[Hypertension and nutrition. Position paper of the Austrian Nutrition Society]. / Hypertonie und Ernährung. Positionspapier der Österreichischen Gesellschaft für Ernährung (ÖGE).

Arterial hypertension is one of the leading causes of overall mortality and is responsible for a high proportion of deaths due to stroke as well as coronary heart disease. It is defined as a pathological elevation of blood pressure which leads to damage of the cardiovascular system. Cut-off values for hypertension are defined as blood pressure levels higher than 140/90 mmHg (systolic/diastolic). In the pathogenesis of hypertension genetic factors, age and sex play a role, as well as body weight and lifestyle factors, such as nutrition and physical exercise. Lifestyle optimization reduces the risk of developing hypertension and contributes to the treatment in patients with established hypertension. Nutritional factors associated with hypertension are discussed in this article and recommendations regarding diet are made based on the literature. The nutritional factors with the highest impact on blood pressure are reduction of salt intake, a diet rich in potassium, weight management, the DASH (dietary approach to stop hypertension) diet and moderation of alcohol consumption. Salt restriction is essential in the prevention and treatment of hypertension. Based on the literature, in this article recommendations for nutrition and hypertension are given.

The novel immunosuppressant FK778 inhibits formation of the immunologic Synapse.

The malononitrilamide FK778 is a derivative of A77 1726, the active metabolite of the antirheumatic drug leflunomide. A77 1726 inhibits de novo pyrimidine synthesis and activity of Src-family kinases; thus, it may interfere with T-cell proliferation as well as with early T-cell signaling. Formation of a stable interaction between T cells and antigen-presenting cells (APC)--the immunologic synapse--has emerged to be of crucial importance for T-cell activation. Here in we show that FK778 inhibits formation of the immunologic synapse by blocking superantigen-stimulated relocalization of adhesion (LFA-1), and signaling molecules (CD3) to the T-cell/APC contact site. These data show that FK778 affects T-cell/APC interactions, particularly events crucial for T-cell adhesion and formation of stable conjugates underlying sustained and effective T-cell activation. Thus, in this model system close to physiologic T-cell stimulation, FK778 affects critical events in the course of T-cell-mediated immune responses earlier than T-cell proliferation, which may contribute to its immunosuppressive potential.

The malononitrilamide FK778 inhibits activation of NF-kappaB in human dendritic cells.

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 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 a crucial cell type in initiation of immune responses including chronic allograft rejection, we investigated whether FK778 affects this peculiar cell population. NF-kappaB is the essential transcription factor involved in DC activation and function. We found that lipopolysaccharide (LPS)-induced activation of NF-kappaB, as assessed using electromobility shift assay, is markedly inhibited by FK778 in human monocyte-derived DCs. Hence, FK778 could exert its immunosuppressive effects via inhibition of activation and thus function of the central antigen-presenting cell, ie, DC.

Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection.

BACKGROUND: Capillary deposition of complement split product C4d has been suggested to be a valuable marker for humoral rejection. In this retrospective study we evaluated the clinical impact of C4d deposition in renal allografts with special emphasis on associations between C4d staining patterns and histological features of acute rejection. METHODS: One hundred and two allograft biopsies obtained from 61 kidney transplants (1-532 days after transplantation; median 14 days) were examined by immunohistochemistry on routine paraffin sections using a novel anti-C4d polyclonal antibody (C4dpAb). RESULTS: Fourty-two of 102 biopsies showed endothelial C4d deposits in peritubular capillaries (PTC). Histopathological analysis revealed a significantly lower frequency of positive C4d staining in biopsies with rather than in those without acute cellular rejection defined by the Banff grading schema (P<0.01). For clinical evaluation, patients were classified according to C4d staining in allografts (C4d(PTC) positive in at least one biopsy, n=31 vs C4d(PTC) negative in all biopsies, n=30). C4d(PTC) positive patients had significantly higher serum creatinine levels than C4d negative patients. Even in the absence of morphological evidence for rejection, differences in serum creatinine levels between C4d(PTC) positive and negative recipients were significant (6 months: 2.01+/-0.75 vs 1.41+/-0.27 mg/dl; 12 months: 1.95+/-0.60 vs 1.36+/- 0.34 mg/dl; 18 months: 1.98+/-0.50 vs 1.47+/-0.31 mg/dl; P<0.05). All patients with rejection resistant to conventional therapy (n=4) were in the C4d(PTC) positive subgroup. All recipients with panel reactive antibodies (PRA) >50% (n=8) were C4d(PTC) positive. CONCLUSIONS: Our data indicate that endothelial C4d deposition is associated with inferior graft outcome. We provide evidence that this immunohistochemical finding and its clinical impact are not associated with morphological signs of cellular rejection.

The effects of lipid-lowering agents on acute renal allograft rejection.

BACKGROUND: Preliminary results from clinical trials suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors may help prevent acute renal allograft rejection. However, the mechanism for this putative effect of 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors, and whether it is independent of lipid-lowering per SE are unknown. METHODS: Immediately after renal transplantation we randomly allocated (proportioned 2:1:2) patients to: 1) simvastatin (10 mg/day, n=53), 2) simvastatin placebo plus gemfibrozil (dose adjusted for renal function, n=36), and 3) simvastatin placebo (n=52). RESULTS: Simvastatin, but not gemfibrozil, reduced total and low density lipoprotein cholesterol during the first 90 days posttransplant. There were no major adverse effects of therapy. However, there were no effects of treatment on acute rejection. Indeed, survival free of acute rejection at 90 days was 72% in the simvastatin group, 72% in the gemfibrozil group, and 77% in the placebo control group (P=0.771). A post hoc power analysis suggested that there was only a 7.5% chance that a true effect of simvastatin on acute rejection (versus placebo) was not detected, and a 2.5% chance that an effect of gemfibrozil on acute rejection (versus placebo) was not detected in this study. CONCLUSION: Lipid-lowering agents may not reduce the incidence of acute renal allograft rejection. However, additional studies are needed to confirm this observation. In the mean time, many if not most renal transplant recipients should be treated with HMG-CoA reductase inhibitors starting early posttransplant to prevent cardiovascular disease complications. The results of this study suggest that starting lipid-lowering therapy immediately after renal transplantation is both safe and effective in lowering total and low density lipoprotein cholesterol.

Comparison of sequence analysis and the INNO-LiPA HBV DR line probe assay for detection of lamivudine-resistant hepatitis B virus strains in patients under various clinical conditions.

A line probe assay (INNO-LiPA HBV DR) detecting drug-resistant hepatitis B virus (HBV) strains was evaluated. Results concordant with sequence analysis were obtained with 48 of 56 serum samples from HBV-infected patients undergoing lamivudine therapy. In eight cases, additional minor subpopulations could be identified by the line probe assay.

A case of continuous ambulatory peritoneal dialysis peritonitis with an uncommon organism and an atypical clinical course.

This report describes a 46-year-old patient who experienced an atypical course of peritonitis while undergoing continuous ambulatory peritoneal dialysis (CAPD). The first sign of peritonitis was progressive impairment of ultrafiltration with increasing fluid absorption. The patient came to the center after 5 days with leg edemas and 645 leukocytes/microL in the first dialysate outflow. On the same day, the dialysate cell count decreased to 208/microL. During the following days, ultrafiltration failure persisted despite spontaneous normalization of PD-fluid leukocytes. No other clinical symptoms were observed, and the serum C-reactive protein (CRP) level remained normal. Magnetic resonance peritoneography and abdominal radiograph did not show dislocation of the catheter, a dialysate leak, or other causes of ultrafiltration failure. At day 14, fever, diarrhea, and an elevated serum CRP level occurred. Dialysate cultures taken on days 8, 11, and 14 showed growth of NEISSERIA: sicca. After initiation of antibiotic therapy with levofloxacine on day 14 ultrafiltration, clinical symptoms and serum CRP normalized within 3 days. In conclusion, Neisseria sicca should be considered as a rare cause of PD peritonitis. Our case report further illustrates the importance of ultrafiltration failure as an early and main symptom of peritoneal inflammation. The frequently used peritonitis criteria may not apply to cases of mild PD peritonitis.

Twelve months of lamivudine treatment for chronic hepatitis B virus infection in renal transplant recipients.

BACKGROUND: Chronic hepatitis B virus (HBV) infection increases morbidity and mortality in renal transplant recipients (RTR). Lamivudine has shown promising results in patients with chronic hepatitis B, but experience with its use in RTR is limited. METHODS: In a prospective, open labeled, uncontrolled trial, 19 HBsAg(+) RTR were treated with lamivudine for 12 months. HBV-serologic analysis, HBV-DNA quantitation, and HBV genome sequence analysis were performed every 3 months. RESULTS: At baseline 16 patients were HBV DNA(+), 12 patients were HBeAg(+)/Ab (-). After 3 months HBV DNA was negative in 80% of patients. In the 3 patients with elevated liver enzymes, normal values were achieved within 12 weeks. At 12 months 4 of 8 HBeAg(+)/Ab(-) patients on treatment showed HBeAb, two of them with loss of HBeAg. Three patients developed mutations of the HBV polymerase gene associated with lamivudine resistance. CONCLUSIONS: Lamivudine is safe and effective in HB-sAg(+) RTR, the rate of HBe-seroconversion and of lamivudine-resistance is comparable to that of nonimmunosuppressed patients.

New developments in clinical immunosuppression.

Over the last few years, the armamentarium of immunosuppressants has been enriched by a variety of new drugs, that have helped to further reduce the incidence of acute rejection episodes after kidney transplantation. Nevertheless the search for new compounds drugs continues, until tolerance, the ultimate goal of transplantation medicine can be achieved. Meanwhile we should appreciate that neither all drugs nor all patients are equal and tailor the immunosuppression to the patients' needs. To define patient groups who benefit most from different immunosuppressive protocols especially in regard to long term allograft and patient survival will warrant further prospective controlled trials.

Long-term evaluation of proliferative donor antigen-specific reactivity in cadaveric kidney transplant recipients.

Development of donor-specific proliferative hyporeactivity has been evaluated in many studies for its usefulness in identifying transplant recipients at low risk of immunological complications. These studies often result in controversial conclusions, however. The authors claim that the discrepancy in the predictive value of mixed lymphocyte culture- (MLC) reactivity might partly be due to differences in presentation and interpretation of results. The purpose of this study is to investigate the usefulness of a normalized evaluation of antigen-specific donor-reactivity in a small number of kidney transplant recipients. This could then serve as a basis for an extended clinical study. Ten cadaveric kidney recipients were tested for proliferative reactivity to donor- and third-party antigens up to 20 months posttransplantation. Expressing donor-specific reactivity as a relation between the percentage of pretransplant responses towards donor splenocytes and the percentage of pretransplant responses towards third-party donor cells should minimize influences of e. g. uremia, current immunosuppression or infections on the evaluation of specific reactivity and thus should allow an evaluation of the donor-specificity of T-cell alloresponses independently of fluctuations in global responsiveness. Four of ten recipients acquired a state of donor-specific hyporeactivity ( < 75 % relative specific reactivity) at 20 months post-transplantation (61 +/- 12%, mean +/- SD). Six patients were classified non-hyporeactive (98 +/- 10% mean relative specific reactivity). Relative specific reactivity did not correlate with the levels of general reactivity. Three of the four hyporeactive and four of the six non-hyporeactive patients developed acute rejection. Stable graft function at 20 months posttransplantation (serum creatinine < or = 2 mg/dl) was not closely related to the reactivity status, as five of eight patients with well-functioning grafts did not develop relative specific hyporeactivity. One recipient with chronic rejection was classified hyporeactive. One non-hyporeactive patient lost his graft due to non-immunological causes. Our data suggest that post-transplant relative specific reactivity does not predict acute rejection. Downregulation of donor-specific reactivity might not be a prerequisite for stable graft function but could help identifying recipients who require less immunosuppression. This, however, remains to be established in a prospective immunosuppression-weaning study.

Monitoring the virus load can predict the emergence of drug-resistant hepatitis B virus strains in renal transplantation patients during lamivudine therapy.

The development of resistant hepatitis B virus (HBV) strains during lamivudine treatment has been described repeatedly. To investigate whether the development of such resistant HBV strains can be predicted in an early phase of therapy, the HBV loads of 11 renal transplantation patients were screened at 3-month intervals by a quantitative HBV polymerase chain reaction (PCR) assay. Lamivudine resistance was detected by sequence analysis. Five patients developed resistance to lamivudine in the 12-15-month follow-up period. In all of them, a virus load of 1x103 HBV DNA copies still was detectable after 3 months of therapy. This was statistically significantly different from those patients who did not develop lamivudine resistance within the observation period, all of whom had no HBV DNA detectable after 3 months of treatment (P=.0022). Thus, virus load testing by use of a sensitive PCR assay allows the early prediction of the emergence of lamivudine-resistant HBV strains.

Beneficial effects of atorvastatin in the treatment of hyperlipidemia after renal transplantation.

Despite the availability of various lipid lowering drugs, the treatment of hyperlipidemia, one of the most important risk factors for morbidity and mortality after organ transplantation, remains a therapeutic challenge. We investigated the safety and efficacy of a new HMG-CoA reductase inhibitor, atorvastatin, in renal transplant patients whose serum lipids were insufficiently controlled by diet and treatment with other lipid lowering drugs. Twenty-four patients (14 males/10 females; mean age 51.2 +/- 2.3 years) were converted to low dose atorvastatin (10 mg/day) at a mean of 67.7 +/- 8.6 months after renal transplantation and prospectively followed for 3 months after initiation of the study drug. HDL, LDL, and total cholesterol, triglycerides, serum creatinine and CPK levels were evaluated pre (-3, -1, 0 months) and post conversion (+1, +3 months). In the eighteen patients who completed the study, low dose atorvastatin therapy led to a significant reduction in total cholesterol (304.6 +/- 13.2 vs. 247.6 +/- 12.0 mg/dl; p = 0.007) and LDL cholesterol (191.9 +/- 9.0 vs. 141.8 +/- 14.7 mg/dl; p < 0.0001) and a modest reduction in serum triglyceride levels at three months after conversion. We conclude that low dose atorvastatin (10 mg/day) can be successfully used and appears to be safe in the treatment of posttransplant hyperlipidemia. Its long-term effects on patient morbidity and mortality as well as graft survival should be investigated in larger and more prolonged prospective trials.

Vasoactive substances in renal transplantation.

During and after transplantation the kidney experiences a variety of insults that result in functional impairment and structural damage. These changes are mediated or influenced by hormones, cytokines, enzymes and growth factors, which are excreted by endothelial, graft parenchymal as well as by graft infiltrating cells. This review evaluates the pathophysiological role of vasoactive substances (for example, the vasoconstrictors angiotensin II and endothelin, as well as vasodilators such as nitric oxide, adrenomedullin and atrial natriuretic peptide) in kidney transplantation and summarizes recent reports that indicate that targeting vasoactive substances may represent effective therapeutic strategies for the achievement of long-term allograft survival.

Role of humoral immune reactions as target for antirejection therapy in recipients of a spousal-donor kidney graft.

Excellent graft outcome has been reported for spousal-donor kidney transplantation. In husband-to-wife transplantation, however, a tendency toward inferior graft survival has been described for recipients who were previously pregnant. In our series of spousal-kidney transplantations (nine transplantations; three female recipients), actual graft survival is 100% (median observation time, 339 days). Five patients experienced early allograft rejection. In four transplant recipients, rejection was easily reversible by conventional antirejection therapy. In a multiparous recipient, however, mild interstitial allograft rejection associated with early graft dysfunction was resistant to anticellular treatment (antilymphocyte antibody, tacrolimus rescue therapy). The particular finding of polymorphonuclear neutrophils in peritubular capillaries and the finding of diffuse capillary deposits of the complement split product, C4d, in a posttransplantation biopsy specimen suggested a role of antibody-mediated graft injury. Retrospective flow cytometry cross-matching showed the presence of preformed immunoglobulin G (IgG) antibodies to HLA class I antigens that were not detectable by pretransplantation lymphocytotoxic cross-match testing or screening for panel reactive antibodies. After transplantation, however, complement-fixing antibodies, also presumably triggered by reexposure to spousal-donor HLA antigens, could be detected in the patient's serum. These findings suggested antibody-mediated allograft rejection and led to the initiation of immunoadsorption therapy (14 sessions) with staphylococcal protein A. Selective removal of recipient IgG resulted in complete reversal of graft dysfunction. Our findings suggest that in husband-to-wife transplantation, donor-specific antibodies, presumably triggered by previous pregnancies, might occasionally induce sustained allograft dysfunction. Thus, in this particular setting, a detailed immunologic and histopathologic work-up regarding antibody-mediated allograft dysfunction is warranted because immunoadsorption may be a highly effective treatment modality.

Basal calcitonin levels and the response to pentagastrin stimulation in patients after kidney transplantation or on chronic hemodialysis as indicators of medullary carcinoma.

Plasma concentrations of calcitonin (hCT) were determined in 150 patients with chronic renal failure on chronic hemodialysis therapy (CHD) and in 800 patients after successful kidney transplantation (KT). Basal hCT concentrations exceeded 10 pg/mL in 44 of 150 patients (29%) with CHD and in 48 of 800 (6%) in patients with KT. Among these patients with elevated basal hCT, pentagastrin-stimulated concentrations of hCT exceeded 100 pg/mL in 4 patients with CHD and in 7 with KT. Thyroidectomy was performed in 8 patients (5 with KT, 3 with CHD) revealing the presence of medullary thyroid carcinoma (MTC) (n = 2) or of C-cell hyperplasia (n = 6). Two patients with C-cell hyperplasia had the neoplastic form of this disorder. One patient with MTC and 1 with C-cell hyperplasia also presented a papillary microcarcinoma. Stimulated concentrations of hCT were only moderately elevated in the remaining 3 patients and follow-up rather than surgery was deemed appropriate due to their concomitant severe medical problems. In conclusion, basal concentrations of hCT higher than 10 pg/mL are more common in patients with CHD (29%) and after successful KT (6%) than previously described in patients with thyroid nodular disease (3%). In spite of various additional factors complicating the interpretation of elevated hCT in CHD, pentagastrin-stimulated values above 100 pg/mL must be considered to indicate the presence of C-cell hyperplasia and/or of medullary thyroid carcinoma. Although thyroidectomy would theoretically be the therapy of choice, the potential benefit of the operation must be seen in the context of the patient's general condition.

Smoking as a risk factor for end-stage renal failure in men with primary renal disease.

BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.

Decreased urinary apolipoprotein (a) excretion in patients with impaired renal function.

BACKGROUND: Plasma lipoprotein (a) [Lp(a)] levels are elevated in patients with kidney disease and are strongly associated with premature cardiovascular disease and stroke. METHODS: As the kidney is suggested to play an important role in apolipoprotein (a) [apo(a)] catabolism and as apo(a) fragments appear in urine, we determined plasma Lp(a) levels and urinary apo(a) excretion in relation to kidney function in a large cohort of renal patients. A total of 368 renal patients with normal or different degrees of impaired renal function and 163 healthy control subjects matched for age and sex were investigated. Plasma Lp(a) and urinary apo(a) were analysed immunochemically. RESULTS: Renal patients were found to have significantly elevated total cholesterol and low-density lipoprotein (LDL)-C values but lower high-density lipoprotein (HDL)-C values than control subjects. Plasma Lp(a) values were significantly higher only in patients with creatinine clearance < 70 mL min-1. There was a significant correlation between urinary apo(a) and plasma Lp(a) in patients and control subjects. Urinary apo(a) excretion was significantly lower in patients than in control subjects and showed no correlation with urinary protein excretion. CONCLUSION: Although it is unlikely that impaired renal excretion of apo(a) fragments largely contributes to increased plasma Lp(a) levels in patients suffering from impaired kidney function, these data suggest that urinary apo(a) excretion is significantly decreased in renal patients and that this might contribute to increased plasma Lp(a) levels in this patient group.