Sabine Schmaldienst

Early Basal Insulin Therapy Decreases New-Onset Diabetes after Renal Transplantation

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better β-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of β cells.

Urinary tract infections after renal transplantation.

Up to now one of the major problems for successful organ transplantation has been the reaction of the immune system of the recipient against the donor organ. This could lead to acute and chronic rejection, and in cases of unsuccessful treatment to the loss of the transplant. In organ graft recipients, immunosuppressive agents are used to prevent or treat rejection episodes and to maintain graft function. Although there is an increasing number of immunosuppressive substances, the immunosuppressive therapy currently in use is relatively unspecific and targets many immunological functions. The net state of immunosuppression is a complex function determined by the interaction of a number of factors, the most important of these are the dose, duration and temporal sequence in which immunosuppressive drugs are employed. Any kind of immunosuppressive protocol is thus associated with an increased infection rate. This has an important socioecological impact, because frequent hospitalizations resulting from infectious complications are necessary, having an overall mortality rate of 3.5% within 2 weeks of admission. The most common cause of septicaemia is urinary tract infection. Frequent urinary tract infections are associated with the early onset of chronic rejection, suggesting a pathogenetic relationship between these two features. The occurrence of chronic rejection has led to reduced transplant survival. The prevention of urinary tract infections, or the early diagnosis and accurate treatment of urinary tract infections is important in renal transplant recipients.

Immunoadsorption and plasma exchange in pregnancy.

Background: During pregnancy, familial hyperlipidemia or systemic lupus erythematosus (SLE) can exacerbate having devastating consequences for both mother and fetus. Immunoadsorption is established for removal of pathogenic proteins lipoproteins or autoantibodies, but this procedure has only rarely been used in pregnancy. Methods: We evaluated retrospectively 126 extracorporeal treatments during six pregnancies. Forty low-density lipoprotein immunoadsorptions, 6 sole plasma exchanges and 36 combined procedures (plasma exchange followed by immunoadsorption) were performed for severe hypertriglyceridemia, complicated by acute pancreatitis. Forty-four IgG immunoadsorptions were executed in 2 pregnant women suffering from SLE with a disastrous course during prior pregnancies. Results: In hyperlipidemic pregnant women, mean triglyceride levels prior to treatment were 3,841 ± 2,076 mg/dl (mean ± SD) and total cholesterol was 617 ± 354 mg/dl. Until delivery, a 27% reduction of triglycerides could be achieved. Clinical and serological signs of pancreatitis disappeared after initiation of extracorporeal therapy. Four healthy babies were delivered (birthweights between 2,250 and 3,360 g). In 1 woman suffering from SLE, intrauterine fetal death occurred in the 22nd week of gestation despite a reduction of cardiolipin antibodies by 69%. The second case (a twin pregnancy) was complicated by steroid-resistant antibody-mediated anemia. Due to frequent immunoadsorptions, red blood cell count improved (reduction of antierythrocyte antibodies by 66.6%) and 2 healthy babies (birthweights 2,120 and 2,350 g) were delivered by cesarean section. Conclusion: Long-term antibody-based immunoadsorption has been demonstrated to be safe and well tolerated in pregnant women and enables normal intrauterine/fetal development. Although rarely indicated during pregnancy, this treatment modality might be a promising new technique for removal of autoantibodies and lipoproteins in patients with serious gestational complications without sufficient response to conventional therapy.

POSTTRANSPLANT HEMOLYTIC UREMIC SYNDROME IN ADULT RETRANSPLANTED KIDNEY GRAFT RECIPIENTS: ADVANTAGE OF FK506 THERAPY?

BACKGROUND Posttransplant hemolytic uremic syndrome (pHUS) is a rare but severe disorder that confers a poor prognosis on an allograft due to thrombotic microangiopathy. Immunosuppression with cyclosporine (CsA) is implicated as a significant risk factor for the development of pHUS. In early reports, it was hypothesized that immunosuppression with FK506 (tacrolimus) would avoid the development of pHUS. However, this initially supposed beneficial effect remains controversial, because pHUS associated with tacrolimus therapy has been published in some later case reports. This article aims to further evaluate FK506 with respect to the development and resolution of pHUS. METHODS We describe the course of seven adult kidney graft recipients with pHUS, treated with FK506 either as initial immunosuppression for retransplantation or after discontinuation of CsA for resolution of pHUS. Work-up for pHUS was initiated when certain clinical features, such as hemolytic anemia, thrombocytopenia, and deterioration of graft function, were found. The diagnosis was confirmed by histologic examination of a renal allograft biopsy specimen (thrombotic microangiopathy). With the onset of pHUS, additional plasma exchange was performed in all patients. RESULTS Two patients suffered from end-stage renal disease due to primary HUS and had a history of recurrent pHUS in previous renal transplants. In both patients, the attempt to regraft was only made because of the early optimistic reports using FK506. Despite initial FK506 therapy, both recipients developed pHUS again, leading to loss of graft function. Two additional kidney graft recipients with primary renal failure other than HUS also received FK506 as initial immunosuppression. One of them (loss of the first kidney graft due to CsA-induced pHUS) was successfully treated with FK506 for his second renal transplant. The other recipient, a patient in whom de novo pHUS had occurred in the first graft despite initial therapy with FK506, was treated with CsA for his second graft and again developed pHUS. The latter process, however, could be reversed by a switch to steroids and azathioprine. In all three patients regrafted for reasons other than pHUS, development of de novo pHUS was treated by CsA withdrawal and a switch to FK506; this approach was effective in two patients. CONCLUSION Our results demonstrate that three of seven renal allograft recipients benefited from FK506 therapy for prevention or resolution of pHUS. Treatment or prophylaxis with FK506 can be considered advantageous in some patients with de novo pHUS, but FK506 fails to prevent recurrent pHUS in patients with primary HUS.

Recombinant human granulocyte colony-stimulating factor after kidney transplantation: a retrospective analysis to evaluate the benefit or risk of immunostimulation.

BACKGROUND Leukopenia due to immunosuppressive drugs represents a well-known complication in graft recipients, which might put patients at an increased risk for infections. In this study, recombinant human granulocyte colony-stimulating factor (rhG-CSF), a hematopoietic growth factor that selectively stimulates neutrophil colony formation and neutrophil cell differentiation, was tested for safety and efficacy. METHODS We evaluated 30 episodes of leukopenia (<2000/mm3) in 19 kidney graft recipients treated with rhG-CSF. This cohort was compared with an age- and sex-matched historical control group without therapy. Peripheral and differential blood cell counts were analyzed, and the duration of leukopenia was estimated. Furthermore, the occurrence of infections associated with leukopenia was investigated. RESULTS All patients responded to rhG-CSF therapy. Peripheral leukocyte counts increased from 1756+/-582 to a peak of 8723+/-3038/mm3 (P<0.0001). On the average, the peak was reached after 2.7 days (range 1 to 8). Furthermore, the effect was fairly persistent, because in 22 of 30 episodes leukocyte counts were within the normal range after 7 days. The elevation of total leukocytes was mainly due to a specific increase in neutrophil granulocytes from 1143+/-514 to 6895+/-1950/mm3 on the peak day (P<0.0001). Patients in the G-CSF group were leukopenic for a mean of 1.29+/-0.59 days, whereas in the control group leukopenia persisted for at least 7 days. Consequently, the rate of infections was significantly higher (P<0.045) in nontreated patients. CONCLUSION rhG-CSF was safe and effective in leukopenic kidney graft recipients. Leukopenic episodes in treated patients were significantly shorter, and infections occurred at a significantly lower rate. No evidence was found that rhG-CSF therapy might trigger rejection episodes, and no side effects were observed.

Multiple-dose pharmacokinetics of cefepime in long-term hemodialysis with high-flux membranes

AbstractObjective: Among uremic patients on hemodialysis, infectious complications leading to a high incidence of morbidity and mortality are a well-documented problem. In this multi-dose study, the safety, tolerance, and pharmacokinetics of cefepime during high-flux hemodialysis were investigated and an improved dosing schedule is presented. Methods: Six long-term hemodialysis patients received 2 g cefepime i.v. at the end of hemodialysis three times per week. Results: Trough levels of cefepime were 23.3 ± 7.3 mg/l and peak serum concentrations 165.6 ± 48.7 mg/l. After 3.5 h of high-flux hemodialysis, 72.2 ± 6.4% of cefepime was eliminated. The intradialytic half-life was 1.6 ± 0.29 h and the interdialytic half-life 22.0 ± 2.14 h. Conclusion: A dosage of 2 g cefepime after each hemodialysis session achieved drug levels well above the minimal inhibitory concentration (MIC)90 for most of the target pathogens. Thus, the described dosing schedule is an efficient and cost saving antmicrobial therapy for severe infections in long-term hemodialysis patients with no residual renal function.

Cytokine release and dynamics of leukocyte populations after CD3/TCR monoclonal antibody treatment

Cytokine release and clinical side effects resulting from the use of OKT3 and BMA 031 monoclonal antibodies in the treatment of kidney graft recipients were evaluated and compared. The rise observed in serum levels of interferon γ, TNFα, and IL-8 was similar after administration of either monoclonal antibody. Furthermore, both OKT3 and BMA 031 resulted in rapid disappearance not only of virtually all T cells, but also of substantial percentages of all major leukocyte populations from the circulation; this effect is probably due to cytokine release activating endothelial cells and thereby causing extravasation even of leukocytes not specifically recognized by the administered antibodies. Evidence has thus been obtained that BMA 031 is as potent as OKT3 in inducing unequivocal signs of T cell activationin vivo. However, while OKT3 therapy was accompanied by adverse side effects in our study as in previous ones, we saw no such reactions in any of the patients receiving BMA 031. This contrast might be due to different mechanisms of leukocyte activation possibly inducing other mediators in the case of OKT3, which then, in combination with the cytokines, could generate treatment-associated morbidity.

Angiogenin: A Novel Inhibitor of Neutrophil Lactoferrin Release during Extracorporeal Circulation

Degranulation of polymorphonuclear leukocytes (PMNL) occurs during extracorporeal circulation. A degranulation-inhibiting protein identical to angiogenin was recently isolated from high-flux dialyzer ultrafiltrate. This protein inhibits the release of lactoferrin and metalloproteinases from PMNL in vitro. In the present study, we investigated end-stage renal disease patients undergoing regular hemodialysis treatment with either high-flux dialyzers (n = 51) or low-flux dialyzers (n = 44), and chronically uremic patients undergoing hemodiafiltration (n = 30). Hemodialysis therapy with low-flux polysulfone or cellulose triacetate membranes caused no or only minimal reduction (≤8%) of plasma angiogenin levels within 2 h of dialysis treatment associated with a 1.6-fold lactoferrin release from PMNL. Hemodialysis therapy with high-flux membranes (e.g. cellulose triacetate, polymethylmethacrylate) or hemodiafiltration resulted in a reduction of plasma angiogenin levels by 20–40% after 2 h associated with a nearly 4-fold PMNL lactoferrin release. The release of PMNL elastase was not affected by the different treatment modalities used. We conclude that high angiogenin plasma levels protect against lactoferrin release from PMNL during extracorporeal circulation in chronically uremic patients. A decrease of plasma angiogenin between 20 and 40% during extracorporeal circulation, however, results in marked PMNL lactoferrin release. This novel mechanism may explain, at least in part, PMNL degranulation also in non complement activating high-flux membranes.

Multiple‐dose pharmacokinetics of cefpirome in long‐term hemodialysis with high‐flux membranes

Cefpirome is a cephalosporin eliminated primarily by kidneys that requires dosage reduction in patients with renal failure. The pharmacokinetic parameters were studied in 10 patients with end‐stage renal disease who were receiving hemodialysis. Repeated intravenous administration of 2 gm cefpirome three times a week resulted in trough levels of 12.2 ± 5.4 μg/ml and peak serum concentrations of 99.6 ± 82.1 μg/ml. After 312 hours of hemodialysis with polysulfone high‐flux membranes, 62.3% ± 23.3% of cefpirome was removed. The interdialytic half‐life was 9.35 ± 0.99 hours, and the intradialytic half‐life was 2.02 ± 0.7 hours.

Prevalence of Atrial Fibrillation and Antithrombotic Therapy in Hemodialysis Patients: Cross-Sectional Results of the Vienna InVestigation of AtriaL Fibrillation and Thromboembolism in Patients on HemoDIalysis (VIVALDI)

Background Atrial fibrillation (AF) adds significant risk of stroke and thromboembolism in patients on hemodialysis (HD). The aim of this study was to investigate the prevalence of AF in a population-based cohort of HD patients and practice patterns of antithrombotic therapy for stroke prevention in AF. Methods The Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemodialysis (VIVALDI), an ongoing prospective observational cohort study, investigates the prevalence of AF and the risk of thromboembolic events in HD patients in Vienna, Austria. We analyzed cross-sectional data of 626 patients (63.4% men, median age 66 years, approx. 73% of HD patients in Vienna), who provided informed consent. A structured interview with each patient was performed, recent and archived ECGs were viewed and medical histories were verified with electronic records. Results The overall prevalence of AF was 26.5% (166 patients, 71.1% men, median age 72 years) of which 57.8% had paroxysmal AF, 3.0% persistent AF, 32.5% permanent AF, and 6.6% of patients had newly diagnosed AF. The median CHA2DS2-VASc Score was 4 [25th-75th percentile 3–5]. In multivariable analysis, AF was independently associated with age (odds ratio: 1.05 per year increase, 95% confidence interval: 1.03–1.07), male sex (1.7, 1.1–2.6), history of venous thromboembolism (2.0, 1.1–3.6), congestive heart failure (1.7, 1.1–2.5), history of or active cancer (1.5, 1.0–2.4) and time on HD (1.08 per year on HD, 1.03–1.13). Antithrombotic treatment was applied in 84.4% of AF patients (anticoagulant agents in 29.5%, antiplatelet agents in 33.7%, and both in 21.1%). In AF patients, vitamin-K-antagonists were used more often than low-molecular-weight heparins (30.1% and 19.9%). Conclusions The prevalence of AF is high amongst HD patients and is associated with age, sex, and distinct comorbidities. Practice patterns of antithrombotic treatment indicate a lack of consensus for stroke prevention in HD patients with AF.