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Introduction: The efficacy of tight glycemic control for the prevention of death and renal failure in the general diabetic population is well established. However, in diabetic renal-allograft recipients, the effect of different treatment strategies on outcomes is undetermined., Methods: We conducted a cohort study of 798 diabetic, renal-allograft recipients transplanted at the Medical University of Vienna between 1990 and 2004. We studied the influence of glucose parameters and diabetes treatment on mortality and graft loss. Marginal-structural models and multivariable Cox regression analysis were used to control for confounding., Results: Maximal glucose levels but not HbA1c were independently associated with mortality. Being in the highest quartile of maximal glucose increased the adjusted risk of death by a factor of 2.2 (P value for trend 0.009). Furthermore, in patients receiving insulin, the risk of death was increased 1.7-fold (95% confidence interval 0.9-3.1) compared with diet and 2.0-fold (95% confidence interval 1.1-3.7) compared with oral medication. Maximal glucose, HbA1c, or diabetes treatment did not influence death-censored functional graft survival., Discussion: In conclusion, maximal glucose levels and insulin treatment were independently associated with higher rates of mortality in our cohort of diabetic, renal-allograft recipients. However, graft survival was unaffected.

Background: It is unclear whether the choice of maintenance immunosuppression modulates the negative effect of advanced donor age on outcome after renal transplantation., Methods: All 1829 patients who received their first transplant between 1990 and 2003 at the Vienna Medical Centre and had a functioning graft after 90 days were studied. At this time point, 1587 received calcineurin inhibitors (CNI+), 242 did not (CNI-). Actual and functional graft survival was analyzed in subgroups based on donor age (<36, 36-49, 50-64, and >64 years) and immunosuppressive therapy., Results: The median follow-up time was 7 years. In total, we observed 312 deaths and 275 graft losses. After adjusting for several variables considered as potential confounders, actual graft survival was better in CNI+ patients compared with CNI- patients only if donor age was less than 36 years (adjusted hazard ratio 0.25, 95% confidence interval 0.17-0.38) or 36 to 49 years (0.43, 95% confidence interval 0.29-0.62). Similar results were obtained for functional graft survival. Patient survival was significantly better in CNI+ subjects irrespective of donor age (0.41, 95% confidence interval 0.30-0.57)., Discussion: Use of CNI 90 days after transplantation is associated with improved patient survival even after adjustment for confounders, but its beneficial association with actual and functional graft survival is lost or at least reduced if kidneys from donors older than 50 years are used.

Background: Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. The mechanism of action is not fully understood. We hypothesized that cinacalcet increases renal elimination of calcium, thereby improving hypercalcemia in kidney transplant recipients., Methods: We prospectively examined the effect of cinacalcet (30 mg/d) during the first 6 weeks of treatment on serum and 24 hrs urinary calcium concentration and calculated fractional calcium excretion in 32 patients with sustained hypercalcemic hyperparathyroidism (Ca >2.6 mmol/L [10.4 mg/dL], intact parathyroid hormone >60 pg/mL). Secondary endpoints were serum phosphate and tubular maximum of phosphate corrected for glomerular filtration rate, intact parathyroid hormone and serum creatinine., Results: Serum calcium concentrations decreased in all patients (from 2.77 to 2.51 mmol/L; P<0.0001), fractional calcium excretion increased rapidly in the first 2 weeks of treatment from 1.06 to 1.78% (P<0.0001), and decreased thereafter to 1.37% (P<0.05 vs. early treatment). Simultaneously serum phosphate and tubular maximum of phosphate corrected for glomerular filtration rate increased significantly from 0.79 to 0.85 to 0.88 mmol/L (P<0.05), and from 0.52 to 0.61 (P<0.005) and 0.62 (P<0.0001 vs. baseline), respectively. Intact parathyroid hormone did not decrease significantly. Serum creatinine remained stable., Conclusion: We provide evidence that the calcium lowering effect of cinacalcet in patients with persistent hyperparathyroidism after kidney transplantation is caused, at least in part, by increased urinary calcium excretion.

Antithymocyte globulin (ATG) is employed for the treatment and prevention of acute organ rejection after transplantation. However, the mechanisms underlying its immunomodulatory capacities beyond cellular depletion remains ill defined. A stable interaction between T-cells and professional antigen-presenting cells (APC) and full T-cell stimulation requires a complex molecular rearrangement at the T-cell/APC interface, the so called immunological synapse. Here we investigated, whether ATG affects T-cell/APC interactions. ATG concentration and time-dependently inhibited relocalization of the T-cell receptor/CD3 complex as well as adhesion molecules and cytoskeletal proteins of human peripheral blood T-cells and a human T-cell line towards the APC contact site. Moreover, ATG-treated peripheral blood T-cells were incapable to form conjugates with APCs. In conclusion, ATG impairs T-cell/APC conjugate formation, a mechanism that may help to understand the functional inactivation of peripheral blood T-cells that have escaped cellular depletion after ATG treatment.

Background: The presence of preformed alloantibodies with the ability to activate complement may pose a particular risk for kidney allograft rejection. The aim of this study was to evaluate variables that determine the complement-fixing capability of human leukocyte antigen (HLA) sensitization., Methods: Sixty-five sensitized patients with > or =10% pretransplant panel-reactive antibody (PRA) levels uncovered by immunoglobulin G [IgG]FlowPRA HLA class I and/or class II screening were included. Applying modified FlowPRA screening, sera were evaluated for patterns of alloreactive IgG subclasses and IgM, and, in parallel, for their complement-activating ability assessed by flow cytometric detection of human complement split product deposition ([C4d]FlowPRA)., Results: Approximately two-thirds (68%) of tested sera were found to contain complement-fixing alloreactivity (> or =10%[C4d]FlowPRA). IgG1 type panel reactivity was predominant (detectable HLA class I and II reactivity in 93% and 91% of IgG-positive sera), followed by IgG3 (49%/44%), IgG2 (44%/27%), and IgG4 (19%/11%). Applying partial correlation we found an independent correlation of both %[IgG1]FlowPRA and %[IgG3]FlowPRA with %[C4d]FlowPRA reactivities (P< or =0.01). In addition, for IgG1 a contribution of the amount of bound alloantibody to complement-fixation was observed. Complement-fixation was also favored by the simultaneous presence of alloreactive IgG1, IgG3, and IgM. Previous grafting, but not pregnancy and transfusion, was independently associated with complement-fixing sensitization (P<0.05), presumably due to increased IgG1 type reactivity., Conclusions: Anti-HLA antibody-triggered complement activation is dependent on both the pattern of Ig reactivities and the amount of bound antibody. Previous transplantation represents a major risk factor for the development of complement-fixing sensitization.

Background: Lower concentrations of endothelial progenitor cells (EPCs) may be associated with increased cardiovascular risk. EPC counts and their correlates have not yet been studied in kidney transplant recipients (KTR)., Methods: We cross-sectionally studied EPC counts in 105 middle-aged KTR (mean estimated glomerular filtration rate 45.2 ml/min/1.73 m; range: 5.4 to 117.5). Using univariate and multivariate linear regression assuming a gamma distribution of the outcome, we examined the associations between counts of cultured EPCs and traditional cardiovascular disease risk factors (hypertension, diabetes, hyperlipidemia, smoking), kidney function, and immunosuppressive agents, amongst others., Results: The median count of cultured EPCs was 34 cells per high-power field (interquartile range: 19 to 64), comparable to healthy individuals. From multivariate analyses, we found independent inverse associations between counts of cultured EPCs and body mass index, mean arterial pressure, and history of cardiovascular disease. Statin use was associated with greater EPC counts, whereas patients receiving azathioprine or angiotensin II receptor treatment had lower EPC counts (all P<0.01)., Conclusions: This study suggests negative associations in KTR between EPC counts and body mass index, and blood pressure, whereas statin use was associated with greater EPC counts. These findings raise the hypothesis whether EPCs are responsible, at least in part, for the well established associations between these factors and cardiovascular outcomes in KTR.

Background: FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in the prevention of chronic allograft rejection. However, the cellular and molecular mechanisms underlying these effects of FK778 have not been investigated yet in detail. Because dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and are essential for the initiation of immune responses including acute and chronic allograft rejection, we investigated whether FK778 affects this particular cell type., Methods: Allogeneic T cell stimulation by FK778-treated human monocyte-derived DCs was determined by mixed leukocyte cultures. Surface molecule expression was analyzed by flow-cytometric analysis and cytokine production by ELISA from culture supernatants. Activation of NF-kappaB in DCs was assessed by electrophoretic mobility shift assays., Results: Treatment of DCs with FK778 inhibited their potency to stimulate allogeneic T cells. In line, LPS- and CD40L-induced upregulation of DC surface activation markers and production of IL-12 was significantly inhibited, irrespective of whether cells were treated during or after the monocyte to DC differentiation period. The effects of FK778 on DCs were not reversible by exogenous uridine indicating that FK778 acts independently of its action as an inhibitor of pyrimidine synthesis. On the signaling level, activation of NF-kappaB, the essential transcription factor involved in DC maturation and function, was markedly inhibited by FK778., Conclusions: Inhibition of activation and function of DCs as the central APCs may significantly contribute to the immunosuppressive profile of FK778 when applied after allogeneic organ transplantation.

Background: The Eurotransplant Senior Program (ESP) was launched in 1999, targeted to increase the supply of donor kidneys to the elderly. This program requires local allocation of kidneys from cadaveric donors >>65 years to recipients >>65 years., Methods: Of all patients >>65 years who received a kidney transplant in 1999-2002 at our center, 59 patients were transplanted through the ESP protocol (ESP group), and 44 patients received a transplant from a younger donor (EuroTransplant Kidney Allocation System, ETKAS group). Recipients were followed for up to 5.3 years using the Austrian Dialysis and Transplant Registry. Outcomes studied included all-cause mortality and allograft loss., Results: Age, sex, and comorbid conditions did not differ by group. Donor age was higher (69 vs. 36 years; P < 0.001) and cold ischemia time shorter in the ESP group (10 vs. 15 hr; P < 0.001). Number of HLA mismatches was greater in the ESP group (3.8 vs. 3.0; P = 0.003). ESP patients were more likely to receive induction therapy and less likely to receive cyclosporine A. Primary nonfunction, delayed graft function, operative mortality, rate of acute rejection episodes, and length of stay did not differ by group. Although serum creatinine at discharge was higher in ESP patients (1.7 vs. 1.4 mg/dL; P < 0.001), 4-year mortality (hazard ratio [HR] = 0.68; 95% CI: 0.31-1.49) and graft loss (HR = 0.61; 95% CI: 0.29-1.28) tended to be less., Conclusions: Long-term patient and graft survival were comparable between elderly patients who received their organ via the ESP and the regular ETKAS algorithm.

Regional citrate anticoagulation during extracorporeal treatment is used in patients at risk for hemorrhage. We conducted a prospective clinical trial on the effect of large- versus small-dose calcium supplementation during citrate anticoagulated hemodialysis on ionized calcium and intact parathyroid hormone (iPTH). Twenty-five treatments were studied in 25 patients with active bleeding or at risk for hemorrhage. Sixteen patients received large-dose calcium (15 mmol/h), and 9 received small-dose calcium (5 mmol/h) substitution during treatment. Ionized calcium increased in 13 of 16 patients in the large-dose calcium group and decreased in 8 of 9 patients in the small-dose calcium group. Intact PTH decreased by 25% in the large-dose group and increased by 121% in the small-dose group (P = 0.0007 for Delta; P = 0.007 for Delta%). In the 14 patients in whom ionized calcium increased, iPTH decreased. In 10 of 11 patients in whom ionized calcium decreased, iPTH increased. The increase or decrease of ionized calcium was more predictive for changes in iPTH than was the calcium-substitution rate (R(2) = 0.5526 versus 0.3962, respectively). We conclude that the behavior of iPTH can be influenced in a predictive manner by adjusting the calcium-substitution rate during treatment.

Background: Capillary deposition of the complement split product C4d has turned out to be a valuable marker of antibody-mediated rejection. The impact of pre- and posttransplant variables including particular immunosuppressive regimens on the frequency of C4d deposition has not yet been systematically investigated in a large multivariate analysis., Methods: In this retrospective study, the authors evaluated the incidence of C4d deposition in 388 kidney transplant recipients subjected to diagnostic biopsy within the first 6 months and analyzed the influence of potential confounders on the rate of C4d-positive graft dysfunction by applying multivariate logistic regression., Results: Sixty-six recipients (17%) developed linear C4d deposits in at least a quarter of peritubular capillaries, a finding associated with inferior 1-year allograft survival (73% vs. 88% in C4d-negative patients, P=0.0003). A 50% reduction in the odds of C4d-positive graft dysfunction was found if calcineurin inhibitor or mycophenolate mofetil (MMF) therapy was started 2 to 4 hr before transplantation when compared with initiation after surgery (adjusted odds ratio [OR], 0.5; P=0.03). No differences with respect to C4d staining results were found for the use of tacrolimus, MMF, or sirolimus, or for cyclosporine C2 monitoring. Retransplantation (OR, 3.6; P<0.001) and presensitization (OR, 3.1; P=0.002) turned out to be strong independent risk factors for C4d deposition., Conclusions: The authors' results suggest a reduced risk of C4d-positive graft dysfunction for patients receiving immunosuppression before transplantation. Apart from first dose timing, no influence of particular immunosuppressive strategies on C4d staining results was found.

Background: The heme oxygenase (HO) isoenzyme HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. Inducibility of this enzyme is modulated by a (GT)n dinucleotide length polymorphism in the HO-1 gene promoter. Short (class S) repeats are associated with greater up-regulation of HO-1 than are long repeats. In the present study we investigated the impact of the promoter polymorphism of kidney allograft donors on clinical outcomes after transplantation., Methods: We enrolled 101 recipients of cadaveric donor kidney allografts (who underwent transplantation between June 1998 and September 1999) in this retrospective study. The HO-1 genotype was assessed using genomic DNA isolated from cryopreserved donor splenocytes., Results: Fifty patients (49.5%) had received a kidney from a donor with at least one class S allele. Recipients of allografts from a class S allele carrier had significantly lower 1-year serum creatinine levels (median 1.46 mg/dL, interquartile range 1.17-1.68 mg/dL) compared with recipients of a non-class S allele donor kidney (median 1.61 mg/dL, interquartile range 1.38-2.22 mg/dL, P =0.01). After adjustment for cold ischemia time, retransplantation, donor age, delayed graft function, and HLA mismatch, recipients of a class S allele transplant had serum creatinine levels 0.81 times (95% confidence interval: 0.70-0.95, P =0.01) those of recipients of a non-class S allele transplant. The two patient groups did not differ significantly with respect to the incidence of delayed graft function, allograft rejection, or immunologic graft loss., Conclusion: Our data suggest an influence of the HO-1 gene promoter polymorphism on kidney allograft function and thus support previous studies indicating a protective effect of HO-1 induction in organ transplantation.

Purpose of Review: Hypertension is very common in renal transplant recipients and is a significant risk factor for mortality from cardiovascular diseases and for development of graft dysfunction., Recent Findings: Recent guidelines for the treatment of hypertension (Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure VI Report and World Health Organization Guidelines) do not directly address post-transplant hypertension. Specific recommendations for the drug treatment of hypertension in renal allograft recipients have not been given in the Clinical Practice Guidelines of the American Society of Transplantation or those of the European Renal Association., Summary: The present paper summarizes some important aspects of post-transplant hypertension and discusses potential treatment strategies aimed at reducing blood pressure and thus improving patient and allograft survival.

Purpose of Review: About a dozen controlled clinical trials examined the effect of anaemia correction on the progression of chronic kidney disease. None of these studies fulfilled the stringent criteria of a randomized controlled trial as suggested by the CONSORT statement, yet evidence emerged that anaemia sustains mitogenic and fibrogenic stimuli by lowering local partial oxygen tension. This review addresses the question of why and how anaemia could possibly enhance the progression of chronic kidney disease, and summarizes relevant clinical trials., Recent Findings: The discovery of hypoxia-inducible factor, a transcription factor stabilized under hypoxic conditions, with DNA-binding properties towards about 50 target genes including erythropoietin, has largely encouraged the hypothesis that tissue hypoxia may serve as another common mechanism for the progression of chronic kidney disease besides hypertension or proteinuria. In addition, anaemia-mediated alterations of renal sympathetic nerve activity and anaemia-related increments of oxidative stress may contribute to a progressive nephron loss. Conclusive evidence from clinical trials is scarce., Summary: Pathophysiological concepts suggest some impact of anaemia on the progression of chronic kidney disease. The urge for more sound clinical intervention trials is met by the ongoing ECAP study (Effect of early Correction of Anaemia on the Progression of chronic kidney disease).

Objective: The genetic background of hypertensive crisis is unknown. We examined the association of polymorphisms in genes involved in the renin-angiotensin-aldosterone-system with hypertensive crisis., Design: Population-based case-control study., Setting: Emergency department at a tertiary care university hospital., Patients: A total of 182 patients with essential hypertension who were admitted to an emergency department for treatment of hypertensive crisis and 182 age- and sex-matched healthy individuals., Interventions: None., Measurements: Analysis of polymorphisms in genes coding for angiotensinogen (AJT 704T-->C), angiotensin II receptor 1 (AGTR1 1166A-->C), renin (REN 2646G-->A), renin-binding protein (RENBP 61T-->C), alpha-adducin (ADD1 1378G-->T), beta-2-adrenergic receptor (ADRB2 46A-->G, 79C-->G), and angiotensin I converting enzyme (ACE I/D) was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. MAIN RESULTS Among patients, the ACE I/D polymorphism showed a deviation from Hardy-Weinberg equilibrium (p =.01). In controls, all polymorphisms were in the Hardy-Weinberg equilibrium. The frequency of the DD genotype was increased in patients (n = 70, 38.5%) vs. controls (n = 51; 28.0%;p =.03; odds ratio, 1.61; 95% confidence interval, 1.03-2.50), which was due to the DD genotype in 40 male patients (44%) vs. 23 in male controls (25.3%;p =.004; odds ratio, 3.48; 95% confidence interval, 1.47-8.30). There were no differences in genotype distributions among other polymorphisms., Conclusion: We demonstrate a possible association of the DD genotype with hypertensive crisis in men.

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.

Background: Successful kidney transplantation normalizes elevated proatrial natriuretic peptide (proANP) plasma concentrations of renal failure patients in the early posttransplant period. We evaluated plasma and urinary proANP fragments in the late posttransplant period., Methods: Immunoreactive proANP(1-30) and proANP(31-67) were determined in 389 renal transplant (Rtx) recipients in the long-term, follow-up period and in 16 healthy controls., Results: Rtx recipients had significantly higher concentrations of proANP(1-30) and proANP(31-67) in both plasma and urine than healthy controls. Although their graft function was normal, all of these long-term Rtx recipients were taking glucocorticoids, which increase proANP(1-30) and proANP(31-67) in the circulation to the extent found in this investigation. Two-thirds of these recipients were also taking cyclosporine, which also increases atrial peptides. Urinary proANP(31-67) was significantly higher than urinary proANP(1-30); 5.5-fold in Rtx patients and 2-fold in controls. Deterioration of renal graft function was associated with a rise of plasma proANP(1-30) from 0.98+/-0.66 to 6.28+/-3.55 nmol/l (P<0.0001) and plasma proANP(31-67) from 1.81+/-1.04 to 7.89+/-3.76 nmol/l (P<0.0001). Urinary excretion of proANP(1-30) increased from 0.27+/-0.34 to 5.96+/-5.07 nmol/24 hr (P<0.0001) and proANP(31-67) from 1.45+/-0.85 to 12.23+/-5.12 nmol/24 hr (P<0.0001). Also proteinuria enhanced plasma and urinary proANP fragments., Conclusions: ProANP(1-30) and proANP(31-67) of Rtx recipients are affected by immunosuppression, hypertension, renal failure, and proteinuria. One would have expected proANP(1-30) and proANP(31-67) not to normalize because of the glucocorticoids that they were receiving.

As the number of elderly patients suffering from end-stage renal disease has increased almost threefold during the past 20 years all over the world, new strategies for the treatment of such patients have been developed. Better screening has made renal transplantation a valuable resource in elderly end-stage renal disease patients. Improved immunosuppressive protocols as well as the expansion of the donor pool by using older and living donors for older recipients have improved patient survival rates as well as the quality of life in this patient population.

Background: Tyrphostin AG490 has recently been shown to block interleukin (IL)-2 receptor gamma-chain-associated Janus kinase 3. Here, we analyzed the effect of AG490 on T-cell alloresponses in vitro., Methods: For the evaluation of T-cell activation, DNA synthesis, surface marker expression, cytokine secretion, intracellular calcium mobilization, early protein tyrosine phosphorylation, and apoptosis were measured., Results: AG490 effectively inhibited T-cell proliferation in human mixed lymphocyte culture (MLC) even when added 4 days after culture initiation. Inhibition of IL-2-dependent proliferation in T-cell blasts and the incapability of IL-2 or IL-15 to restore proliferation in AG490-treated MLC suggests interference with cytokine receptor signaling. T-cell receptor-triggered early protein tyrosine phosphorylation, calcium mobilization, up-regulation of CD69, and initial CD25 expression were not affected. Interestingly, AG490 substantially inhibited production of IL-2 and interferon-gamma in T cells stimulated with alloantigen or via CD3 and CD28. In CD28-independent activation models (e.g., stimulation with phorbol myristate acetate plus ionomycin), however, cytokine secretion was not inhibited. Pretreatment of primary MLC with AG490 resulted in substantial down-regulation of secondary responses to cells from the original donor as opposed to third-party cells or phytohemagglutinin. Unresponsiveness was induced also in T cells stimulated with CD3 monoclonal antibody. Induction of apoptosis in polyclonally activated T cells and the incapability of IL-2 to reverse specific hyporesponsiveness, suggest programmed cell death as an important mechanism underlying antigen-specific down-regulation of alloresponses., Conclusions: We demonstrate that AG490 blocks different manifestations of T-cell activation. This and its ability to induce alloantigen-specific hyporesponsiveness point to a potential use for interfering with alloreactivities in vivo.

Objective: The polymorphism 825C-->T in exon 10 of the gene GNB3 encoding the beta3 subunit of heterotrimeric guanine nucleotide binding regulatory proteins (G-proteins) results in a splicing variant (GNB3-s) in which the nucleotides 498-620 of exon 9 are deleted. The T allele has been shown to be overrepresented in patients with essential hypertension. Because GNB3-s may support the development of severe elevation of blood pressure, we hypothesized that GNB3 825C-->T may be present more frequently in patients with hypertensive crisis., Design: Case control study., Setting: Department of Emergency Medicine at the University Hospital of Vienna, Vienna, Austria., Patients: A total of 174 patients admitted to an emergency department for treatment of hypertensive crisis diagnosed as suffering from essential hypertension., Interventions: None., Measurements and Main Results: Patients were genotyped for the 825C-->T transition in GNB3. An equal number of age- and gender-matched normotensive, healthy individuals served as the control population. The allele frequency of 825C-->T in the GNB3 gene was 0.310 in patients with hypertensive crisis and 0.342 in the control group. There was no difference in genotype distribution and allele frequency between the patients and the age- and gender-matched control group or between the observed prevalence and the occurrence rate expected from the Hardy-Weinberg principle within each group., Conclusions: GNB3 825C-->T is not associated with the phenotype of hypertensive crisis in patients suffering from essential hypertension. Furthermore, our data do not support the concept that the 825C-->T transition in the GNB3 gene is associated with essential hypertension.

Objective: To test the hypothesis that the prevalence of hyperhomocysteinemia is increased in critically ill patients and correlates with disease severity and mortality in these patients., Design: A prospective study., Setting: Three medical intensive care units at the University of vienna Medical School serving both medical and surgical patients., Patients: All consecutive admissions (n = 56) during a period of 4 wks. A total of 112 age- and gender-matched healthy individuals constituted the control group., Interventions: None., Measurements and Main Results: Blood samples were drawn within 24 hrs after admission for analysis of total homocysteine (tHcy), folate, vitamin B6 levels, and vitamin B12 levels as well as to identify the 677C-->T polymorphism in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase. Acute Physiology and Chronic Health Evaluation III scores at admission and 24 hrs after admission as well as 30-day survival were documented in all patients. Hyperhomocysteinemia was more prevalent in critically ill patients (16.1%; 95% confidence interval, 7.6% to 28.3%) compared with age- and gender-matched healthy individuals (5.4%; 95% confidence interval, 2.0% to 11.3%; chi-square test; p = .022). There was no difference in tHcy plasma concentrations in the first 24 hrs after admission to an intensive care unit between survivors and nonsurvivors. The 5,10-methylenetetrahydrofolate reductase 677C-->T polymorphism had no influence on tHcy levels and survival of intensive care unit patients., Conclusions: The prevalence of hyperhomocysteinemia is increased in critically ill patients compared to age- and gender-matched healthy individuals. The clinical significance of this finding remains to be determined.

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.

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.

Background: Tumors of the bladder termed nephrogenic adenomas in kidney allograft recipients are believed to develop as urothelial metaplastic proliferations in response to mechanical trauma, chemical noxae, irradiation, and bacterial or viral pathogens. We report on the incidence of nephrogenic adenoma of the bladder in patients who received renal transplants during a period of 7 years and 3 months at the University Hospital of Vienna., Methods: Diagnosis was obtained by cystoscopy and histological analysis. Nephrogenic adenoma was treated by transurethral electroresection and administration of antibiotics in case of urinary tract infections. Follow-up consisted of cytological controls of urine and bladder irrigation fluid as well as of cystoscopy every 3 months., Results: In 7 of 1328 renal allograft recipients, nephrogenic adenoma could be detected after 7 to 60 months following renal transplantation. In five patients, recurrence was detected 9 to 23 months after diagnosis of the initial lesion. No evidence of malignant degeneration was observed in any patient. Nephrogenic adenoma was not related to immunosuppressive therapy, cytomegalovirus disease, or gancyclovir therapy., Conclusions: We suggest that after successful transurethral electroresection of nephrogenic adenomas, cytological controls are adequate every 3 months. Only in renal transplant patients with recurrence of voiding disturbances, macrohematuria, or urinary tract infection are cystoscopy and biopsy indicated in the routine follow-up regimen.

Almost all patients with end-stage renal disease suffer from renal anaemia of multifactorial pathogenesis. The use of recombinant human erythropoietin to raise the haematocrit has been a major advance in the care of patients with end-stage renal disease. The majority of these patients develop absolute or functional iron deficiency. However, the diagnosis of iron deficiency is hindered by the inaccuracy of commonly used tests. Serum ferritin and transferrin saturations are frequently used, but limitations with both parameters in end-stage renal disease patients have resulted in the development of new tests to assess iron sufficiency. The percentage of hypochromic red blood cells and particularly reticulocyte haemoglobin content are new measures of iron status in end-stage renal disease patients. An enhanced knowledge of the interpretation of available laboratory parameters will ensure that the patients receive the full benefit from their treatment with recombinant human erythropoietin and iron.

Chronic (CRF) and acute renal failure (ARF) are accompanied by cardiac dysfunction, particularly if ARF is complicated by sepsis. Intermyocardiocytic fibrosis is described in CRF, but there is also evidence for functional cardiomyopathy. Acetate ion (present in the dialysate) and secondary hyperparathyroidism do not appear to be clinically relevant myocardial depressant factors in uremia. The role of carnitine deficiency is not clarified, because most of the data are evaluated in poorly controlled study trials. Multiple effects of serum fractions and ultrafiltrates obtained from CRF and ARF patients during dialysis suggest the existence of myocardial depressant factor(s). Beneficial effects of continuous hemofiltration in multiorgan failure give evidence for the pathogenetic role of this substance(s). One group of experiments suggests a molecular weight between 500 and 5,000 d; other experiments suggest activity at > 10,000 d. It is currently believed that myocardial depressant substance is a water-soluble molecule weighing 10,000-30,000 d. The data confirm the existence of "specific cardiomyopathy" caused by a functional defect related to filterable toxins. There are different myocardial depressant factors in CRF, ARF, and sepsis.

Plasma levels of main granulocyte components of patients after cadaveric renal transplantation were compared 9 days postoperative with the plasma levels of patients undergoing aortofemoral and iliacofemoral bypass operation or abdominal surgery. Lactoferrin values were significantly lower in patients under immunosuppression with cyclosporine and prednisolone, whereas plasma levels of myeloperoxidase were comparable in all 3 groups of patients. Plasma E-alpha 1 PI values were significantly lower in patients undergoing bypass operation compared to abdominal surgery but did not differ from patients undergoing cadaveric kidney transplantation. Within 22 days postoperatively, there was no difference in the plasma levels of main granulocyte components in patients after kidney transplantation with and without postoperative complications. In vitro incubation of heparinized whole blood and isolated granulocytes obtained from healthy subjects in the presence of CsA, azathioprine, or prednisolone were performed. Only CsA caused inhibition of spontaneous degranulation of polymorphonuclear neutrophils showing significant lower elastase and lactoferrin release. However, in vivo administration of CsA and prednisolone in transplant patients displayed no effect on in vitro degranulation of both whole blood samples and isolated granulocytes. Our data demonstrate that CsA after in vitro incubation inhibits spontaneous granulocyte degranulation but not after in vivo administration. However, in vivo administration of CsA and prednisolone reduces lactoferrin release under certain conditions, e.g., postoperative stress or during hemodialysis therapy.