Primary Epstein-Barr virus infection, seroconversion, and post-transplant lymphoproliferative disorder in seronegative renal allograft recipients: a prospective cohort study.

BACKGROUND: Epstein-Barr virus (EBV)-seronegative renal transplant recipients are at risk of post-transplant lymphoproliferative disorder (PTLD). We compared primary EBV infection, seroconversion, and PTLD in EBV-seronegative patients who received renal allograft from seropositive or seronegative donors (D+/R- and D-/R-, respectively). METHODS: We prospectively followed 25 D+/R- and 8 D-/R- recipients. We followed patients from January 1999 to June 2009 with clinical visits, monthly EBV polymerase chain reaction tests, and serologic tests for a period of 1 year after kidney transplantation and on an individual basis thereafter. RESULTS: Three patients (9%) developed PTLD including 2 early-onset (<12 months) and 1 late-onset (>12 months) disease. In D+/R- and D-/R- patients, the frequencies of PTLD (8% vs. 12.5%, P = 0.7), EBV seroconversion (64% vs. 50%, P = 0.4), and EBV viremia (40% vs. 25%, P = 0.6) were not significantly different. Clinical, serologic, and virologic surveillance as well as reduction in immunosuppression after evidence of primary EBV infection resulted in a PTLD rate of 9%, despite a seroconversion rate of 60.6%. Rate of graft loss after reduction in immunosuppression was 10% (2 of 20), which was not significantly different from 13 patients without EBV seroconversion (no graft loss, P = 0.5). Rates of viremia, seroconversion, and PTLD in D+/R- and D-/R- patients appear to be similar. CONCLUSIONS: The incidence of PTLD in renal transplants ranges from 0.5% to 2.9%. Our data show a significantly higher rate in EBV-seronegative renal allograft recipients, suggesting the need for close surveillance. Our data also suggest that donors for EBV-seronegative recipients may be accepted irrespective of positive or negative serostatus, with ongoing surveillance important in either circumstance.

Fate of the mate: the influence of delayed graft function in renal transplantation on the mate recipient.

Delayed graft function (DGF) in a deceased-donor renal recipient is associated with allograft dysfunction 1-year posttransplant. There is limited research about the influence to allograft function on the mate of a DGF recipient over time. Using a retrospective cohort design, we studied 55 recipients from a single center. The primary outcome was the change in glomerular filtration rate (GFR) 1-year posttransplant. The secondary outcome was the GFR at baseline. We found that mates to DGF recipients had a mean change in GFR 1-year posttransplant of -11.2 mL/min, while the control group had a mean change of -0.4 mL/min. The difference in the primary outcome was significant (p = 0.025) in a multivariate analysis, adjusting for cold ischemic time, panel reactive antibody level, allograft loss, human leukocyte antibody (HLA)-B mismatches and HLA-DR mismatches. No significant difference between groups was found in baseline GFR. In conclusion, mates to DGF recipients had a significantly larger decline in allograft function 1-year posttransplant compared to controls with similar renal function at baseline. We believe strategies that may preserve allograft function in these'at-risk'recipients should be developed and tested.

Cardiovascular risk in hemodialysis patients: a mechanistic approach.

A new formula is proposed to express the excess burden of cardiovascular risk faced by hemodialysis patients as a function of various inherent, acquired and potentially modifiable factors. The proposed equation CVR(HD) = CVR(B) X f(([CKD+HD]/[HD(tech)+Dr])+X) includes the terms: CVR(HD) (cardiovascular risk in hemodialysis patients); CVR(B) (baseline cardiovascular risk); CKD (risk associated with chronic kidney disease); HD (risks associated with the process of hemodialysis); HD(tech) (benefits of new hemodialysis technologies); Dr (benefits of drug therapies) and X (unknown or putative factors influencing cardiovascular morbidity). We review the various factors included in this proposed formula, touching upon the epidemiology, pathophysiology and therapeutic implications, including possible strategies to modify risk. As is apparent from the formula, CKD and HD in particular act as risk multipliers in augmenting or amplifying the baseline cardiovascular risk, while new hemodialysis technologies may provide an opportunity for "cardioprotective dialysis". Drug treatment may serve to mitigate some of the risk unique to this population.

Anti-inflammatory drugs and the kidney.

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) enjoy widespread use in clinical practice, leading to a remarkable frequency of unwanted renal side effects. In most cases, NSAID-induced acute renal failure or acute kidney injury is hemodynamically mediated. Clinical syndromes associated with NSAID use include acute renal failure, acute interstitial nephritis, worsening of chronic kidney disease (CKD), salt and water retention and hypertension. Careful monitoring of renal function is advisable in patients at increased risk such as elderly individuals with compromised cardiac reserve, and diabetics.

Integration of blood volume, blood pressure, heart rate and bioimpedance monitoring for the achievement of optimal dry body weight during chronic hemodialysis.

BACKGROUND: Achieving optimal dry body weight in hemodialysis is challenging. Clinical assessment alone is inadequate, and methods such as bioimpedance monitoring may be impractical for every patient treatment. Continuous blood volume monitoring, blood pressure and heart rate variability inform clinical decision-making, but integrated use of multiple methodologies to achieve dry weight and understand patient factors has not yet been described. METHODS: Nineteen chronic hemodialysis patients underwent thrice-weekly treatments for two weeks. Baseline hydration status and target weight were determined by bioimpedance. During subsequent treatments, ultrafiltration was adjusted and relative blood volume, blood pressure and pulse were recorded non-invasively. Bioimpedance was repeated to assess hydration. Response of variables to progressive change in weight was assessed and selected patients underwent additional autonomic function testing. RESULTS: Four distinct hemodynamic patterns emerged. Profile A: 4 patients demonstrated overhydration at baseline. With decreasing target, pulse and blood pressure remained stable while blood volume and bioimpedance demonstrated achievement of dry weight. Profile B: 8 patients demonstrated overhydration at baseline. With decreasing target, blood pressure remained stable while pulse increased. Profile C: 5 patients were overhydrated, but as weight decreased, blood pressure became unstable and heart rate failed to compensate. Further testing confirmed autonomic dysfunction. Profile D: 2 patients were dehydrated, and with increasing target demonstrated stable pulse and pressure, while blood volume and bioimpedance revealed achievement of dry weight. CONCLUSIONS: Integrating existing non-invasive, continuous monitoring during hemodialysis enabled achievement of dry weight and identified distinct profiles of the patients, some with autonomic dysfunction. This strategy may contribute to achieving optimum dry weight while improving cardiovascular tolerability of hemodialysis.

Randomized trial of high-flux vs low-flux haemodialysis: effects on homocysteine and lipids.

BACKGROUND: Uncontrolled studies have found that high-flux haemodialysis favourably modifies homocysteine and lipid profiles. We sought to confirm these findings by carrying out a randomized prospective comparison of high-flux and low-flux polysulphone in chronic, stable dialysis patients. METHODS: Forty-eight patients were randomly assigned to either high or low-flux dialysis for 3 months. Serum levels of homocysteine, lipoprotein (a), and lipids were compared between the treatment groups at monthly intervals. RESULTS: All patient characteristics and laboratory variables were equally distributed between the groups at baseline. Over the study duration, we observed no differences between high- and low-flux treatment groups for the following outcomes: pre-dialysis homocysteine, lipoprotein (a), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides (all P>0.05). Geometric mean (interquartile range) homocysteine at baseline was 20.0 (16.8-24.5) and 19.5 (15.3-22.0) micromol/l for the high-and low-flux groups respectively (P=0.80), and levels did not change significantly during the study. We did demonstrate a more pronounced intradialytic effect of high-flux dialysis on homocysteine levels, which fell during dialysis by 42%, compared to 32% with low-flux dialysis (P<0. 001). CONCLUSIONS: In this randomized controlled trial, the effects of high-flux and low-flux haemodialysis on homocysteine and lipid profiles were comparable. The greater intradialytic effect of high-flux dialysis on homocysteine did not translate into a significant difference in pre-dialysis levels after 3 months of study.

A tale of two syndromes: ovarian hyperstimulation and abdominal compartment.

Abdominal compartment syndrome complicated severe ovarian hyperstimulation in a 35 year old woman with multiple bowel resections due to Crohn's disease. Pain from ovarian enlargement necessitated hospital admission. Despite intravenous fluid administration and heparin prophylaxis, ilio-femoral deep vein thrombosis developed. Treatment by intravenous heparin was complicated by repeated intra-ovarian bleeding, anaemia and acute renal failure requiring haemodialysis. Intra-abdominal pressures were elevated. After placement of an inferior vena caval filter and discontinuation of heparin, there was slow spontaneous recovery without surgery.

Effect of multivitamins on plasma homocysteine and folate levels in patients on hemodialysis.

Hyperhomocysteinemia is a risk factor for cardiovascular disease in patients on hemodialysis. Causes include genetic enzyme deficiencies, chronic renal failure, and vitamin deficiencies. Homocysteine correlates negatively with folate status. In patients on hemodialysis, supraphysiologic doses of B vitamins and folate reduce homocysteine by 26-33%. No study has examined the effect of a standard multivitamin (Nephro-Vite Rx), containing B vitamins and 1 mg of folate, on erythrocyte-folate (RBC-folate) and homocysteine in patients on dialysis. We examined RBC-folate and homocysteine levels in 11 stable chronic patients on hemodialysis, mean duration of dialysis 9.8+/-4.1 months, who were not on vitamin or folate supplements, and repeated these levels after 3 weeks of once daily Nephro-Vite Rx dosage. Plasma homocysteine levels fell by 23.7% from 27.8+/-5.9 to 21.2+/-6.6 micromol/L (p = 0.007), whereas RBC-folate levels rose 60% from 631.2+/-208.3 to 1007.5+/-423.7 nmol/L (p = 0.001). The optimum dose of B vitamins and folate remains to be established, and a clinical benefit from lowering homocysteine has not yet been demonstrated. In summary, a standard multivitamin such as Nephro-Vite Rx reduces plasma homocysteine levels and increases RBC-folate levels in patients on hemodialysis. Our results may have implications for the modification of cardiovascular risk in these patients.

Increased mortality in hemodialyzed patients with elevated serum troponin T: a one-year outcome study.

OBJECTIVES: To determine the significance of elevated serum troponin T (cTnT) occurring in hemodialysis patients in the absence of clinical evidence of acute coronary ischemia. DESIGN AND METHODS: Twelve-month follow-up of cohort of 172 hemodialyzed patients with known serum cTnT concentration. The cohort consisted of patients undergoing hemodialysis in a hospital unit over a 5-month period, with one to four measurements of cTnT. The main outcome measure was death. Cause of death was determined by autopsy in six patients. RESULTS: Of the 31 deaths, 12 were due to acute coronary disease, 14 were noncoronary, and 5 were undefined. Death rates of patients with cTnT <0.1, 0.1-0.2, and >0.2 microg/L were 9.9% (11/111), 32.4% (12/37), and 33.3% (8/24), respectively. The increase in death rate with cTnT > or =0.1 microg/L was significant (p<0.001) for noncoronary deaths, but not for acute coronary deaths. The risk ratios for noncoronary deaths in the subgroups were: nondiabetics 6.6 (95% CI 1.9-23.6), patients with no coronary artery disease 7.3 (1.6-32.4), patients with no peripheral vascular disease 8.9 (2.0-39.7), and hypertensives 9.0 (1.1-76.5). Significant increase in coronary deaths was seen only in patients without hypertension and those aged > or =50 years. The risk ratios for these groups were 9.3 (1.2-74.3) and 3.3 (1.0-10.6), respectively. CONCLUSIONS: Serum cTnT is a potential prognostic marker of mortality in hemodialyzed patient, with increase in death from coronary and noncoronary causes.

Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities.

BACKGROUND: Before the routine use of recombinant human erythropoietin (rHuEpo), patients dialysed by peritoneal dialysis (PD) received fewer blood transfusions than patients on haemodialysis (HD). We compared transfusion practices in these groups now that the use of rHuEpo has become standard, while controlling for variables known to influence anaemia of end-stage renal disease (ESRD). Maintenance rHuEpo doses were also compared. METHODS: Data were examined for 157 HD and 126 PD patients during a 2-year period. Potential confounders included age, gender, albumin, iron deficiency, parathyroid hormone (PTH), underlying renal disease, comorbid illness, renal transplant, dialysis adequacy and duration. An intent-to-treat analysis was used, with sensitivity analyses to account for change in treatment and transplant. RESULTS: Mean haemoglobin (Hb) was not different (10.47 g/dl for HD, 10.71 g/dl for PD; P = 0.45). Mean monthly transfusion rate was higher for HD (0.47 units per month vs 0.19; P < 0.01). More HD patients received at least one transfusion (52.9 vs 40.9%; P < 0.01). The maintenance rHuEpo dose was higher for HD (7370 U/week vs 5790 U/week; P = 0.01). The only factors associated with risk of being transfused were dialysis duration and mode of dialysis (less risk for PD, odds-ratio 0.57; 95% confidence interval 0.35-0.92). CONCLUSIONS: Despite the routine use of rHuEpo, HD patients received more blood and rHuEpo than PD patients to achieve the same Hb. No patient factors were identified to account for this difference. The use of fewer transfusions and less rHuEpo in PD represents an advantage over HD in terms of both cost and safety.

Cardiac troponin T in hemodialyzed patients.

We studied the extent and pattern of increased cardiac troponin T (cTnT) concentrations in 174 hemodialyzed patients. cTnT concentrations were above 0.10 and 0.20 microg/L in 29% and 10% of patients, respectively. In patients without acute coronary disease, the highest value observed was 3.2 microg/L. cTnT increased after dialysis in 10 of 12 patients, with a mean increase of 0.14 microg/L. In 125 patients with samples taken at 1-month intervals, 34% of patients showed differences <20%, but 16% of patients had differences greater than twofold. Serum creatinine and urea, adequacy of dialysis, and duration on dialysis did not explain increased concentrations. Sixty percent of 57 diabetic patients had increased concentrations; the patients with multiple diabetic complications had the highest positivity. cTnT was increased in all eight patients with complications of neuropathy, retinopathy, coronary, and peripheral vascular disease; in 80% of patients with neuropathy; in 77% with peripheral vascular disease; in 73% with retinopathy; and in 70% with coronary artery disease.

Right heart failure due to ventricular adiposity: 'adipositas cordis'--an old diagnosis revisited.

Adiposity of the heart is characterized by an increase in the amount of epicardial and other adipose tissue. The most pronounced changes involve the right ventricle. The adipocytes may be interposed between myocytes, and in severe cases the normal mechanics and function of the ventricle are impaired. Adiposity of the heart is usually an incidental finding at autopsy, and only rarely is it of clinical significance. This report describes a 46-year-old female with multiorgan failure secondary to bronchopneumonia, purulent pericarditis, tamponade and sepsis, whose clinical course was altered due to severe adiposity of the heart, so-called 'adipositas cordis'.

Mechanism-based inactivation of cytochrome P450 1A1 by N-aralkyl-1-aminobenzotriazoles in guinea pig kidney in vivo and in vitro: minimal effects on metabolism of arachidonic acid by renal P450-dependent monooxygenases.

Guinea pig renal microsomes convert arachidonic acid to two classes of P450-dependent metabolites, epoxyeicosatrienoic acids (EET), and 16- through 20-hydroxyeicosatetraenoic acids [(16-20)-OH-AA)]. The rate of formation of these metabolites was not altered by beta-naphthoflavone induction, which increased P450 1A1-dependent 7-ethoxyresorufin O-deethylation activity approximately 100-fold. alpha-Naphthoflavone, which inhibits renal P450 1A1 in vitro, did not inhibit the formation of these metabolites in microsomes from induced animals. In induced animals, N-benzyl-1-aminobenzotriazole and N-alpha-methylbenzyl-1-aminobenzotriazole, administered i.v., inhibited microsomal 7-ethoxyresorufin O-deethylation activity by approximately 50% without inhibiting the formation of either class of arachidonic acid metabolites. In vitro these mechanism-based inhibitors inactivated 1A1 by > 90% without inhibiting EET or (16-20)-OH-AA formation. These data show that P450 1A1 does not bioactivate arachidonic acid to either (16-20)-OH-AA or EET in guinea pig kidney, and that N-benzyl-1-aminobenzotriazole and N-alpha-methylbenzyl-1-aminobenzotriazole selectively inactivate P450 1A1 in comparison to the P450 isozyme(s) that metabolize arachidonic acid in the kidney. In guinea pig liver beta-naphthoflavone treatment, which induces P450 1A1 and 1A2, increased the rate of the formation of (16-20)-OH-AA and EET and in vitro alpha-naphthoflavone inhibited the formation of these metabolites in induced hepatic microsomes by approximately 50 and approximately 35%, respectively. These data demonstrate that a beta-naphthoflavone-inducible isozyme, most likely 1A2, converts arachidonic acid to both (16-20)-OH-AA and EET in guinea pig liver.