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Introduction: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear., Methods: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers., Results: Mean age was 66.3 years, mean blood pressure 146/76 mm Hg, mean time suffering from diabetes 18.1 years, and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP, and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we also did not detect any significant mortality prediction for PP, SBP, DBP, or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70-80 mm Hg., Discussion: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and CVM that may no longer be significantly modulated by blood pressure control., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: "Dynamic" baseline serum creatinine (sCr), based on a rolling 48-h window, and a static baseline sCr (previous outpatient sCr) were used to define acute kidney injury (AKI)., Methods: Retrospective cohort study of adult admissions to the University of Alabama (UAB) Health System hospitals for years 2016-2018. Included admissions had >1- and <180-day length of stay, >2 inpatient sCr measurements, and an averaged estimated glomerular filtration rate >15 mL/min/1.73 m2. The final cohort of 62,380 patients included 100,570 admissions, 3,509 inpatient deaths, and 1,916 admissions with inpatient dialysis. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria and a static or dynamic baseline sCr. Discrimination was evaluated with area under receiver operator curves (AUC), logistic regression, and net reclassification improvement (NRI)., Results: Preadmission outpatient "static" sCr values were available for 43,433 admissions. The lowest sCr value during a rolling 48-h window before each inpatient sCr defined a "dynamic" baseline sCr. Using point-wise comparisons, the dynamic baseline sCr performed better than static baseline sCr for inpatient mortality (AUC [0.819 vs. 0.741; p < 0.001] and NRI ≥0.306 [p < 0.001]) and inpatient dialysis (AUC [0.903 vs. 0.864; p < 0.001] and NRI ≥0.317 [p < 0.001])., Conclusions: The dynamic baseline sCr is available without reference to preadmission sCr values and avoids confounding associated with missing outpatient sCr values. AKI defined with the dynamic baseline sCr significantly improved discrimination of risk for inpatient mortality and dialysis compared to static baseline sCr., (© 2021 S. Karger AG, Basel.)

Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney function induced by bardoxolone methyl., Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive once-daily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation)., Results: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001)., Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Data concerning long-term mortality predictors among large, purely diabetic hemodialysis collectives are scarce., Methods: We used data from a multicenter, prospective, randomized trial among 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) and its observational follow-up study. The association of 10 baseline candidate variables with mortality was assessed by Cox proportional hazards regression., Results: Overall, 103 participants survived the median follow-up of 11.5 years. Significant predictors of mortality were age (hazard ratio [HR] 1.03, 95% CI 1.02-1.04), cardiovascular (HR 1.42, 95% CI 1.25-1.62) and peripheral vascular disease (HR 1.55, 95% CI 1.36-1.76), higher hemoglobin A1c (HbA1c; HR 1.08, 95% CI 1.03-1.14), and loss of self-dependency (HR 1.20, 95% CI 1.03-1.39). Higher albumin (HR 0.72, 95% CI 0.59-0.89) and body mass index (BMI; HR 0.98, 95% CI 0.96-0.99) had protective associations. There was no significant association with sex, diabetes duration, and cerebrovascular diseases. Subgroup analyses by age and diabetes duration showed stronger associations of cardiovascular disease, HbA1c, albumin, BMI, and loss of self-dependency in younger patients and/or shorter diabetes duration. Loss of self-dependency and energy resources (albumin, BMI) increased mortality more severely in women, whilst the impact of cardiovascular and peripheral vascular diseases was more pronounced in men., Conclusion: Long-term mortality risk in patients with T2DM on hemodialysis was associated with higher age, vascular diseases, HbA1c, loss of self-dependency, and low energy resources. Interestingly, it does not vary between sexes. Further individualized prognosis estimation and therapy should strongly depend on age, diabetes duration, and gender., (© 2018 S. Karger AG, Basel.)

Purpose: To evaluate the efficacy of intravitreal dexamethasone implant for the treatment of postoperative persistent cystoid macular edema (CME) following macular pucker surgery., Methods: In this multicenter study, we retrospectively reviewed the data of 37 patients (39 eyes) who had been treated with intravitreal dexamethasone implant (Ozurdex®) for persistent CME following macular pucker surgery. Main outcome measures were change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT)., Results: All eyes underwent spectral domain optical coherence tomography examination within 130 days after implantation. We observed a significant decrease in mean CRT from 519.9 to 392.9 µm (p < 0.0001). By this time, mean BCVA had improved from 0.60 to 0.43 logMAR (p = 0.003). Seventeen eyes (43.6%) required at least 1 repeat injection of dexamethasone. Of these, 8 (47%) eyes received a total number of 3 or more dexamethasone injections., Conclusion: Intravitreal dexamethasone implant injection is an effective treatment option for persistent CME following macular pucker surgery., (© 2017 S. Karger AG, Basel.)

Anderson-Fabry disease is a potentially life-threatening hereditary lysosomal storage disorder taking origin in over 1,000 known pathogenic mutations in the alpha-galactosidase A encoding gene. Over the past 15 years, intravenous replacement therapy of the deficient alpha agalsidase A enzyme has been well-established retarding the progression of a multisystemic disease and organ involvement. Despite this innovative treatment approach, premature deaths still do occur. The response to enzyme replacement therapy (ERT) varies considerably and appears to depend on gender, genotype (classic or later onset/non-classic), stage of disease or age and agalsidase inhibition by anti-agalsidase antibodies. Early ERT treatment at young age, a personalized approach, and adjunctive therapies for specific disease manifestations appear to impact on prognosis and are currently favored with the expectance of more effective intravenous and oral treatments in the short future., (© 2016 S. Karger AG, Basel.)

Background/aims: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c)., Methods: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period., Results: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal., Conclusion: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels., (© 2015 S. Karger AG, Basel.)

Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach., Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures., Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046)., Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness., (© 2014 S. Karger AG, Basel)

Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD., Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality., Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events., Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD., (Copyright © 2013 S. Karger AG, Basel.)

Despite best treatment efforts reducing low-density lipoprotein cholesterol, a substantial number of type 2 diabetes mellitus patients still experience progression of cardiovascular risk. Even with intensification of statin therapy, a substantial residual cardiovascular risk remains and atherogenic dyslipidemia is an important driver of this so-called residual risk. Besides statin therapy, new strategies evaluate the role of intensive combination lipid treatment for the entire type 2 diabetic population. The results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial suggest that there is a lipid-related modifiable component to cardiovascular residual risk in statin-treated type 2 diabetic patients, and that further research should address patients with triglycerides above 204 mg/dl and high-density lipoprotein cholesterol below 34 mg/dl. Based on their respective lipid-modifying activity, the combination of a fibrate and statin is a logical approach to improving achievement of lipid targets in statin-treated patients with a glomerular filtration rate of >60 ml/min/1.73 m(2) and with residual atherogenic dyslipidemia. The link between dyslipidemia treatment and diabetic retinopathy, nephropathy and neuropathy is an emerging new field and microvascular complications are targets for new treatments., (Copyright © 2011 S. Karger AG, Basel.)

Background: In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models., Methods: PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study., Results: LVMI was 33.0 ± 7.5 g/m(2.7) for males and 30.8 ± 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 ± 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis., Conclusion: Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146., (Copyright © 2011 S. Karger AG, Basel.)

Background/aims: Recent in vivo data indicate that indomethacin improves renal outcome after ischemia via improvement of renal cell survival and function. To examine direct effects of indomethacin on isolated proximal tubular cells, we investigated the influence of indomethacin on markers of ischemia/reperfusion (I/R) damage in an established in vitro model of ischemia and reperfusion., Methods: Ischemia was applied for 2 h followed by reperfusion for up to 48 h. Indomethacin was added at the beginning of reperfusion. Parameters were investigated after 6, 24 or 48 h of reperfusion., Results: Indomethacin diminished cell death by necrosis and apoptosis, release of prostaglandin E2, induction of I/R-induced protein, dedifferentiation or induction of inducible nitric oxide synthase. Moreover, indomethacin totally prevented the ischemia-induced inhibition of basolateral organic anion transport. Indomethacin did not affect ischemia-mediated induction of nuclear factor-kappaB or monocyte chemoattractant protein 1. Ischemia did not induce matrix protein synthesis., Conclusions: We have shown that: (a) indomethacin applied after ischemia has a beneficial effect on proximal tubule cell survival after model ischemia and impairs changes of parameters characteristically induced by ischemia via direct action on proximal tubule cells; (b) the inflammatory response of proximal tubule cells was not affected by indomethacin, and (c) fibrosis does not take place after model ischemia in isolated proximal tubule cells., (Copyright 2010 S. Karger AG, Basel.)

Background/aims: Despite improved efficacy, modern immunosuppressive agents may show unanticipated side effects. In this study we investigated the possible interactions of mycophenolate mofetil (MMF) with wound healing and lymphocele formation., Methods: We conducted a retrospective single-center analysis in 144 patients receiving a cyclosporine A-based immunosuppression with prednisolone and either MMF (n = 77) or azathioprine (AZA, n = 77). Endpoints were incidences of lymphocele formation and non-primary wound healing during 6 months' follow-up., Results: AZA-treated patients had more rejection episodes and consecutively more steroid pulses, both being potential risk factors for endpoints. No graft was lost in any group and graft function was comparable. AZA patients demonstrated a trend for more frequent wound infections. Fluid accumulation around the graft, however, was more frequent in the MMF group (OR = 2.6; p = 0.03). Consequently, more drainage maneuvers (17 vs. 5 interventions) and sclerotherapies (8 vs. 0 interventions) were undertaken in MMF patients. Pre-assigned risk factors for lymphoceles reported before did not differ between both cohorts; patients experiencing acute rejection episodes had even less symptomatic lymphoceles (n = 23)., Conclusion: We found a possible relationship between the administration of MMF and lymphocele formation. To avoid the hazard of reinterventions, the prolongation of hospitalization and impairment of graft function, it requires awareness and attention in patients treated with this immunosuppressant., (Copyright 2010 S. Karger AG, Basel.)

Background: Type 2 diabetes is a leading cause of chronic kidney disease (CKD). The purpose of the Individual Risk-Profiling and Treatment in Diabetes Management (IRIDIEM) study was to evaluate the characteristics of CKD and associated comorbidities in patients with type 2 diabetes and CKD., Methods: IRIDIEM was conducted as a cross-sectional survey in 109 centres in 11 countries and included 1,205 patients aged >or=50 years with type 2 diabetes for >or=5 years and CKD stage 2-4., Results: 50% of patients were in CKD stage 4; 42% had CKD stage 3, and 4% were in CKD stage 2. Concomitant risk factors for cardiovascular disease and/or progression of CKD included hypertension (92% of patients), proteinuria (74%), hypercholesterolaemia (65%), and hypertriglyceridaemia (44%). Only 64% of patients with hypertension had received antihypertensive medication. Anaemia was present in 34% of patients and increased markedly with advanced CKD stages. Of patients with documented anaemia, only 19% had received epoetin and only 7% had received iron treatment., Conclusion: IRIDIEM documents the need to improve adherence to current best practice guidelines for management of cardiorenal risk factors including earlier initiation of antihypertensive treatment, lipid and anaemia management in this high-risk patient population., (Copyright 2010 S. Karger AG, Basel.)

Background/aims: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension., Methods: Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively., Results: Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups., Conclusion: In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition., (Copyright 2006 S. Karger AG, Basel.)

Background/aim: Hypertension is one of the main cardiovascular risk factors and has an impact also on long-term kidney graft survival. In addition to their lipid-lowering properties, it was shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors also have a blood pressure lowering effect. We examined whether treatment with a statin interferes with blood pressure regulation and antihypertensive treatment after renal transplantation., Methods: 74 patients were treated with initially 20 mg of pravastatin daily immediately after kidney transplantation. This group was compared to a matched cohort of 76 patients without statin treatment. All patients received standard immunosuppressive triple therapy with ciclosporin A microemulsion together with an antiproliferative agent and prednisolone. Primary objective of this analysis was systolic and diastolic blood pressure regulation with and without pravastatin. Furthermore, graft function expressed as creatinine clearance and proteinuria, immunosuppressive regimen, and incidence of cardiovascular events and graft loss were recorded for 48 months., Results: The blood pressure regulation was comparable in both groups; however, to achieve this, significantly more antihypertensive drugs had to be used in the statin-treated patients as compared with the controls (2.9 vs. 2.2 agents at 48 months). A slightly higher ciclosporin A exposure of the statin-treated patients could have contributed to this observation. The graft function after 4 years was comparable between the groups (creatinine clearance 56.9 vs. 57.0 ml/min), and a trend of reduced proteinuria could be demonstrated after 4 years of statin treatment (0.4 vs. 0.9 g/day). The low-density lipoprotein cholesterol levels decreased as expected during treatment (3.1 vs. 3.7 mmol/l at 48 months), but the recommended target levels for patients with a high cardiovascular risk have not been reached. A trend towards lower incidences of acute rejection, chronic allograft nephropathy, and graft loss was noted in the statin-treated group. Adverse effects of statin treatment have not been observed., Conclusion: Treatment with pravastatin at low to average dosages does not result in improved blood pressure regulation after kidney transplantation., (Copyright 2006 S. Karger AG, Basel.)

Background: L-Arginine (L-Arg), a substrate of nitric oxide synthases, improves renal function in ischemic acute renal failure (iARF). We evaluated whether L-Arg improves renal morphology and cell survival in the course of iARF., Methods and Results: iARF was induced in rats by bilateral clamping of renal arteries for 45 min. L-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Morphology and cell survival of renal cortical and medullar tissue was analyzed on days 1, 3, 7, and 14 of follow-up, using toluidine blue staining and immunohistochemistry of perfusion-fixated tissue, and Western blot analysis of tissue homogenate. Renal tubular injury showed typical features of necrosis and was most severe on days 1 and 3 after clamping, predominantly in S3 segments, with almost complete recovery by day 14. Enhanced medullar monocyte infiltration, determined by ED-1 expression as well as by immunohistochemistry, and enhanced expression of proliferating cell nuclear antigen (PCNA), indicative of proliferation and regeneration, accompanied these morphological changes. Compared to controls, L-Arg had no impact on renal morphology, ED-1, and PCNA expression. Furthermore, expression of markers of apoptosis Bcl-2, Bax, and cleaved caspase-3 was only slightly increased in iARF rats, compared to sham-operated animals, and was also not influenced by L-Arg., Conclusion: Despite its repeatedly reported positive impact on renal function as also shown in our model, L-Arg does not alter cell death and proliferation in the course of iARF in our model. Thus, different mechanisms have to be considered, in particular improved intrarenal hemodynamics., (Copyright 2005 S. Karger AG, Basel.)

Patients with type 2 diabetes on dialysis are at a substantially increased risk of cardiovascular and cerebrovascular diseases. Dyslipidemia characterized by moderately elevated low-density lipoprotein cholesterol and high triglycerides and low high-density lipoprotein cholesterol levels is common in this population. We hypothesized that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors would reduce vascular morbidity and mortality in this patient group. The 'Deutsche Diabetes Dialyse Studie' (4D study) is a prospective, randomized, double-blind study involving 178 dialysis centers throughout Germany. Between March 1998 and October 2002, 1,255 patients were randomized to either atorvastatin 20 mg or placebo; 677 men and 578 women, aged 30-83 years, have been enrolled. The study will be terminated as soon as the predefined number of 424 patients with primary combined end points (i.e., cardiovascular death, nonfatal myocardial infarction, or fatal/nonfatal stroke) will have occurred. The total cohort had the following characteristics at baseline: the mean age was 65.7 years, 54% were men, 89% had a history of hypertension, 21% had coronary artery disease, 17.8% had a history of stroke or a transient ischemic attack, and 45% suffered from peripheral arterial disease. The mean time interval between the diagnosis of diabetes and the onset of dialysis was 17.4 years. On average, the patients were on hemodialysis for 8.3 months. Mean lipid and lipoprotein levels were: total cholesterol 219 +/- 43 mg/dl, low-density lipoprotein cholesterol 126 +/- 30 mg/dl, high-density lipoprotein cholesterol 36 +/- 13 mg/dl, and triglycerides 264 +/- 167 mg/dl. The results of the study will provide important information on the efficacy and safety of atorvastatin to support its use in patients with an impaired renal function who are at a high risk of vascular morbidity and mortality., (Copyright 2004 S. Karger AG, Basel)

Type 2 diabetic nephropathy is the most common cause of end-stage renal disease in western Europe and the United States. Although patients with overt nephropathy generally experience greater cumulative glycemic exposure, the difference in glycemic control between patients developing nephropathy and to those who did not could not be demonstrated. This observation is consistent with the finding that factors other than glycemic control are involved in the development of nephropathy. Genetic factors which specifically increase the susceptibility to nephropathy in patients with diabetes have been proposed. A range of linkage, association, and gene expression studies have been performed for revealing the genetic background of diabetic nephropathy but were not yet successful in identifying mutations which could explain the development of diabetic nephropathy in the majority of diabetic patients. Because of relatively small case numbers of all studies being performed so far, conclusions from those studies are limited. With the development of better technologies for an affordable genomewide association study using thousands of markers, it might become possible to unravel the genetic susceptibility factors for diabetic nephropathy. Comparing the expression levels of thousands of genes in patients and controls may identify key players in the pathogenesis of diabetic nephropathy and targets for pharmacologic intervention in the future., (Copyright 2003 S. Karger AG, Basel)

Uremic patients suffer to an extremely high degree from cardiovascular disease. Cardiovascular disease results mainly from atherosclerotic remodeling of the arterial system. Inflammation is considered to contribute significantly to development of atherosclerosis, and albeit many different factors may lead to inflammation, generation of enhanced oxidative stress is believed to be an important common feature of pro-inflammatory causes. Studies in the general population without renal disease could clearly show that markers of inflammation, in particular C-reactive protein, predict the cardiovascular risk. In this review article, we discuss the presence and the predictive value of inflammation in patients with end-stage renal disease, and analyze whether uremic patients are exposed to specific pro-inflammatory and pro-oxidative conditions. Particular emphasis is set on oxidative stress induced by oxidatively modified lipoproteins and angiotensin II. Based on pathophysiological considerations valid for uremic patients, we discuss therapeutical options that might help to reduce cardiovascular disease in uremic patients., (Copyright 2003 S. Karger AG, Basel)

Lipoprotein modification occurs in uremic patients and in patients with end stage kidney disease under chronic renal replacement therapy. Forms of lipoprotein modification include lipid peroxidation, glycation, and carbamoylation. In this short review, we discuss the presence of these forms of lipoprotein modification and their association with various renal diseases. Methods to analyze lipoprotein modification are introduced, and functional consequences related to vascular and renal function are presented.

Lipoprotein(a) [Lp(a)] may be elevated in patients with the nephrotic syndrome and patients on hemodialysis or continuous ambulatory peritoneal dialysis. High levels of Lp(a) are due to proteinuria or an activated acute-phase response. Serum concentrations greater than 30 mg/dl are independently associated with coronary heart disease. Data from cell culture studies suggest that it is not uptake of Lp(a) by mesangial cells but trapping by matrix proteins that contributes to the generation of glomerular apo(a) deposits. Lp(a) alters mesangial cell DNA synthesis and stimulates the generation of reactive oxygen species. Prolonged exposure to Lp(a) causes mesangial cell death in vitro culture' experiments. Lp(a) does not alter autocrine transforming growth factor-beta transcription in human mesangial cells and has, unlike low-density lipoprotein, no effect on the production of the extracellular matrix protein fibronectin. Future cell culture studies on the role of Lp(a) in renal disease have to address whether Lp(a) induces cell death via apoptosis and to what extent the generation of oxygen radicals is involved in this process.

During the last decade, our understanding of the role of nitric oxide for central renal functions has greatly been enhanced. We know now that nitric oxide is produced in renal arteries, macula densa, glomeruli, and tubules by different NO-synthases. Nitric oxide contributes to physiological regulation of renal blood flow, renal autoregulation, tubuloglomerular feedback, renin release, pressure natriuresis, and tubular function. The physiological role of nitric oxide can be modulated by a variety of pathophysiological influences, such as dyslipidemia, diabetes mellitus, hypertension, specific drugs, or radiocontrast agents. In this article, the possible interactions between nitric oxide and atherogenic lipoproteins with regard to important renal functions and development of glomerulosclerosis have been stressed. Atherogenic lipoproteins impair endothelium-dependent, nitric oxide-mediated dilations of renal arteries. The underlying mechanism involves formation of reactive oxygen species which inactivate nitric oxide. Lipoproteins induce formation of oxygen radicals not only in arteries, but also in glomeruli and juxtaglomerular cells, causing, e.g., stimulation of renin release. Although interactions between lipoprotein and nitric oxide take place at different levels, they finally may contribute to renovascular hypertension. Future studies will have to prove that treating hyperlipidemia has a positive influence on nitric oxide-mediated renal functions.

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise metabolism of human lipoproteins by human glomerular cells and the effects of abnormalities in lipid and protein composition on this process have not been defined. This study examined the effects of apoB-100 containing low-density-lipoprotein (LDL) and apo B,E, containing intermediate-density lipoprotein (IDL), isolated from patients with the nephrotic syndrome (n = 6), on intracellular sterol synthesis and cholesterol esterification by human glomerular epithelial and mesangial cells. For comparison studies, human skin fibroblasts and Hep G2 cells were used. In the patients, serum LDL cholesterol level was increased threefold and IDL tenfold as compared to healthy subjects. LDL of nephrotic patients showed no differences in lipid/protein composition as compared to control LDL but IDL contained 58% more cholesterol than IDL from healthy controls. Therefore, nephrotic and control LDL showed identical inhibition of intracellular sterol synthesis and similar cholesteryl ester formation in all the four cell types. In contrast, cholesterol-rich IDL of nephrotic patients suppressed intracellular sterol synthesis more effectively than control IDL. The cholesterol esterification rate of IDL from patients was enhanced three fold on average as compared to control IDL. The various cell types differed in their rate of LDL esterification. The data indicate that the enhanced inhibition of intracellular sterol synthesis and cholesterol esterification by apo E-containing cholesterol-ester-rich IDL, which accumulate in nephrotic patients, may render these lipoproteins possible candidates for glomerular lipid deposition and progressive renal injury.

Human low-density lipoprotein (LDL) is taken up by rat mesangial cells in a receptor-dependent manner, although lipoprotein metabolism and lipoprotein receptors differ substantially between rodents and humans. We therefore compared binding and uptake kinetics as well as intracellular cholesterol metabolism of apoB- and apoB,E-containing lipoproteins in rat and human mesangial cells. Uptake of very-low-density lipoprotein (VLDL) and LDL in both human and rat mesangial cells occurred in a receptor-specific, concentration-dependent manner and the process was saturable. However, LDL uptake specificity, receptor affinity and maximal degradation capacity was remarkably lower in rat than in human mesangial cells. Exposure of cells to LDL suppressed intracellular sterol synthesis more effectively in the human than in the rat cell line (87 vs. 36%, respectively). Additionally, cholesteryl ester formation was enhanced 23-fold by LDL in human as compared to rat mesangial cells. In contrast, degradation capacities of VLDL were higher in rat and uptake specificity as well as receptor affinity were similar. Inhibition of intracellular cholesterol synthesis and oleate formation rate by VLDL occurred to a similar extent in both cell lines. The data demonstrate that mesangial cell uptake of apoB-containing lipoproteins depends on the species investigated, whereas apoE-rich lipoprotein particles are taken up independent of species. Therefore, human mesangial cells should be preferred over rat mesangial cells when investigating lipoprotein metabolism to elucidate the potential role of lipoproteins in mediating glomerular injury and progression of renal disease in man.

Lipoprotein(a) [Lp(a)] is a plasma lipoprotein whose structure and composition closely resemble that of low-density lipoproteins, but contains an additional protein called apolipoprotein(a) [apo(a)]. Factors which modulate plasma Lp(a) concentrations are poorly understood. The influence of nephrotic syndrome on Lp(a) levels was investigated in 103 patients with nephrotic syndrome: 72 with primary kidney disease and 31 with diabetic nephropathy. Nephrotic patients had significantly higher Lp(a) levels (mean 63 +/- 7 mg/dl; median 42 mg/dl) compared with controls (mean 22 +/- 2 mg/dl; median 8 mg/dl). Fifty-seven percent of the patients and 22% of the controls had values greater than 30 mg/dl. Within all apo(a) isoform classes, higher concentrations of Lp(a) were seen in the nephrotic patients compared with controls. In 17 patients with primary kidney disease remission of the nephrotic syndrome was induced by immunosuppressive treatment and Lp(a) concentration dropped in parallel with the reduction of proteinuria (pretreatment mean, 98 +/- 9 mg/dl vs. remission mean, 25 +/- 5 mg/dl). In 9 patients where multiple measurements were done, multiple regression analysis showed a strong relation of Lp(a) with the amount of proteinuria (p < 0.01). We conclude that most patients with the nephrotic syndrome have Lp(a) concentrations which are substantially elevated compared with control subjects of the same apo(a) isoform. Because Lp(a) concentrations are substantially reduced when remission of the nephrotic syndrome is induced by immunosuppressive drugs, it is likely that nephrotic syndrome directly results in elevation of Lp(a). The high levels of Lp(a) in nephrotic syndrome could potentially cause glomerular injury as well as increase the risk of atherosclerosis and thrombotic events associated with this disorder.

Four patients with antineutrophil cytoplasm antibody (ANCA)-positive vasculitis were followed over a period from 27 to 54 months after successful kidney transplantation under immunosuppressive treatment with ciclosporine. ANCA titer prior to transplantation was markedly elevated and decreased in 1 of 4 patients under therapy with ciclosporine. Despite adequate ciclosporine blood trough levels, a relapse occurred in 2 patients 18 and 24 months after transplantation but therapy with cyclophosphamide induced remission and no patient lost his graft due to relapse of vasculitis. This observation demonstrates that kidney transplantation may be offered to ANCA-positive patients with end-stage renal disease due to vasculitis. However, patients under ciclosporine therapy are still at risk for the development of relapsing disease and cyclophosphamide has to be added to or substituted in part for standard immunosuppressive therapy in order to reverse clinical symptoms and prevent rapid deterioration of kidney function.

The effect of bradykinin (BK) on the intracellular free calcium activity [Ca2+]i and phosphoinositide (PI) turnover was investigated in human glomerular epithelial cells (GEC) in culture. Human GEC exhibited a baseline [Ca2+]i of 114 +/- 3 nmol (n = 81). BK (ED50 10(-9) mol/l) caused a rapid and transient increase in [Ca2+]i, which could also be observed in the absence of extracellular calcium. The effect of BK (10(-8) mol/l) on the [Ca2+]i was inhibited by the BK2 antagonist Hoe 140 (IC50 10(-8) mol/l). BK also induced PI turnover in a time- and dose-dependent manner. A transient increase in (1,4,5)-inositol-triphosphate (InsP3) formation from 1,445 +/- 119 to 4,629 +/- 323 cpm occurred after 5 s. Stimulation of protein kinase C (PKC) by short-term preincubation (15 min) of human GEC with phorbol-12-myristate-13-acetate (PMA) induced a dose-dependent inhibition of the BK-stimulated (10(-7) mol/l) inositol-phosphate formation. Downregulation of PKC by preincubation of human GEC with PMA (24 h, 10(-6) mol/l) or inhibition of PKC by pretreatment with staurosporin (1 h, 10(-6) mol/l) resulted in a slight but significant augmentation of the BK-induced InsP3 stimulation. The data indicate that BK induces stimulation of [Ca2+]i and PI turnover via a BK2 receptor in human GEC. PKC might exert a negative feedback function for the BK-induced PI turnover.

The efficacy of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, was investigated in 12 patients treated with continuous ambulatory peritoneal dialysis (CAPD), displaying hypercholesterolemia and moderate hypertriglyceridemia. After a 4-week placebo period, simvastatin was administered in increasing doses over a period of 3 months (1st month 10 mg; 2nd month 20 mg and 3rd month 40 mg day-1). Simvastatin reduced total serum cholesterol (300.0 +/- 15.5 vs. 193.0 +/- 8.0; -35%), LDL cholesterol (203.8 +/- 13.0 vs. 104.7 +/- 6.0; -48.0%) as well as apolipoprotein B (132.3 +/- 6.6 vs. 77.8 +/- 2.7 mg/dl; -40%). Furthermore, the ratio of LDL apo B/LDL cholesterol increased significantly (0.55 +/- 0.016 vs. 0.64 +/- 0.027). Another remarkable effect was the reduction of cholesterol concentration in VLDL (47.8 +/- 5.6 vs. 30.4 +/- 5.2; -35%). Therefore, the ratio of triglycerides/cholesterol in VLDL increased (3.57 +/- 0.3 vs. 4.28 +/- 0.29), indicating VLDL formation poor in cholesterol and rich in triglycerides. However, HDL cholesterol increased significantly from 48.6 +/- 4.4 to 57.9 +/- 5.3 mg/dl (23%). Lipoprotein(a) levels were increased as compared to controls (420 +/- 73 vs. 145 +/- 26 U/l), but were not influenced significantly by simvastatin treatment (539 +/- 99 U/l, 3rd month). No evidence for notable clinical side effects and laboratory abnormalities were reported. Measurement of simvastatin plasma levels 12 h after drug administration (single dose 40 mg) showed no detectable plasma values. At present, it appears that CAPD patients with high serum cholesterol are good candidates for the treatment with HMG-CoA reductase inhibitors.

Dyslipidemia of chronic renal failure is of multifactorial origin. Decreased activity of lipoprotein lipase and hepatic triglyceride lipase, peripheral insulin resistance, hyperparathyroidism and L-carnitine deficiency are the contributing factors. This results in a disturbed catabolism of chylomicron, accumulation of very-low-density (VLDL) and intermediate-density (IDL) lipoproteins as well as incompletely cleared remnant particles, whereas low-density lipoprotein (LDL) levels are diminished. There is current debate as to whether cardiovascular disease is accelerated and whether hyperlipidemia should specifically be treated. In addition, there have been few means of influencing these metabolic alterations. Drug incompatibility and consequently side effects render treatment difficult. The drugs that have been most tested for lipid lowering in chronic renal failure are the fibric acids. By their mode of action, they are the logical choice. Dose reduction overcomes major side effects such as myopathy and rhabdomyolysis. The second generation of fibric acid derivatives (gemfibrozil and beclobrate) show several advantages over formerly used derivatives. Treatment with lovastatin and simvastatin appears to be safe and is recommended in a minority of patients with predominantly elevations of LDL. HMG-CoA reductase inhibitors also lower remnant particles effectively in hemodialysis (HD) patients. L-Carnitine and low-molecular-weight heparin have been shown to influence VLDL rich in triglycerides in a subset of patients on HD. In posttransplant hyperlipidemia, diet remains the first course of action in all patients. When this approach fails, the new lipid-lowering agents, especially fibric acids, appear to be safe in short-term studies in azathioprine- and ciclosporin-treated patients. Lovastatin has been shown to be safe in stable renal transplant patients. Its toxicity seems to depend mainly on high ciclosporin whole blood through or plasma levels.

Complement activation occurs during hemodialysis, and its intensity depends on the type of dialyzer and whether it is new or reused. Neutrophil degranulation also occurs during hemodialysis with release of lactoferrin, myeloperoxidase and elastase. However, it is unclear whether this event is induced by complement activation and whether it is attenuated by reuse. We examined complement activation and neutrophil degranulation during 10 consecutive hemodialyses using the same cuprophane dialyzer. Also the effect of rinsing the latter with 25% human albumin was studied. The rise in plasma C3a and C5a was markedly higher (p less than 0.01) during the first than the second use. Plasma levels of lactoferrin and myeloperoxidase increased significantly (p less than 0.01) during the first use, and levels were not affected by reuse. In contrast, plasma elastase increased with the first use and decreased with each subsequent use. Treatment of the dialyzer with albumin did not affect the magnitude of rise in plasma levels of C3a or lactoferrin but was associated with a significant reduction in plasma elastase. The data show that neutrophil degranulation is not dependent on complement activation and that the two processes could be dissociated.

In the present study 43 patients with unilateral parenchymatous kidney disease and hypertension were investigated. 20 patients were nephrectomized, 23 treated with antihypertensive drugs. Both therapeutic approaches showed an excellent and sustained blood pressure-(BP)-lowering effect. BP fell from 185 +/- 27/116 +/- 13 to 138 +/- 20/86 +/- 10 mm Hg in the operated and from 194 +/- 32/116 +/- 13 to 149 +/- 22/95 +/- 12 mm Hg in the medically treated patients after 2 and 6 weeks, respectively (p less than 0.001). BP was 142 +/- 16/89 +/- 11 and 136 +/- 16/90 +/- 10 mm Hg at the long-term follow-up in the 2 subgroups. In the operated group 70% (n = 14) were cured, 20% (n = 4) were improved and 10% (n = 2) unimproved. In the medically treated group 65% (n = 15) were normotensive, 26% (n = 6) improved and 9% (n = 2) treatment resistant. No significant correlation between postoperative BP reduction and lateralization of renin secretion (PRA-ratio greater than or equal to 1.5) was found. Although cured patients showed a higher mean PRA-ratio, 4 patients with a PRA-ratio less than 1.5 were cured (n = 2) or improved (n = 2) postoperatively. Our results document an excellent and sustained antihypertensive effect of both nephrectomy and medical treatment in patients with unilateral parenchymatous kidney disease and hypertension. They further limit the predictive value of renal venous renin determination in the preoperative workup.

The effect of different dialyzer membrane materials (cuprophan, cellulose hydrate, polyacrylonitrile, polymethylmethacrylate, ethylene-vinyl alcohol copolymer) on the ultrafiltrate proteinase activity was investigated in 26 patients with acute renal failure (ARF) and 40 patients undergoing regular hemodialysis treatment (RDT). Furthermore, the proteinase activity was characterized in vitro using azocasein and phosphorylase kinase as substrates in the absence and presence of different proteinase inhibitors. Proteinase activity of ultrafiltrates obtained from ARF patients was significantly enhanced with the dialyzer KF 101 (ethylene-vinyl alcohol copolymer). The digestion pattern of phosphorylase kinase revealed an identical type of proteinases in ultrafiltrates of ARF and RDT patients. The pH optimum of this proteinase was at alkaline pH. The proteinase activity could be inhibited in the presence of EDTA, whereas serine proteinase inhibitors were ineffective. Furthermore, the inactivated proteinase after Sephadex G-10 chromatography (in order to separate ultrafiltrate electrolytes and trace elements from protein) could be reactivated after the addition of Mg++ and/or Ca++. We conclude that a metalloproteinase can be found in ARF and RDT patients, and that KF 101 is more effectively eliminating the proteinase activity in ARF patients than other dialyzer membranes.

Serum free and esterified carnitine levels as well as lipids were investigated in patients undergoing regular hemodialysis (HD) treatment before and during 12 weeks of treatment with L-carnitine (1 g i.v.) at the end of each HD. The results were compared with those obtained in patients on continuous ambulatory peritoneal dialysis (CAPD; n = 15) or intermittent peritoneal dialysis (IPD; n = 3) and healthy controls (CO; n = 20). In HD patients (n = 23) total carnitine (TC) was 49.9 +/- 3.9 (CO: 46.0 +/- 2.5; NS), free carnitine (FC) was 31.6 +/- 2.8 (CO: 37.4 +/- 1.3; p less than 0.05), short-chain acylcarnitine (SCC) was 17.0 +/- 1.8 (CO: 7.2 +/- 0.9; p less than 0.0001) and long-chain acylcarnitine (LCC) was 1.2 +/- 0.2 mumol/l (CO: 0.6 +/- 0.1; p less than 0.05). FC was in the normal range in CAPD (35.6 +/- 3.2) and IPD (44.5 +/- 8.0 mumol/l) patients, whereas SCC (30.1 +/- 3.5) and LCC (2.9 +/- 0.2) levels were maximal elevated in IPD patients (11.8 +/- 0.8 and 1.5 +/- 0.2 on CAPD). Therefore, TC was higher in IPD than in CAPD patients (77.5 +/- 5.0 vs. 49.0 +/- 3.5 mumol/l). 12 weeks after L-carnitine supplementation in HD patients, TC was 313.9 +/- 22.6, FC was 207.7 +/- 12.4, SCC was 99.6 +/- 12.1 and LCC was 7.1 +/- 0.6 mumol/l. TC and FC were significantly lower in females compared with males. Total cholesterol and ketone bodies were normal, HDL cholesterol was significantly decreased before and after L-carnitine supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

In the present study, the frequency and the mechanism of hypertension associated with unilateral hydronephrosis (UHY) were investigated in 115 patients. Hypertension (blood pressure greater than 140/90 mm Hg) was found in 20% of 101 consecutive patients with UHY. Twenty-six patients with UHY and hypertension were followed for 35 months and the effect of surgery on blood pressure was analyzed. Blood pressure fell from 178 +/- 4/108 +/- 4 to 135 +/- 2/84 +/- 2 mm Hg after surgery. Hypertension was cured in 62%, improved in 19% and unchanged in 19%. In 73% of the cured patients the PRA-ratio was greater than or equal to 1.5, while all unchanged patients had a value of less than 1.5. Hypertensive patients were significantly older than normotensive patients, but did not differ in kidney function, underlying cause of hydronephrosis, incidence of urinary tract infection or frequency of interstitial nephritis. We conclude that in UHY the incidence of hypertension is not particularly high. However, in a substantial number of patients, high blood pressure is reversible by surgery. In most of these patients the renin-angiotensin-aldosterone system seems to play an important role in sustaining high blood pressure, although in some patients other mechanisms might be operative as well. Since the overall incidence of hypertension is not particularly high in UHY, this secondary form of hypertension appears to be rare.

Unilateral parenchymatous kidney disease associated with high blood pressure represents a potentially curable form of hypertension. Surgery may normalize blood pressure in a substantial number of these patients. Curable renal parenchymatous hypertension includes unilateral tubulointerstitial kidney diseases such as chronic pyelonephritis, reflux nephropathy, segmental hypoplasia and radiation nephritis, hydronephrosis, simple renal cysts, traumatic kidney lesions and renal tumors associated with high blood pressure. Renal ischemia and in turn activation of the renin angiotensin system is involved in the pathogenesis of hypertension in most of these patients. In patients with unilateral kidney disease and hypertension, both an operative and a medical therapeutic approach have a high success rate. Good candidates for nephrectomy are young patients with severe hypertension, strict unilateral disease, normal plasma creatinine levels and minimal function of the involved kidney. In unilateral hydronephrosis reconstructive surgery or nephrectomy may cure or improve hypertension in the vast majority of the patients. Surgically correctable hypertension has also been reported in some patients with large renal cysts and renal tumors (hemangiopericytoma, Wilm's tumor, hypernephroma, renal pelvic tumor).

Plasma levels of pancreatic secretory trypsin inhibitor (PSTI), lipase and amylase were measured in patients with chronic renal failure (CRF), patients undergoing regular hemodialysis treatment (RDT) or continuous ambulatory peritoneal dialysis (CAPD), patients with acute renal failure (ARF) and patients following successful cadaveric kidney transplantation. Plasma PSTI values were 9.2 +/- 0.8 ng/ml in controls (CO), 156.9 +/- 16.2 ng/ml in CRF patients, 257.6 +/- 22.3 ng/ml in RDT patients, 376.8 +/- 57.5 ng/ml in CAPD patients and 2,300 +/- 276.9 ng/ml in patients with posttraumatic ARF. RDT patients with malignant diseases displayed significantly higher PSTI values (1,014 +/- 148.7 ng/ml; p less than 0.01) than RDT patients without malignancy. Transplant patients with normal kidney function (creatinine 1.25 +/- 0.1 mg/dl) showed significantly lower PSTI values (16.7 +/- 2.1 ng/ml) than transplant patients with impaired renal function (creatinine 4.7 +/- 0.5 mg/dl; PSTI 72.8 +/- 11.8 ng/ml; p less than 0.01). Daily urinary excretion of PSTI increased from 26.7 +/- 3.1 micrograms (CO) to 551.8 +/- 54.8 micrograms in CRF patients. In CAPD patients, daily peritoneal loss of PSTI was 164.3 +/- 58.4 micrograms. Plasma PSTI values increased during hemodialysis with dialyzers made of cuprophan (317.0 +/- 32.6 vs. 422.0 +/- 46.2 ng/ml; p less than 0.05) and decreased with polysulfone dialyzers (226.6 +/- 19.9 vs. 86.6 +/- 18.1 ng/ml). There was no correlation between PSTI and urea, creatinine, lipase or amylase in each tested group. Our results document markedly elevated plasma PSTI values in all forms of renal insufficiency, suggesting extrapancreatic PSTI production and/or reduced renal elimination.