Mild Renal Function Impairment Research Articles

Spectrum of Clinical Presentations in Human Immunodeficiency Virus (HIV) Infected Patients with Renal Disease.

HIV infection is a multiorgan disease with the kidney not spared. A variety of renal syndromes with varying clinical presentations has been reported amongst HIV infected patients. This study aims to highlight the spectrum of clinical presentations in HIV infected patients with renal disease. HIV infected patients presenting at University of Benin Teaching Hospital (UBTH) Benin City were the study population. A total of 383 patients were studied. Their biodata, clinical presentations and laboratory investigations including serum urea, creatinine and albumin, urine protein and creatinine were assessed. Their glomerular filtration rate (GFR) and protein urine excretion were calculated using six equations of modification of diet in renal disease (MDRD) and protein: creatinine ratio respectively. Patients were stratified according to their renal functions into normal, mild, moderate and severe renal function impairment. The data was analysed using statistical software program SPSS Vs 15.0. 53.3% of 383 patients screened had renal function impairment, 40.2% mild, 37.7% moderate and 22.2% severe impairment. Mean age was 35.6±8.3, 36.0±9.9 and 36.3±8.3 years for mild, moderate and severe renal function impairment (RFI) respectively. Easy fatigability was the commonest symptoms occurring in 47.5%, 30.0%, 37.5% and 22.5% of control, mild RFI, moderate RFI and severe RFI subjects respectively (p = 0.568). Oliguria, facial and body swelling occurred more in patients with RFI especially in patients with severe renal impairment. The difference is statistically significant (p = 0.046, 0.041, and 0.033 respectively). Pallor was the commonest clinical sign occurring in 32.5%, 50.0%, 35.0% and 62.5% of control and patients with mild, moderate, and severe RFI respectively; the difference was not statistically significant (p = 0.459). Ascites, facial puffiness and pedal oedema were commoner in patients with RFI especially those with severe RFI. The differences were statistically significant. (p = 0.048, 0.019, and 0.008 respectively). In conclusion spectrum of clinical presentations in HIV patients with renal impairment are many but few are specific to these patients.

High Cefepime Plasma Concentrations and Neurological Toxicity in Febrile Neutropenic Patients with Mild Impairment of Renal Function

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats

Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.

Moderate Renal Function Impairment Does Not Affect Outcomes of Reduced-Intensity Conditioning with Fludarabine and Melphalan for Allogeneic Hematopoietic Stem Cell Transplantation

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

Between hyperfiltration and impairment: Demystifying early renal functional changes in diabetic nephropathy

Renal functional changes in diabetic nephropathy conventionally have been linked to progression of urinary albumin excretion. This paradigm was based on historic evidence noting that hyperfiltration occurred in the setting of normoalbuminuria and microalbuminuria and that loss of renal function began in the context of proteinuria. More contemporaneous research findings, using serum cystatin-C-based estimates of glomerular filtration rate (cC-GFR), have challenged this paradigm. Rather, the process of renal function loss appears to begin prior to the onset of proteinuria. In the 2nd Joslin Kidney Study on the Natural History of Microalbuminuria, over one-third of type 1 diabetes (T1DM) patients with microalbuminuria at the time of enrollment already had evidence of mild (cC-GFR < 90) or moderate (cC-GFR < 60 ml/min) renal function impairment. Understanding the mechanisms underlying this phenomenon of early renal function impairment may allow for interventions directed at altering or retarding early renal function decline. To date, serum uric acid and components of the TNFα pathway appear to be involved.

Predictors of change in estimated GFR: a population-based 7-year follow-up from the Tromso study

Chronic kidney disease is associated with increased cardiovascular mortality, and even mild impairment of renal function is a cardiovascular risk factor. Several studies have investigated the risk factors for the development of end-stage renal disease, but little is known about predictors of change in renal function in the general population. The present study included 2249 men and 2192 women without signs of kidney disease at baseline who were followed for 7 years from 1994 to 1995 in the Tromsø Study. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease study equation. Gender-specific multiple linear regression analyses were used to assess predictors of change in eGFR (DeltaGFR). Change in eGFR, measured in ml/min/1.73 m(2)/year, was associated with systolic blood pressure (SBP) [beta-value for a 10-mmHg increase in SBP, men = -0.14, 95% confidence interval (CI) = -0.18 to -0.09; women = -0.07, 95% CI = -0.11 to -0.03] and fibrinogen [beta-value for 1 SD increase in fibrinogen, men (1 SD: 0.85 g/L) = -0.12, 95% CI -0.20 to -0.03; women (1 SD: 0.80) = -0.11, 95% CI -0.20 to -0.02]. High alcohol consumption in men and high physical activity in women predicted an increase in eGFR. Higher albumin/creatinine ratio was associated with a decline in eGFR in men only. Some risk factors for change in GFR seem to be gender specific but both high SBP and high levels of fibrinogen contribute to a more rapid decline in GFR for both men and women.

Relations between markers of renal function, coronary risk factors and the occurrence and severity of coronary artery disease

ObjectiveWhile renal failure greatly increases coronary risk, mild renal impairment is not usually considered a major risk factor. To explore this we assessed relations between measures of mild impairment of renal function and coronary artery disease (CAD) together with other risk factors. Methods and resultsIn 408 consecutive patients aged 75 years or less with angiographically defined normal or obstructed coronary arteries and an estimated glomerular filtration rate (eGFR) >45mL/min per 1.73m2, we assessed relations between severity of CAD and levels of plasma cystatin C, creatinine, eGFR, lipid profile, C-reactive protein (CRP), homocysteine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). With univariate ANOVA, the severity of CAD was significantly associated with all indices of renal function: increased plasma cystatin C (p=0.003) and creatinine (p=0.004) and decreased eGFR (p=0.008). An elevated plasma cystatin C was associated with increases in ADMA, SDMA, CRP, homocysteine and age. ADMA, SDMA, CRP and homocysteine levels were not associated with CAD severity. eGFR was negatively associated only with SDMA and homocysteine. In multivariate analysis, increased plasma cystatin C predicted both the occurrence and the severity of CAD more strongly than other measures of renal function. ConclusionsWe conclude that mild renal impairment detected by elevated cystatin C is associated with both the occurrence and the severity of CAD, independent of the other risk factors we measured and that mild renal impairment results in increased plasma levels of homocysteine, ADMA and SDMA. Our findings suggest a possible mechanistic link between CAD and mild renal impairment in which cystatin C may serve as an early marker for CAD and may also participate directly in atherogenesis.

Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients

Visceral leishmaniasis (VL) is characterized by frequent relapses in HIV-infected patients, even in those who receive secondary prophylaxis. The aim of our study was to evaluate the efficacy of liposomal amphotericin B (L-AMB) for secondary prophylaxis of VL in HIV-infected patients. From January 2001 to December 2005, 17 HIV patients, with at least one previous episode of VL who received L-AMB as secondary prophylaxis for VL, were included in the study. Efficacy was measured as the proportion of patients remaining free (non-relapse) of VL at different time points. Relapses were analysed as time-to-relapse distribution and were evaluated by survival analysis using the Kaplan-Meier method. Twenty-one episodes of VL were diagnosed and nine relapsed. The median follow-up time was 14 (5-44) months. The probability of remaining free of relapse at 6 months was 89.7% (95% CI, 76.2-100); at 12 months, the probability was 79.1% (95% CI, 61-97.2) and at 24 and 36 months, the probability was 55.9% (95% CI, 30.5-81.3). In the non-relapsing group, patients had a significant increase in CD4 cell levels of 102 (10-174) and 126 (4-159) cells/mm(3) at 12 and 24 months, respectively (P = 0.037), whereas in the relapsing group, no significant increase was observed. Prophylaxis with L-AMB was well tolerated and only three patients had a mild impairment of renal function without requiring any change in treatment. L-AMB is well tolerated and useful for secondary prophylaxis of VL.

Renal Function Impairment and Outcomes of Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation.

Non-relapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We hypothesized that moderate to mild renal function impairment increases NRM in this setting.Methods: We studied 141 patients diagnosed with AML (n=131) or high-risk MDS (n=10) who underwent allogeneic transplantation with Fludarabine (Flu)/Melphalan (Mel)-based regimens between August 1996, and May 2006 in our institution. Flu dose was 30–40mg/m2 for 4 days and Mel doses were100–180mg/m2. ATG was added for recipients of unrelated donor (UD) HSCT. GVHD prophylaxis was tacrolimus and mini-methotrexate for all but 2 patients. Donors were HLA-compatible siblings (n=69) and matched UD (n=72). Disease status at transplant was complete remission (n=56, 40%) or active disease (n=85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplant on outcomes was analyzed. GFR was calculated by both the Cockcroft Gault (CG) and the Modified Diet in Renal Disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. We considered GFR ≥ 90 as normal and GFR < 90 as decreased. Evaluated outcomes were overall survival, NRM, and regimen-related mortality (RRM) at day 100 and 1-year post transplant.Results: Median age was 55 years (range, 21–74); 59% of the patients were male. Estimated GFR by CG was normal for 45 patients (32%), and decreased for 96 patients (68%). When estimated by MDRD, 65 patients (46%) had normal and 76 (54%) had reduced GFR. The majority of patients by both estimations had a GFR between 60 and 89 (n= 78 by CG and n= 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (p>0.05). There was no difference in overall and NRM at day 100 and 1 year post transplant in both groups by any GFR estimation method. There was a small trend towards lower RRM at day-100 for patients with GFR ≥ 90 when using CG, but this was not statistically significant.Conclusion: A mild to moderate decrease in GFR is not associated with an increase in non-relapse mortality.Transplant outcomes as a function of GFR at start of conditioning regimenOutcomeN100-Day MortalityHRp1-year MortalityHRpSurvival- GFR ≥ 904511 (25%)0.90.924 (53%)1.20.5Survival- GFR < 909624 (25%)44 (46%)NRM* - GFR ≥ 90459 (21%)0.90.914 (31%)0.980.9NRM* - GFR < 909619 (20%)31 (32%)RRM* - GFR ≥ 90453 (7%)0.50.36 (13%)0.90.9RRM* - GFR < 909612 (13%)14 (15%)Abbreviations: NRM: non-relapse mortality; RRM: regimen-related mortality (excludes deaths due to GVHD); GFR: glomerular filtration rate (estimated by CG)

Iron sucrose induced morphological and functional changes in the rat kidney

Treatment of anemia in uremic patients requires simultaneous supplementation of erythropoietin and iron. Because of the impaired iron absorption from the gastrointestinal tract in conditions of renal insufficiency, intravenous supplementation is a treatment of choice in such conditions. Iron compounds used for intravenous supplementation induce several systemic side effects, and therefore, we studied the effect of chronic exposure to iron sucrose in rats on renal function. Experiments were performed on male Wistar rats, which were infused intraperitoneally every 4 days, for 28 days with iron sucrose in a dose 1 mg/kg bw or 10 mg/kg bw diluted in 20 mL of the dialysis fluid. Control animals were infused with plain dialysis fluid. Renal function was evaluated at the beginning and at the end of the study. Additionally morphology of the kidneys was evaluated in all animals after 28 days of the study. Chronic exposure of rats to iron sucrose resulted in increased accumulation of PAS-positive material in their glomeruli: + 38% at Fe 1 mg/kg bw P < 0.05 and + 42% at Fe 10 mg/kg/bw P < 0.01 and collagen in the peritubular area: + 40% at Fe 1 mg/kg bw P < 0.005 and + 77% at Fe 10 mg/kg/bw P < 0.001. Only renal clearance of urea was decreased by 53%, P < 0.01 in rats exposed to iron sucrose at a dose of 10 mg/kg bw. Chronic exposure of rats to iron sucrose results in morphologic changes of the kidney; however, mild impairment in renal function was observed only at the highest (10 mg Fe/kg bw) concentration of iron sucrose.

Safety and effects on the lipid and C-reactive protein plasma concentration of the association of ezetimibe plus atorvastatin in renal transplant patients treated by cyclosporine-A: a pilot study

Ezetimibe (E) is a new cholesterol adsorption inhibitor which prevents the adsorption of dietary and biliary cholesterol by binding to a recently described cholesterol transporter. This pilot study was performed to evaluate the safety and the low-density lipoprotein (LDL)-C and C-reactive protein lowering efficacy of atorvastatin (A) and of the association of A plus E in five renal transplant patients with hypercholesterolemia and mild renal functional impairment receiving cyclosporine-A (CsA). Patients received for three periods, each of 3 weeks, A at a dose of 20 mg/day; A at a dose of 10 mg/day and finally, A 10 mg plus E 10 mg daily. The medications were well-tolerated and no important clinical or laboratory (muscle enzyme, creatinine clearance and CsA concentration) abnormalities were observed throughout the study period. A alone lead to target LDL-C values only in two of five patients and did not significantly reduce the mean CRP values. The combination of E plus A produced the lowest lipid levels and significantly reduced CRP mean values and allowed all patients to attain target levels of LDL-C: total cholesterol decreased from 240 ± 42 (mean ± S.D.) to 171 ± 34 mg/dl, LDL-C from 129 ± 32 to 87 ± 21 mg/dl, plasma triglycerides from 330 ± 54 to 194 ± 71 mg/dl and CRP from 6.2 ± 1.9 to 3.9 ± 2.4 mg/l ( P < 0.05 for all). This pilot study suggests that the co-administration of E and A at 10 mg/day in renal transplant patients receiving CsA is well-tolerated and effective in reducing important cardiovascular risk factors.

Vascular Function and Mild Renal Impairment in Stable Coronary Artery Disease

In patients with coronary artery disease, the concomitant presence of renal function impairment is associated with decreased survival. We aimed to assess whether in coronary artery diseased patients renal function impairment is associated with systemic vascular function, functional parameters of the renin-angiotensin system, or inflammation as potential mediators for cardiovascular risk. We studied 125 patients, 87% male, with a mean age of 62.2+/-8.2 years; 72% had 3-vessel disease, and mean renal function was 74+/-13 mL/min per 1.73 m2. Internal thoracic artery rings were sampled during coronary bypass surgery and used for in vitro vascular measurements. We could not establish an association between endothelium-dependent vasorelaxation (response to methacholine) and renal function. In addition, vascular response to potassium chloride, phenylephrine, and angiotensin II were not associated with renal function. Finally, serum angiotensin-converting enzyme (ACE) activity, usage of ACE inhibitors, C-reactive protein, and soluble intercellular adhesion molecule 1 were not related to renal function. In coronary artery disease patients, mild renal function impairment is not associated with systemic vasomotor responsiveness, inflammation, or functional systemic parameters of the renin-angiotensin system. The relation between systemic endothelial dysfunction and mild renal insufficiency might be more complicated than previously thought.

Mild renal insufficiency is associated with increased left ventricular mass in men, but not in women: An arterial stiffness-related phenomenon—The Hoorn Study

Mild renal insufficiency has recently been recognized as an important risk factor for cardiovascular disease (CVD). The mechanisms underlying this association are incompletely understood. Increased left ventricular mass (LVM) is an independent risk factor for CVD, which is particularly common in end-stage renal disease (ESRD) and which has been shown to be associated with mild renal insufficiency. Increased arterial stiffness has also been shown to be an independent risk factor for CVD in ESRD and has also been associated with mild renal insufficiency. We hypothesized that the association between mild renal insufficiency and increased LVM could be mediated through increased arterial stiffness, and that this may be one of the pathways linking mild renal insufficiency to CVD. We therefore investigated, in a cross-sectional population-based study, the influence of increased arterial stiffness on the association between renal function and LVM. The study population consisted of 742 elderly individuals (373 men and 369 women). Renal function was estimated by the serum creatinine level in micromol/L; by the Cockcroft-Gault formula in mL/min and by the Modification of Diet in Renal Disease (MDRD) formula. LVM was obtained by echocardiography. The mean estimates of renal function in men and women were, respectively, 103.7 (SD 17.0) and 86.8 (SD 11.2) micromol/L for the serum creatinine level; 63.4 (SD 12.9) and 61.4 (SD 11.0) mL/min/1.73 m(2) for the Cockcroft-Gault formula; and 59.7 (SD 10.8) and 60.9 (SD 10.5) mL/min per 1.73 m(2) for the MDRD formula. LVM was 93.1 (SD 26.4) g/m(2) in men and 86.7 (SD 22.3) g/m(2) in women. In men, impaired renal function, as estimated by the Cockcroft-Gault and the MDRD formula, was significantly associated with greater LVM after adjustment for age, glucose tolerance, hypertension, and prior CVD [regression coefficient beta (95% CI), 1.28 (0.22 to 2.33) g/m(2) and 1.63 (0.41 to 2.86) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. However, the association between impaired renal function and increased LVM was not statistically significant after adjustment for arterial stiffness estimates [regression coefficient beta (95% CI), 0.02 (-1.60 to 1.64) g/m(2) and 0.54 (-1.25 to 2.33) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. In women, impaired renal function was not significantly associated with greater LVM. Our study shows that in a general elderly population, even mild impairment of renal function is associated with adverse changes in left ventricular structure. In men, but not in women, this leads to greater LVM, a process that may be related to increases in arterial stiffness. Importantly, these novel findings suggest that such changes occur early in the process of renal functional deterioration, which may explain, in part, the increase in cardiovascular risk in men with mildly impaired renal function.

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

Clinical and Hemodynamic Follow-up of a Patient After Operation for Dissection of an Ascending Aortic Aneurysm Secondary to Coarctation of the Aorta

We present clinical follow-up of a 20-year-old male with an aortic aneurysm secondary to aortic coarctation. The diagnosis of aortic aneurysm secondary to aortic coarctation was made in 1997. The patient did not agree to undergo any invasive or therapeutic procedures at that time. He presented to an emergency unit with severe chest pain after chest trauma obtained during judo exercises in 1998. Two-dimensional echocardiography showed bicuspid aortic valves, an ascending aortic aneurysm 6 cm in diameter with an intimal flap and false lumen, aortic coarctation distal to the left subclavian artery, and aortic insufficiency secondary to annular dilatation. Type II aortic dissection was confirmed by transesophageal echocardiography, which showed the dissection was confined to the ascending aorta. The dissection extended to the beginning of the arcus aorta. Following stabilization of the patient's clinical condition, balloon coarctation angioplasty was performed to reduce afterload and hypertension and to facilitate femoral artery cannulation for cardiopulmonary bypass. Surgical procedures included resection of the aortic valve and prosthetic valve implantation, resection of the ascending aorta, and interposition of a 22 mm Hamashied tubular vascular graft. At a follow-up visit 6 years later, the patient reported being easily fatigued and having palpitations. He had been suffering from hemolytic anemia and mild renal function impairment. Cardiac catheterisation and angiography showed a 40 mmHg gradient due to kinking of the aortic graft and no gradient at the coarctation site. We postulated the kinking of the aortic vascular graft may be related to an inappropriate vascular graft length. We also thought that the severe hemolysis was attributable to the disturbance of blood flow by a jet of blood at the site of the kinking aortic vascular graft. A second operation was performed because the renal function of the patient had decreased progressively and hemolysis symptoms increased. After the second operation, hemolysis on peripheral blood smears had disappeared and renal function had shown progressive improvements.

PK/PD and Safety of a Single Dose of TMX‐67 (Febuxostat) in Subjects with Mild and Moderate Renal Impairment

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2‐fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre‐dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.

Pilot study of the optimum hematocrit for patients in the predialysis stage after renal transplantation

Anemia is a common complication in patients with chronic kidney diseases including posttransplant patients. Guidelines for the treatment of anemia in chronic kidney disease published by NHF-K/DOQI recommend the target hemoglobin and hematocrit (Hb and Ht) levels to be in the 11 to 12 g/dL and 33% to 36% ranges, respectively, which are somewhat higher than those recommended in Japan (Ht = 30%). However, these guidelines were established mainly from the data on hemodialysis patients with only limited information available as to the impact of anemia control in posttransplant patients. The aim of the present study was to evaluate cardiac function and quality of life (QOL) when the Ht was raised to about 36% by administration of recombinant-human-erythropoietin (rHuEPO) to patients with mild impairment of renal function (s-Cre < 2.0 mg/dL) after renal transplantation. Twenty-five patients were analyzed for cardiac function, blood data, and QOL in a prospective study encompassing 8 months of rHuEPO treatment. Using a once weekly subcutaneous dose of 6000 IU of Epoetin-β, the Ht became 33% to 36% and Hb was 11 to 12 g/dL. Among the cardiac function tests, left ventricular end-diastolic diameter and left ventricular mass index decreased significantly. QOL did not show any significant changes after administration of rHuEPO. In conclusion, we demonstrated a potential benefit of using rHuEPO to maintain the Hb between 11 and 12 g/dL and the Ht between 33% and 36% in posttransplant patients with regard to the prevention of cardiovascular complications. Further study is required to establish the benefits of correcting anemia by rHuEPO on the outcome of posttransplant patients.

Membranoproliferative glomerulonephritis in association with chronic lymphocytic leukaemia: a report of three cases

The reported association of glomerular disease with chronic lymphocytic leukaemia (CLL) is rare despite the relative frequency of this type of leukaemia. Hence, we have examined the renal biopsies in three patients with CLL and glomerulonephritis. Renal biopsies were examined by light microscopy, immunofluorescence microscopy and electron microscopy. One of two patients with mild impairment of renal function and an active urinary sediment had ultrastructural features of idiopathic type I membranoproliferative glomerulonephritis (MPGN), and the other had features of fibrillary/ immunotactoid glomerulonephritis with deposits of IgG and C3. One patient with nephrotic syndrome had characteristic electron microscopic appearances of type III MPGN. In all three there was an association with monoclonal gammopathy. The parameters of glomerular damage improved in association with response to drug treatment of the CLL. There is a spectrum of types of MPGN seen in patients with CLL and there appears to be an association with the presence of monoclonal gammopathy. This is the first reported case of type III MPGN in CLL.

Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis.

An increasingly important approach to the management of patients with severe psoriasis is the concurrent use of two systemic treatments. Previous guidelines have advised against the use of methotrexate and cyclosporin in combination. We report the successful use of a combination of methotrexate and cyclosporin in the treatment of 19 patients with severe, recalcitrant psoriasis, 15 of whom had psoriatic arthropathy. Most patients had previously received two or more systemic treatments. Before combination treatment was started nine of the patients were taking methotrexate and 10 were taking cyclosporin at the maximum tolerated doses. The duration of combination treatment was bimodally distributed, with seven patients having short-term treatment (mean +/- SD duration 18. 9 +/- 15.7 weeks) and 12 patients having long-term treatment (mean +/- SD duration 193.2 +/- 160.6 weeks). Those patients who received short-term treatment did not develop any evidence of toxicity from either agent. Of those patients on long-term treatment, three developed mild impairment of renal function that returned to normal following a reduction in dose of cyclosporin, and three had impairment of renal function (following long-term cyclosporin monotherapy) that improved, but did not normalize, following a reduction in dose of cyclosporin. In each case, combination treatment for psoriasis resulted in good control of both skin and joint problems using lower doses of each agent than would have been used for monotherapy. We conclude that the combination of methotrexate and cyclosporin is an effective treatment for this group of patients.

Urinary excretion of paclitaxel and metabolites in a large series study

Objective. Paclitaxel is an antineoplastic agent with significant activity against several tumour types. The major portion of the drug disposition (80-90%) in volves metabolism and biliary excretion. The purpose of this study was to investigate the relationships between the mean urinary paclitaxel excretion frac tion and the administered dose, creatinine clearance, or the measured paclitaxel area under the plasma concentration versus time curve. Design. The design used was a retrospective convenience sample study. Setting. The setting for this study was a hospi talised care center. Patients. A total of 103 24-hour urine collections from 60 patients treated with paclitaxel were used to investigate these relationships. Results. In this large series study, the paclitaxel urinary fraction was 5 ± 3% (mean ± SD) as a fraction of the administered paclitaxel dose. No correlations were found between the paclitaxel urinary excretion fraction and the administered dose, creatinine clear ance, and plasma concentration-time curve. In addi tion, the paclitaxel metabolites 6α-hydroxypaclitaxel, 3'- p-hydroxypaclitaxel and some unidentified com pounds were detected in the 24-hour urine samples of two patients, of whom one had a mild impaired renal function. Conclusions. Considering the low urinary ex cretion of paclitaxel, it is anticipated that patients with renal dysfunction require no dose adjustments. Metabolites were found in the urine.