection of 0.5 mL of plasma I.P. followed 120 minutes later by an IV plasma injection of 0.2 mL priming dose and infusion of 1.8 mL of plasma at 0.01 mL/min in Sprague Dawley rats. MEASUREMENTS: Renal clearance studies were performed in subjects and in rats exposed to the plasma of study subjects. We measured serum urate concentration and fractional excretion (FE) of urate in subjects and FE sodium and FE lithium in rats. RESULTS: Serum urate was lower and FE urate higher in 18 AD patients compared with six patients with MID, P < 0.05 and P < 0.005, and 11 C, P < 0.02 and P < 0.005, respectively. Higher FE sodium and FE lithium were noted in rats given plasma from 19 AD patients compared with 12 with MID, P < 0.005 and P < 0.0025, and 14 C, P < 0.0025 and P < 0.0005, respectively. FE sodium and FE lithium decreased progressively after serial dilutions of three AD plasmas and FE lithium was negatively correlated with MMSE scores only in AD, r = -0.71 and P < 0.0005. CONCLUSIONS: In AD there is defective tubular urate transport and a plasma natriuretic factor(s). FE sodium and/or FE lithium in rats exposed to plasma of demented patients may differentiate AD from MID and estimate the severity of AD.

Occupational lead nephropathy.

Among eight subjects suspected of excessive occupational exposure to lead, detailed examination of renal function identified abnormalities in four. Glomerular filtration rate was less than 87 ml/mim/1.73 m2 in one subject with asymptomatic renal failure, and in three subjects with preclinical renal dysfunction. In the subject with asymptomatic renal failure, chelation therapy increased the glomerular filtration rate, p-aminohippurate (PAH) extraction, the maximal PAH secretion rate (TmPAH) and improved proximal tubule ultrastructure, despite decreased renal plasma flow. This improvement in PAH transport was associated with correction of a proximal tubule defect in tritiated PAH uptake detected by section freeze-dry autoradiography of renal biopsy specimens. In three subjects, the etiologic diagnosis of lead-induced nephropathy was established by exclusion, but tubular dysfunction did not obviously exceed the reduction in blomerular filtration. Proximal tubule abnormalities were seen in each of the three patients who underwent biopsy. These studies suggest that lead nephropathy may be an important occupational hazard in the United States lead industry.