Aldosterone in metabolic alkalosis.

Studies have been carried out in human volunteer subjects to evaluate the role of aldosterone in the development, maintenance, and correction of metabolic alkalosis induced by selective depletion of hydrochloric acid. During the first phase of our study the rate of aldosterone secretion was measured before the induction of alkalosis (while the subjects were on a low salt diet) and again after a steady state of metabolic alkalosis had been established. The data demonstrate a fall in aldosterone secretion from a value of approximately 500 mug/day to a value of approximately 200 mug/day. Thus, it appears that an increased rate of aldosterone secretion is not a prerequisite to the elevation of the renal bicarbonate threshold. During the second phase of our study, aldosterone was administered to the alkalotic subjects in doses of 1000 mug/day (or deoxycorticosterone acetate in doses of 40 mg/day) in order to determine the effects of a persistent steroid excess on the ability of sodium chloride to correct the acid-base disturbance. The data demonstrate that despite the administration of steroid, the ingestion of sodium chloride led to a reduction in plasma bicarbonate concentration from 39 to 29 mEq/liter, accompanied by a suppression of renal acid excretion. This reduction in plasma bicarbonate concentration occurred without a concomitant retention of potassium, a deficit of as much as 400-500 mEq of potassium persisting during repair of the acid-base disturbance. Our findings suggest that "saline-resistant" alkalosis, when it occurs in the absence of primary hyperadrenalism, cannot be attributed to aldosterone excess and/or potassium depletion of the magnitude seen in our study. We also suggest the need for a reappraisal of the way in which aldosterone excess contributes to the genesis and maintenance of alkalosis in primary aldosteronism.

Increased serum aluminum. An independent risk factor for mortality in patients undergoing long-term hemodialysis.

The annual mortality rate among patients receiving long-term hemodialysis has been rising over the past decade. The prevalences of known risk factors such as older age, male sex, duration of dialysis, presence of diabetes, coronary artery disease, or hypertension do not seem to have changed during this time. However, evidence suggests that an increased body aluminum level may have an adverse effect on survival even in the absence of overt aluminum toxic reaction. Therefore, we evaluated the correlation between serum aluminum levels and mortality in 10 646 patients undergoing long-term hemodialysis. Mortalities were 18% higher for patients with serum aluminum levels between 1520 and 2220 nmol/L and progressively increased to 60% higher for patients with aluminum levels above 7410 nmol/L. Serum aluminum level was an important predictor of survival even after other known risk factors had been controlled. These data strongly suggest that patients undergoing long-term hemodialysis should have periodic surveillance of the serum aluminum levels, and in those patients who have plasma levels of 1520 to 2220 nmol/L or higher, one should seriously consider discontinuing aluminum salts and giving therapy to decrease body aluminum level if it is found to be increased.

Transfusion and long-term hemodialysis.

We analyzed the transfusion practice at a large regional renal dialysis center. More than half of all long-term dialysis patients received at least one transfusion annually, and the average transfused patient received 10 U of blood. A review of data on 318 dialysis patients over one year showed there is a sizable group (15.0%) who require greater than ten transfusions of blood. This group of intensely transfused dialysis (ITD) patients account for a disproportionate 67% of all units transfused. The majority of these patients (73%) were women, which may have been related to the relatively small proportion (12.5%) of women undergoing dialysis who were treated with synthetic androgens. These ITD patients were older and underwent dialysis longer than others in the population studied. One year mortality in the ITD group was 27%; more than twice that of the entire group (12.8%). A retrospective examination of transfusion practice in the five years preceding the present study showed that the number of transfusion recipients was essentially a constant fraction of the dialysis population. However, there was a significant trend to less intense transfusion of each transfused patient. Most of the ITD group had significant iron overload, and attending physicians indicated that concern about transfusion related hemosiderosis outranked other reasons including acquired immunodeficiency syndrome, that would account for the more conservative transfusion practice of recent years.

Increased body aluminum. An independent risk factor in patients undergoing long-term hemodialysis?

The clinical course and aluminum status of 38 patients who had been receiving dialysis for at least eight years and were still undergoing dialysis in 1985 were evaluated. Twenty-nine had evidence of increased aluminum burden, although only three had evidence of overt aluminum toxicity, and nine did not have evidence of increased aluminum burden. The patients in both the high- and low-aluminum group were similar with regard to age, the cause of their renal failure, presence of hypertension or coronary artery disease, previous parathyroidectomy, and a number of biochemical parameters, along with the amount of prescribed aluminum. All patients were followed up for the next two years or until they died. The amount of ingested aluminum was reduced, and in selected patients, treatment with intermittent infusions of deferoxamine mesylate was instituted. There were no deaths in the low-aluminum group, but ten of 29 died in the high-aluminum group: seven of vascular disease and three of infection. In addition, morbidity as defined by hospitalization for coronary or cerebral vascular disease or infection occurred in only two of the nine patients in the low-aluminum group and in 19 of the 29 patients in the high-aluminum group. These observations imply that the occurrence of increased body aluminum, as suggested by aluminum blood levels or by results of bone biopsies in some patients, has an adverse effect on morbidity and mortality and should be considered as a possible independent risk factor in patients who are receiving long-term hemodialysis.

Oral estrogens decrease bleeding time and improve clinical bleeding in patients with renal failure.

PURPOSE: A prolonged bleeding time is associated with platelet dysfunction and clinical bleeding in patients with renal failure. Parenteral estrogens have been shown to shorten the prolonged bleeding time in patients with chronic renal failure, although the mechanism of action is unknown. We conducted a study to evaluate the efficacy of oral conjugated estrogens in this setting. PATIENTS AND METHODS: Four patients with renal failure, prolonged bleeding time, and clinical bleeding were given 50 mg of conjugated estrogen (Premarin) daily. RESULTS: Bleeding time normalized in two cases and was reduced to less than 50% of the pretreatment value in one of the remaining two cases. Bleeding stopped in all patients within two days. Ten dialysis patients with prolonged bleeding time were randomized to a course of 50 mg of Premarin daily or placebo. The bleeding time in all five patients in the Premarin group normalized or decreased to below 50% of the pretreatment value after 7.0 +/- 4.2 days of therapy. The bleeding time did not normalize in the five patients treated with placebo. No side effects attributable to therapy were reported. CONCLUSION: We conclude that orally administered conjugated estrogens effectively improve the bleeding tendency in patients with chronic renal failure.

Fibrillary (immunotactoid) glomerulopathy. A possible role for kappa light chain in its etiology and/or pathogenesis.

The initial clinical manifestations, course, and immunopathologic findings of renal biopsies of nine patients with fibrillary glomerulopathy are reported. Their first symptoms and courses were variable, but proteinuria and renal failure were common. While some patients required hemodialysis soon after coming for treatment, others progressed to renal failure over several years. Three patients had monoclonal gammopathy; one of them had an isolated, transient, Bence-Jones proteinuria. The main pathologic features are glomerular enlargement, mesangial expansion, and mild hypercellularity. Congo red and thioflavin stains were negative. Kappa chain, either alone or with lambda chain and IgG, were the predominant immunoreactants. Ultrastructurally, the presence of coarse fibrils of 15-25 nm was characteristic, but there were also granular deposits in the capillary wall that occurred in a band-like pattern in the inner half of the glomerular basement membrane in a manner similar to the deposits seen in light chain deposit disease. The immunofluorescence and ultrastructural findings suggest that light chains (especially kappa) may be significant in the pathogenesis of fibrillary glomerulopathy and that there may be a relationship with light chain deposit disease.

Renal parenchymal malakoplakia. Histologic spectrum and its relationship to megalocytic interstitial nephritis and xanthogranulomatous pyelonephritis.

We report five cases of renal parenchymal malakoplakia. They represent a histologic spectrum of this uncommon inflammatory process as it involves the renal parenchyma. Only one of these five cases presented the classical histologic picture of malakoplakia ("diagnostic stage"). Two cases--although with similar cellular infiltrate--had a marked paucity of Michaelis-Gutmann bodies and thus might have been classified as megalocytic interstitial nephritis were it not for the identification of such calcific intracellular inclusions under the electron microscope. The fourth case presented a pseudosarcomatous morphology and is similar to what has been described as a late or fibrous stage in malakoplakia of the urinary bladder. The last case had a destructive, frankly granulomatous histologic picture with a preponderance of foamy histiocytes reminiscent of xanthogranulomatous pyelonephritis, but with clusters of von Kossa-positive Michaelis-Gutmann bodies. The last two forms of the disease have not been previously reported to occur in the kidney. We believe that these cases represent various stages of development of the disease.

Effect of aminoglycoside use on residual renal function in peritoneal dialysis patients.

Residual renal function (RRF) is a major contributor to total solute clearance in peritoneal dialysis (PD) patients, and maintenance of RRF has been linked to decreased morbidity and mortality in PD. There have been few clinical studies examining the impact of factors that potentially affect RRF in PD. This is a prospective observational study that examines the effects of parenteral aminoglycosides, a common nephrotoxin in the general population, on RRF in a cohort of PD patients. Seventy-two patients from two Rhode Island PD units were observed over 4 years. Twenty-four-hour renal creatinine clearances and urine volumes were measured every 4 to 6 months. The patients were divided into three groups, depending on exposure to peritonitis and aminoglycoside use. Group I included patients without peritonitis who received no intravenous (IV) or intraperitoneal (IP) antibiotics. Group II included patients with peritonitis who received IV or IP penicillins, cephalosporins, vancomycin, or quinolones, but no aminoglycosides. Group III included patients with peritonitis who received IV or IP aminoglycosides for at least 3 days. Patients in group III had a more rapid decline in renal creatinine clearance (-0.66 +/- 0.58 mL/min/mon) than groups I and II (P < 0.005) and had a more rapid decline in daily urine volume (-74 +/- 62 mL/d/mon) than groups I and II (P < 0.01). We conclude that IV or IP aminoglycosides seem to increase the rapidity of decline in RRF in PD patients. In patients with solute clearance dependent on RRF, it seems reasonable to withhold aminoglycosides, especially if other antibiotics are available and appropriate.

Serum creatinine concentration at the onset of uremia: higher levels in black males.

We compared serum creatinine and blood urea nitrogen concentrations, estimated creatinine clearances and frequency of uremic symptoms at the start of chronic hemodialysis in all 20 black and 179 white males treated between 1969 and 1983. Serum creatinine concentrations were significantly higher in black males (16.5 +/- 5.9 mg/dl) than in white males (11.7 +/- 4.7 mg/dl; p = 0.016). There were no significant differences in blood urea nitrogen concentration, estimated creatinine clearance and frequency of uremic symptoms between the two groups. Blood urea nitrogen to serum creatinine ratios were lower in black males, (7.3 +/- 1.9) than in white males (11.4 +/- 3.8; p = 0.0001), and only one black male had a ratio greater than 10 compared to 60% of whites. We concluded that black males tend to have higher serum creatinine concentrations than white males at the onset of uremic symptoms, and that higher striated muscle creatinine production in black males and not lower renal function may be the cause.

The clinical spectrum of renal osteodystrophy in 57 chronic hemodialysis patients: a correlation between biochemical parameters and bone pathology findings.

Fifty-nine chronic hemodialysis patients who had been on dialysis for an average of 77 months underwent bone biopsies and the pathologic findings were correlated with biochemical and demographic data. All but two had evidence of renal osteodystrophy, 23 with osteitis fibrosa (OF), 19 with osteomalacia and/or adynamic disease (OM/AD), and 15 with mixed osteodystrophy (MOD). Patients in each group were similar with regard to age, sex distribution, duration of dialysis, unstimulated serum aluminum, calcium and phosphorus. Patients with osteitis fibrosa (OF) had statistically higher DFO stimulated aluminum, alkaline phosphatase and PTHC levels than the other two groups although there was marked individual variation. The bone biopsies were also evaluated for the amount of aluminum deposited in the osteoid seam. All 23 of the patients with OF and 11 of the 15 patients with MOD had no, mild, or minimal aluminum deposition but 12 of the 19 patients with OM/AD had moderate to marked aluminum deposition. Patients with minimal to mild aluminum deposition were similar in age, duration of dialysis, sex distribution, unstimulated and DFO stimulated aluminum levels, calcium, phosphorus, alkaline phosphatase to those with moderate to marked deposition but had significantly higher parathormone levels. All patients had been treated in a similar fashion regarding diet, oral phosphate binders and vitamin D; therefore, the observed differences in bone pathology were not readily explicable. However, patients who were found to have osteitis fibrosa and those with minimal to mild aluminum deposition had significantly higher parathormone levels when compared with patients in the other groups at the inception of dialysis.

The relevance of mineralization lag time in the evaluation of histologic changes in renal osteodystrophy.

We examined bone biopsies from 47 patients on chronic hemodialysis, and analyzed the histomorphometric and biochemical findings and histologic quantitation of bone aluminium, looking primarily at mineralization lag time (Mlt) to evaluate its usefulness in categorization of renal osteodystrophy (ROD). The patients were categorized as having either relatively normal Mlt (< 35 days, n = 21 patients), moderately prolonged Mlt (35-100 days, n = 13 patients) or markedly prolonged Mlt (> 100 days, n = 13 patients). The group with relatively normal Mlt showed significantly higher C-terminal parathyroid hormone (PTHc) levels (26,141 +/- 19,270 vs 7,226 +/- 6,073 and 4,434 +/- 4,000 pg/ml) than the moderately or markedly prolonged Mlt groups (p < .01) and was associated with histologic characteristics of osteitis fibrosa or mild hyperparathyroidism (BFR/BS range 0.146-0.947 mcm3/mcm2/d). The group with markedly prolonged Mlt included one patient with classic and 11 with adynamic osteomalacia (BFR/BS range 0.009-0.099) and had greater bone aluminum (Al.S/OS 35.3 +/- 26.7% vs 7.2 +/- 9.0%) than the normal Mlt group (p < .01). The group with moderately prolonged Mlt included two patients with aplastic bone disease (Mlt 80.0 and 84.6 days, and Al.S/OS 100.0 and 72.3%) and 11 patients with features of hyperparathyroidism and osteomalacia (BFR/BS range 0.068-0.243) with variable but generally intermediate bone aluminum deposition (Al.S/OS 22.5 +/- 19.9%). Like BFR/BS and other dynamic parameters Mlt correlates with morphologic types of ROD which primarily reflect bone turnover, but it may also suggest varying degrees of mineralization impairment in a spectrum ranging from high to low turnover types of ROD. Its usefulness in this respect should not be overlooked.

Blood rheology and 2,3-diphosphoglycerate levels after erythropoietin treatment.

Twenty-seven transfusion dependent patients with end-stage renal disease on long-term dialysis had blood cell counts, serum chemistries, blood pressure, and whole blood viscosity measured, as well as having transfusion requirements assessed. Three months after the institution of recombinant human erythropoietin (rHU-EPO) (75 u per kg per wk), there was an 88 percent fall in transfusion requirement. After four months, the hematocrit increased from 24 +/- 3.8 to 25.6 +/- 4.2 percent, mean corpuscular volume from 93 +/- 4.9 to 97 +/- 6.6 fl, 2-3-diphosphoglycerate (2,3-DPG) from 13.2 +/- 3.2 to 15.6 +/- 4.3 microM per g of Hb. Whole blood viscosity fell from 14.1 +/- 2.1 to 12.7 +/- 2.3 seconds, and ferritin levels fell from 3282 +/- 3889 to 2131 +/- 2441 ng per ml. In eight patients in whom the dose of rHU-EPO was further increased by up to 50 units per kg three times weekly for three months, the hematocrit rose further to 29.3 +/- 3.0 percent and the rise in hematocrit was accompanied by a further increase in 2,3-DPG to 17.9 +/- 2.8 microM per g of Hb (p < 0.03). There were no major side effects or vascular complications.

Renal osteodystrophy and dialysis artifacts as indicators of identification.

Evidence of rare disease may be useful in the identification of unknown remains. Osteodystrophy is a condition commonly associated with chronic renal failure. The presence of renal osteodystrophy and medical artifacts associated with the treatment of kidney failure in human remains may provide information about the individual's medical history. Currently, there are more than 100,000 patients with end stage renal disease in the United States receiving dialysis treatments to replace kidney function, and hundreds of thousands more who have significant chronic kidney failure and are not yet treated with dialysis. Chronic renal failure frequently leads to disorders in the metabolism of vitamin D, calcium, and parathyroid hormone which are extremely difficult to correct. At least three patterns of skeletal change may result: osteitis fibrosa, characterized by increased bone remodelling, increased osteoclastic activity, peritrabecular fibrosis, and a normal mineralization pattern; osteomalacia, with a markedly increased osteoid surface and volume, and impaired mineralization; and mixed osteodystrophy, with increased bone remodelling and moderately impaired mineralization. While these bone changes may not have any clinical manifestations in most patients, they can been seen radiographically and histologically. This evidence may be useful in identifying remains which have been skeletonized, burned, decomposed, or dismembered. Medical artifacts associated with dialysis treatment, such as catheters, polytetrafluoroethylene grafts, and evidence of surgical procedures, are also useful for identification.