Unanticipated favorable effects of correcting iron deficiency in chronic hemodialysis patients.

BACKGROUND: Correction of anemia in hemodialysis patients is seldom completely attained, and the response of parameters other than hemoglobin concentration to anemia correction has not been evaluated in detail. METHODS: Laboratory parameters that suggest iron deficiency occurred in 10-15% of 206 recombinant human erythropoietin (rhEPO)-treated patients. Oral iron was given for 9 months and intravenous iron thereafter on a patient-specific basis when iron deficiency was evident. Eighty-seven hemodialysis patients with data for 12 months were followed for another 12 months. A computerized information system enabled data management and analysis. RESULTS: With oral iron, serum ferritin decreased (P < 0.001), indicating further iron depletion. With intravenous iron, hemoglobin increased, evidence of iron deficiency decreased, and less rhEPO was needed. Striking macrocytosis appeared. Serum albumin and serum creatinine/kg body weight (an index of muscle mass) increased, while blood pressure decreased. Data were reanalyzed in four mean corpuscular volume (MCV) quartiles and two ferritin subsets at study onset. Iron deficient erythropoiesis (low MCV, mean corpuscular hemoglobin [MCH], and transferrin saturation) was striking in quartile 1; low ferritin was prevalent in all quartiles. With intravenous iron, hemoglobin increased only in quartile 1, the quartile with the greatest decrease (52%) in rhEPO dose. MCV increased in all quartiles (P < 0.001). Serum albumin increased in all MCV quartiles and both ferritin subsets, but significant creatinine/kg increase and blood pressure decrease occurred only in the low-ferritin subset. CONCLUSIONS: Macrocytosis occurred with intravenous iron replacement. The universal MCV increase suggests unrecognized, inadequately treated, folic acid deficiency unmasked by an adequate iron supply. There was also improved well being. Effects were most clearly evident in patients with deficient iron stores.

Glomerular thrombosis predicts progression of glomerulonephritis: can we prevent progression?

The evidence for the important role of coagulation in the genesis and perpetuation of glomerular injury in diffuse proliferative lupus glomerulonephritis is reviewed. The importance of early detection is emphasized, so that treatment can be started before irreversible glomerular injury has occurred. Urinalysis and simple tests of renal function are effective means of early detection.

Pancreatitis in patients with end-stage renal disease.

In a population of 716 patients with end-stage renal disease (ESRD), 46 patients (6.4%) were identified as having pancreatitis. Pancreatitis was significantly more common in those with alcohol abuse, systemic lupus erythematosus (SLE), and polycystic kidney disease. It was not significantly associated with hyperlipidemia, biliary tract disease, or hypercalcemia. Acute pancreatitis occurring before the patient developed ESRD was mainly alcohol-related and did not appear to be a significant risk factor for future episodes of pancreatitis during dialysis. Chronic calcific pancreatitis diagnosed before ESRD was almost invariably due to alcohol abuse, and tended to be a marker for recurrent acute exacerbation after development of ESRD, whether alcohol consumption continued or not. Pancreatitis occurring for the first time after ESRD in patients on dialysis was generally benign, and was usually accompanied by an uneventful recovery and few recurrent episodes. However, a significant elevation of the calcium x phosphate product was observed in these patients, occurring in about half the patients without any known precipitating factor. After kidney transplantation, the development of pancreatitis was associated with higher morbidity and mortality. Chronic calcific pancreatitis diagnosed after ESRD occurred only in patients with SLE; reported here for the first time, it may be a manifestation of long-standing disease, chronic steroid therapy, or both.

A case study of a recent decline in the dialysis fatality rate.

Geoffrey Berlyne, whom we honor in this Festschrift, has contributed much to the modern understanding of diseases of the kidney, and of the clinical and metabolic disorders that occur in acute and chronic renal failure. The Festschrift highlights the many areas of his contributions. It is important to note that underlying them all is astute clinical observation, incisive analysis and reasoning, a breadth of approach, experimentation that facilitated understanding of the relevant clinical issues, and an unusual clarity of exposition in the literature. As author, editor, and teacher, Geoffrey Berlyne has brought this clarity of approach to a generation in nephrology. The following analysis of clinical data from a working dialysis unit, rendering care to a predominantly underprivileged patient population, is presented in the hope that it throws light on everyday problems in nephrology in a manner similar to that in which Geoffrey has guided the nephrology community.

Continuous quality improvement in chronic disease: a computerized medical record enables description of a severity index to evaluate outcomes in end-stage renal disease.

We have previously derived an index, based on retrospective data, for mortality in patients with end-stage renal disease (ESRD) treated by dialysis and transplantation. We used this index to calculate probability of death and rates of hospitalization, two measures of severity of illness, for 436 patients enrolled in our ESRD program after the original index was derived. Applied when ESRD treatment was initiated, it predicted future mortality and hospitalization rates. We then analyzed clinical characteristics, including variables in the predictive model, in all 718 patients enrolled in 3-year cohorts from 1976 to 1989. Over time, there was trend toward enrolling patients with a higher likelihood of dying, ie, more severely ill. The severity index facilitated description of the patients and their changing characteristics over time, and proved useful in comparing the degree of illness in different population groups.

Diffuse proliferative lupus nephritis: long-term observations in patients treated with ancrod.

Twenty-two patients with histologically demonstrated diffuse proliferative lupus nephritis (DPLN) and glomerular thrombosis received a 14-day course of ancrod, followed in most by nitrogen mustard (mechlorethamine hydrochloride) 0.4 mg/kg. Many were referred when renal function was deteriorating despite large doses of prednisone. The patients had severe disease; there was a high degree of glomerular sclerosis; the median serum creatinine was 137 mumol/l, the diastolic blood pressure 101 mm Hg. Reported previously was a short-term improvement in renal function, blood pressure, and renal histology. Reported here is the long-term follow-up on all 22 patients for an average of 58 months. Three died of causes other than renal failure. Eleven developed end-stage renal disease an average of 27 months after ancrod treatment. The other 8 are alive with no deterioration of renal function after an average of 70 months. This outcome seems satisfactory when disease severity is taken into consideration. Factors present at treatment start that might be associated with subsequent renal function deterioration were: prior prolonged prednisone treatment, extensive glomerular sclerosis, high plasma alpha 2-antiplasmin and possibly triglycerides. During the follow-up period after completion of treatment, later relapses of SLE and DPLN appeared to be an important predictor of deterioration of renal function.

Anthropometric norms for the dialysis population.

Although norms are available for healthy subjects, it is preferable, when interpreting anthropometry in individual dialysis patients, to compare measurements with norms for the stable dialysis population. The purpose of this study was to develop these reference anthropometric norms for dialysis patients. Triceps skinfold (TSF), subscapular skinfold (SSF), and mid-upper arm circumference (MUAC) measurements were made in 925 patients with no major illness, who were being treated by chronic maintenance dialysis in 27 dialysis facilities. Of these, 609 patients treated by hemodialysis (HD) were in subgroups large enough to compare with those from the National Health and Nutrition Examination Survey (NHANES) II. Diabetic patients were significantly different from nondiabetic patients; therefore, the two groups were analyzed separately. Male HD patients (diabetic and nondiabetic) did not differ significantly from the NHANES II data. Diabetic HD females did not differ significantly from the NHANES II data, except for the TSF of black women older than 55 years. Measurements of nondiabetic HD females (black and white) were significantly below the NHANES II data. In 138 continuous ambulatory peritoneal dialysis (CAPD) patients, measurements were similar to those of HD patients.

Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus.

An increased risk of end-stage renal disease (ESRD) among blacks has been previously shown for most causes of chronic renal failure, including diabetes. Most previous studies have not considered the higher prevalence of diabetes in the black population and have not analyzed relative risk by type of diabetes. We found that the incidence of ESRD among blacks with diabetes was 3.6 times the rate in whites with diabetes. The relative risk for blacks increases progressively with age, reaching a maximum of 6.9 in persons over the age of 65. The incidence of ESRD due to diabetes is higher in the population with type I diabetes (492 per 100,000) than in the population with type II diabetes (71 per 100,000). Blacks have a higher incidence of ESRD in both type I diabetes (odds ratio, 2.96; 95% confidence interval, 1.8 to 4.9) and type II diabetes (odds ratio, 4.9; 95% confidence interval, 3.6 to 6.5). The incidence of ESRD in patients with diabetes varies with age, race, and type of diabetes.

Ancrod causes rapid thrombolysis in patients with acute stroke.

Clot lysis is desirable in patients with thrombi in arteries and arterioles by a safe rapidly-acting thrombolytic agent. Ancrod cleaves fibrinogen; the resulting circulating ancrod-fibrin stimulates fibrinolysis. Ancrod action and effect were studied in 20 patients with acute developing stroke in a double-blind, placebo-controlled study. Patients were randomly assigned to one of two treatment groups, and received either normal saline or ancrod 0.5 mu/kg in normal saline administered as a constant-rate intravenous infusion over 6 hours. Subsequent doses of ancrod (or saline placebo) were determined daily thereafter for a total treatment period of 7 days. Neither bleeding nor re-thrombosis occurred within the 90 day follow-up period. That ancrod acted rapidly was shown by a significant decrease in functional plasminogen activator inhibitor (PA-I) within 60 minutes, and by significant elevations of fibrin(ogen) degradation products (FDP) and D-dimer within 3 and 4 hours. The biological effect of fibrinolysis in ancrod infused patients was demonstrated by a greater improvement in stroke score when compared to those infused with saline.

Beta 2-microglobulin kinetics in maintenance hemodialysis: a comparison of conventional and high-flux dialyzers and the effects of dialyzer reuse.

beta 2-Microglobulin (beta 2M) forms synovial and bony amyloid deposits in long-term hemodialysis patients. To define the kinetics of beta 2M during hemodialysis and the effects of dialyzer reprocessing, we measured serum beta 2M, plasma C3a, and neutrophil counts immediately predialysis; 15, 90, and 180 minutes after beginning dialysis; and 15 minutes postdialysis in ten chronic hemodialysis patients. The studies were performed during first and third uses of cuprammonium rayon and polysulfone dialyzers processed by rinsing with water, then bleach, in an automated system (Seratronics DRS 4) and then packed in 1.5% formaldehyde. Mean serum beta 2M (corrected for ultrafiltration) decreased by 16.6% +/- 18.1% with new cuprammonium dialyzers and 57.1% +/- 12.8% with new polysulfone dialyzers. Dialyzer reprocessing had no significant effect on this decline. Predialysis serum beta 2M decreased by 30.4% +/- 15.5% 1 month after switching from cuprammonium to polysulfone dialyzers; these levels remained stable after 3 months of dialysis with polysulfone. Complement activation and neutropenia during dialysis were significantly more marked with cuprammonium, but were not affected by reprocessing of either dialyzer. In vitro adsorption of 124I-beta 2M to polysulfone fibers was greater than to cuprammonium; adsorption was not influenced by dialyzer reprocessing.

Glomerular eicosanoid production in acute serum sickness nephritis.

To determine if the induction of immune-mediated glomerular injury influences the formation of glomerular cyclooxygenase products, we measured thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) production by isolated glomeruli of rabbits induced with acute serum sickness nephritis by the administration of bovine serum ablumin (BSA). Animals were randomly assigned to one of three experimental groups: animals injected with BSA (BSA group; n = 11); animals injected with normal saline (control group; n = 11); and animals injected with BSA which were treated with the thromboxane synthetase inhibitor, OKY-046 (BSA + OKY-046; n = 6). Animals in the BSA and BSA + OKY groups developed severe proteinuria and glomerular histologic lesions of nephritis. No differences in proteinuria, serum creatinine and severity of histologic nephritis were observed between the two groups. Examination of glomerular eicosanoid production at the end of the experiment showed a marked reduction of glomerular PGE2 and 6-keto-PGF1 alpha production with a smaller reduction of glomerular TXB2 production in the BSA group. In the BSA + OKY-046 group, the production of TXB2 was significantly less than that in the BSA group; despite this, no effect on proteinuria could be discerned.

A diet containing n-3 and n-6 fatty acids favorably alters the renal phospholipids, eicosanoid synthesis and plasma lipids in nephrotic rats.

The nephrotic syndrome was induced in rats by intravenous adriamycin (3 mg/kg). The rats were then divided into four groups which, for six weeks, were pair-fed diets containing beef tallow (BT), fish oil (FO), a source of n-3 fatty acids, evening primrose oil (EPO), a source of n-6 fatty acids, or a combination of evening primrose oil and fish oil, 75:25 (EPO:FO). The fat content of the diets was 15%. Significant incorporation of the fatty acids into kidney phospholipids was demonstrated. Diets containing FO, EPO and EPO:FO lowered plasma triglycerides and total cholesterol levels as compared with diets containing BT. Only EPO:FO raised high density lipoprotein (HDL) cholesterol levels, as compared with BT. The combination EPO:FO prevented the tenfold suppression of aortic 6-keto-PGF1 alpha caused by FO. These changes in plasma lipids and eicosanoid production are potentially antiatherogenic and may prevent glomerular sclerosis. The combination of EPO and FO, containing n-6 and n-3 fatty acids may offer advantages over either family of fatty acids in this model of nephrotic syndrome.

Use of ancrod in acute or progressing ischemic cerebral infarction.

Ancrod has been used in Europe for over 15 years for peripheral vascular disease, deep vein thrombosis, and central retinal venous thrombosis, and in patients at risk for thromboembolism. In a double-blind, randomized, placebo-controlled study at University Hospitals in Cincinnati, 20 acute cerebral infarction patients received a series of IV infusions of ancrod (ten) or placebo (ten) for seven days. Early fibrinolysis with a small decrease in fibrinogen was observed, and d-dimers were elevated at four hours, indicating early clot lysis. At three months, patients with moderate to severe strokes (less than 40 on the Scandinavian Stroke Scale) in the ancrod group showed average improvement by a factor of 3 over the placebo group. No bleeding, abnormal laboratory results, or deaths occurred, but ancrod was discontinued in one patient who had seizures. As a result of this study, a double-blind multicenter international clinical trial to further assess the safety and effectiveness of ancrod is being planned.

Fibrinolysis in glomerulonephritis treated with ancrod: renal functional, immunologic and histopathologic effects.

The effects of a 14-day course of ancrod on fibrinolysis, renal function and structure, and immunologic findings are reported in 37 patients with glomerulonephritis. Patients were divided into two groups. In the first, the level of fibrin degradation products within 48 h was relatively low (less than 1 mg/ml). In these patients there was a linear relationship between changes in levels of fibrin degradation products and fibrinogen, suggesting that fibrin degradation products derived from ancrod-cleaved-fibrinogen in the circulating pool; in most, level of plasma alpha 2-antiplasmin before treatment was elevated. In the second, the level of fibrin degradation products within 48 h was high (greater than 1 mg/ml). Compared with the change in fibrinogen, a disproportionate increase in levels of fibrin degradation products suggested that a significant amount derived from sources other than plasmin digested ancrod-cleaved-fibrinogen, thus reflecting effective fibrinolysis, perhaps also in tissues; in most, the level of plasma alpha 2-antiplasmin was normal before treatment. In those with initial high levels of fibrin degradation products, higher levels persisted throughout treatment, changes in other fibrinolysis components were greater, and plasminogen activator inhibitor levels became normal. In patients with initial high but not with initial low response in fibrin degradation products renal function improved within 24 to 48 h and continued to improve thereafter; there was an immediate but temporary increase in proteinuria. Microvascular thrombosis decreased significantly, indicating effective removal of fibrin from glomeruli. The relation of early fibrinolysis to changes in immunologic and histopathologic findings was analyzed in patients with lupus nephritis. With ancrod, there was an increase toward normal of serum C3 and C4, a decrease in serum Igs, gamma globulin and anti-dsDNA antibody and in glomerular C3 and Ig deposits, suggesting that ancrod had favorable effects on immunologic factors. There were no clinical differences in patients with initial high and low responses, but the relationship of microvascular and inflammatory indexes before treatment differed. Initial renal biopsies and those after treatment were carried out on average 28 days apart. Inflammatory and microvascular indexes and glomerular thrombi decreased in patients with initial high levels of fibrin degradation products; fibrosclerosis index and glomerular sclerosis increased in patients with initial low levels of fibrin degradation products. Fibrinolysis expressed as the 48 h (fibrin degradation products/fibrinogen) ratio, correlated inversely with change in fibrosclerosis index and glomerular sclerosis in the whole group, and especially in those with initial high levels of fibrin degradation products.(ABSTRACT TRUNCATED AT 400 WORDS)