Diagnostic value of iron indices in hemodialysis patients receiving epoetin.

BACKGROUND: Iron deficiency remains a common cause of hyporesponsiveness to epoetin in hemodialysis patients. However, considerable controversy exists regarding the best strategies for diagnosis and treatment. METHODS: As part of a multicenter randomized clinical trial of intravenous versus subcutaneous administration of epoetin, we made monthly determinations of serum iron, total iron binding capacity, percentage transferrin saturation, and serum ferritin. If a patient had serum ferritin <100 ng/mL or the combination of serum ferritin <400 ng/mL and a transferrin saturation <20%, he/she received parenteral iron, given as iron dextran 100 mg at ten consecutive dialysis sessions. We analyzed parenteral iron use during the trial, the effect of its administration on iron indices and epoetin dose, and the ability of the iron indices to predict a reduction in epoetin dose in response to parenteral iron administration. RESULTS: Eighty-seven percent of the 208 patients required parenteral iron to maintain adequate iron stores at an average dose of 1516 mg over 41.7 weeks, or 36 mg/week. Only two of 180 patients experienced serious reactions to intravenous iron administration. Two thirds of the patients receiving parenteral iron had a decrease in their epoetin requirement of at least 30 U/kg/week compared with 29% of patients who did not receive iron (P = 0.004). The average dose decrease 12 weeks after initiating iron therapy was 1763 U/week. A serum ferritin <200 ng/mL had the best positive predictive value (76%) for predicting a response to parenteral iron administration, but it still had limited clinical utility. CONCLUSIONS: Iron deficiency commonly develops during epoetin therapy, and parenteral iron administration may result in a clinically significant reduction in epoetin dose. The use of transferrin saturation or serum ferritin as an indicator for parenteral iron administration has limited utility.

Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt-depleted rats.

BACKGROUND: Long-term cyclosporine (CsA) treatment leads to a decreased glomerular filtration rate, hyalinosis of afferent arterioles, and striped cortical tubulo-interstitial fibrosis. We showed previously that pentosan polysulfate (SP54) prevented the development of microvascular and interstitial lesions in mouse models of progressive glomerulosclerosis. In this study, we examined the effect of pentosan polysulfate on the development of CsA nephropathy. METHODS: Pair-fed Sprague-Dawley rats were fed a low-sodium (0.03%) diet and received CsA (15 mg/kg, subcutaneously, in olive oil)/5% glucose, pentosan polysulfate (10 mg/kg, subcutaneously in 5% glucose) plus CsA, olive oil/pentosan polysulfate, or olive oil/5% glucose for 30 days. Creatinine clearance (CrCl) was determined at three time points. Afferent arteriolar lesions, glomerular volume, and tubulo-interstitial lesions were quantitated. RNA was extracted from cortex. RESULTS: Severe lesions were found in the CsA group. A reduction in the number of affected arterioles (32%) and the degree of chronic tubulo-interstitial lesions (44%) was found in pentosan polysulfate/CsA-treated rats. A 20% decrease in glomerular volume was found in CsA rats, but not in pentosan polysulfate/CsA-treated rats. Pentosan polysulfate treatment did not prevent the CsA-induced decrease in CrCl (approximately 30%) at 4 weeks. CsA did not affect cortical endothelial or neuronal nitric-oxide synthase or mRNA levels, but there was small increase in neuronal nitric-oxide synthase mRNA levels in the pentosan polysulfate/CsA-treated group. CONCLUSIONS: Pentosan polysulfate reduced structural renal lesions in CsA-treated, salt-depleted Sprague-Dawley rats.

Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients.

BACKGROUND: Several studies have suggested that if recombinant human erythropoietin (epoetin) is administered subcutaneously rather than intravenously, a lower dose may be sufficient to maintain the hematocrit at a given level. METHODS: In a randomized, unblinded trial conducted at 24 hemodialysis units at Veterans Affairs medical centers, we assigned 208 patients who were receiving long-term hemodialysis and epoetin therapy to treatment with either subcutaneous or intravenous epoetin. The dose was initially reduced until the hematocrit was below 30 percent and then was gradually increased to a level that would maintain the hematocrit in the range of 30 to 33 percent for 26 weeks. We compared the average doses in the 26-week maintenance phase and the discomfort associated with the two routes of administration. RESULTS: For the 107 patients treated by the subcutaneous route, the average weekly dose of epoetin during the maintenance phase was 32 percent less than that for the 101 patients treated by the intravenous route (mean [+/-SD], 95.1+/-75.0 vs. 140.3+/-88.5 U per kilogram of body weight per week; P<0.001). Only one patient in the subcutaneous-therapy group withdrew from the study because of pain at the injection site, and 86 percent rated the pain associated with subcutaneous administration as ranging from absent to mild. CONCLUSIONS: In patients receiving hemodialysis, subcutaneous administration of epoetin can maintain the hematocrit in a desired target range, with an average weekly dose of epoetin that is lower than with intravenous administration.

Drug-induced nephrotoxicity: the crucial role of risk factors.

Although the exact incidence of drug-induced nephrotoxicity is not known, it is important for clinicians to be aware of the risks in certain patients and to know which drugs are the most commonly implicated. The latter include radiocontrast agents, aminoglycosides, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors. Other medications also have nephrotoxic potential when they are prescribed in specific patient populations. Renal injury may be transient and mild in many cases, but recognition of the patient at high risk and application of preventive measures are essential to avoid a severe and protracted course.

Nephrotic syndrome in autosomal dominant polycystic kidney disease.

Urinary protein excretion is generally less than 1 g/24 h in autosomal dominant polycystic kidney disease (ADPKD), and the association of the nephrotic syndrome with this condition is considered rare. A patient with ADPKD associated with nephrotic-range proteinuria is described. She exhibited a relatively rapid impairment of her renal function. An open renal biopsy revealed focal segmental glomerulosclerosis (FGS) with features consistent with secondary FGS. Twenty-one patients with ADPKD and nephrotic syndrome were retrieved from the literature. Fourteen of them (including this case) had a histopathologic evaluation, and FGS was the dominant diagnoses (five patients). Next in frequency were minimal-change disease and membranous nephropathy, with two patients each. Five other patients had a variety of diagnoses. Thus, it is difficult to ascertain if these associations are coincidental or represent a specific pathogenetic relationship. The evaluation of the data also suggests that the presence of proteinuria and nephrotic syndrome accelerates the course of ADPKD toward ESRD.

Insulin reverses the protection given by diabetes against gentamicin nephrotoxicity in the rat.

Rats with untreated diabetes mellitus are protected from gentamicin-induced nephrotoxicity. In order to evaluate the role of hyperglycemia, glycosuria, and polyuria in this phenomenon, miniosmotic pumps filled with insulin were implanted for 15 days in seven female Sprague-Dawley rats with streptozotocin-induced diabetes mellitus. Plasma glucose levels were successfully maintained under 126 mg/dl. To serve as the control group, eight age-matched diabetic (plasma glucose > 400 mg/dl) rats had miniosmotic pumps placed delivering only Ringer's solution. Six days after placement of the pumps, gentamicin (40 mg/Kg/day) was administered to all animals for 9 days. The insulin-treated diabetic rats exhibited clear signs of nephrotoxicity by Day 6 of gentamicin, whereas the diabetic control group remained free from any functional or morphological evidence of proximal tubular damage throughout the 9 days of the aminoglycoside administration. At the end of the experiment, the creatinine clearance in the insulin-treated diabetic group was 45% lower than in the untreated diabetic group (P < 0.005). In addition, there was a rise in plasma creatinine (P < 0.02), muramidase appeared in the urine, and mild patchy acute tubular necrosis of the renal cortex was observed by light microscopic examination. The insulin-treated group also accumulated more gentamicin in the renal cortex than the untreated animals (P < 0.005). It is concluded that protection against the nephrotoxic effects of gentamicin is a feature of untreated experimental diabetes mellitus in the rat and that correction of the hyperglycemic state with insulin reverses this resistance.

Acute renal failure due to rhabdomyolysis associated with the extreme lithotomy position.

A patient who developed acute renal failure secondary to rhabdomyolysis associated with the use of the extreme lithotomy position for 6 hours during radical perineal prostatectomy is described. It appears that muscle ischemia due to compression of the lumbar and pelvic muscles resulted in muscle injury. Intense muscle uptake of technetium 99m methylene diphosphonate assisted in localizing the muscles involved and ascertaining the extent of the injury. Review of the literature disclosed seven other patients with a similar association. All patients complained of muscle pain shortly after recovery from anesthesia. Early recognition and aggressive treatment with intravenous fluids may prevent the development of acute renal failure.

The protection against gentamicin nephrotoxicity in the streptozotocin-induced diabetic rat is not related to gender.

Since gender can influence the renal toxicity of a drug in a given species, the present study was undertaken to evaluate the role of sex in the protection against gentamicin (G)-induced nephrotoxicity afforded by diabetes mellitus (DM) in the rat. We have compared the effects of administration of G (40 mg/kg/day, for 14 days) on male and female DM Sprague-Dawley rats. Non-diabetic animals of both sexes receiving identical doses of G served as controls. At the end of the experiment on day 14, both female (F) and male (M) control groups had similar and marked evidence of nephrotoxicity: elevation of plasma creatinine (F 1.7 +/- 0.7; M 2.8 +/- 0.6 mg/dl), decrease in endogenous 24-h creatinine clearance (Ccr) (F0.3 +/- 0.1; M 0.2 +/- 0.1 ml/min/100 g BW), and histological evidence of severe acute tubular necrosis. In marked contrast, the DM rats showed no functional or morphological evidence of renal damage throughout the study regardless of their gender (day 14: plasma creatinine: F 0.2 +/- 0.03; M 0.2 +/- 0.02; Ccr: F 1.2 +/- 0.1; M 1.6 +/- 0.1 ml/min/100 g BW), and they also accumulated less G in their kidney cortex than the C rats. The male controls exhibited higher renal cortex accumulation of G than the female controls (p < 0.05), whereas the opposite occurred in the DM groups (p < 0.01). Because the validity of using Ccr for the evaluation of GFR changes in experimental nephrotoxicity has been questioned, we have compared, in a separate experiment, three different methods of estimation of GFR (simultaneous short clearances of inulin and Ccr, and 24-h Ccr) in conscious female Sprague-Dawley rats undergoing the same treatment with G described above. At no time during the study did the method used for estimation of the GFR influence the results. We conclude that male and female Sprague-Dawley rats with diabetes are functionally and morphologically equally protected against G. Furthermore, no gender-related differences in the magnitude of G-induced nephrotoxicity was demonstrated in the non-diabetic control animals.

Serum sulfate concentration and the anion gap in hemodialysis patients.

First-of-the-month predialysis serum sulfate (SO4) and other blood chemistry values were measured prospectively for 5 to 7 months in 14 patients undergoing single pass chronic tri-weekly maintenance hemodialysis with bicarbonate dialysate. Blood was also obtained predialysis and again immediately postdialysis from seven patients (five of whom also participated in the chronic study). As expected, the patients manifested a high anion gap (AG) metabolic acidosis. Serum SO4 was only moderately stable from month to month (the average coefficient of variation was 0.30; correlation between the serum SO4 value of month one and months two and five were r = 0.59, p = 0.026; and r = 0.38, p = 0.182, respectively). The ratio of mean serum SO4 to mean AG (5.0 +/- 0.4 [SE] mEq/L divided by 19.1 +/- 0.5 mEq/L) was 0.26. Although there was a statistically significant correlation between the serum SO4 and the blood urea nitrogen (BUN), there was no such correlation between SO4 and AG. A single hemodialysis reduced serum SO4 by 54% (from 3.5 +/- 0.5 mEq/L to 1.6 +/- 0.1 mEq/L), but there was no correlation between the change in SO4 and the change in AG. The authors concluded that SO4 contributes importantly to the elevated AG in patients receiving chronic hemodialysis. Single pass bicarbonate hemodialysis temporarily reduces, but does not normalize, both the serum SO4 and the AG of such patients.

Hepatitis C infection in two urban hemodialysis units.

We determined the prevalence of antibodies to the hepatitis C virus (anti-HCV) in 90 patients and 37 staff members of two hemodialysis units utilizing a recently developed anti-HCV recombinant based assay. Eleven patients (12%) were anti-HCV(+). Of these, eight (73%) had antibodies to the hepatitis B core antigen (anti-HBc) indicating prior hepatitis B infection; one patient was hepatitis B surface antigen (HBsAg)(+). All staff members were anti-HCV(-), although seven (19%) of them were anti-HBc(+). Alanine aminotransferase elevations were present at the time of the study in four anti-HCV(-) patients and in only one anti-HCV(+) patient. All anti-HCV(+) (mean 59 +/- 74; range 3 to 269 units) and 85% of anti-HCV(-) patients (mean 16 +/- 27; range 0 to 204 units) had received multiple blood transfusions (P = 0.348). Among 50 patients tested for human immunodeficiency virus (HIV), 43% of anti-HCV(+) as compared to only 7% anti-HCV(-) were positive (P = 0.003). There was a history of intravenous drug abuse (IVDA) in eight (72%) of the anti-HCV(+) patients and in only seven (9%) of the anti-HCV(-) group (P = 0.00001). The results of this serologic survey suggests that anti-HCV positivity is prevalent, although much less than anti-HBc, among our dialysis patients, whereas it was not detected among staff members. The prevalence rate of anti-HCV was statistically significantly higher among anti-HIV(+) and IVDA patients but not in multi-transfused patients.

Influence of magnesium sulfate-induced hypermagnesemia on the anion gap: role of hypersulfatemia.

Although hypermagnesemia purportedly lowers the anion gap (AG), we have shown previously that increases in the serum concentration of the unmeasured cation (UC) Mg due to therapeutic infusion of MgSO4 are not associated with AG reduction. To assess our hypothesis that increases in serum SO4 (unmeasured anion, UA) offset the effect of elevated serum Mg on the AG, we prospectively studied 11 patients receiving MgSO4 intravenously for toxemia of pregnancy. After 6 h of MgSO4 infusion, serum Mg increased by 2.1 +/- 0.2 (SE) mEq/l (p less than 0.001) without a significant decrease in the AG. Concomitantly, serum SO4 increased by 1.4 +/- 0.2 mEq/l. Comparison of the renal handling of SO4 versus Mg showed a higher fractional excretion of the former, probably accounting in part for the smaller increment of serum SO4 than of Mg. Comparison of the change in serum SO4 minus that of Mg indicated that, on the average, 70% of the observed 1.0 +/- 0.7 mEq/l reduction in AG was accounted for by the observed changes in the two pertinent unmeasured ions. A small decrement in serum Ca probably was a quantitatively minor factor tending to obviate a greater decrease in AG. We conclude that hypersulfatemia attenuates the reduction in AG that would otherwise accompany MgSO4-induced hypermagnesemia.

Effect of hypercalcemia on the anion gap.

It has been assumed, but not documented, that hypercalcemia induces an appreciable reduction in the serum anion gap (AG) because it represents an increase in the level of unmeasured cations. To test this question, we retrospectively compared the data of 59 hypercalcemic patients with malignancy [group 1, serum Ca 13.3 +/- SE 0.3 mg/dl] with those of 108 patients whose hypercalcemia was of parathyroid origin (group 2, serum Ca 12.1 +/- 0.1 mg/dl), and those of 51 control subjects (group 3, serum Ca 9.5 +/- 0.1 mg/dl). The AG of group 2 subjects (8.7 +/- 0.3 mEq/l) was significantly lower than that of the other two groups (p less than 0.001 for both) despite their higher serum albumin and lower serum Ca in comparison to group 1. The AGs of group 1 (11.1 +/- 0.4 mEq/l) and group 3 (11.1 +/- 0.3 mEq/l) were identical. There was no statistically significant correlation between the AG and serum Ca in the hypercalcemic patients. The major finding that the association of hypercalcemia with reduced AG is seen in hyperparathyroidism, but not in malignancy-related hypercalcemia, is not explained by differences in serum albumin, renal function, or acid-base status. Overlap of values between groups limits the diagnostic usefulness of the AG in an individual patient. Nevertheless, in the absence of multiple myeloma, the finding of an AG of 5 mEq/l or less in a hypercalcemic patient may be a helpful clue suggesting that malignancy is not the etiology.

The anion gap of patients receiving bicarbonate maintenance hemodialysis.

To compare the effect of maintenance bicarbonate hemodialysis on the serum anion gap (AG) and the serum HCO3, the authors retrospectively evaluated the data of 28 patients using the first-of-the-month blood chemistries. Data were available for at least 9 of the previous 12 months in each case. For the entire group, the average AG was 15.8 +/- 0.1 mEq/L and the HCO3 21.7 +/- 0.2 mEq/L. Comparing these values with the data compiled recently by three different groups of investigators in undialyzed patients with severe chronic renal failure indicates that the AG of the dialyzed patients was similar to that of untreated patients, but the HCO3 levels of dialyzed patients averaged 2 to 3 mEq/L higher. Separate prospective evaluation of the acute effect of two consecutive bicarbonate dialyses in 31 patients revealed that the average acute (immediate postdialysis) decrease (from predialysis values) in AG was only about 40% of that of the increase in HCO3. The authors conclude that bicarbonate dialysis is more effective in improving serum HCO3 than AG.

The effects of administration of lithium salts and magnesium sulfate on the serum anion gap.

Whether or not an increased serum level of an unmeasured cation will reduce the anion gap (AG) depends on concomitant changes (or lack thereof) in serum unmeasured anions. In the present retrospective study, we sought to determine the effect of lithium carbonate or citrate and magnesium sulfate on the AG. Two groups of psychiatric patients whose average serum lithium levels were 0.6 and 1.0 mEq/L were studied. The AG in each group (10.2 +/- 0.3 [SE] and 9.0 +/- 0.4 mEq/L, respectively) was significantly (P less than 0.05) lower than that of a control group (11.1 +/- 0.3 mEq/L). Separately, we collected 87 pairs of AG and serum magnesium data of patients with toxemia of pregnancy. These included those of 15 patients evaluated both before and during magnesium sulfate infusion. Despite an average serum magnesium level of 4.1 +/- 0.2 mEq/L, the AG of the latter subjects tended to increase slightly from 10.8 +/- 0.5 to 11.7 +/- 0.7 mEq/L during magnesium infusion, instead of decreasing. The other data (72 determinations in the 55 patients without preinfusion values) revealed a mean AG of 11.0 +/- 0.3 mEq/L, coexisting with an elevated serum magnesium of 4.1 +/- 0.1 mEq/L. None of the above-mentioned three mean AG values differed significantly from that of the control group. We conclude that hypermagnesemia resulting from the administration of magnesium sulfate does not reduce the AG, probably because of a concomitant and proportional increase in serum sulfate. The present data reemphasize the need to assess the anion gap as the result of concomitant changes in both unmeasured anions and cations.

Phlorizin-induced glycosuria does not prevent gentamicin nephrotoxicity in rats.

Because rats with streptozotocin-induced diabetes mellitus (DM) have a high solute diuresis (glycosuria of 10 to 12 g/day), we have suggested that this may in part be responsible for their resistance to gentamicin-induced acute renal failure (ARF). The protection from gentamicin nephrotoxicity was studied in non-diabetic rats with chronic solute diuresis induced by blockage of tubular glucose reabsorption with phlorizin (P). DM rats with mild glycosuria (similar in degree to that of the P treated animals) were also studied. Unanesthetized adult female, Sprague-Dawley rats were divided in four groups and studied for 15 days. Group 1 (P alone) received P, 360 mg/day, for 15 days; Group II (P + gentamicin); Group III (gentamicin alone) and Group IV (mild DM + gentamicin). Nephrotoxic doses (40 mg/kg body wt/day) of gentamicin were injected during the last nine days of study to the animals of groups II to IV. In Group I, P induced a moderate and stable glycosuria (3.9 +/- 0.1 g/day, SE), and no functional or morphologic evidence of renal dysfunction (baseline CCr 2.1 +/- 0.1 ml/min, undetectable lysozymuria) or damage (tubular necrosis score [maximum 4], zero). In Group II, P did not prevent gentamicin-ARF (maximal decrease in CCr at day 9.89%, P less than 0.001; peak lysozymuria, 1863 +/- 321 micrograms/day; and tubular necrosis score, 3.9 +/- 0.1). These values were not different from those of Group III: maximal decrease in CCr 73% (P less than 0.001); lysozymuria, 2147 +/- 701 micrograms/day; tubular necrosis score, 3.8 +/- 0.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic renal effects of radiocontrast in diabetic rats. Role of anesthesia and risk factors.

The acute and chronic renal effects of the intravenous injection of meglumine diatrizoate sodium 76% (CM), 5 mL/kg body weight were studied in diabetic (DM) and age-matched normal (C) female Sprague-Dawley rats. In acute studies, the effect of anesthesia was assessed for 2 hours. Although anesthesia decreased 14C-inulin clearance (Cin) in both DM and C rats (P less than .001 vs. conscious values), there was no impairment of Cin in either group after administration of CM. In chronic studies, creatinine clearance (Ccr) was followed for 3-4 days after CM administration. Four protocols to assess risk factors in DM and C were used: adult rats with normal hydration (2A); old dehydrated rats with DM of long duration (2B); rats with prior decreased Ccr (remnant kidney, 2C); and DM rats treated with insulin (2D). No clear-cut nephrotoxicity was apparent in these studies, except that proteinuria increased with CM in Study 2C. A greater severity of renal dysfunction, renal disease, or the association of multiple risk factors may be necessary to induce CM-related nephrotoxicity in the experimental animal. The rat, diabetic or not, may have an inherent resistance to CM-induced renal injury.

Blunted kaliuresis after an acute oral potassium load in diabetes mellitus.

It is unknown whether diabetic patients without renal failure or aldosterone deficiency respond normally to potassium administration. Acute oral potassium-loading was carried out in eight diabetic patients with modestly reduced creatinine clearance (Ccr) and in 11 diabetic patients and 13 controls with normal clearances. Only one diabetic patient manifested an inappropriately low upright plasma aldosterone level (6 ng/dL). The percentage of potassium excreted in 4 hour by both groups of diabetic patients was significantly less than that of the controls (decreased Ccr:21% +/- 6%, normal Ccr:36% +/- 5%, controls:54% +/- 5%; p less than 0.01 and 0.05 respectively). On the other hand, the estimated amount of potassium translocated intracellularly tended to be greater in the diabetic patients (18 +/- 3 mmol; 11 +/- 3 mmol) than controls(7 +/- 2 mmol; p less than 0.005 and 0.1 respectively), and the ratio of the increase in plasma (K) to the amount of potassium retained, was lower in diabetic patients, probably indicating enhanced intracellular potassium translocation. The authors conclude that diabetic patients with normal or only slightly reduced renal function (and no aldosterone deficiency) may have a reduced capacity to excrete an acute potassium load but an enhanced capacity to transfer potassium intracellularly.

The stability of pH, PCO2, and calculated [HCO3] of urine samples collected under oil.

In order to determine the stability of directly measured pH and PCO2, and calculated [HCO3] in stored urine, 11 alkali-loaded normal subjects provided 33 spot and sixteen 24-hour mineral oil-covered, thymol-preserved, refrigerated urine samples. For the spot samples, pH and PCO2 were measured immediately and again at 4 and 24 h. In addition, immediately after voiding, 24 of the spot samples were split into oil-covered and no-oil moieties and analyzed immediately and again at 4 and 24 h. pH and PCO2 measurements of the 24-hour collections were carried out immediately after completion and again 24 h later. The results demonstrated the importance of using oil to limit the escape of CO2 from stored urine. Thus, after 24 h the oil-uncovered subgroup of 24 spot urine samples sustained a 82% decline in PCO2 and 20% fall in [HCO3]. In contrast, the corresponding percentage decrements in the oil-covered samples were 16 and 1%, respectively. The results also indicated that even with oil there is loss of CO2, which increases with time and which shows a statistically significant direct correlation with the baseline level of PCO2. Nevertheless, modest loss of CO2 usually produces only slight decrements in [HCO3] because of the countervailing influence of the resultant increase in pH. We conclude that the use of mineral oil is necessary in order to obtain adequate stability of PCO2, pH and [HCO3] in refrigerated urine requiring several hours or more of storage.