Collectin Liver 1 and Collectin Kidney 1 of the Lectin Complement Pathway Are Associated With Mortality After Kidney Transplantation.

Kidney transplanted patients still have significantly higher mortality compared with the general population. The innate immune system may play an important role during periods, with suppression of the adaptive immune system. In the present study, two soluble pattern recognition molecules of the innate immune system were investigated, collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). Potential associations of their pretransplant levels and long-term graft and recipient survival were examined. The levels of CL-L1 and CL-K1 were measured at the time of transplantation in 382 patients (≥17 years) transplanted in 2000-2001. The cohort was subsequently followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Both high CL-L1 (≥376 ng/mL) and high CL-K1 (≥304 ng/mL) levels were significantly associated with overall mortality in multivariate Cox analyses with hazard ration (HR) 1.50, 95% confidence interval (CI) 1.09-2.07, p = 0.013 and HR 1.43, 95% CI 1.02-1.99, p = 0.038, respectively. Moreover, high CL-K1 levels were significantly associated with cardiovascular mortality. No association between measured biomarkers and death-censored graft loss was found. Finally, there was a significant correlation between these two collectins, r = 0.83 (95% CI 0.80-0.86). In conclusion, CL-L1 and CL-K1 were significantly associated with mortality in kidney transplant recipients.

A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation.

The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated.

Renal amyloidosis in intravenous heroin addicts with nephrotic syndrome and renal failure.

BACKGROUND: Renal amyloidosis has emerged as an important differential diagnosis when heroin addicts are admitted to renal clinics with proteinuria and nephrotic syndrome. MATERIAL: We present nine heroin addicts with renal AA amyloidosis, a condition previously not encountered in Norway, who were admitted to our renal clinic during the last 3.5 years. In the same time period a total of 209 patients were biopsied from native kidneys. RESULTS: Heroin abuse was associated with 70% of all biopsy-verified renal AA amyloidosis during this time period. Renal amyloidosis was found in 9 of the 12 heroin addicts that were biopsied. 6 of the 9 heroin addicts with amyloidosis required dialysis within 13 months after admission. CONCLUSION: Renal AA amyloidosis among heroin addicts seems to be associated with chronic suppurative skin infections. AA amyloidosis should always be considered in chronic heroin addicts presenting with proteinuria and renal impairment.

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events.

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; cardiac death or nonfatal acute myocardial infarction) and patient survival. Diabetic status and CV risk factors were assessed in 201 consecutive renal allograft recipients 3 months after transplantation (baseline) during a period of 16 months (1995-96). Follow-up data until January 1, 2004 were obtained from the Norwegian Renal Registry. The 8-year (range 7-9 years) cumulative incidence of MCEs was 7% (nine out of 138) in recipients without diabetes, 20% (seven out of 35) in patients with new-onset PTDM and 21% (six out of 28) in patients with diabetes mellitus before transplantation (DM). Proportional hazards regression analyses (forward stepwise regression) revealed that patients with PTDM had an approximately three-fold increased risk of MCEs as compared with nondiabetic patients (hazard ratio (HR)=3.27, 95% confidence interval (CI)=1.22-8.80, P=0.019). A total of 61 patients (30%) died. Eight-year patient survival was 80% in the nondiabetic group, 63% in the PTDM group and 29% in the DM group, respectively. Pretransplant diabetes (HR=5.09, 95% CI=2.60-9.96, P<0.001), age (HR=1.03, 95% CI=1.01-1.05, P=0.016), cytomegalovirus (CMV) infection (HR=2.66, 95% CI=1.27-5.53, P=0.009), and creatinine clearance (HR=0.98, 95% CI=0.96-1.00, P=0.046), but not PTDM (HR=1.20, 95% CI=0.58-2.49, P=0.621), were independent predictors of death in the multiple Cox regression model. Early-diagnosed PTDM is a predictor of MCEs, but not of all-cause mortality, the first 8 years after renal transplantation.

The impact of early cytomegalovirus infection and disease in renal transplant recipients.

Human cytomegalovirus (HCMV) infection is the single most frequent infectious complication in the early period after kidney transplantation. The HCMV load in blood, measured by HCMV PCR or the HCMV pp65 antigen test, is a predictor of HCMV disease in seropositive recipients. However, plasma virus load measurements are of only modest value in predicting the risk of HCMV disease in seronegative recipients of kidneys from seropositive donors. HCMV infection is an independent risk-factor for acute kidney graft rejection. There is also evidence that HCMV is associated with an increased long-term mortality and post-transplant diabetes mellitus. Whether pre-emptive or prophylactic therapy should be the preferred strategy is not yet decided. Some studies indicate that HCMV prophylaxis may reduce the risk of acute rejection, and thereby increase long-term graft survival in seronegative recipients of kidneys from seropositive donors.

Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation.

AIMS/HYPOTHESIS: The human cytomegalovirus (CMV) may increase the risk of diabetes mellitus, but the literature is scarce. The present study was designed to test the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset diabetes after renal transplantation, and to assess the impact of asymptomatic CMV infection on OGTT-derived estimates of insulin release and insulin action. METHODS: A total of 160 consecutive non-diabetic renal transplant recipients on cyclosporine (Sandimmun Neoral)-based immunosuppression were closely monitored for CMV infection during the first 3 months after transplantation. All patients underwent a 75-g OGTT at 10 weeks. Excluded from the analyses were 36 patients with symptomatic CMV infection (disease). RESULTS: The incidence of new-onset diabetes was 6% in a control group of recipients without CMV infection (4/63) and 26% in the group with asymptomatic CMV infection (16/61). Asymptomatic CMV infection was associated with a significantly increased risk of new-onset diabetes (adjusted odds ratio: 4.00; 95% CI: 1.19 to 13.43, p=0.025). The group of patients with CMV infection had a significantly lower median insulin release than controls. CONCLUSIONS/INTERPRETATION: Our findings support the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset post-transplant diabetes mellitus, and suggest that impaired insulin release may involve one pathogenetic mechanism.

Cytomegalovirus DNA concentration in plasma predicts development of cytomegalovirus disease in kidney transplant recipients.

The clinical significance of cytomegalovirus (CMV) DNA detection in post-kidney transplantation infection surveillance was examined by comparing the performance of three assays for detection of CMV in blood: the test for CMV-pp65-antigen in leukocytes, which is routinely employed in our laboratory, the quantitative plasma CMV-DNA-polymerase chain reaction (PCR; Cobas Amplicor CMV Monitor test) and the qualitative plasma CMV-DNA-PCR (Amplicor CMV test). Thirteen kidney transplant recipients were monitored with serial samples taken over a period of 3 months following transplantation. The quantitative CMV-PCR was the test with highest sensitivity, 95.9%, vs. 88.9% and 76.9% for the CMV-pp65 antigen assay and qualitative CMV-PCR, respectively. The virus load in the first positive specimens, assessed as DNA-copies/mL, was significantly associated with CMV disease because five of the six patients who developed disease, but only one of the seven who did not develop disease, had more than 3000 CMV-DNA-copies/mL. The number of CMV-pp65 antigen-positive cells in the first positive specimens did not have predictive value for development of CMV disease. Assessment of CMV in plasma by the quantitative CMV-PCR is especially useful since it has a high sensitivity and the amount of CMV DNA in plasma is a good predictor of CMV disease.

Anticoagulation intensity sufficient for haemodialysis does not prevent activation of coagulation and platelets.

BACKGROUND: A single bolus of dalteparin at the start of haemodialysis (HD) may prevent clot formation, but subclinical activation of platelets and coagulation may still occur. Consequently, the relationship between clinical clotting events and activation markers of platelets and coagulation before and during HD is of interest. METHODS: The effect of tapered doses of dalteparin during 84 HD sessions (4-4.5 h) was prospectively examined in 12 patients. Six of the patients were treated with warfarin. The initial dalteparin dose was reduced to 50% if no clotting was observed. Clinical clotting was evaluated by inspection of the air trap every hour and by inspection of the dialyser after each session. Anti-FXa activity was measured for assessment of dalteparin activity. Markers of activated plasma coagulation, (thrombin-antithrombin (TAT) and prothrombin fragment 1+2 (PF1+2)) and a marker of platelet activation (beta-thromboglobulin, beta-TG), were measured before the start of and after 3 and 4 h of dialysis. Ten pre-dialytic patients with chronic renal failure served as a control group. A total of 230 measurements of each parameter were performed. RESULTS: An anti-FXa activity above 0.4 IU/ml at the end of HD inhibits overt clot formation for 4 h. This was obtained by an intravenous dalteparin dose of about 5000 IU. TAT and PF1+2 correlated to clinical clotting episodes (r=0.50 and 0.47, P<0.001). beta-TG was not significantly correlated to clinical clotting. All parameters increased during the sessions (TAT, PF1+2, beta-TG, P<0.001). When measurements during clinical clotting episodes were disregarded, all parameters were still markedly increased. Warfarin-treated patients had lower TAT and PF1+2. Dialysis patients had higher beta-TG values than pre-dialytic patients. CONCLUSION: Despite clinically effective anticoagulation, obtained by dalteparin administration, platelets and coagulation are activated by HD, resulting in a potentially thrombophilic state. Warfarin treatment reduces clinical clot formation and subclinical activation of coagulation.

A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is the single most frequent infectious complication in renal transplant recipients. Because no CMV-prophylaxis is given and ganciclovir is used only as deferred therapy for CMV disease at our center, we have been able to study the natural course of CMV infections. The aim was to assess risk factors for CMV infection and disease and thus identify subgroups of patients likely to benefit from CMV prophylaxis or preemptive therapy. METHODS: Between October 1994 and July 1997, 477 consecutive renal transplant recipients (397 first transplants and 80 retransplants) were included in the study. The patients were followed prospectively for 3 months with serial measurements of CMV pp65 antigen for monitoring activity of CMV infections. RESULTS: The incidence of CMV infections in first transplants was 68% in D+R- and D+/-R+ serostatus groups, whereas the incidence of CMV disease was higher in D+R- (56%) than in D+/-R+ (20%, P<0.001). No difference in severity of CMV disease in D+R- and D+/-R+ was seen except for an increased incidence of hepatitis in primary infections. One of 14 deaths could be associated with CMV disease in a seropositive recipient. Cox regression analysis showed that rejection (RR 2.5, P<0.01) and serostatus group D+R- (RR 3.9, P<0.001) were significant risk factors for development of CMV disease. The maximum CMV pp65 antigen count had significant correlation to disease only in CMV seropositive recipients, P<0.001. Conclusion. Renal transplant recipients can safely be given deferred ganciclovir therapy for CMV disease if they are intensively monitored for CMV infection. Patients with primary CMV infection (D+R-), CMV infected patients undergoing anti-rejection therapy and R+ patients with high CMV pp65 counts seem to have a particular potential for benefit from preemptive anti-CMV-therapy.

A single dose of dalteparin effectively prevents clotting during haemodialysis.

BACKGROUND: A single bolus dose of LMW heparin at the start of haemodialysis effectively prevents clot formation in the dialyser and bubble trap. However, there are few studies on the appropriate dosage of LMW heparins in haemodialysis. Therefore we examined the relationship between the anticoagulant effect of dalteparin and clinical clotting during haemodialysis. METHODS: We performed an open, prospective study on the effect of decreasing doses of dalteparin in 12 haemodialysis patients during a total of 84 sessions (4-4.5 h). The normally applied dose of dalteparin in each patient was reduced by 25% for each session down to 50% of initial dose if no clotting was observed. Clinical clotting (grade 1-4) was evaluated by visual inspection after blood draining of the air trap every hour and by inspection of the dialyser after each session and compared to corresponding values for anti-FXa activity and dialysis time. Blood flow and ultrafiltration rate were kept within narrow limits throughout the study. RESULTS: No episodes of grade 4 clotting occurred, and no session was interrupted. Eighteen episodes of grade 3 clinical clotting (11%) were observed in patients without warfarin treatment, none with an anti-FXa activity >0.43 IU/ml. Oral warfarin treatment reduced the clinical clotting, and only one grade 3 episode was observed in patients on warfarin therapy. Anti-FXa activity and haemodialysis time were the only factors independently correlated to clotting in a logistic regression model. CONCLUSION: An anti-FXa activity above 0.4 IU/ml after 4 h of dialysis inhibits significant clotting during haemodialysis. A bolus dose of dalteparin of 70 IU/kg usually seems appropriate, but may be reduced in patients on warfarin treatment. Dialysis time is an independent risk factor for clinical clotting.

Glipizide treatment of post-transplant diabetes does not interfere with cyclosporine pharmacokinetics in renal allograft recipients.

BACKGROUND: Glipizide is an oral antidiabetic drug that has been used in the treatment of post-transplant diabetes mellitus (PTDM). However, a published case report has indicated a possible interaction of glipizide with cyclosporine (CsA) pharmacokinetics in two renal transplant (tx) patients. The aim of this open prospective study was to investigate whether glipizide interacts with CsA pharmacokinetics in renal tx patients with PTDM. METHODS: Eleven renal tx patients (29-74 years of age) with PTDM who received Sandimmun Neoral as part of their immunosuppressive therapy were investigated. No patients had suffered any significant rise in serum creatinine (20%) from any cause over the last 2 wk before the study. Mean S-creatinine was 137 mumol/L (87-220). The mean CsA dose and whole blood concentration remained unchanged during the study. CsA whole blood concentrations were monitored over 12 h in all patients in random order, both on and off glipizide treatment. Blood samples were drawn immediately before the morning dose of CsA was given (trough) and 0.5, 1, 1.5, 2, 3, 4, 6 and 12 h after administration. RESULTS: Whole blood trough CsA concentration was not altered by glipizide treatment, 256 +/- 76 micrograms/L off and 242 +/- 73 micrograms/L (mean +/- SD) with glipizide coadministration. The area under the curve (AUC) and terminal half-life of CsA remained unchanged with glipizide treatment: 6391 +/- 1483 micrograms/L per h and 7.3 +/- 1.5 h without; and 6279 +/- 1601 micrograms/L per h and 7.1 +/- 1.8 h with glipizide, respectively. No change in the CsA peak concentration (Cmax) was observed: 1507 +/- 406 micrograms/L without and 1469 +/- 538 micrograms/L with glipizide coadministration. CONCLUSION: CsA pharmacokinetics is not significantly altered by glipizide coadministration.

Diagnosis of cytomegalovirus infection in kidney transplant recipients by a quantitative RNA-DNA hybrid capture assay for cytomegalovirus DNA in leukocytes.

The clinical value of a new RNA-DNA hybridization assay for quantification of cytomegalovirus (CMV) DNA in leukocytes [Hybrid Capture CMV DNA Assay (HCA); Murex Biotech, UK] was evaluated. The HCA was compared with an assay for CMV pp65 antigen in leukocytes and an in-house CMV polymerase chain reaction PCR (CMV-PCR) on parallel blood samples. The HCA and the CMV-PCR were less sensitive than the CMV pp65 assay, but the positive predictive value of all three methods for CMV disease was 50% or less. However, when quantitation of viral load by HCA and CMV pp65 assay was taken into consideration, both assays were superior to CMV-PCR in predicting CMV disease.