Anne-Lise Kamper

Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease: A Meta-Analysis of Patient-Level Data

Chronic renal disease is a major public health problem in the United States. According to the 1999 Annual Data Report of the U.S. Renal Data System, more than 357 000 people have end-stage renal disease (ESRD), and the annual cost of treatment with dialysis and renal transplantation exceeds

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

15.6 billion (1). Patients undergoing dialysis have reduced quality of life, a high morbidity rate, and an annual mortality rate of 20% to 25% (1). Identification of therapies to prevent ESRD is an important public health goal. Angiotensin-converting enzyme (ACE) inhibitors are highly effective in slowing the progression of renal disease due to type 1 diabetes (26), and evidence of their efficacy in type 2 diabetes is growing (712). However, although 14 randomized, controlled trials have been completed (1325; Brenner BM; Toto R. Personal communications), no consensus exists on the use of ACE inhibitors in nondiabetic renal disease (2628). In a previous meta-analysis of 11 randomized, controlled trials, we found that therapy with ACE inhibitors slowed the progression of nondiabetic renal disease (29). Since our meta-analysis was performed on group data rather than individual-patient data, we could not fully assess the relationship between the effect of ACE inhibitors and blood pressure, urinary protein excretion, or other patient characteristics (30). Thus, we could not determine whether an equal reduction in blood pressure or urinary protein excretion by using other antihypertensive agents would be as effective in slowing the progression of renal disease. Nor could we determine whether the baseline blood pressure, urinary protein excretion, or other patient characteristics modified the response to treatment. In the current report, we used pooled analysis of individual-patient data to answer these questions. We reasoned that the large number of patients in the pooled analysis would provide sufficient statistical power to detect relationships between patient characteristics and risk for progression of renal disease and interactions of patient characteristics with treatment effect. In principle, strong and consistent results from analysis of this large database would clarify the effects of ACE inhibitors for treatment of nondiabetic renal disease. Methods Study Design We obtained individual-patient data from nine published (1322) and two unpublished (Brenner BM; Toto R. Personal communications) randomized, controlled trials assessing the effects of ACE inhibitors on renal disease progression in predominantly nondiabetic patients. Search strategies used to identify clinical trials have been described elsewhere and are reviewed in Appendix 2. We included 11 randomized trials on progression of renal disease that compared the effects of antihypertensive regimens including ACE inhibitors to the effects of regimens without ACE inhibitors, with a follow-up of at least 1 year. In these studies, the institutional review board at each participating center approved the study, and all patients gave informed consent. Patients underwent randomization between March 1986 and April 1996. Hypertension or decreased renal function was required for entry into all studies. Exclusion criteria common to all studies were acute renal failure, treatment with immunosuppressive medications, clinically significant congestive heart failure, obstructive uropathy, renal artery stenosis, active systemic disease, insulin-dependent diabetes mellitus, history of transplantation, history of allergy to ACE inhibitors, and pregnancy. Table 1 shows characteristics of the patients in each study. Table 1. Study and Patient Characteristics in the Randomized, Controlled Trials Included in the Pooled Analysis Before randomization, patients already taking an ACE inhibitor were switched to alternative medications for at least 3 weeks. After randomization, the ACE inhibitor groups received enalapril in seven studies (1419; Brenner BM; Toto R. Personal communications) and captopril (13), benazepril (20), cilazapril (18), and ramipril (21, 22) in one study each. The control groups received placebo in five studies (1922; Brenner BM; Toto R. Personal communications), a specified medication in five studies (nifedipine in two studies [13, 17] and atenolol or acebutolol in three studies [15, 16, 18]), and no specified medication in one study (14). Other antihypertensive medications were used in both groups to reach the target blood pressure, which was less than 140/90 mm Hg in all studies. All patients were followed at least once every 6 months for the first year and at least once yearly thereafter. Blood pressure and laboratory variables were measured at each visit. Table 1 shows outcomes of each study. We pooled the 11 clinical trials on the basis of similarity of study designs and patient characteristics. In addition, the presence of preexisting hypertension and use of antihypertensive agents in most patients in the control groups in each clinical trial justified pooling data from placebo-controlled and active-controlled trials. Thus, the pooled analysis addresses the clinically relevant question of whether antihypertensive regimens including ACE inhibitors are more effective than anti-hypertensive regimens not including ACE inhibitors in slowing the progression of nondiabetic renal disease. Outcomes Two primary outcomes were defined: ESRD, defined as the initiation of long-term dialysis therapy, and a combined outcome of a twofold increase in serum creatinine concentration from baseline values or ESRD. Because ESRD is a clinically important outcome, we believed that definitive results of analyses using this outcome would be clinically relevant. However, because most chronic renal diseases progress slowly, few patients might reach this outcome during the relatively brief follow-up of these clinical trials, resulting in relatively low statistical power for these analyses. Doubling of baseline serum creatinine is a well-accepted surrogate outcome for progression of renal disease in studies of antihypertensive agents (2, 20) and would be expected to occur more frequently than ESRD, providing higher statistical power for analyses using this outcome. Doubling of baseline serum creatinine concentration was confirmed by repeated evaluation in only one study, which used this variable as the primary outcome. Therefore, we did not require confirmation of doubling for our analysis. Other outcomes included death and a composite outcome of ESRD and death. Withdrawal was defined as discontinuation of follow-up before the occurrence of an outcome or study end. Reasons for withdrawal were 1) nonfatal side effects possibly due to ACE inhibitors, including hyperkalemia, cough, angioedema, acute renal failure, or hypotension; 2) nonfatal cardiovascular disease events, including myo-cardial infarction, congestive heart failure, stroke, transient ischemic attack, or claudication; 3) other nonfatal events, such as malignant disease, pneumonia, cellulitis, headache, or gastrointestinal disturbance; and 4) other reasons, including loss to follow-up, protocol violation, or unknown. Statistical Analysis Five investigators participated in data cleaning. Summary tables were compiled from the individual-patient data from each study and checked against tables in published and unpublished reports. Discrepancies were resolved by contacting investigators at the clinical or data coordinating centers whenever possible. Because the studies followed different protocols, we had to standardize the variable definitions, follow-up intervals, and run-in periods; details of our approach are provided in Appendix 2. S-Plus (MathSoft, Inc., Seattle, Washington) and SAS (SAS Institute, Inc., Cary, North Carolina) software programs were used for all statistical analyses (31, 32). Univariate analysis was performed to detect associations between the covariates and outcomes. Baseline patient characteristics were treatment assignment (ACE inhibitor vs. control), age (logarithmic transformation), sex, ethnicity, systolic blood pressure, diastolic blood pressure, mean arterial pressure, serum creatinine concentration (reciprocal transformation), and urinary protein excretion. Study characteristics were blinding, type of antihypertensive regimen in the control group, planned duration of follow-up, whether dietary protein or sodium was restricted, and year of publication. Baseline patient characteristics and study characteristics were introduced as fixed covariates. Since renal biopsy was not performed in most cases and since criteria for classification of cause of renal disease were not defined, the cause of renal disease was not included as a variable in the analysis. Follow-up patient characteristics (blood pressure and urinary protein excretion) were adjusted as time-dependent covariates; the value recorded at the beginning of each time segment was used for that segment. This convention was used so that each outcome would be determined only by previous exposure. The intention-to-treat principle was followed for comparison of randomized groups. Cox proportional-hazards regression models were used to determine the effect of assignment to ACE inhibitors (treatment effect) and other covariates on risk for ESRD and the combined outcome (33, 34). Multivariable models were built by using candidate predictors that were associated with the outcome (P<0.2) in the univariate analysis. Each model was adjusted for study, but since some studies had no events, we could not include a dummy variable for each study. Rather, we adjusted models for studies that differed significantly from the rest (studies 2 [14], 5 [15], 10 [20], and 11 [21, 22]). We also performed tests for interactions between all covariates and treatment effect. All P values were based on two-sided tests, and significance was set at a P value less than 0.05. Results are expressed as relative risks with 95% CIs. Residual diagnostics were performed on these final models (33, 34)

Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.

BACKGROUND Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions. METHODS Using Danish national registries, we identified all patients discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation between 1997 and 2008. The risk of stroke or systemic thromboembolism and bleeding associated with non-end-stage chronic kidney disease and with end-stage chronic kidney disease (i.e., disease requiring renal-replacement therapy) was estimated with the use of time-dependent Cox regression analyses. In addition, the effects of treatment with warfarin, aspirin, or both in patients with chronic kidney disease were compared with the effects in patients with no renal disease. RESULTS Of 132,372 patients included in the analysis, 3587 (2.7%) had non-end-stage chronic kidney disease and 901 (0.7%) required renal-replacement therapy at the time of inclusion. As compared with patients who did not have renal disease, patients with non-end-stage chronic kidney disease had an increased risk of stroke or systemic thromboembolism (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to 1.59; P<0.001), as did those requiring renal-replacement therapy (hazard ratio, 1.83; 95% CI, 1.57 to 2.14; P<0.001); this risk was significantly decreased for both groups of patients with warfarin but not with aspirin. The risk of bleeding was also increased among patients who had non-end-stage chronic kidney disease or required renal-replacement therapy and was further increased with warfarin, aspirin, or both. CONCLUSIONS Chronic kidney disease was associated with an increased risk of stroke or systemic thromboembolism and bleeding among patients with atrial fibrillation. Warfarin treatment was associated with a decreased risk of stroke or systemic thromboembolism among patients with chronic kidney disease, whereas warfarin and aspirin were associated with an increased risk of bleeding. (Funded by the Lundbeck Foundation.).

Original InvestigationNet Clinical Benefit of Antithrombotic Therapy in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Nationwide Observational Cohort Study

BACKGROUND The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial. OBJECTIVES This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort. METHODS By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death. RESULTS From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69). CONCLUSIONS CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.

Long-Term Mortality and Renal Outcome in a Cohort of 100 Patients With Lupus Nephritis

BACKGROUND The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial. OBJECTIVES This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort. METHODS By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death. RESULTS From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69). CONCLUSIONS CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.

The Danish Registry on Regular Dialysis and Transplantation:completeness and validity of incident patient registration

To evaluate the long‐term mortality and renal outcome in a cohort of Danish patients with lupus nephritis (LN) and to identify outcome predictors among findings registered at the time of the first renal biopsy.

Pulse-wave morphology and pulse-wave velocity in healthy human volunteers: examination conditions.

BACKGROUND The Danish National Registry on Regular Dialysis and Transplantation (NRDT) provides systematic information on the epidemiology and treatment of end-stage chronic kidney disease in Denmark. It is therefore of major importance that the registry is valid and complete. The aim of the present study was to evaluate the registration of incident patients on chronic renal replacement therapy (RRT). METHODS Incident patients on chronic RRT in the period 2001-2004 were identified in NRDT and in the National Patient Registry, which contains information on hospital admissions and treatments. In the National Patient Registry, identification of patients was as follows: patients receiving the procedure of dialysis during a minimum of 90 days and for a minimum of 12 times or the procedure of renal transplantation. Only patients with at least 2 years of dialysis-free interval before and never being transplanted were included. The completeness of NRDT was calculated as the percentage of new patients on chronic RRT registered in the National Patient Registry also found in NRDT. Validity of data in NRDT was assessed by information from medical records and analysed using kappa statistics. RESULTS Completeness of NRDT: Of 3020 patients registered in the National Patient Registry as incident chronic RRT patients, 97.2% were found in NRDT but 22.5% with another year of entry. There were no differences in completeness between hospitals or regions. Validity of NRDT: Validity of common renal diagnoses and RRT modality was high: diabetic nephropathy (kappa = 0.98), adult polycystic kidney disease (kappa = 0.95), chronic glomerulonephritis (kappa = 0.78) and RRT modality (kappa = 0.94). The diagnosis CKD of unknown aetiology and type of diabetes were less valid (kappa = 0.62, 0.60 and 0.73, respectively). The date of RRT start had also high validity. CONCLUSIONS Completeness of incident patient registration in NRDT was highly acceptable. Validity of incident patient data was also good, except for type of diabetes.

Circulating chromatin–anti-chromatin antibody complexes bind with high affinity to dermo-epidermal structures in murine and human lupus nephritis

Objective. Applanation tonometry for pulse‐wave analysis (PWA) and determination of pulse‐wave velocity (PWV) is a non‐invasive method for assessment of the central aortic pressure waveform and indices of arterial stiffness. The objective of this study was to examine the influence of eating and smoking on PWA and PWV measurements in order to establish standard examination conditions. Furthermore, intra‐ and interobserver reproducibility and the effects of varying the site of measurements were observed. Material and methods. Duplicate measurements of the radial pressure waveform and of the brachial and aortic PWV on the right and left side of the body were recorded in 23 healthy subjects by two trained observers. Measurements were performed in the fasting state and 3 h after a high‐calorie meal, and before and 1 h after smoking a cigarette. Results. Intake of a high‐calorie meal as well as smoking caused significant changes in both PWA and PWV parameters and an inter‐arm difference was observed. Intra‐ and interobserver reproducibility was good. Conclusions. Pulse‐wave measurements by applanation tonometry should be undertaken in the same arm during fasting and smoking abstinence.

High Risk of Ischemic Heart Disease in Patients with Lupus Nephritis

Murine and human lupus nephritis are characterized by glomerular deposits of electron-dense structures (EDS). Dominant components of EDS are chromatin fragments and IgG antibodies. Whether glomerular EDS predispose for similar deposits in skin is unknown. We analysed (i) whether dermo-epidermal immune complex deposits have similar molecular composition as glomerular deposits, (ii) whether chromatin fragments bind dermo-epidermal structures, and (iii) whether deposits in nephritic glomeruli predispose for accumulation of similar deposits in skin. Paired skin and kidney biopsies from nephritic (NZBxNZW)F1 and MRL-lpr/lpr mice and from five patients with lupus nephritis were analysed by immunofluorescence, immune electron microscopy (IEM) and co-localization TUNEL IEM. Affinity of chromatin fragments for membrane structures was determined by surface plasmon resonance. Results demonstrated (i) presence of EDS containing chromatin fragments and IgG in both organs in nephritic patients, (ii) chromatin fragments possessed high affinity for dermo-epidermal laminins and collagens, (iii) glomerular immune complex deposits did not predict similar interstitial deposits in skin, although such complexes were present in capillary lumina in glomeruli and skin of all nephritic individuals. Thus, chromatin-IgG complexes accounting for lupus nephritis seem to reach skin through circulation, but other undetermined factors are required for these complexes to deposit within skin membranes.

The importance of early referral for the treatment of chronic kidney disease: a Danish nationwide cohort study

Objective. To investigate the occurrence of ischemic heart disease (IHD) in a cohort of 104 Danish patients with biopsy-proven lupus nephritis (LN). Methods. Information on all hospitalizations in Denmark for IHD between 1977 and 2006 was obtained from the Danish National Hospital Register. Occurrence of IHD after date of first renal biopsy in the LN cohort was compared to the occurrence of IHD in the general population by calculation of standardized ratios of observed to expected events (O:E ratios) for different manifestations of IHD registered during inpatient and outpatient hospital visits. Results. The median duration of followup was 14.7 (range 0.1–30.0) years. Thirty-one first-time hospitalizations for IHD occurred in the cohort, yielding an overall O:E ratio for IHD of 6.8 (95% CI 4.6–9.7). Increased risks were found for angina pectoris (O:E ratio 6.0, 95% CI 3.0–11), myocardial infarction (O:E ratio 7.9, 95% CI 3.8–15), and other IHD-related diagnoses combined (O:E ratio 6.9, 95% CI 3.3–13). A high IHD risk was observed for patients aged < 31 years at time of first renal biopsy (O:E ratio 17.1, 95% CI 9.1–29) and for patients aged 30–39 years during followup (O:E ratio 42.3, 95% CI 21–76). Patients undergoing chronic renal replacement therapy also had a pronounced risk of IHD (O:E ratio 19.4, 95% CI 7.8–40). Conclusion. LN is associated with markedly increased morbidity from IHD. Our findings indicate that patients with early-onset LN have a disturbingly high risk of IHD compared to the general population.