Optimizing the use of patients' individual outcome information - Development and usability tests of a Chronic Kidney Disease dashboard.

BACKGROUND: Reporting individual clinical and patient-reported outcomes to patients during consultations may add to patients' disease knowledge and activation and stimulate Shared Decision Making (SDM). These outcomes can be presented over time in a clear way by the means of dashboarding. We aimed to systematically develop a Chronic Kidney Disease (CKD) dashboard designed to support consultations, test its usability and explore conditions for optimal use in practice. METHODS: For development a participatory approach with patients and healthcare professionals (HCPs) from three hospitals was used. Working groups and patient focus groups were conducted to identify needs and inform the dashboard's design. Usability was tested in patient interviews. A focus group with HCPs was held to identify conditions for optimal use of the dashboard in daily practice. RESULTS: A dashboard was developed for CKD patients stage 3b-4 visualizing both clinical and patient-reported outcomes over time for use during consultations and accessible for patients at home. Both HCPs and patients indicated that the dashboard can: motivate patients in their treatment by providing feedback on outcomes over time; improve consultation conversations by enhanced preparation of both HCPs and patients; better inform patients, thereby facilitating shared decision making. HCPs and patients both stated that setting a topic agenda for the consultation together is important in effectively discussing the dashboard during consultations. Moreover, the dashboard should not dominate the conversation. Lastly, findings of the usability tests provided design requirements for optimal user-friendliness and clarity. CONCLUSIONS: Dashboarding can be a valuable way of reporting individual outcome information to patients and their clinicians as findings suggest it may stimulate patient activation and facilitate decision making. Co-creation with patients and HCPs was essential for successful development of the dashboard. Gained knowledge from the co-creation process can inform others wishing to develop similar digital tools for use in clinical practice.

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome.

Protein-bound uremic toxins (PBUTs) are predominantly excreted by renal tubular secretion and hardly removed by traditional hemodialysis (HD). Accumulation of PBUTs is proposed to contribute to the increased morbidity and mortality of patients with end-stage kidney disease (ESKD). Preserved PBUT excretion in patients with residual kidney function (RKF) and/or increased PBUT clearance with improved dialysis techniques might improve the prognosis of patients with ESKD. The aims of this study are to explore determinants of PBUTs in HD patients, and investigate whether hemodiafiltration (HDF) lowers PBUT plasma concentrations, and whether PBUTs are related to the outcome. Predialysis total plasma concentrations of kynurenine, kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl sulfate, p-cresyl glucuronide, and hippuric acid were measured by UHPLC-MS at baseline and after 6 months of follow-up in the first 80 patients participating in the CONvective TRAnsport Study (CONTRAST), a randomized controlled trial that compared the effects of online HDF versus low-flux HD on all-cause mortality and new cardiovascular events. RKF was inversely related to kynurenic acid (p < 0.001), indoxyl sulfate (p = 0.001), indole-3-acetic acid (p = 0.024), p-cresyl glucuronide (p = 0.004) and hippuric acid (p < 0.001) plasma concentrations. Only indoxyl sulfate decreased by 8.0% (-15.3 to 34.6) in patients treated with HDF and increased by 11.9% (-15.4 to 31.9) in HD patients after 6 months of follow-up (HDF vs. HD: p = 0.045). No independent associations were found between PBUT plasma concentrations and either risk of all-cause mortality or new cardiovascular events. In summary, in the current population, RKF is an important determinant of PBUT plasma concentrations in HD patients. The addition of convective transport did not consistently decrease PBUT plasma concentrations and no relation was found between PBUTs and cardiovascular endpoints.

Quality of life as indicator of poor outcome in hemodialysis: relation with mortality in different age groups.

BACKGROUND: Physical, cognitive and psychosocial functioning are frequently impaired in dialysis patients and impairment in these domains relates to poor outcome. The aim of this analysis was to compare the prevalence of impairment as measured by the Kidney Disease Quality of Life- Short Form (KDQOL-SF) subscales between the different age categories and to assess whether the association of these subscales with mortality differs between younger and older dialysis patients. METHODS: This study included data from 714 prevalent hemodialysis patients, from 26 centres, who were enrolled in the CONvective TRAnsport STudy (CONTRAST NCT00205556, 09-12-2005). Baseline HRQOL domains were evaluated for patients <65 years, 65-74 years and over 75 years. Multivariable Cox proportional hazards analyses were performed to assess the relation between the separate domains and 2-year mortality. RESULTS: Emotional health was higher in patients over the age of 75 compared to younger patients (mean level 71, 73 and 77 for increasing age categories respectively, p = 0.02), whilst physical functioning was significantly lower in older patients (mean level 60, 48 and 40, p < 0.01). A low level of physical functioning (Hazard Ratio (HR) 1.72 [95%Confidence Interval (CI) 1.02-2.73]), emotional health (HR 1.85 [95% 1.30-2.63]), and social functioning (HR 1.59 [95% CI 1.12-2.26]), was individually associated with an increased 2-year mortality within the whole population. The absence of effect modification suggests no evidence for different relations within the older age groups. CONCLUSIONS: In dialysis patients, older age is associated with lower levels of physical functioning, whilst the level of emotional health is not associated with age. KDQOL-SF domains physical functioning, emotional health and social functioning are independently associated with mortality in prevalent younger and older hemodialysis patients.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

[New study evaluating online haemodiafiltration for the reduction of cardiovascular morbidity and mortality in patients undergoing chronic haemodialysis]. / Nieuw onderzoek naar online-hemodiafiltratie voor de vermindering van cardiovasculaire morbiditeit en mortaliteit bij patiënten die chronisch worden behandeld met hemodialyse.

Removal of uraemic toxins can be increased by online haemodiafiltration. At present, it is unclear whether online haemodia-filtration ultimately improves clinical outcomes in chronic haemodialysis patients. The Dutch 'Convective transport study' (CONTRAST) is an ongoing trial comparing standard haemodialysis with online haemodiafiltration. This randomised controlled trial will provide substantial clinical evidence on the effects of haemodiafiltration on fatal and non-fatal cardiovascular events and all-cause mortality, compared with standard haemodialysis.

Autogenous radial-cephalic or prosthetic brachial-antecubital forearm loop AVF in patients with compromised vessels? A randomized, multicenter study of the patency of primary hemodialysis access.

OBJECTIVE: The construction of an autogenous radial-cephalic direct wrist arteriovenous fistula (RCAVF) is the primary and best option for vascular access for hemodialysis. However, 10%-24% of RCAVFs thrombose directly after operation or do not function adequately due to failure of maturation. In case of poor arterial and/or poor venous vessels for anastomosis, the outcome of RCAVFs may be worse and an alternative vascular access is probably indicated. A prosthetic graft implant may be a second best option. Therefore, a randomized multicenter study comparing RCAVF with prosthetic (polytetrafluoroethylene [PTFE]) graft implantation in patients with poor vessels was performed. METHODS: A total of 383 consecutive new patients needing primary vascular access were screened for enrollment in a prospective randomized study. According to defined vessel criteria from the preoperative duplex scanning, 140 patients were allocated to primary placement of an RCAVF and 61 patients to primary prosthetic graft implantation. The remaining 182 patients were randomized to receive either an RCAVF (n = 92) or prosthetic graft implant (n = 90). Patency rate was defined as the percentage of AVFs that functioned well after implantation. RESULTS: Primary and assisted primary 1-year patencies were 33% +/- 5.3% vs 44% +/- 6.2% (P = .03) and 48% +/- 5.5% vs 63% +/- 5.9% (P = .035) for the RCAVF and prosthetic AVF, respectively. Secondary patencies were 52% +/- 5.5% vs 79% +/- 5.1% (P = .0001) for the RCAVF and prosthetic AVF, respectively. Patients with RCAVFs developed a total of 102 (1.19/patient-year [py]) vs 122 (1.45/py; P = .739) complications in the prosthetic AVFs. A total of 43 (0.50/py) interventions in the RCAVF group and 79 (0.94/py) in the prosthetic graft group were needed for access salvage (P = .077). CONCLUSIONS: Although there were more interventions needed for access salvage in the patients with prosthetic graft implants, we may conclude that patients with poor forearm vessels do benefit from implantation of a prosthetic graft for vascular access.

Hypotension during hemodialysis results from an impairment of arteriolar tone and left ventricular function.

AIMS: Hypotensive episodes are a major complication of hemodialysis. Hypotension during dialysis could be directly related to a reduction in blood volume or to a decrease in cardiovascular activation as a response to decreased cardiac filling. A decreased cardiovascular activation could be due to patient-related or to dialysis-related factors. In order to study the isolated effect of a reduction in filling pressure, lower body negative pressure (LBNP) causes activation of the cardiovascular reactivity with a decrease in cardiac filling, but without the influence of the dialysis procedure that could affect cardiovascular reactivity. METHODS: We studied the relationship between relative blood volume (RBV), central venous pressure (CVP), systolic arterial pressure, heart rate, stroke volume index (SI), and total peripheral resistance index (TPRI) during a combined dialysis/ultrafiltration and during LBNP to -40 mmHg in 21 hemodialysis patients with a high incidence of hypotension. Systolic arterial pressure, heart rate, SI and TPRI were measured by Finapres. CVP was measured after cannulation of the jugular vein. During dialysis RBV was measured by a blood volume monitor (BVM). In order to study the conditions in which hypotension occurred after dialysis, we divided the patients into 2 groups: hypotensive (H) and non-hypotensive (NH) during dialysis. RESULTS: Baseline levels did not show any significant differences. During dialysis systolic arterial pressure declined gradually in the H group from 30 minutes before the onset of hypotension. There was a similar decrease of RBV and increase of heart rate in both groups with a large interindividual variation. At hypotension, H patients showed a significantly smaller increase in TPRI as compared to NH patients. The reduction in SI tended to be greater at hypotension, while CVP decreased to a similar extent in both groups. Moreover, during LBNP, a similar reduction in CVP resulted in a much smaller decrease in SI. Systolic arterial pressure was only slightly lowered due to a much greater increase in TPRI. CONCLUSION: We conclude that dialysis-related hypotension in our patient group did not result from an inability to maintain blood volume or from decreased cardiac filling. Hypotension appeared to result from the inability to adequately increase arteriolar tone and a reduction in left ventricular function. Both vascular tone and left ventricular function appeared to be impaired by the dialysis procedure.

Graft surveillance: venous pressure, access flow, or the combination?

BACKGROUND: Increased venous pressure (VP) and decreased access flow (Qa) are predictors of dialysis access graft thrombosis. VP is easily obtainable. Qa assessment requires a special device and takes more time. The aims of our randomized multicenter studies were to compare outcome in patients with grafts monitored by VP or Qa (study A) or monitored by VP or the combination of VP and Qa (study B). METHODS: We performed VP measurements consisting of weekly VP at a pump flow of 200 mL/min (VP200) and the ratio of VP0/MAP. Qa was measured every eight weeks with the Transonic HD01 hemodialysis monitor. Threshold levels for referral for angiography were VP200> 150 mm Hg or VP0/MAP> 0.5 (both at 3 consecutive dialysis sessions) or Qa <600 mL/min. Subsequent therapy consisted of either percutaneous transluminal angioplasty (PTA) or surgery. RESULTS: Total follow-up was 80.5 patient-years for 125 grafts. The vast majority of a total of 131 positive tests was followed by angiography and corrective intervention. In study A, the rate of thromboses not preceded by a positive test was 0.19 and 0.24 per patient-year (P = NS), and in study B, it was 0.32 versus 0.28 per patient-year (P = NS). Survival curves were not significantly different between the subgroups. CONCLUSIONS: These data demonstrate that standardized monitoring of either VP or Qa or the combination of both and subsequent corrective intervention can reduce thrombosis rate in grafts to below the recommended quality of care standard (that is, 0.5 per patient-year, NKF-DOQI). These surveillance strategies are equally effective in reducing thrombosis rates.

Gustatory sweating and diabetes.

Gustatory sweating as a feature of autonomic neuropathy is an unusual phenomenon in diabetes mellitus. We describe a patient with type 1 diabetes mellitus complicated by retinopathy, nephropathy and neuropathy. This patient presented with bilateral diffuse facial sweating during eating. She was treated with the antimuscarine agent oxybutynine, which provided a striking relief from the gustatory sweating.

Cardiac evaluation in hypotension-prone and hypotension-resistant hemodialysis patients.

BACKGROUND: Hypotension during hemodialysis occurs frequently, but the precise mechanism remains unclear. In this study, the presence of myocardial ischemia and myocardial contractile reserve during infusions of the beta-adrenergic receptor agonist dobutamine was assessed by means of dobutamine-atropine stress echocardiography (DSE) in hypotension-prone (HP) and hypotension-resistant (HR) hemodialysis patients. METHODS: Eighteen HP patients (age 53 +/- 6 years) were compared with 18 HR patients (age 53 +/- 3 years), matched with respect to the duration of hemodialysis and cardiovascular history. New wall abnormalities during dobutamine stress reflect the presence of myocardial ischemia, whereas the increase in stroke index and cardiac index reflects myocardial contractile reserve. RESULTS: Wall motion score at rest (1.42 +/- 0.53 vs. 1.44 +/- 0.57) and dobutamine-induced new wall motion abnormalities (4 vs. 3 patients) between HP and HR patients were similar, but responses of cardiac index, stroke index, and systolic blood pressure to do butamine between the two groups were different. Not withstanding a similar cardiac index at rest (2.4 +/- 1.1 liter/min/m2 in HP and 2.8 +/- 1.2 liter/min/m2 in HR patients), dobutamine-induced increments in the cardiac index were considerably smaller in the former (0.8 +/- 1.3 liter/min/m2) than in the latter patients (2.3 +/- 1.6 liter/min/m2, P = 0.002), predominantly because of a progressive decrease in the stroke index in the HP patients. CONCLUSION: Impaired myocardial contractile reserve rather than ischemia is predominant in HP patients. This impaired myocardial contractile reserve may play a role in the development of hemodialysis-induced hypotension.

Beneficial effects of conversion from cyclosporine to azathioprine on fibrinolysis in renal transplant recipients.

Cyclosporin A (CsA) has been implicated as one of the factors contributing to the high cardiovascular morbidity and mortality after renal transplantation. This may be mediated by either a high prevalence of conventional risk factors for atherosclerosis, such as hypertension, hypercholesterolemia, and diabetes mellitus, or by impairment of the fibrinolytic activity evoked by CsA, possibly through interference with prostanoid metabolism. We therefore assessed the impact of conversion of CsA to azathioprine immunosuppressive treatment on parameters of fibrinolytic activity and plasma concentration of the prostanoids prostaglandin E2 and thromboxane B2 in 18 stable renal transplant recipients. During CsA, mean arterial pressure and serum creatinine were significantly higher than during azathioprine (116+/-15 mm Hg versus 106+/-13 mm Hg, P=0.0003; and 147+/-34 micromol/L versus 127+/-35 micromol/L, P=0.002; mean+/-SD). On conversion, the plasma tissue plasminogen activator activity increased from 1.2 (1.1 to 1.7; median, 95% CI) to 1.8 (1.6 to 2.0) IU/mL (P=0.011), without a significant change of the plasminogen activator antigen concentration. This was associated with a substantial decrease in plasminogen activator inhibitor-1 activity from 10.4 (8.5 to 16.7) to 6.4 (5.6 to 9.2) IU/mL (P=0.009). Furthermore, plasma levels of prostaglandin E2 and thromboxane B2 markedly decreased (from 9.7 [7.4 to 12.9] to 4.6 [4.3 to 8.1] pg/mL, P=0.0006; and from 106.1 [91.7 to 214.2] to 70.2 [50.3 to 85.6] pg/mL, P=0.002, respectively). During CsA, but not azathioprine, plasma tissue plasminogen activator antigen and plasminogen activator inhibitor-1 levels correlated significantly with prostaglandin E2 (r=0.53, P=0.02; and r=0.60, P=0.008, respectively), and thromboxane B2 (r=0.75, P=0.0001; and r=0.77, P=0.0001, respectively) levels. In conclusion, CsA induced substantial impairment of fibrinolytic activity, which recovered after conversion to azathioprine. The impaired fibrinolysis observed during CsA treatment may be caused by modulation of eicosanoid production or metabolism in vascular endothelial cells and possibly contributes to the high incidence of cardiovascular disease after kidney transplantation.

Forearm vasorelaxation in hypertensive renal transplant patients: the impact of withdrawal of cyclosporine.

OBJECTIVE: To determine whether cyclosporine A-induced hypertension in renal transplant recipients is accompanied by impairment of endothelium-dependent vasodilatation, which has been suggested by in-vitro and in-vivo animal experiments. DESIGN AND METHODS: In-vivo endothelium-dependent and endothelium-independent vasodilatation, and plasma concentrations of vasoactive hormones in 16 renal transplant patients were determined while they were being treated with cyclosporine A, and 16 weeks later, after their treatment had been changed to azathioprine therapy. The vasodilator response of the forearm vascular bed was measured by strain gauge venous occlusion plethysmography during intra-arterial infusion of acetylcholine (endothelium-dependent vasodilatation) and nitroprusside (endothelium-independent vasodilatation). Postischemic reactive flow was measured after 10 min of arterial occlusion. In addition, plasma concentrations of norepinephrine, and the prostanoids prostaglandin E2 and thromboxane B2, and also concentration of cyclosporine A in blood, were measured. Glomerular filtration rate and renal blood flow were estimated 1 day before the plethysmography study during each treatment period. RESULTS: Upon changing from cyclosporine A to azathioprine treatment, mean arterial pressure fell significantly by 12+/-3% (P< 0.05). Glomerular filtration rate and renal blood flow increased by 13+/-5 and 19+/-8%, respectively (both P< 0.05), while renal vascular resistance fell by 48+/-11% (P< 0.01). Both baseline forearm blood flow and baseline forearm resistance did not change after conversion (5.7+/-0.7 versus 4.9+/-0.6 ml/100 ml/min, and 27.3+/-4.2 versus 26.2+/-3.2 arbitrary units). The absolute and relative forearm blood flow responses, and forearm vascular resistance responses to infusions of acetylcholine and nitroprusside were similar during treatments with cyclosporine A and azathioprine. Peak postischaemic forearm blood flow was 42+/-12% higher during cyclosporine A treatment than it was during azathioprine treatment (P< 0.05), but the minimal postischaemic forearm vascular resistance did not differ for these treatments. Plasma prostaglandin E2 and thromboxane B2 levels decreased by 34+/-7 and 45+/-8%, respectively, after changing treatment, but norepinephrine levels did not change. CONCLUSIONS: Our data indicate that cyclosporine A-induced hypertension in renal transplant recipients is not accompanied by an increase in forearm vascular resistance. In addition, changing from cyclosporine A to azathioprine treatment did not cause changes in endothelial vasodilator functioning, although mean arterial pressure decreased significantly. Our results do not support the hypothesis that attenuation of endothelial vasodilator functioning contributes to the development of cyclosporine A-induced hypertension.

Conversion from cyclosporine A to azathioprine treatment improves LDL oxidation in kidney transplant recipients.

The use of the immuno-suppressant cyclosporine A (CsA) after transplantation has been associated with less favorable plasma lipid profiles, which may contribute to the high incidence of cardiovascular morbidity and mortality in transplant recipients. Recent studies have suggested that oxidative modification of LDL plays an important role in the initiation and progression of atherosclerosis. It has also been demonstrated that CsA may facilitate lipid peroxidation in vitro and in vivo. Therefore, we determined several parameters of LDL oxidizability in renal transplant recipients who were switched from CsA to azathioprine (AZA)-based immunosuppressive treatment. The susceptibility of LDL to in vitro oxidation, LDL particle size, plasma titers of IgG and IgM antibodies against oxidized LDL and plasma LDL subclass patterns in 19 renal transplant recipients were determined during CsA treatment and 16 weeks after these patients were converted to AZA treatment. In addition, mean arterial pressure was recorded, and glomerular filtration rate and renal blood flow were estimated from the clearance of radiolabeled thalamate and hippurate. After conversion, the plasma concentrations of total cholesterol, LDL cholesterol and triglyceride decreased, while plasma HDL cholesterol did not change. During CsA therapy plasma LDL was significantly more susceptible to in vitro oxidation than during AZA, as reflected by a longer lag phase during in vitro oxidation (98.9 +/- 24.3 vs. 114.7 +/- 17.3 min, P = 0.031). In addition, the LDL size increased (236.5 +/- 7.3 vs. 240.7 +/- 6.8 nm, P = 0.00001), and the titers of IgM- and IgG-autoantibodies against oxidized LDL decreased significantly after patients were converted from CsA to AZA. The more atherogenic LDL subclass pattern B was present in 13 out of 19 patients during CsA. In five patients, pattern B changed into pattern A after conversion. The subclass B pattern was maintained in eight patients and subclass A pattern in six patients. In all patients the lag time of in vitro LDL oxidation increased, although the biggest changes were found in those patients in whom the LDL subclass changed from pattern B to pattern A. Mean arterial pressure decreased and renal function improved significantly after conversion. No correlation between parameters of lipid peroxidation and changes in blood pressure or renal function upon conversion, underlying renal disease, time since transplantation, or antihypertensive treatment was found. Our study demonstrates that treatment with CsA increases the susceptibility of LDL to in vitro oxidation, and also enhances the oxidation of LDL in vivo. In addition, conversion to AZA results in a more favorable lipid profile, which in combination with a lower arterial pressure and better renal function may decrease the risk for atherosclerosis. These factors may account for the cardiovascular complications during CsA treatment after organ transplantation, and also when CsA is used for other diseases.

Cyclosporin A impairs the nocturnal blood pressure fall in renal transplant recipients.

In renal transplant recipients, hypertension and a diminished nocturnal blood pressure fall are frequently found. To investigate whether this diminished nocturnal blood pressure fall is related to the use of cyclosporin A or to other factors, such as the use of glucocorticoids, we measured 24-hour ambulatory blood pressure in 18 renal transplant recipients both before and 16 weeks after conversion from cyclosporin A to azathioprine. Renal blood flow and glomerular filtration rate were estimated from 131I-hippurate and 125I-iothalamate clearances, respectively, and plasma concentrations of renin, atrial natriuretic peptide, norepinephrine, prostaglandin E2, and thromboxane B2 were determined. During cyclosporin A treatment, mean 24-hour blood pressure was 117 +/- 3 mm Hg, and the nocturnal fall in blood pressure was 4 +/- 9 mm Hg. A nondipping diurnal blood pressure pattern was present in 13 patients. After conversion to azathioprine, mean 24-hour blood pressure decreased to 109 +/- 3 mm Hg (P < .001), the nocturnal fall increased to 9 +/- 6 mm Hg, and the number of patients with a nondipping diurnal blood pressure pattern decreased to 9. The nocturnal fall in heart rate (17 +/- 10 beats per minute) during cyclosporin A did not change after conversion. Body weight and plasma concentrations of norepinephrine and renin did not change. Plasma concentrations of prostaglandin E2 and thromboxane B2 decreased after conversion, as did plasma atrial natriuretic peptide. Renal blood flow and glomerular filtration rate increased after conversion. In conclusion, cyclosporin A appears to be involved in the disturbance of the circadian blood pressure rhythm in renal transplant recipients. Although the precise mechanism is unclear. the elevated plasma atrial natriuretic peptide and slightly suppressed plasma renin concentrations suggest that intravascular volume expansion may contribute to the observed hemodynamic alterations.

Increased low density lipoprotein oxidation in stable kidney transplant recipients.

We studied factors that may add to the high risk of atherosclerosis in kidney transplant recipients. Plasma lipoprotein concentrations and parameters of low density lipoprotein (LDL) oxidation were determined in 19 clinically stable kidney recipients and 19 healthy controls. Plasma triglycerides and total cholesterol were increased in the patients. High density lipoprotein-cholesterol (HDL-c) was in the normal range. The mean LDL diameter was smaller in patients than in controls (236.5 +/- 7.3 A vs. 247.8 +/- 11.6 A, P < 0.002), which was due to a higher frequency of the LDL subclass pattern B in the patients than in controls (58% vs. 28%). The lag time of copper-induced in vitro LDL oxidation was shorter in patients than in controls (101 +/- 23 min vs. 148 +/- 81 min, P = 0.02). The titer and concentration of autoantibodies against malondialdehyde-modified (MDA-LDL) determined by ELISA were higher in the patients than in the controls. This difference was found in both IgG (titer + 9%, concentration + 75%; P < 0.05) and IgM (titer + 35%, concentration + 102%; P < 0.001). Based on these results, we propose that there is in vitro and in vivo evidence of enhanced LDL oxidation in patients post-renal transplantation. This might represent one cause for the clinical finding of advanced atherosclerosis in these patients.

Low-density lipoprotein oxidation is increased in kidney transplant recipients.

Oxidative modification of low-density lipoproteins (LDL) plays an important role in the pathogenesis of atherosclerosis. In addition, there is evidence that chronic vascular allograft rejection may be mediated by oxidised LDL. Plasma lipoprotein concentrations and parameters of LDL oxidation were determined in 19 kidney transplant recipients and 19 healthy controls. Plasma triglycerides and total cholesterol was significantly higher in patients than in the controls. The mean LDL diameter was smaller in patients than in the controls (23.6 +/- 0.71 nm vs 27.78 +/- 1.16 nm, P < 0.002). Furthermore, the lag time of copper-induced in vitro LDL oxidation was shorter in patients than in the controls (101 +/- 23 min vs 148 +/- 81 min, P = 0.02). The titre and concentration of both IgG and IgM autoantibodies against malondialdehyde-modified LDL (MDA-LDL) were higher in the patients. We conclude that there is in vitro and in vivo evidence of increased LDL oxidation in renal transplant recipients. This might facilitate the progression of atherosclerosis and enhance the process of chronic vascular rejection.

Prophylactic isradipine treatment after kidney transplantation: a prospective double-blind placebo-controlled randomized trial.

There is evidence that calcium antagonists may have a beneficial effect on cyclosporine-induced nephropathy after transplantation. We treated 50 consecutive non-diabetic patients receiving their first cadaveric transplant with isradipine, a dihydropyridine calcium antagonist, or placebo in a double-blind, randomized, placebo-controlled trial. There were no significant differences between the two groups as regards age, weight, sex, HLA matching and ischaemic periods. To achieve optimal vasodilation, treatment was started intravenously 2 h before the transplantation procedure, and continued orally afterwards for 3 months. The immunosuppressive treatment included rabbit antithymocyte globulin on day 0, and oral cyclosporine from day 5. In both groups 7 patients had primary non-functioning grafts, but the incidence of never functioning kidneys due to vascular and thrombotic complications was significantly higher in the placebo group (0 vs 4 patients, P < 0.05). Hypertension was treated with oral labetolol in combination with guanfacine if necessary. In the placebo group antihypertensive medication had to be prescribed significantly more often (67% vs 33% of patients, P < 0.05), but resulted in similar blood pressure recordings in the two study groups. Cyclosporin A (CsA) plasma concentrations were also comparable but in the isradipine group a significantly higher dose of CsA was needed to achieve adequate levels (8.0 +/- 0.5 vs 6.2 +/- 0.5 mg/kg per day, P < 0.01). However, in the isradipine-treated patients creatinine clearance was significantly higher (66.1 +/- 4.5 vs 55.6 +/- 6.2 ml/min, P < 0.05) after 3 months. We conclude that isradipine is an effective antihypertensive agent after kidney transplantation. Isradipine ameliorates CsA-induced nephropathy and seems to protect against early postoperative vascular complications.