Consequences of treated versus untreated asymptomatic bacteriuria in the first year following kidney transplantation: retrospective observational study.

Asymptomatic bacteriuria (AB) is frequent among kidney transplant patients during the first year post transplantation. Currently, there are no clear guidelines for the antibiotic treatment of AB among these patients. We examined the outcomes of treatment versus no treatment of AB in kidney transplant patients during the first year post transplantation. A retrospective cohort study including adults >16 years of age transplanted in one center between 1/2004 and 12/2010 was undertaken. The primary outcome was a composite of hospitalization for symptomatic urinary tract infection (UTI) or more than 25 % reduction in the estimated glomerular filtration rate (eGFR) 30 days after the documentation of AB. Secondary outcomes included symptomatic UTIs following the episode of AB, persistent recurrent AB, total days in hospital, mortality, adverse events, and resistance development. A total of 112 patients with AB fulfilled the inclusion criteria. Twenty-two patients received antibiotic treatment (19.6 %), while 90 patients did not. The primary outcome occurred in 4/22 (18.2 %) of the treated patients versus 5/90 (5.6 %) of the untreated patients [odds ratio (OR) = 3.78, 95 % confidence interval (CI) 0.9-15]. The risk of developing symptomatic UTI after AB was almost three times higher (p < 0.05) and the total number of hospitalization days at 6 months post AB was also significantly higher (p < 0.026) in the treated group. No patient died during the study period. UTI caused by bacteria resistant to the antibiotic used for the treatment of AB occurred in 36 % of the treated patients. We observed no benefit for the antibiotic treatment of AB in the short- and long-term follow-up. A prospective observational study is needed.

Antibiotic prophylaxis for urinary tract infections in renal transplant recipients: a systematic review and meta-analysis.

Urinary tract infection (UTI) is the most common bacterial infection in renal transplant recipients. To date there are no guidelines on antibiotic prophylaxis for UTI in this population. We conducted a systematic review and meta-analysis of randomized controlled trials comparing antibiotic prophylaxis vs. placebo, no intervention, or different antibiotics, all beginning postoperatively and continued for at least 1 month during the first 6 months post transplantation. The search included CENTRAL, PubMed, LILACS, and relevant conference abstracts up to August 2009. The primary outcome was graft loss. Six trials were included in this review, including 545 patients. No significant difference was seen in graft loss (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.91-1.81). Prophylaxis lowered the risk for developing sepsis with bacteremia by 87% (RR 0.13, 95% CI 0.02-0.7) and the risk for developing bacteriuria (symptomatic or asymptomatic) by 60% (RR 0.41, 95% CI 0.31-0.56; 3 trials). Symptomatic UTI and pyelonephritis were not reported. No significant reduction was found in all-cause mortality and adverse events rates; conflicting results were reported for the development of resistant bacteria. Very few trials assessed the efficacy of prophylaxis for UTI following renal transplantation. Prophylaxis reduced bacteriuria and sepsis with bacteremia; effects on graft survival could not be demonstrated.

Effect of sevelamer hydrochloride exposure on carotid intima media thickness in hemodialysis patients.

BACKGROUND: Elevated phosphorus (P) and calcium (Ca)-P product (Ca × P) are associated with vascular calcification and cardiovascular disease (CVD) morbidity and CVD and all-cause mortality. OBJECTIVES: This study examined the effect of sevelamer hydrochloride exposure (regardless of calcium carbonate exposure) on carotid and femoral intima media thickness (IMT), reliable surrogate measures of prospective intimal thickening, in end-stage renal disease patients on maintenance hemodialysis. METHODS: The present cross-sectional study is nested in the Sevelamer hydrochloride and ultrasound-measured femoral and carotid intima media thickness progression in end-stage renal disease (SUMMER) clinical trial. Carotid and femoral arteries were visualized in B-mode ultrasonography. Log-transformed IMT was compared by sevelamer hydrochloride exposure and modeled using multiple linear regression. RESULTS: Forty-five subjects were exposed to sevelamer hydrochloride and 130 were not. Exposed subjects had significantly lower carotid IMT, an association which persisted in the multiple linear regression model even after controlling for potentially confounding variables including serum Ca, history of CVD and body weight. Exposed subjects had lower low-density lipoprotein cholesterol levels and significantly higher parathyroid hormone, but no differences in P, Ca and Ca × P. CONCLUSIONS: Sevelamer hydrochloride was associated with lower carotid IMT. This association may be mediated through reduction in Ca load, low-density lipoprotein cholesterol lowering or some other pleiotropic effect.

Celiac territory ischemic syndrome in a patient on chronic hemodialysis.

Mesenteric ischemia among chronic dialysis patients is usually of the nonocclusive type. Chronic occlusive mesenteric ischemia has been reported rarely in the dialysis population. The subset of"celiac-territory ischemic syndrome" has not been described in dialysis. The current report involves a 66-year-old female on chronic dialysis for 11 years. She experienced abdominal pain following sessions of hemodialysis, that later became more pronounced after eating. Abdominal angiography showed heavily calcified aorta, celiac trunk and superior mesenteric artery (SMA), with a 50% narrowing of the celiac and superior mesenteric arteries. During the following 9 months the symptoms worsened and weight loss set in. She was admitted with an episode of upper abdominal pain. Acalculous cholecystitis was found, along with multiple gastric and duodenal erosions including the second part, with an antral ulcer and multiple duodenal bulb ulcers. Repeated abdominal angiography showed progression of the stenotic lesions with significant narrowing of both the celiac trunk and the SMA. A stent was placed in the SMA. Following the procedure, the patient noted marked symptomatic improvement. On follow-up gastroduodenoscopy, all ischemic ulcers had healed completely. Serum albumin rose from a nadir of 31 to 40 g/l, and an extremely elevated c-reactive protein of 205,000 microg/l returned to normal (8,000 microg/l). The diagnosis of chronic occlusive mesenteric ischemia should be suspected among dialysis patients with post-prandial pain and weight loss in the face of calcified vessels. Predominant celiac territory ischemic syndrome presents as gastric and duodenal erosions and ulcers with or without acalculous cholecystitis.

Synergistic effect of AS101 and Bryostatin-1 on myeloid leukemia cell differentiation in vitro and in an animal model.

We evaluated the synergistic activity of AS101 (ammonium trichloro-(dioxoethylene-0-0')-tellurate) with the protein kinase C (PKC) activators, Bryostatin-1 and phorbol-12-myristate-13-acetate (PMA), on human myelocytic leukemia cell differentiation in vitro, and in a mouse model. Use of AS101 with Bryostatin-1 or with a low concentration of PMA resulted in the differentiation of HL-60 cell line to cells with characteristics of macrophages. A similar synergistic effect was found in vivo. Compared with mice treated with AS101 alone or with Bryostatin-1 alone, the infiltration of leukemic cells into the spleen and the peritoneum of mice treated with both compounds, as well as the number of the HL-60 colonies extracted from those organs, were markedly reduced. The antitumor effects were associated with significantly prolonged survival (100% for 125 days) of the treated mice. Finally, the mechanism of action of this antitumor effect was explored, and was found to involve the Ras/extracellular signal-regulated kinase signaling pathway. Combined treatment with AS101 and Bryostatin-1 synergistically increased p21(waf1) expression levels independently of p53. Upregulation of p21(waf1) was necessary for HL-60 cell differentiation, which was found to be both c-raf-1 and mitogen-activated protein kinase dependent. This study may have implications for the development of strategies to induce differentiation in myeloid leukemias, myelodysplasias and possibly in other malignancies.

Elevated serum alkaline phosphatase levels in a renal transplant patient precede colitis.

An asymptomatic, but highly significant, rise in serum alkaline phosphatase (AP) levels developed in a renal transplant recipient. Investigations ruled out bony or hepatobiliary disease. Subsequent diarrhea and weight loss led to a diagnosis of cytomegalovirus (CMV) colitis, which was confirmed with a positive CMV pp65 antigenemia test and an endoscopic finding of multiple colonic erosions. Intravenous ganciclovir led to complete patient recovery and a swift reduction of serum AP levels to normal. Normally, intestinal AP isoenzymes are cleared quickly from the circulation. However, acute bowel diseases, especially when inflammatory in origin, can produce high serum AP levels. In this presented patient, the rise in serum AP levels preceded symptomatic manifestations of CMV colitis, and fell with successful therapy. Acute CMV disease in solid organ transplant recipients is common, can take many shapes, and needs to be diagnosed quickly. An unexplained rise in serum AP levels should lead to a search for inflammatory bowel disease, specifically CMV colitis, in transplanted patients.

A questionnaire for the assessment of pruritus: validation in uremic patients.

A questionnaire was constructed for the evaluation and measurement of pruritus. The questionnaire, based on the short form of the McGill Pain Questionnaire, was tested in 145 patients suffering from uremic pruritus and currently undergoing hemodialysis treatment in 3 centers. The newly developed questionnaire proved to be reliable and provided valid data on the sensory, affective and overall intensity of uremic pruritus. The data suggest that uremic pruritus tends to be prolonged, frequently intense and a major source of distress to the patient. Dialysis was not found to influence the pruritus. The questionnaire may also be useful in pruritus secondary to other causes.

Delayed branching of endothelial capillary-like cords in glycated collagen I is mediated by early induction of PAI-1.

Development of micro- and macrovascular disease in diabetes mellitus (DM) warrants a thorough investigation into the repertoire of endothelial cell (EC) responses to diabetic environmental cues. Using human umbilical vein EC (HUVEC) cultured in three-dimensional (3-D) native collagen I (NC) or glycated collagen I (GC), we observed capillary cord formation that showed a significant reduction in branching when cells were cultured in GC. To gain insight into the molecular determinants of this phenomenon, HUVEC subjected to GC vs. NC were studied using a PCR-selected subtraction approach. Nine different genes were identified as up- or downregulated in response to GC; among those, plasminogen activator inhibitor-1 (PAI-1) mRNA was found to be upregulated by GC. Western blot analysis of HUVEC cultured on GC showed an increase in PAI-1 expression. The addition of a neutralizing anti-PAI-1 antibody to HUVEC cultured in GC restored the branching pattern of formed capillary cords. In contrast, supplementation of culture medium with the constitutively active PAI-1 reproduced defective branching patterns in HUVEC cultured in NC. Ex vivo capillary sprouting in GC was unaffected in PAI-1 knockout mice but was inhibited in wild-type mice. This difference persisted in diabetic mice. In conclusion, the PCR-selected subtraction technique identified PAI-1 as one of the genes characterizing an early response of HUVEC to the diabetic-like interstitial environment modeled by GC and responsible for the defective branching of endothelial cells. We propose that an upregulation of PAI-1 is causatively linked to the defective formation of capillary networks during wound healing and eventual vascular dropout characteristic of diabetic nephropathy.

Hepatitis C infection in dialysis patients in Israel.

BACKGROUND: Hepatitis C virus is the major cause of acute and chronic hepatitis in patients with end-stage renal disease receiving replacement therapy. OBJECTIVES: To define the prevalence of HCV RNA in a population of patients on dialysis in Israel, to determine the relative risk of acquiring HCV infection while treated by hemodialysis or chronic ambulatory peritoneal dialysis, and to define the HCV genotypes in this population. METHODS: During 1995 we studied 162 dialysis patients. Information was obtained regarding the mode of dialysis, years of treatment, number of blood transfusions, and results of serological testing for HCV, hepatitis B virus, and human immunodeficiency virus. Anti-HCV antibodies were tested by a third-generation microparticle enzyme immunoassay. HCV RNA was determined by polymerase chain reaction. HCV genotyping was performed by a hybridization assay. RESULTS: HCV RNA was detected in 18% of the HD group and 7% of the CAPD group. The number of HCV RNA-positive patients was significantly higher in the HD than the CAPD group (P < 0.05). HCV RNA-positive HD patients were treated longer than the HCV RNA-negative patients (P < 0.02). CONCLUSIONS: Third-generation immunoassay proved to be highly sensitive (94%) and specific (91%) in identifying HCV RNA positivity. Several HCV subtypes were detected, 1b being the most frequent. Identification and isolation of infected HCV patients may minimize its spread in dialysis units and prevent cross-infection.

Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients.

Cancer incidence is enhanced in transplant recipients. Decreased DNA repair ability is associated with increased cancer incidence. Transplanted patients with cancer were found to have reduced DNA repair. We hypothesized that immunosuppressive therapy may impair DNA repair and thus contribute to the increased cancer incidence in transplanted patients. The objectives of this study were (1) to investigate the effect of two immunosuppressive treatment protocols on DNA repair in kidney transplant recipients; (2) to evaluate the cancer incidence in these patients; and (3) to study the in vitro effect of cyclosporin A (CsA), azathioprine, and prednisolone-separately and in various combinations-on DNA repair. Three groups were studied: (1) a control group; (2) patients treated with azathioprine and prednisone (double-therapy group); and (3) patients treated with CsA, azathioprine, and prednisone (triple-therapy group). The two patient groups did not differ in age, gender, time on dialysis before transplantation, or kidney function or in the number of acute rejections. However, the interval from transplantation to the DNA repair study was shorter in the triple-therapy group (P <.01). DNA repair was induced in peripheral blood mononuclear cells (PBMCs) by ultraviolet irradiation and expressed as tritiated thymidine uptake by these cells. DNA repair in the triple-therapy group was 679 +/- 64 cpm/10(6) cells, significantly less than that in the control group (1049 +/- 69 cpm/10(6) cells, P <.02). In the double-therapy group, DNA repair was similar to that in the control group. The follow-up period was shorter in the triple-therapy group (116 +/- 19 months vs 174 +/- 29 months, P <.01). Five tumors developed in the triple-therapy group, but only one developed in the double-therapy group (P =.05). The in vitro study showed a dose-dependent reduction in PBMC DNA repair by CsA. Azathioprine and prednisolone reduced DNA repair slightly, but CsA reduced DNA repair significantly more than either one or a combination of them. In summary, triple therapy was associated with impaired PBMC DNA repair and increased cancer incidence. CsA was responsible in large part for the reduction in DNA repair ability found in the in vitro and in vivo studies. This may have partly contributed to the enhanced cancer incidence in the kidney transplant recipients.

Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.

BACKGROUND: Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease. METHODS: Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40-75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality. FINDINGS: A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0.46 [95% CI 0.27-0.78], p=0.014). Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarction (0.3 [0.11-0.78], p=0.016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected. INTERPRETATION: In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction.

Haemolysis in haemodialysis patients: evidence for impaired defence mechanisms against oxidative stress.

BACKGROUND: Uraemic patients have a decreased ability to withstand oxidative stress. It is postulated that their antioxidant capacity is reduced, yet the mechanism remains unclear. Recently 33 haemodialysis (HD) patients were exposed to chloramine contamination in the water supply. This led to haemolysis in 24 patients, while nine were unaffected. In the former group haemoglobin decreased from 11.7+/-1.1 to 8.5+/- 1.4 g/dl (P<0.0001) and returned to 11.4+/-0.9 g/dl (P<0.0001) following recovery. During haemolysis, haptoglobin was 38.4+/-10.6 vs 138.1+/-8.3 ng/dl (P<0.0001) following recovery. METHODS: To explore the factors affecting the severity of haemolysis we studied extracellular and intracellular anti-oxidant defence mechanisms 3 months after recovery. In 29 patients and 20 controls we determined plasma glutathione (GSH), and the erythrocyte enzymes glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rx), and superoxide dismutase (SOD). Serum malondialdehyde (MDA) was measured as a marker of oxidative stress. RESULTS: Plasma GSH was lower in patients as compared to controls (5.49+/-0.26 vs 7.4+/-0.5 micromol/l, P<0.005). There was an inverse correlation between GSH and the degree of haemolysis (r=-0.42, P<0.02). Patients had higher GSH-Rx (4.64+/-0.15 vs 3.97+/-0.12 U/gHb, P<0.02), lower GSH-Px (29. 7+/-1.85 vs 35.5+/-1.62 U/gHb, P<0.001), and similar SOD (0.63+/-0. 02 vs 0.51+/-0.02 U/mgHb) as compared to controls. There was no correlation between the enzyme levels and the degree of haemolysis. MDA was higher in patients (2.37+/-0.07 vs 0.97+/-0.1 nmol/ml, P<0. 0001). There was a correlation between MDA and the years patients were on HD (r=0.43, P<0.02). CONCLUSIONS: These data indicate that HD patients have an impaired anti-oxidant response, which may be attributed in part, to plasma GSH deficiency. Patients with the lowest plasma GSH levels are more susceptible to oxidative stress and consequent haemolysis.

Pregnancy outcome in women with primary renal disease.

BACKGROUND: The preconception and intraconception parameters that are relevant to outcome in women with underlying renal disease remain controversial. OBJECTIVES: To analyze the types and frequencies of short- and long-term (2 years after delivery) maternal and neonatal complications in 38 patients with primary renal disease (46 pregnancies), most of them with mild renal insufficiency. METHODS: Logistic regression models were formulated to predict successful outcome. RESULTS: Successful pregnancy outcome (live, healthy infant without severe handicap 2 years after delivery) was observed in 98% of the patients with primary renal disease. Factors found to be significantly predictive of successful outcome were absence of pre-existing hypertension, in addition to low preconception serum uric acid level. CONCLUSIONS: Most women with primary renal disease who receive proper prenatal care have a successful pregnancy outcome. Worse pregnancy outcome was observed in women with moderate or severe renal failure. Fitted logistic models may provide useful guidelines for counseling women with preexisting renal disease about their prospects for a successful pregnancy in terms of immediate and long-term maternal and neonatal outcome.

Glomerular hemodynamics in severe obesity.

Differential solute clearances were used to characterize glomerular function in 12 nondiabetic subjects with severe obesity (body mass index >38). Nine healthy subjects served as the control group. In the obese group, glomerular filtration rate (GFR) and renal plasma flow (RPF) exceeded the control value by 51 and 31%, respectively. Consequently, filtration fraction increased. The augmented RPF suggested a state of renal vasodilatation involving, mainly or solely, the afferent arteriole. Albumin excretion rate and fractional albumin clearance increased by 89 and 78%, respectively. Oral glucose tolerance tests were suggestive of insulin resistance. Insulin resistance was positively correlated with GFR (r = 0.88, P<0.001) and RPF (r = 0.72, P <0.001). Mean arterial pressure was higher than in the control group. Fractional clearances of dextrans of broad size distribution tended to be lowered. The determinants of the GFR were estimated qualitatively by using a theoretical model of dextran transport through a heteroporous membrane. This analysis suggests that the high GFR in very obese subjects may be the result of an increase in transcapillary hydraulic pressure difference (DeltaP). An abnormal transmission of increased arterial pressure to the glomerular capillaries through a dilated afferent arteriole could account for the augmentation in DeltaP.

Lymphocytic intracellular calcium in a patient with complicated verapamil overdose.

Overdose with calcium channel blockers (CCBs) may lead to serious complications. CCBs act by blocking calcium entry into the cell, thus lowering intracellular calcium ([Ca2+]i). [Ca2+]i during CCB overdose has not yet been reported. We measured [Ca2+]i in lymphocytes of a patient with acute verapamil overdose with a complex clinical picture. A 59-year-old woman was admitted after a suicidal ingestion of 7200 mg of a sustained-release verapamil preparation. She presented with hypotension, complete atrioventricular block, stupor, hypokalemia, and hyperglycemia. Acute oliguric renal failure, acute pancreatitis, and the adult respiratory distress syndrome further complicated her medical course. Treatment was supportive and she recovered completely. Intracellular calcium ([Ca2+]i) was measured in the patient's lymphocytes using a spectrofluorometer with the calcium-sensitive dye Fura-2-acetoxymethyl ester. Thirty nine hours after the ingestion, [Ca2+]i was low at 52 nM (compared with 80 nM in a healthy control subject). Lymphocytic [Ca2+]i did not respond to stimulation with phytohemagglutinin (PHA). Fourteen days after the verapamil overdose, after the patient had recovered completely, lymphocytic [Ca2+]i was still low at 55 nM. At this time, there was an incomplete response to PHA in the lymphocytes. Three months after the ingestion, [Ca2+]i was normal, with a normal response to PHA. Verapamil overdose may run a complex clinical course, but full recovery is to be hoped for with full supportive care. Cellular intoxication, as reflected by low lymphocytic [Ca2+]i, is prolonged and lags behind the clinical recovery by weeks.

Erythropoietin, folic acid deficiency and hyperhomocysteinemia: is there a possible relationship in chronically hemodialyzed patients?

AIMS: To examine the possible relationships between recombinant human erythropoietin (rhEPO) therapy, serum folic acid and homocysteine levels in a cohort of stable, chronically hemodialyzed patients. MATERIAL AND METHODS: The study was cross-sectional in its first phase and consisted of 3 groups of subjects (group 1:6 healthy controls; group 2:7 dialyzed patients not receiving rhEPO; group 3: 14 patients on rhEPO therapy). Hematological and biochemical parameters were taken after an overnight fast in all subjects. The second phase of the study was prospective, and included 8 dialyzed patients, and investigated the effects of a 6-month period of folic acid supplementation (10 mg, 3 times a week) on the same parameters examined in the first phase of the study. RESULTS: In the first part of the study hemoglobin levels were near-normal, or normal, in all patients. No differences in hemoglobin or hematocrit values were observed in the 3 groups. 80% of all hemodialyzed patients had low serum folic acid levels, irrespective of whether they were receiving rhEPO. Serum erythropoietin level was elevated in group 3 (23.3+/-10.4 mIU/ml). In group 2, serum erythropoietin level was not different from that of the healthy controls (13.5+/-11.2 vs. 8.0+/-5.4 mIU/ml, p = n.s.). Total serum homocysteine levels were elevated in all dialyzed patients (group 2: 24.7+/-9.2 micromol/l; group 3: 31.6+/-14.4 micromol/l), with a significant difference seen when comparing controls and those dialyzed patients on rhEPO therapy (8.7+/-2.2 vs. 31.6+/-14.4 micromol/l; p<0.05). Significant correlations (ANOVA) were observed between serum erythropoietin and folic acid levels (r = -0.382; p = 0.049), and between folic acid and homocysteine levels (r = -0.560; p = 0.002). In the second part of the study folic acid supplementation led to a highly significant reduction in homocysteine levels (20.9+/-4.9 vs. 11.9+/-2.5 micromol/l; p<0.0005). Two of 3 patients receiving rhEPO therapy, had rhEPO discontinued after commencing folic acid, as hemoglobin levels remained adequate, even without rhEPO. CONCLUSIONS: In hemodialyzed patients, the presence of a near-normal hemoglobin level, irrespective of rhEPO therapy, implies efficient erythropoiesis. Without adequate folic acid reserves, folic acid deficiency may develop in these patients and this will aggravate already high homocysteine levels. Therefore, folic acid supplementation is warranted in hemodialyzed patients, especially in those patients with hemoglobin levels approaching normal. This treatment is safe and effective in reducing homocysteine levels, especially when given in high doses for prolonged periods of time.