Showing papers in "Journal of The American Society of Nephrology in 1996"

Hemodialysis vascular access morbidity.

Abstract: Complications associated with hemodialysis vascular access represent one of the most important sources of morbidity among ESRD patients in the United States today. In this study, new data on the magnitude and growth of vascular access-related hospitalization in the United States is presented, demonstrating that the costs of this morbidity will soon exceed $1 billion per yr. This study also reviews published literature on the morbidity associated specifically with native arteriovenous fistulae, polytetrafluoroethylene bridge grafts, and permanent central venous catheters. Next, new information on the changing patterns of vascular access type in the United States is presented, demonstrating the continuing evolution of medical practice away from the use of arteriovenous fistulae in favor of more reliance on synthetic bridge grafts. Based on these data, a discussion is provided of the tradeoffs among the most commonly available modalities of vascular access today. Although radial arteriovenous fistulae continue to represent the optimal access modality, the appropriate roles for brachial arteriovenous fistulae, synthetic bridge grafts, and central venous catheters are less certain because of inadequate data on the long-term function of the first and the high rates of complications associated with the latter two. To reduce vascular access-related morbidity, strategies must be developed not only to prevent and detect appropriately early synthetic vascular access dysfunction, but to better identify the patients in a whom radial arteriovenous fistula is a viable clinical option.

Cardiovascular disease after renal transplantation.

Abstract: Although cardiovascular disease is a major cause of morbidity and mortality after renal transplantation, its pathogenesis and treatment are poorly understood. We conducted separate analyses of risk factors for ischemic heart disease, cerebral, and peripheral vascular disease after 706 renal transplants, all of which functioned for at least 6 months. We used Cox proportional hazards analysis to examine the effects of multiple pretransplant and posttransplant risk factors and included time-dependent variables measured at 3, 6, and 12 months, and annually to last follow-up at 7.0 +/- 4.2 yr. The independent relative risk (RR) of diabetes was 3.25 for ischemic heart disease, 3.21 for cerebral vascular disease, and 28.18 peripheral vascular disease (P

Molecular insights into renal interstitial fibrosis.

Abstract: Progressive interstitial fibrosis accompanied by loss of renal tubules and interstitial capillaries typifies all progressive renal diseases. Dynamic and complex, the process evidently overlaps with matrix remodeling; it may even be reversible. The interstitial fibrous tissue comprises several normal and novel matrix proteins, proteoglycans, and glycoproteins. Interstitial myofibroblasts are a major site of matrix protein overproduction, although resident fibroblasts, tubular cells, and inflammatory cells may contribute. Inadequate matrix degradation also appears to contribute to the fibrogenic process. Two protease cascades, the metalloproteinases and the plasminogen activator/ plasmin family of serine proteases, are implicated in the turnover of interstitial matrix proteins; upregulated expression of protease inhibitors has been observed in each. Increased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 levels suggest that the intrinsic renal activity of the metalloproteinases and serine proteases are inhibited while matrix proteins accumulate in the interstitium. Several signals that may direct the interstitial fibrogenic process have been identified, but not yet proved to cause it. Upregulated expression of transforming growth factor beta-1, the proteotypic fibrogenic cytokine, has been observed in experimental and human models; it probably does not act alone. There may be supportive roles for platelet-derived growth factor, interleukin-1, basic fibroblast growth factor, angiotensin II, and endothelin-1. Although it is not known why interstitial fibrosis compromises renal function, atrophy of renal tubules may be pivotal. Ischemic necrosis and/or apoptosis may generate nonfunctioning atubular and sclerotic glomeruli. Future studies must delineate the molecular basis of the differences between renal repair and renal destruction by fibrosis, two processes that share many common features.

Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease

Abstract: A cohort of 432 ESRD (261 hemodialysis and 171 peritoneal dialysis) patients was followed up prospectively for an average of 41 months. Baseline and annual demographic, clinical, and echocardiographic assessments were performed, as well as serial clinical and laboratory tests measured monthly while patients were on dialysis therapy. Among hemodialysis patients, after adjustment was made for age, diabetes, and ischemic heart disease, as well as hemoglobin and blood pressure levels measured serially, a 10-g/L fall in mean serum albumin level was independently associated with the the development of de novo (relative risk [RR], 2.22; P = 0.001) and recurrent cardiac failure (RR, 3.84; P = 0.003), de novo (RR, 5.29; P = 0.001) and recurrent ischemic heart disease (RR, 4.24; P = 0.005), cardiac mortality (RR, 5.60; P = 0.001), and overall mortality (RR, 4.33; P < 0.001). Among peritoneal dialysis patients, a 10-g/L fall in mean serum albumin level was independently associated with the progression of left ventricular dilation as seen on follow-up echocardiography (beta, 13.4 mL/m2; P = 0.014), the development of de novo cardiac failure (RR, 4.16; P = 0.003), and overall mortality (RR, 2.06; P < 0.001). Hypoalbuminemia, a major adverse prognostic factor in dialysis patients, is strongly associated with cardiac disease.

Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.

Abstract: The purpose of this study was to determine the prognostic value of clinical, laboratory, and pathologic features at the time of presentation on patient and renal survival in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated microscopic polyangiitis and glomerulonephritis (excluding Wegener's granulomatosis). One hundred seven ANCA-positive patients with necrotizing and crescentic glomerulonephritis, including 69 with evidence for microscopic polyangiitis, were evaluated for this study. The relative risk of death was calculated for the following potential prognostic indicators: (1) ANCA pattern; (2) pulmonary hemorrhage at onset; (3) presence of extrarenal manifestations versus renal limited disease; and (4) treatment with corticosteroids and cyclophosphamide (intravenous or oral), compared with corticosteroids alone. Cox's proportional hazard model was used to assess the predictive value of the following variables on renal survival: (1) age; (2) race; (3) pulmonary symptoms at onset of disease; (4) renal pathology; (5) ANCA pattern; and (6) peak serum creatinine values obtained near the time of renal biopsy. Patients were followed prospectively for 2.5 yr (range, 5 days to 12 yr 2 months). There were 12 disease-related deaths and 46 patients who reached ESRD. The relative risk (and 95% confidence interval) of patient death was 8.65 (3.36, 22.2) times greater in patients who presented with pulmonary hemorrhage, and 3.78 (1.22, 11.70) times greater in patients with cytoplasmic ANCA compared to those with perinuclear ANCA. The relative risk of pulmonary hemorrhage was no different by ANCA pattern. The risk of death was 5.56 times lower in the cyclophosphamide-treated patients versus those treated with corticosteroids alone. The predictors of renal survival were entry serum creatinine value (P = 0.0002), race (African Americans having a worse outcome compared with Caucasians, P = 0.0008), and the presence of arterial sclerosis on kidney biopsy (P = 0.0076) when controlling for age, ANCA pattern, microscopic polyangiitis versus glomerulonephritis alone, and pulmonary involvement. Pathology indices such as glomerular necrosis, glomerular crescents, glomerular sclerosis, and interstitial sclerosis were not predictive of renal survival when controlling for entry serum creatinine value, race, and arterial sclerosis. However, in the subgroup of patients with a peak creatinine value of < or = 3.0 mg/dL (N = 29), increased interstitial sclerosis was a predictor of a poor renal outcome (P = 0.04).

Aging and the kidney.

Abstract: A host of abnormalities of renal structure and function accompanies advancing age. An appreciation of methodologic considerations, including population selection, that might confound the assessment of the effects of aging on renal function has prompted a recent reappraisal. Earlier studies assessed the effects of aging by utilizing cross-sectional studies and institutionalized elderly subjects, with their attendant drawbacks. Recent longitudinal studies have utilized appropriate patient cohorts, selected for lock of renal disease, including potential kidney transplant donors. These studies indicate that the morphological and functional changes of aging tend to be less marked than previously thought. The common denominator of these functional changes is a diminution in renal reserve, along with constraints on the kidney's ability to respond appropriately to challenges of either excesses or deficits. Although these alterations are unlikely to be of major clinical consequence under everyday conditions, they attain clinical significance when residual renal function is challenged by the superimposition of an acute illness. Finally, it should be emphasized that elderly patients frequently suffer from comorbid conditions, such as hypertension and heart disease, that may be additive to the changes of aging, thereby amplifying these abnormalities.

Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio.

Abstract: The objective of this study was to determine the prevalence of stages of diabetic nephropathy, defined by the albumin/creatinine ratio (AC ratio) in repeated measurements in random urine samples. Over a 30-month interval, 1613 patients with Type I diabetes (IDDM) (aged 15 to 44 yr, IDDM duration 1 to 39 yr), and 218 healthy control subjects provided multiple urine specimens. AC ratios measured in urine samples taken 5 months apart were highly reproducible (Spearman r = 0.83). A criterion for the boundary between normoalbuminuria and microalbuminuria was obtained by searching for a cutpoint that optimized agreement between serial specimens on individuals. The result was lower in men than women: 17 as compared with 25 micrograms/mg. These two values corresponded to the 95th percentiles of the respective distributions of the AC ratio in healthy control subjects. Also these sex-specific cutpoints, when converted to albumin excretion rates, became almost equal: 30 and 31 micrograms/min. Microalbuminuria appeared early in the course of IDDM (6% of those with only 1 to 3 yr of diabetes) and then increased rapidly during two intervals, the first and third decades, before leveling off at 52%. By that time the cumulative risk of overt proteinuria had risen to 27%. Determinations of the AC ratio in random urine samples are easily obtained and are reliable indices of elevated urinary albumin excretion (microalbuminuria) in IDDM. The pattern of occurrence of microalbuminuria according to duration of IDDM suggests that there may be two subsets of diabetic nephropathy, one appearing early and the other late. Patients with microalbuminuria and 25 yr of postpubertal IDDM have low risk of progression to advanced diabetic nephropathy.

Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.

Abstract: In this study, the rate of remission, relapse, and treatment resistance in 107 patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies were assessed. Patients with Wegener's granulomatosis were excluded. Prospective criteria were identified to assess remission, relapse, and resistant disease. Ninety-seven of the 107 patients received treatment with corticosteroids (N = 25) or with cyclophosphamide and corticosteroids (N = 72). Of these patients, 75 (77.3%) went into remission (complete remission, N = 61; remission on therapy, N = 14). Of the 75 responders, 32 patients (43%) remained in long-term remission, for a mean follow-up of 44 +/- 29 months; 15 patients (20%) progressed to ESRD without signs of relapse, for a mean of 21.4 +/- 22.8 months after the end of treatment; 6 patients died. Twenty-two of the 75 patients who initially responded to treatment (29%) suffered a relapse that occurred within 18 months of the end of therapy and usually affected the same organ systems as on initial presentation. There was a significant difference in the remission rate between the corticosteroid-treated patients and the cyclophosphamide-treated patients (56% versus 84.7%, P = 0.003), and the cyclophosphamide-treated patients had three times less risk of experiencing a relapse than did corticosteroid-treated patients (0.31, 95% Cl = (0.12, 0.84)). Seventy-seven percent (17 of 22 patients) of treatment resistance occurred in patients who presented with fulminant disease or advanced and severe renal disease. It was concluded that most patients with microscopic polyangiitis or necrotizing and crescentic glomerulonephritis achieve remission with therapy. Relapses occur in 29% of patients and generally respond to retreatment. Initial treatment with cyclophosphamide and corticosteroids rather than corticosteroids alone results in a lower frequency of relapse. Even patients who require dialysis at presentation may benefit from treatment, however, patients who are not treated until the disease process is life-threatening may die before induction therapy is complete, indicating the continued need for early diagnosis and therapy.

Peritonitis influences mortality in peritoneal dialysis patients.

Abstract: Mortality remains high in peritoneal dialysis (PD) patients. Known risk factors for mortality include age, diabetes, race, initial albumin level, and cardiovascular disease. Peritonitis is reported to cause death in 1 to 6% of PD patients but has not been well studied as a risk factor for mortality. This study examined 516 adults with a total of 896 yr on PD at one center to determine if peritonitis influenced mortality. Time at risk began on Day 1 of training and ended at death, transplant, or 60 days after transfer to hemodialysis or intermittent peritoneal dialysis. The overall mortality rate was 17.4/100 patient yr. Survival was lower for whites, men, diabetic patients, and older patients. Independent risk factors for mortality (by Cox proportional hazards) were race, diabetes, increased age, and increased peritonitis rate. Use of the Y-set was not associated with decreased mortality. Peritonitis was a risk factor only in whites, nondiabetic patients, and those patients over the age of 60. For every 0.5/yr increase in the peritonitis rate, the risk of death increased 10% in whites, 11% in those patients who were over the age of 60, and 4% for nondiabetic patients. Mortality rates did not decrease over time (1979 to 1995), although peritonitis rates fell significantly (P < 0.001). Rates of Gram-negative and fungal peritonitis showed no trend over time. Peritonitis contributed to 25 of 158 (15.8%) of deaths. Gram-negative/fungal peritonitis accounted for 14 deaths (9.5% of all Gram-negative/fungal episodes) whereas Staphylococcus epidermidis accounted for only 1 death (0.5% of all S. epidermidis episodes) (P < 0.001). Cardiovascular disease was more common in those patients whose deaths were unrelated to peritonitis (P < 0.01), whereas an infectious cause was more common in those patients whose deaths were peritonitis-related (P < 0.001). In this study, peritonitis was a risk factor for death in whites, nondiabetic patients, and older patients. However, the Y-set did not improve survival, perhaps because it does not decrease Gram-negative/fungal peritonitis. To have an impact on survival, efforts are needed to reduce the peritonitis that results from these more serious pathogens.

Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients.

Abstract: Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients. Plasma bone-specific alkaline phosphatase (bAP) has been demonstrated to be more reliable than total alkaline phosphatases (tAP) in providing information about bone turnover in patients with metabolic bone diseases. This study surveyed 42 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Plasma bAP was determined by using a new immunoassay (Tandem-R Ostase, Hybritech, Liege, Belgium). Plasma bAP values were compared with those of two other plasma markers of bone metabolism, namely tAP and intact parathyroid hormone (iPTH), for the correlations with bone histomorphometric parameters. Patients with high-turnover bone disease (HTBD) (N = 32) had significantly higher plasma bAP levels than patients with normal or low bone turnover (N/LTBD) (N = 10) (66.9 +/- 63.5 ng/mL versus 10.8 +/- 4.2 ng/mL, respectively). Bone formation and resorption were highly correlated in these patients, and plasma bAP levels were positively correlated with bone resorption parameters, including osteoclast surface (r = 0.39, P

Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: renal implications in the pathophysiology of pentosidine.

Abstract: Pentosidine is an advanced glycation end product and its formation is shown to be closely related to oxidative processes. Recent studies have shown that pentosidine levels are increased not only in plasma and matrix proteins from diabetic patients, but also markedly in nondiabetic hemodialysis patients. Currently, the mechanism of accumulation and kinetics of pentosidine formation in hemodialysis patients remain unknown. Gel filtration of uremic plasma revealed that plasma pentosidine exists in the albumin fraction (approximately 90%) and, interestingly, in free form (approximately 5%) as well. Plasma free pentosidine was undetectable in subjects with normal renal function. There was a significant correlation between the plasma levels of albumin-linked and free pentosidine in hemodialysis patients. Kinetic studies indicated that dietary pentosidine was absorbed into the circulation and that, after either oral or intravenous administration of pentosidine to intact or nephrectomized rats, the plasma free pentosidine level was closely linked to the level of renal function. These findings demonstrate that: (1) Pentosidine accumulates as albumin-linked and in free form in the circulation of uremic patients; (2) dietary pentosidine can be absorbed into the circulation, thus being one possible origin of circulating free pentosidine; (3) free pentosidine may accumulate as a result of decreased glomerular filtration; and (4) the mechanism of accumulation of albumin-linked pentosidine is not related to high glucose levels. It suggests the simultaneous accumulation, during renal failure, of either unknown pentosidine precursor(s) or catalyst(s) of glycoxidation, independent of glucose.

Calciphylaxis in chronic renal failure.

Abstract: Calciphylaxis is a rare and life-threatening complication that is estimated to occur in 1% of patients with ESRD each year. Typically, extensive microvascular calcification and occlusion/thrombosis leads to violaceous skin lesions, which progress to nonhealing ulcers and sepsis. Secondary infection of skin lesions is common, often leading to sepsis and death. The lower extremities are predominantly involved (roughly 90% of patients). Patients with skin involvement over the trunk or proximal extremities have a poorer prognosis. Although most calciphylaxis patients have abnormalities of the calcium:phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder, and the etiology of calciphylaxis remains unclear. Recently, functional protein C deficiency has been hypothesized to cause a hypercoagulable state that could induce thrombosis in small vessels, with resulting skin ischemia, necrosis, and gangrene. The lack of understanding of the pathophysiology of the disease results in treatments that are equally unsatisfactory. Patients who undergo parathyroidectomy have a tendency to improve, but the prognosis for the disease is poor and mortality remains high.

The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients.

Abstract: As a component of the open-label, multicenter National Cooperative Recombinant Human Erythropoietin (Epo) Study, the health-related quality-of-life effects of Epo therapy were assessed in 484 dialysis patients who had not previously been treated with Epo therapy (New-to-Epo) and 520 dialysis patients who were already receiving Epo therapy at the time of study enrollment (Old-to-Epo). Using scales from the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), health-related quality of life was assessed on study enrollment (baseline) and at an average of 99 days follow-up. At baseline, SF-36 scores for Old- and New-to-Epo patients were well below those observed in the general population, reflecting substantial impairments in functional status and well-being among patients with chronic renal failure. Significant improvements from baseline to follow-up were observed among New-to-Epo patients in vitality, physical functioning, social functioning, mental health, looking after the home, social life, hobbies, and satisfaction with sexual activity (P < 0.05 for each). The mean improvements in hematocrit values among New-to-Epo and Old-to Epo patients were 4.6 and 0.3, respectively. At the time of follow-up, SF-36 scores for New-to-Epo patients were comparable with those observed among Old-to-Epo patients, whose scores did not change significantly from baseline to follow-up. Analysis of the relationship between Epo therapy, hematocrit values, and health-related quality of life suggest that some of the beneficial quality-of-life effects of Epo are mediated through a change in hematocrit level.

Actions of epoxygenase metabolites on the preglomerular vasculature.

Abstract: Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow. This study examined the preglomerular actions of various epoxyeicosatrienoic acids (EET). By use of the in vitro blood-perfused juxtamedullary nephron preparation, interlobular and afferent arteriolar diameter responses to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diameters of interlobular and afferent arterioles preconstricted with 0.5 microM norepinephrine averaged 24 +/- 1 microns (N = 27) and 17 +/- 1 microns (N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diameters of the interlobular and afferent arterioles. At a dose of 100 nM, 11,12-EET increased the diameters of the interlobular and afferent arterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. The vasodilatory response to 11,12-EET was stereoselective because 11,12(R,S)-EET but not 11,12(S,R)-EET increased the diameters of the interlobular and afferent arterioles. 14,15-EET had a much smaller effect and increased the diameters of the these vessels by 10%; 8,9-EET did not significantly affect vascular diameters. In contrast, 5,6-EET constricted the interlobular and afferent arterioles by 16 +/- 3% (N = 6) and 21 +/- 3% (N = 7), respectively. The corresponding diols, 5,6-DIHETE and 11,12-DIHETE, had no effect on diameters of the interlobular and afferent arterioles at concentrations up to 1 microM. The vasodilatory response to 11,12-EET was not affected by removal of the endothelium or by inhibition of cyclooxygenase with indomethacin. In contrast, the vasoconstrictor response to 5,6-EET was abolished by both removal of the endothelium or cyclooxygenase inhibition. The thromboxane/ enderoperoxide receptor inhibitor, SQ 29,548, resulted in a 60% attenuation of the afferent arteriolar vasconstriction to 5,6-EET. These results indicate that the preglomerular vasoconstriction to 5,6-EET is cyclooxygenase dependent and requires an intact endothelium, whereas the vasodilation to 11,12-EET is stereoselective and is the result of direct action of the epoxide on the preglomerular vascular smooth muscle.

Measurement of residual renal function in patients treated with continuous ambulatory peritoneal dialysis.

Abstract: Renal function contributes markedly to the adequacy of continuous ambulatory peritoneal dialysis (CAPD). The best way to measure it in clinical practice has not been established. Ten stable CAPD patients with residual renal function were investigated to compare the GFR measured as inulin clearance (Cli) with the creatinine clearance (Clc), the urea clearance (Clu), and with 0.5(Clc + Clu). Thereafter, an analysis of whether the administration of cimetidine could improve the accuracy of these clearances was performed. Two clearance periods (CP) of 24 h were investigated. During CP-2, patients received 400 mg cimetidine twice daily, for a total dose of 1200 mg. Two h before the urine and dialysate collection period, inulin was administered iv. Calculations were done for each CP for Cli, Clc, Clu, Clc-Cli, the Clc/Cli ratio, and the tubular secretion of creatinine (TSc). No differences between CP-1 and CP-2 were present for urinary excretion of volume and solutes, and clearance rates of inulin and urea. The median TSc decreased from 0.71 mumol/min (range, -0.24 to 5.90) in CP-1 to 0.30 mumol/min (range, -0.18 to 0.64) in CP-2 (P < 0.05). Therefore, the median ratio of Clc/Cli decreased from 1.23 (range, 0.87 to 2.20) in CP-1 to 1.11 (range, 0.95 to 1.51) in CP-2 (P < 0.05). The median overestimation of the Cli in CP-1 by the Clc was 0.90 mL/min (range, -0.28 to 3.80) and by the 0.5(Clc + Clu) was 0.30 (range, -0.67 to 1.52). The median overestimation of Cli during cimetidine treatment in CP-2 was 0.43 mL/min (range, -0.21 to 1.20). The range, in differences between Cli and Clc, in CP-2 was smaller than that between Cli and 0.5(Clc + Clu) in CP-1. The difference between the clearance rate of inulin and creatinine or the combined clearance rate of urea and creatinine was not influenced by the magnitude of the average GFR. It can be concluded that the administration of cimetidine improved the accuracy of measuring the GFR with the Clc in CAPD patients.

Heparin use in continuous renal replacement procedures: the struggle between filter coagulation and patient hemorrhage.

Abstract: Heparin is the most widely used anticoagulant in continuous renal replacement procedures but little is known about the balance between filter coagulation and patient hemorrhage during treatment. Filter survival and hemorrhagic complications during 240 filter periods in 78 critically ill patients, treated with continuous arteriovenous hemofiltration and hemodiafiltration, were studied for this article. The crude incidence of filter coagulation was 17.7 +/- 2.5 (mean +/- SE) per 1000 h at an activated partial thromboplastin time (APTT) of 15 to 35 s, as determined in systemic blood samples. The incidence of filter coagulation gradually decreased to 9.0 +/- 2.7 per 1000 h at an APTT of 45 to 55 s (P = 0.031). The crude incidence of patient hemorrhage was 2.9 +/- 1.0 per 1000 h at an APTT of 15 to 35 s and increased almost threefold to 7.4 +/- 2.4 per 1000 h when the APTT was 45 to 55 s (P = 0.009). There was no difference in filter survival between treatment with hemofiltration only and hemodiafiltration. Mean survival of acrylonitrile filters (33.8 +/- 4.3) was significantly lower compared with the survival of polyamide filters (104.1 +/- 14.4 h, P = 0.003). After adjustment for the type of the filter, mean arterial blood pressure, and platelet count, the risk for filter coagulation decreased 25% (relative risk, 0.77; 95% confidence interval [CI], 0.62 to 0.96) for every 10-s increase in APTT. At the same time, the risk for patient hemorrhage increased 50% (relative risk, 1.57; 95% CI, 1.43 to 1.72). The occurrence of filter coagulation or hemorrhages were not correlated with the administered dose of heparin. Concurrent use of coumarin derivatives had a positive effect on filter survival, without increasing the overall incidence of hemorrhages. It was concluded that the systemic APTT is a good predictor of the risk for filter coagulation and patient hemorrhage. Safety and efficacy of heparin therapy seems optimal at an APTT between 35 and 45 s.

Early death in dialysis patients: risk factors and impact on incidence and mortality rates.

Abstract: Patients who die within the first 90 days after beginning dialysis are not included in mortality rates and may be absent from incidence counts. To identify factors associated with mortality within 3 months of the initiation of dialysis for ESRD and to estimate the impact of early deaths on ESRD incidence and mortality rates, this study investigated 15,245 patients who began dialysis in Georgia, North Carolina, and South Carolina over a 5-yr period. Data were collected by dialysis facility staff and reported to an ESRD registry. Six percent of all new patients died within 90 days of dialysis initiation (32% of all deaths occurring in the first year of treatment). Characteristics independently associated with increased risk of early death included older age, white race, male gender, physical and nutritional impairment, smoking, and the presence of cancer, congestive heart failure, clinical depression, and history of myocardial infarction. Depending on race-gender group, age-adjusted mortality rates based on this cohort were underestimated by 3 to 12% when patients who died early were excluded. These results suggest that certain patient characteristics-some potentially modifiable-confer increased risk of early death, and that the systematic exclusion of patients who die early from the U.S. national registry substantially influences ESRD mortality rates.

Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases.

Abstract: Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a potent enhancer of microvascular permeability and a selective endothelial cell growth factor. In normal human kidney, VPF/VEGF mRNA and protein are strongly expressed by visceral glomerular epithelial cells, and VPF/VEGF may be an important regulator of glomerular endothelial cell function. This study examined 47 renal biopsies from patients with a variety of glomerular diseases for expression of VPF/VEGF mRNA and protein by in situ hybridization and immunohisto-chemistry. In many glomerular diseases, VPF/VEGF-expressing cells were decreased in number or absent in areas of focal or global glomerular sclerosis. Decreased numbers of VPF/VEGF-expressing cells in glomeruli were also noted in amyloidosis, diabetes, crescentic glomerulonephritis, and diffuse endocapillary proliferative glomerulonephritis associated with systemic lupus erythematosus. Normally, release of VPF/ VEGF must be under strict control because it is some 50,000 times more potent than histamine as an inducer of microvascular permeability. Damage to visceral epithelial cells in a variety of glomerular diseases has the potential for releasing relatively large amounts of VPF/VEGF locally, leading to increased glomerular permeability. In addition, because VPF/ VEGF is also an endothelial growth factor, the loss of normal, controlled secretion of VPF/VEGF after damage to visceral epithelial cells could lead to important alterations in glomerular endothelial cell function.

Increased energy expenditure in hemodialysis patients.

Abstract: Malnutrition is prevalent in chronic hemodialysis patients and is related to multiple factors; the hemodialysis procedure itself has been suggested as a catabolic factor. To examine the possible role of hemodialysis on energy metabolism, resting energy expenditure and respiratory quotient in ten chronic hemodialysis patients was measured in this study, using a whole-room indirect calorimeter. Measurements were done continuously: for 2 h before hemodialysis, during 4 h of hemodialysis, for 2 h after hemodialysis, and separately on a nondialysis day after 12 h of fasting. Age-, sex-, and body mass index-matched healthy volunteers were used as control subjects. Chronic hemodialysis patients have a significantly higher resting energy expenditure on a nondialysis day (1.18 +/- 0.15 kcal/min; P < 0.01) as compared with control subjects (1.10 +/- 0.16 kcal/ min). Resting energy expenditure further increased significantly during the hemodialysis procedure (1.32 +/- 0.18 kcal/min, averaged over the 4 h of hemodialysis; P < 0.01 versus predialysis) and was also significantly higher compared with the postdialysis period and nondialysis day resting energy expenditure (P < 0.001 for both). This effect was most pronounced during the first (1.37 +/- 0.19 kcal/min) and second (1.33 +/- 0.18 kcal/min) hours of hemodialysis (P < 0.001 for both). Respiratory quotient was not significantly affected by hemodialysis. It was concluded that chronic hemodialysis patients have higher than normal resting energy expenditure levels, which is further increased during hemodialysis. This process may significantly potentiate the protein-calorie malnutrition seen in this patient population.

Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics.

Abstract: The normalized protein catabolic rate (PCRn) can be calculated from predialysis and postdialysis BUN measurements in patients receiving intermittent dialysis. This measure of net protein catabolism, adjusted for body size, is a useful clinical measure of nutrition that correlates with patient outcome and, in patients who are in nitrogen balance, is a reasonable estimate of dietary protein intake. Whereas simplified formulae that estimate the per-treatment dose of hemodialysis, expressed as Kt/Vurea (Kt/V), are in common use, simplified methods for determining PCRn have only recently appeared. In the study presented here, equations were derived for calculating PCRn from the predialysis BUN and Kt/V. The equations were of the general form: PCRn = C0/(a + bKt/V + c/(Kt/NLL)) + 0.168, where Co is the predialysis BUN in mg/dL. Three sets of coefficients were developed for patients dialyzed thrice weekly: one for patients dialyzed after the long interval at the beginning of the week, one for patients dialyzed at midweek, and the third for patients dialyzed at the end of the week. Two similar sets of coefficients were developed for patients dialyzed twice weekly. For patients with remaining function in the native kidney remnant, equations were developed and refined for upgrading PCRn by adjusting C0 upward. The equations were validated by comparing the calculated PCRn with PCRn determined by a formal iterative model of urea kinetics in a series of 119 dialyses in 51 patients dialyzed thrice weekly (r = 0.9952; mean absolute error, 1.97 +/- 1.39%) and in a series of 71 dialyses in 25 patients dialyzed twice weekly (r = 0.9956; mean absolute error, 2.17 +/- 1.56%). These simple yet accurate equations should be useful in epidemiologic studies or in clinical laboratories where limited data are available for each patient or when iterative computer techniques cannot be applied.

A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children.

Abstract: There is no generally accepted treatment for primary focal segmental glomerulosclerosis (FSGS). Steroids alone and steroids plus cyclophosphamide can be expected to induce a remission of the proteinuria in only 27% of patients. Probably the majority of FSGS patients will reach ESRD over the extended course of their disease. In addition to the work presented in this study, there have been many reports of the potential effectiveness of cyclosporine (CSA) on reducing the proteinuria of FSGS. This study was undertaken to test the efficacy and safety of a 6-month course of CSA in a double-blinded, prospectively randomized, placebo-controlled trial in children with corticosteroid-resistant FSGS. The potential inhibitory effect of hypercholesterolemia on the proteinuria-reducing actions of CSA was also assessed. Twenty-five patients with FSGS were randomized to receive either placebo or CSA for 6 months. Twelve of the 12 patients that received CSA experienced a diminution of their proteinuria as opposed to only two of the 12 placebo-treated patients. Proteinuria was significantly reduced from 151.7 +/- 162.4 mg/kg per 24 h at Week 0 to 36.9 +/- 42.3 at the end of the study in the group that received CSA (P < 0.05). There was no significant change in the proteinuria of the patients in the placebo group. A significant correlation between the percentage change of proteinuria over the 6 months of the study and the prestudy serum cholesterol levels (r = 0.79, P < 0.05) was seen in the CSA group. A partial correlation analysis controlling for the effects of serum cholesterol uncovered a significant relationship between average CSA level and proteinuria change (r = -0.76, P < 0.05). The fractional decline in GFR over the course of the study was not significantly different between the CSA and placebo-treated groups. In conclusion, CSA reduces proteinuria, increases serum albumin levels, and can be expected, therefore, to reduce the symptoms of nephrotic syndrome. Hypercholesterolemia antagonizes this effect of CSA.

Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitment.

Abstract: Tubulointerstitial damage is a common histopathological feature of acute and chronic renal diseases and a prognostic indicator of renal function outcome. Monocytes infiltrating the interstitium, through the release of cytokines and/or growth factors, may play a key role in the pathogenesis of tubulointerstitial damage. Monocyte chemotactic peptide-1 (MCP-1) is a specific and powerful chemoattractant and activating factor for monocytes. This study investigated MCP-1 expression and its correlation with monocyte infiltration and tubulointerstitial damage in biopsies of patients with acute interstitial nephritis (AIN) and a chronic glomerulonephritis, namely immunoglobulin. A nephropathy (IgAN), often characterized by tubulointerstitial involvement. Six patients with AIN and 20 patients with IgAN, nine with mild (G1 to 2) and 11 with moderate to severe histologic lesions (G3 to 5), were studied. MCP-1 gene and protein expression were evaluated by in situ hybridization and immunohistochemistry. Infiltrating CD68-positive cells were identified as monocytes. MCP-1, weakly expressed in normal kidneys, was clearly upregulated in AIN biopsies. The gene and the protein expression were primarily localized in tubular and glomerular parietal epithelial cells, as well as in infiltrating mononuclear cells. In IgAN, a striking increase in MCP-1 mRNA and protein expression was observed only in the biopsies with moderate to severe lesions, with a pattern of expression similar to AIN. The MCP-1 expression strictly correlated with monocyte infiltrates and tubulointerstitial damage. In addition, the urinary excretion of this chemokine was studied in 17 IgAN patients. MCP-1 protein concentration was higher, compared with healthy subjects, in IgAN patients, especially in the G3 to 5 group, and directly correlated with the renal MCP-1 gene expression. In conclusion, these data suggest that production of MCP-1 in the tubulointerstitial compartment may play a key role in modulating monocytes influx and, consequently, tubulointerstitial damage.

The evaluation of iron status in hemodialysis patients.

Abstract: Effective treatment of anemia in hemodialysis patients requires ongoing monitoring of iron status. The purpose of this study was to determine levels of commonly used iron indices predictive of iron deficiency in this population. Forty-seven patients with baseline serum ferritin levels 80%). Two tests had marginal utility, serum ferritin at a level of < 150 ng/mL, and transferrin saturation < 21%. It was concluded that because of the tests' marginal utility, they should only be interpreted in the context of the patient's underlying erythropoietin, responsiveness. In patients who are responsive to erythropoietin, a transferrin saturation value < 18% or serum ferritin level < 100 ng/mL should be used to indicate inadequate iron. When erythropoietin resistance is present, transferrin saturation of < 27% or serum ferritin < 300 ng/mL should be used to guide iron management.

Lupus nephritis in children: a longitudinal study of prognostic factors and therapy.

Abstract: There are only a few studies in the pediatric literature that have analyzed risk factors for renal failure in childhood lupus nephritis. This study reviewed the outcome of 56 children (4 to 18 yr of age) with lupus nephritis seen at the authors' institution over a 27-yr period (1965 to 1992), in relation to risk factors and therapy. All children underwent percutaneous renal biopsy before the institution of therapy. From 1965 to 1987, treatment for Class III and IV lupus nephritis consisted of high-dose pulse methylprednisolone, 500 mg daily for 10 days, followed by oral prednisone. From 1987 to 1992, IV cyclophosphamide was given monthly for 6 months and then every 3 months for a period of 3 yr for patients with Class III and Class IV disease. Of 56 children, 42% had Class IV and 21% had Class III histology at onset. The mean follow-up period was 4 yr and ranged from 0.5 to 20.3 yr. Life-table analysis showed that the cumulative proportion of patients surviving was 82.8% at 5 yr and 67.7% at 10 yr. Renal survival was 44.4% at 5 yr and 29% at 10 yr, after the initial diagnosis of lupus nephritis was made. Age at diagnosis, race, sex, initial serum creatinine level, and the presence of proteinuria, hypertension, and DNA antibody titers were reviewed with respect to disease progression, as was the histological class at diagnosis. The effect of the different therapies was also examined. Univariate analysis revealed a significant association of progression to ESRD with an elevated serum creatinine level (P = 0.021), decreased C3 complement (P = 0.024), hypertension (P = 0.053), and histological classification of Class IV lupus nephritis (P = 0.031). Multivariate analysis demonstrated that progression to ESRD was independently associated with an initial Class IV histology (relative risk, 1.78; P < 0.003), hypertension at presentation (relative risk, 1.67; P < 0.003), and a low C3 complement level in conjuction with a high creatinine level (relative risk, 1.52; P < 0.028). Among children with lupus nephritis, those with Class IV disease, hypertension, high creatinine levels, and low C3 complement levels at the time of diagnosis are at increased risk for ESRD. Initial histological classification of lupus nephritis was the most reliable prognostic factor for disease progression. This study was unable to detect a difference in outcome for the two treatment groups.

Angiotensin in progressive renal diseases: theory and practice.

Abstract: Experimental studies indicate that Angll is involved in the process of tissue destruction in chronic renal diseases. This notion has been verified in a number of small-to large-scale clinical studies using angiotensin (ANG) I converting enzyme inhibitors (ACEI). Although the repertoire of the pathophysiologic cascade underlying the progressive destruction of renal tissue has continued to expand over recent years, from proteinuria and physical forces to growth factors and metalloproteinase disregulations, studies now suggest that Angll is involved in many, if not all, of these processes. Because these expanded pathophysiologic potentials of Angll are based primarily on observations in vitro, their significance in vivo, and in humans in particular, needs to be established. Recent studies in animals and humans indicate that the role of Angll in renal tissue destruction is subject to the modulation of multiple environmental and genetic factors, such as dietary habit and ACE genotype. Further delineation of the role of Angll in this respect for specific renal diseases and patients will enable us to design an efficient therapeutic intervention for this otherwise most complex problem of today's nephrology.

Functional and molecular aspects of renal prostaglandin receptors.

Abstract: The diverse intrarenal effects of the prostaglandins (PG) are mediated by distinct guanine nucleotide regulatory protein (G-protein)-coupled receptors. The cDNA for these receptors have been cloned, their signal transduction mechanisms determined, and their intrarenal distribution mapped. PGE2, the major intrarenal prostaglandin, interacts with at least three distinct E-prostanoid (EP) receptors that are highly expressed in specific regions of the kidney. Each EP receptor not only selectively binds PGE2, but also preferentially couples to different signal transduction pathways, including: stimulation of cAMP generation, via Gq (EP2 and EP4 receptors); inhibition of cAMP generation, via Gi (EP3 receptors); and activation of phosphatidylinositol hydrolysis (EP1 receptor), via one of the Gq family members. Activation of each these EP receptors is responsible for a distinct renal effect of PGE2, including its well-described renal hemodynamic and transport effects along the nephron. Other intrarenal prostanoid receptors include the PGF2 alpha receptor (FP), the thromboxane A2 receptor (TP) and the prostacyclin receptor (IP). Knowledge about localization of these receptors and their affinities for receptor-selective agonists and antagonists should aid in the understanding of renal disease and the development of therapeutic strategies for the use of these prostaglandin analogs in select renal diseases.

Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2.

Abstract: Linkage analysis was performed on 49 Catalan families with autosomal dominant polycystic kidney disease obtained via the Nephrology Department and related nephrology centers. A total of 336 subjects, 267 at risk for the disease, were investigated using three microsatellites linked to polycystic kidney disease Type 1 (PKD1) and three microsatellites linked to PKD2. All of the subjects underwent physical and sonographic examination. The results demonstrate locus heterogeneity, with 0.85 as the maximum likelihood for the proportion of families linked to PKD1. All of the remaining families were found to be linked to PKD2. Analysis of clinical data in the PKD1 group (N = 146) versus the PKD2 group (N = 20) showed a milder form of the disease in the latter, with a later age at diagnosis (27.4 versus 41.4 yr, P = 0.0002), later age of onset of ESRD (53.4 versus 72.7 yr, P < 0.0001), later age of diagnosis of hypertension (34.8 versus 49.7 yr, P = 0.001) and lower prevalence of hypertension at younger ages. Sonographic findings did not differ significantly between both groups. Although anticipation was observed in both groups, it did not affect the majority of families. No signs of imprinting were found in this study, and the only gender effect was an earlier age of onset of ESRD in men than in women (49.5 versus 53.1 yr in PKD1, P < 0.01 and 70.57 versus 73.6 yr in PKD2, P = 0.1). Molecular analysis of autosomal-dominant polycystic kidney disease allows presymptomatic diagnosis in individuals younger than age 30, and helps in establishing prognosis.

Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis)

Abstract: The molecular pathogenesis of human membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular immune disease. Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in proteinuria. In HN, the antigenic targets of immune deposit-forming antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd glycoprotein (megalin, or gp330), which is a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44-kd protein (receptor associated protein, RAP). One epitope was recently narrowed to 14 amino acids in RAP, and several others on megalin/gp330 are under investigation. Proteinuria requires formation of the complement C5b-9 membrane attack complex, which is presumably triggered by antibodies directed against lipid antigens that associate with immune deposit-forming megalin/gp330 immune complexes. Sublytic C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently, reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist probucol reduces proteinuria by < 80%. Intact or fragmented apoprotein E-containing lipoproteins were identified as potential sources of the polyunsaturated lipids required for the production of LPO adducts. Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.

Is erythropoietin a survival factor for red blood cells

Abstract: Recombinant human erythropoietin (rhuEPO) therapy has been reported to maintain corrected hematocrit values by increasing the length of red blood cell (RBC) survival. This article presents a controlled study that assessed the RBC survival before, during, and after termination of prolonged rhuEPO treatment of chronic hemodialysis patients. Two groups of 20 patients were studied. The hematocrit value of each patient was below 28 vol%. One group (Group A) was treated with rhuEPO for 1 yr and then treatment was stopped because of the unavailability of the drug. The second group (Group B) was treated for 2 yr. Epoetin beta was administered subcutaneously. The initial dose was 20 U per kg body weight three times weekly. Upon reaching the target hematocrit value of 30 to 35 vol%, the dose was individualized for each patient, to maintain target range. RBC survival was determined by the chromium-51 technique. In Group A, RBC survival was determined: (1) before, (2) at 12 months, and (3) 1 yr after cessation of rhuEPO treatment. In Group B, RBC survival was determined: (1) at 24 months of therapy, and (2) 1 yr after cessation of rhuEPO treatment. RBC survival increased significantly in both patient groups under rhuEPO treatment. After cessation of therapy, the RBC survival decreased to pretreatment values. During the correction period, reticulocyte counts increased significantly in both groups. Over the maintenance period, they slightly decreased, and after termination of rhuEPO therapy, they decreased to the pretreatment values. The results of this study could suggest the possibility that RBC survival was prolonged by the action of EPO on the erythroid progenitors, resulting in the production of RBC with improved viability.