Distinct phenotypes of hospitalized patients with hyperkalemia by machine learning consensus clustering and associated mortality risks.

BACKGROUND: Hospitalized patients with hyperkalemia are heterogeneous, and cluster approaches may identify specific homogenous groups. This study aimed to cluster patients with hyperkalemia on admission using unsupervised machine learning (ML) consensus clustering approach, and to compare characteristics and outcomes among these distinct clusters. METHODS: Consensus cluster analysis was performed in 5133 hospitalized adult patients with admission hyperkalemia, based on available clinical and laboratory data. The standardized mean difference was used to identify each cluster's key clinical features. The association of hyperkalemia clusters with hospital and 1-year mortality was assessed using logistic and Cox proportional hazard regression. RESULTS: Three distinct clusters of hyperkalemia patients were identified using consensus cluster analysis: 1661 (32%) in cluster 1, 2455 (48%) in cluster 2 and 1017 (20%) in cluster 3. Cluster 1 was mainly characterized by older age, higher serum chloride and acute kidney injury (AKI), but lower estimated glomerular filtration rate (eGFR), serum bicarbonate and hemoglobin. Cluster 2 was mainly characterized by higher eGFR, serum bicarbonate and hemoglobin, but lower comorbidity burden, serum potassium and AKI. Cluster 3 was mainly characterized by higher comorbidity burden, particularly diabetes and end-stage kidney disease, AKI, serum potassium, anion gap, but lower eGFR, serum sodium, chloride and bicarbonate. Hospital and 1-year mortality risk was significantly different among the three identified clusters, with highest mortality in cluster 3, followed by cluster 1 and then cluster 2. CONCLUSION: In a heterogeneous cohort of hyperkalemia patients, three distinct clusters were identified using unsupervised ML. These three clusters had different clinical characteristics and outcomes.

Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis.

BACKGROUND: Hepatitis E virus (HEV) infection appears to be more common than previously thought. HEV seroprevalence in patients on maintenance haemodialysis (HD) is unclear with a range from 0% to 44%. In addition, risk factors of transmission of HEV in patients on haemodialysis are unknown. AIM: To perform a systematic review and meta-analysis of HEV seroprevalence in HD patients compared with controls. METHODS: A systematic search of several databases identified all observational studies with comparative arms. Two reviewers extracted data and assessed the methodological quality. A random-effects model was used for pooled odds ratio (OR) and 95% confidence interval (CI) of positive anti-HEV IgG in both groups. Heterogeneity and publication bias were assessed with appropriate tests. RESULTS: We identified 31 studies from 17 countries between 1994 and 2016. Sixteen studies were judged to have adequate quality and 15 to have moderate limitations. HEV infection was more prevalent in patients on haemodialysis compared with controls (OR 2.47, 95% CI 1.79-3.40, I2 = 75.2%, P < .01). We conducted several subgroup analyses without difference in results. Egger regression test did not suggest publication bias (P = .83). Specific risk factors of HEV transmission in patients on haemodialysis were not clearly identified. CONCLUSIONS: Hepatitis E virus infection is more prevalent in patients on haemodialysis compared with non-haemodialysis control groups. Further studies are needed to determine risk factors of acquisition, impact on health, and risk for chronic HEV especially among those patients going to receive organ transplantation.

Rituximab treatment of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome whose pathogenesis may involve B-cell functions. Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells thereby deleting them. We conducted an open-label pilot trial of rituximab treatment in 15 severely nephrotic patients with proteinuria refractory to angiotensin-converting enzyme inhibition and/or receptor blockade but with adequately controlled blood pressure. Rituximab was given 2 weeks apart and, at 6 months, patients who remained proteinuric but had recovered B-cell counts were given a second course of treatment. Proteinuria was significantly decreased by about half at 12 months. Of the 14 patients who completed follow-up, full remission was achieved in two and partial remission in six patients based upon the degree of proteinuria. Side effects were minor; however, we found no relationship between the response and number of B cells in the blood, CD20 cells in the kidney biopsy, degree of tubulointerstitial fibrosis, starting proteinuria or creatinine values. Rituximab appears effective in reducing proteinuria in some patients with idiopathic membranous nephropathy but prospective identification of responsive patients was not possible.

Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, node-positive breast cancer.

Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tomoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.

An outbreak of bloodstream infections arising from hemodialysis equipment.

An outbreak of 29 cases of bloodstream infection by 16 pathogens occurred during 8 months at two chronic hemodialysis centers. Consequences included 21 hospital admissions and removal of 23 dialysis catheters. An epidemiologic investigation comparing case-patients with uninfected controls showed that risk was significantly (P < .05) associated with having a catheter for vascular access; receiving treatment on a Monday, Wednesday, Friday schedule; and receiving treatment on one heavily contaminated dialysis machine. Culture studies and mock trials showed that bloodstream pathogens were present in a recently installed, commercially marketed attachment for disposal of spent priming saline and could enter blood line tubing directly or indirectly during dialyzer priming and tubing assembly. The outbreak was halted by measures directed at the attachment. Investigation of this problem demonstrated that microbial overgrowth in the attachment caused bloodstream infections and underscores the importance of microbiologic considerations in the design and use of hemodialysis equipment.

Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis.

Randomized, prospective studies comparing BUCY to TBI conditioning regimens for allogeneic bone marrow transplantation have yielded conflicting results. We investigated the overall survival, the disease-free survival and the toxicities of BUCY vs TBI-based regimens by conducting a meta-analysis of all published, randomized, prospective trials comparing these regimens. Five studies were analyzed. We evaluated six endpoints: survival, disease-free survival, veno-occlusive disease (VOD) of the liver, acute GVHD, chronic GVHD, and interstitial pneumonitis. We combined individual study results using a random effects model. Survival and disease-free survival were better with TBI-based regimens than with BUCY, but these differences were not statistically significant (survival odds ratio 1.4, 95% confidence interval 0.9-2.2, P = 0.09; disease-free survival odds ratio 1.2, 95% confidence interval 0.7-2.1, P = 0.44). A power analysis indicated that BUCY was unlikely to have a clinically relevant survival or disease-free survival advantage. The power analysis could not exclude the possibility of such an advantage for TBI-based regimens. A significantly greater incidence of VOD occurred with BUCY (odds ratio 2.5, 95% confidence interval 1.2-5.2, P = 0.02). For the other side-effects, there were no significant differences. We concluded that TBI-based regimens cause less VOD than BUCY and are at least as good for survival and disease-free survival.

An analysis of hepatic retransplantation in children.

BACKGROUND: The limited supply of organ donors has led some groups to reconsider the role of retransplantation. Historically, except for children with malignancies, extrahepatic sources of sepsis, or severe irreversible neurologic injuries, our institution has offered all children with failing liver grafts the option of retransplantation regardless of their current severity of illness. The purpose of this study was to examine the outcome of hepatic retransplantation in children in an attempt to identify factors predictive of outcome and to assess the results of our approach to retransplantation. METHODS: Between October 1984 and December 1995, 314 children less than 15 years of age underwent a total of 441 liver transplants. Data were obtained retrospectively by review of hospital records. RESULTS: With a mean follow-up period of 5.3+/-2.7 years, the overall patient survival rates at 1 and 5 years were 77.1% and 67.1%, respectively. Primary allograft survival rates were 65.6% and 56.5%, respectively. Of the 137 patients who developed failure of their primary allograft, 92 underwent retransplantation (29.3% of all primary transplants). Both patient and allograft survival rates were significantly decreased after retransplantation (P<0.0001 versus primary transplants). Univariate and multivariate analysis of retransplanted patients revealed only two factors that were statistically related to patient and graft survival: age at the time of retransplantation (P<0.02 univariate and P<0.05 multivariate) and retransplantation with a reduced-size allograft (P<0.005 univariate and P<0.05 multivariate). In this series, the effect on patient survival of differences in medical condition as reflected by United Network for Organ Sharing (UNOS) status approached, but did not achieve, significance (P=0.08 for UNOS 1 versus UNOS 2 and 3). UNOS status did not affect graft survival. Neither the cause of primary allograft loss or the timing of retransplantation relative to the first transplant were related to outcome. CONCLUSIONS: These data demonstrate that the failure of primary hepatic allografts remains a major problem in pediatric liver transplantation and that the overall results of retransplantation were significantly worse than those associated with primary transplants. We have identified a group of children who experienced a significantly worse outcome after retransplantation. This group consisted of children less than 3 years of age retransplanted using reduced-size grafts. Based on this finding, we now attempt to avoid retransplanting young children with reduced-size grafts. By using this approach, we hope to be able to offer children the option of retransplantation with improved results and simultaneously minimize the negative impact on patients awaiting primary transplants.

Fish oil therapy for IgA nephropathy: efficacy and interstudy variability.

Published reports examining the efficacy of fish oil for preserving renal function in immunoglobulin A (IgA) nephropathy have yielded conflicting results. This investigation was a meta-analysis conducted to determine whether the medical literature supports this therapy. In addition, the sources of variability among published findings were examined. Studies were combined using a random effects model. Five controlled studies were identified, two with positive results and three with negative results. Forty-four percent of the between-study variance could be attributed to differences in follow-up times and, less significantly, the number of renal function measurements; a weighting procedure was developed, eliminating this variance from the combined result. When all studies were combined, the mean effect, +0.25 +/- 0.23 SD (positive effects indicate that treatment was superior to control), was not statistically significant; however, the probability of at least a minor beneficial effect was 75%. Mixed-effects regression suggested that this therapy may be more effective among individuals with more proteinuria. The medical literature, therefore, does not prove the efficacy of fish oil therapy in IgA nephropathy, but suggests that an additional placebo-controlled trial is warranted. A sample-size calculation indicated that such a trial should be larger than those to date or should attempt to increase the treatment effect, perhaps by treating for more than 2 yr or enrolling more severely proteinuric individuals.

Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate.

The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.

Rapid-onset diabetic nephropathy in type II diabetes mellitus.

We report a case of rapidly progressive diabetic nephropathy, from little diabetic change on renal biopsy to severe, nodular, diabetic nephrosclerosis over 32 months. The patient was taking an angiotensin converting enzyme inhibitor and had a mean arterial pressure of 95 mm Hg over this time period. Her dietary protein intake was low, at least upon presentation. She had three additional mechanisms or potential mechanisms of injury: monoclonal kappa light chains; IgA immune deposits on the first, but not the second biopsy; and longstanding hypertension. Her renal histology was typical for diabetic nephropathy but was not characteristic of kappa light chain disease. We suggest that diabetic nephropathy may develop more rapidly than previously assumed, especially when additional mechanisms of injury, or additional promoters of mesangial matrix accumulation are present.

Effect of chronic human recombinant erythropoietin therapy on antibody responses to immunization in chronic hemodialysis patients.

There are multiple lines of evidence suggesting that human recombinant erythropoietin (rEPO) could influence immune responses by direct effects of rEPO on T or B cells. The present study tested this hypothesis by measuring antibody responses after immunization to tetanus toxoid (TT, a T cell dependent antigen) or pneumococcal capsular polysaccharide antigen (PA, a T cell independent antigen). The patients chosen for this prospective study were chronic hemodialysis patients receiving chronic rEPO therapy, and a comparable group of chronic hemodialysis patients not receiving rEPO therapy. We found that the patients immunized with PA and receiving rEPO therapy (N = 15) had IgG anti-PA responses comparable to that of those not receiving rEPO therapy (N = 15). In contrast, in the patients immunized with TT, those receiving rEPO (N = 15) developed significantly higher IgG anti-TT levels than those not receiving rEPO (N = 14) (time-group interaction P = 0.005). The peak difference between these groups was at two weeks, where the rEPO-treated patients developed a 4.1-fold mean increase in IgG anti-TT level and those not receiving rEPO developed only a 1.4-fold mean increase in IgG anti-TT level (P < 0.01). The difference in immune response to TT in the rEPO compared to the non-rEPO-treated patients could not be explained by differences between the groups in any of the parameters measured at baseline or during the post-immunization period. In conclusion, rEPO therapy increased immune response to TT but not PA, which suggests that rEPO enhances immune response to T cell dependent antigens.

Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus.

The purpose of the study was to determine the extent to which urinary sediment findings (changes in red blood cells [RBCs], white blood cells [WBCs], and the appearance of RBC and WBC casts) predict the onset of renal relapse (defined as a specific increase in proteinuria and/or serum creatinine level) in patients with systemic lupus erythematosus (SLE). Seventeen SLE patients with biopsy-proven diffuse proliferative glomerulonephritis at initial presentation were followed prospectively for 1,129 patient-months under a study protocol. Semiquantitative urinalyses were performed at 2-month intervals during periods with little or no SLE activity and, more frequently, during periods with increased SLE activity. Each urinalysis was accompanied by a clinical evaluation and a panel of screening tests relevant to the evaluation of SLE activity. During this study, 877 semiquantitative urinalyses were performed and 43 renal relapses were observed in 14 patients. No relapse occurred in three patients. Of the renal relapses, 30 were defined as proteinuria relapses (mean baseline proteinuria increased from 0.8 +/- 0.1 g/24 hr to 2.7 +/- 0.3 g/24 hr; P < 0.001) and 13 were defined as serum creatinine relapses (mean baseline serum creatinine increased from 2.7 +/- 0.4 mg/dL to 3.8 +/- 0.5 mg/dL; P < 0.001). Red blood cell and/or WBC casts (cellular casts) were observed before or at the onset of 35 of the 43 renal relapses (sensitivity, 81%). The mean and median intervals between the appearance of cellular casts and the onset of renal relapse was 10 +/- 2 weeks and 8 weeks, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Racial differences in renal allograft survival: the role of systemic hypertension.

The rate of decline in the number of functioning renal allografts beyond the first year after transplantation has changed little in the last 25 years, and during long-term follow-up most allografts are lost due to chronic transplant rejection or patient death. The recipient race correlates with allograft survival, and African American recipients have a lower allograft survival than Caucasians. The goal of the present study was to identify clinical variables present during the first six months after transplantation that predict the loss of renal allografts beyond six months after transplantation, and in particular to determine the role of systemic hypertension on renal allograft survival in black and white recipients. This study includes 547 recipients of first cadaveric renal allografts performed at The Ohio State University. All patients were treated with a uniform immunosuppressive protocol and had a follow-up of at least three years. By multivariate analysis the following variables correlate with poor allograft survival: an elevated serum creatinine concentration measured six months after transplantation (SCr6mo) (P < 0.0001); black race (P < 0.0001); increasing numbers of acute rejection episodes (ATR) (P = 0.002); and young recipients (P = 0.026). Allograft survival is significantly worse in black (mean allograft half-life of 7.7 +/- 1.3 years) than in white recipients (24 +/- 3 years) (P < 0.0001). Black recipients also have a significantly higher six month average mean arterial blood pressure (MAP) (105 +/- 8 mm Hg) than white recipients (102 +/- 7 mm Hg) (P = 0.002). However, the prevalence of hypertension is not significantly different in black (33%) than in white recipients (26%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of recombinant erythropoietin therapy on autoimmunity in systemic lupus erythematosus.

Previous studies of the in vitro effects of recombinant erythropoietin (rEPO) on T and B cells and studies of lymphocyte subsets in dialysis patients receiving rEPO therapy suggest that rEPO might augment immune responses. In the present study indices of autoimmunity (antinuclear antibody, anti-double-stranded DNA, and antiphospholipid antibody [immunoglobulins G and M]) were measured before, during, and after rEPO therapy in five systemic lupus erythematosus patients without renal failure (mean serum creatinine, 1.5 +/- 0.3 mg/dL). The rEPO therapy was self-administered by subcutaneous injection in doses ranging from 4,000 units once weekly to 3,000 units three times weekly for 3 to 7 months. On rEPO therapy, each patient experienced an increase in hematocrit. The mean baseline hematocrit increased from 32 +/- 2.0 to a peak of 42.2 +/- 3 (P < 0.001) at 3 to 7 months and then decreased to baseline values 1 to 2 months after rEPO was discontinued. During this time the indices of autoimmunity were not significantly changed by rEPO therapy. Systemic lupus erythematosus activity, assessed by serum C3, serum creatinine, urinalysis, and 24-hour proteinuria, also was unchanged by rEPO therapy. The rEPO therapy was generally well tolerated. However, one patient, who was also receiving replacement estrogen therapy and had high-titer antiphospholipid antibody, experienced episodes of thrombophlebitis while on rEPO therapy. In conclusion, we found no evidence that rEPO increases autoimmunity in systemic lupus erythematosus. However, we observed a temporal relationship between episodes of thrombophlebitis and rEPO therapy in a single patient with high-titer anticardiolipin antibody who was also receiving replacement estrogen therapy. These associations require further investigation.

Erythropoietin therapy in humans increases erythrocyte expression of complement receptor type 1 (CD35).

The expression of complement receptor Type 1 (CR1, CD35) on erythrocytes (E) is unique to humans and other primates. E-CR1, a C3b/C4b receptor that also acts as cofactor for Factor I, appears to be important in clearing C3/C4-opsonized immune complexes from the circulation, in controlling complement activation in the circulation, and in regulating antibody formation. This study was undertaken to determine whether therapy with recombinant human erythropoietin (rEPO) might increase E-CR1 expression in humans. The rationale is that young erythrocytes express more E-CR1 than old erythrocytes. Thus, conditions that stimulate erythropoiesis should increase E-CR1 expression. The hypothesis that stimulating erythropoiesis by rEPO therapy can increase E-CR1 expression was tested in six anemic chronic hemodialysis (ESRD) patients and five systemic lupus erythematosus (SLE) patients without renal failure. Before the rEPO therapy, three of the SLE patients were anemic and two were not. The ESRD patients were studied before and during 9 or 10 mo of rEPO therapy. The SLE patients were studied before, during, and after 7 mo of rEPO given by sc injection two or three times weekly. It was found that rEPO therapy was associated with a progressive increase in the average number of CR1/E in each of the ESRD patients and in the anemic SLE patients: mean baseline CR1/E was 210 +/- 50 (SE) for the ESRD patients and 125 +/- 35 for the SLE patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of chronically increased erythrocyte complement receptors on immune complex nephritis.

Experimental studies in humans and other primates have shown that the erythrocyte (E) complement receptor Type 1 (CR1), which is unique to the primate, plays an important role in clearing immune complexes (IC) from the circulation by binding C3b/C4b opsonized immune complexes and carrying the IC to liver and spleen for disposal. The results of these acute experiments suggest that increasing E-CR1 levels chronically should protect against IC-mediated glomerulonephritis (IC-GN) induced by chronic formation of IC in the circulation. In the present study this hypothesis was tested in the cynomolgus monkey (CYN). IC-GN was induced by daily bolus intravenous infusion of BGG into immunized CYN for 8, 10, or 14 weeks. Prior to and during the daily bolus infusions of BGG, sustained differences in E-CR1 levels were achieved between the experimental group (increased E-CR1 levels) and the control group (maintained or decreased E-CR1 levels), by one of two methods: (1) Twice weekly exchange transfusion. The CYN donors were blood type compatible with the recipients and had either constitutive high E-CR1 expression (3,000 to 5,000 CR1/E) or constitutive low E-CR1 expression (< 100 CR/E). The recipients of the exchange transfusions (N = 2) had constitutive mid-level E-CR1 expression. (2) Weekly phlebotomy (PL) or sham PL. CYN with mid-level E-CR1 expression were randomly assigned to receive weekly either PL (causing increased E-CR1 expression by stimulating erythropoiesis) (N = 8) or sham PL (which has no effect on E-CR1 expression (N = 9).(ABSTRACT TRUNCATED AT 250 WORDS)

The quantitative relationship between treated blood pressure and progression of diabetic renal disease.

Antihypertensive therapy reduces the rate at which glomerular filtration rate (GFR) declines (delta GFR) in diabetic nephropathy; however, the optimal blood pressure is unknown. The quantitative relationship between treated blood pressure and delta GFR was analyzed retrospectively in 59 patients with established diabetic nephropathy and treated hypertension using weighted univariate and weighted multivariate regression. The GFR was calculated using the Cockcroft and Gault formula. More rapid GFR loss correlated most strongly with higher diastolic blood pressures (r = 0.70; P < 0.0001); for each millimeter of mercury of diastolic blood pressure, the GFR decreased by 0.69 mL/min/yr. This relationship remained present if those individuals with diastolic pressures greater than 90 mm Hg were eliminated from the study (r = 0.50; P < 0.001). The correlation for systolic blood pressure was weaker (r = 0.30; P < 0.05) and explained completely by covariance between systolic and diastolic blood pressures. The correlation for mean blood pressure (r = 0.59; P < 0.0001) fell between the correlations for diastolic and systolic blood pressures. Proteinuria, serum albumin concentration, and serum cholesterol concentration also correlated with delta GFR. In multivariate analysis, neither these indices of disease severity nor the initial GFR explained the correlation between delta GFR and diastolic blood pressure. Age, sex, race, type of diabetes, and percentage of glycosylated hemoglobin did not correlate with delta GFR.

Effect of oxypurinol on renal reperfusion injury in the rat.

Oxygen-based free radicals produced by the enzyme xanthine oxidase may be involved in postischemic reperfusion injury. To determine whether oxypurinol, a xanthine oxidase inhibitor and the major metabolite of allopurinol, attenuates renal ischemic reperfusion injury, and, if so, to determine its most effective dose, oxypurinol 2.5, 5, 10 or 20 mg/kg BW was infused 20 min prior to 20 min of complete renal ischemia in uniephrectomized rats. Animals treated with 5 mg/kg BW oxypurinol had significantly higher creatinine clearances on the first and second days postischemia than did untreated animals. In other animals given either buffered saline or oxypurinol at 5 mg/kg BW i.v. 20 min before ischemia, the inulin clearance (CIn) returned to near-control values within 1 h after ischemia. At 24 h there was a secondary decline in the CIn in animals receiving buffered saline, whereas in the animals treated with oxypurinol, this decline was less evident. In animals given oxypurinol at 5 mg/kg BW 40 min after ischemia, the CIn was significantly greater than in those receiving buffered saline. No changes in renal blood flow or renal vascular resistance were observed, suggesting that the effect of oxypurinol was not hemodynamically mediated. Analysis of plasma hypoxanthine, xanthine, uric acid and oxypurinol levels by high-pressure liquid chromatography revealed that in the absence of oxypurinol, a significant increase in uric acid production occurred between 20 and 170 min after the period of ischemia. In the presence of oxypurinol, there was a marked reduction in the rate of production of uric acid for the first 3 h postischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary renovascular effects of erythromycin in the rat: relationship to cyclosporine nephrotoxicity.

Erythromycin is known to exacerbate cyclosporine nephrotoxicity. This has been attributed to the potential of erythromycin to reduce the hepatic microsomal metabolism and clearance of cyclosporine. Erythromycin may also be nephrotoxic. We tested the hypothesis that erythromycin may have direct effects on the renal vasculature which are additive or synergistic with the effects of cyclosporine. Sprague-Dawley rats were administered graded doses of either erythromycin, 2.5, 5, 7.5, and 10 mg/kg BW/min i.v. over consecutive 10-min intervals; cyclosporine, 1, 2, 3, and 4 mg/kg BW/min i.v. over consecutive 10-min intervals; or both drugs simultaneously. In separate experiments, identical doses of erythromycin or cyclosporine were infused intravenously following acute unilateral renal denervation. Infusion of erythromycin led to an initial decline in arterial blood pressure whereas infusion of cyclosporine resulted in a dose-related increase in arterial blood pressure. Despite these different systemic effects, each drug alone produced a striking decrease in renal blood flow. This effect was more pronounced when the drugs were infused concomitantly. The reduction in renal blood flow occurred in an additive manner as a direct consequence of increased renal vascular resistance. Prior renal denervation did not modify the response to either erythromycin or cyclosporine. These results demonstrate that cyclosporine-induced vasoconstriction is exacerbated by erythromycin and suggest that the decline in renal function observed in patients coadministered these drugs may be due in part to additive renovascular toxicity.