The Safety and Short-Term Efficacy of Aliskiren in the Treatment of Immunoglobulin A Nephropathy – A Randomized Cross-Over Study

<div><p>Background</p><p>Laboratory research and previous study suggest that aliskiren, a direct renin inhibitor, has anti-proteinuric effects. We conducted a randomized crossover study to evaluate the anti-proteinuric effect of aliskiren in patients with immunoglobulin A (IgA) nephropathy.</p><p>Methods</p><p>We studied 22 patients with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either oral aliskiren 300 mg/day or placebo for 16 weeks and then crossed over to the other treatment arm after a washout period. Proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and serum potassium were monitored.</p><p>Results</p><p>After aliskiren treatment, there was a significant reduction in proteinuria in 4 weeks (1.76±0.95 to 1.03±0.69 g:g-Cr, p<0.0001), which remained at a low level throughout the treatment period. There was a significant difference in proteinuria between the aliskiren and placebo groups from 4 to 16 weeks after treatment (p<0.01 for all comparisons). After aliskiren treatment, there were modest but statistically significant reductions in eGFR (57.2±29.1 to 54.8±29.3 ml/min/1.73 m², p = 0.013) and diastolic blood pressure (72.6±12.3 to 66.2±11.2 mmHg, p<0.0001). None of the patient developed severe hyperkalemia (serum potassium ≥6.0 mmol/l) during the study period.</p><p>Conclusions</p><p>Aliskiren has anti-proteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE inhibitor or ARB. Further studies are needed to confirm the renal protecting effect of direct renin inhibition in chronic proteinuric kidney diseases.</p><p>Trial Registration</p><p><a href="http://tinyurl.com/bvez4qn" target="_blank">ClinicalTrials.gov NCT00870493</a></p></div

Circulating Bacterial-Derived DNA Fragment Level Is a Strong Predictor of Cardiovascular Disease in Peritoneal Dialysis Patients

<div><p>Background</p><p>Circulating bacterial DNA fragment is related to systemic inflammatory state in peritoneal dialysis (PD) patients. We hypothesize that plasma bacterial DNA level predicts cardiovascular events in new PD patients.</p><p>Methods</p><p>We measured plasma bacterial DNA level in 191 new PD patients, who were then followed for at least a year for the development of cardiovascular event, hospitalization, and patient survival.</p><p>Results</p><p>The average age was 59.3 ± 11.8 years; plasma bacterial DNA level 34.9 ± 1.5 cycles; average follow up 23.2 ± 9.7 months. At 24 months, the event-free survival was 86.1%, 69.8%, 55.4% and 30.8% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (p < 0.0001). After adjusting for confounders, plasma bacterial DNA level, baseline residual renal function and malnutrition-inflammation score were independent predictors of composite cardiovascular end-point; each doubling in plasma bacterial DNA level confers a 26.9% (95% confidence interval, 13.0 – 42.5%) excess in risk. Plasma bacterial DNA also correlated with the number of hospital admission (r = -0.379, p < 0.0001) and duration of hospitalization for cardiovascular reasons (r = -0.386, p < 0.0001). Plasma bacterial DNA level did not correlate with baseline arterial pulse wave velocity (PWV), but with the change in carotid-radial PWV in one year (r = -0.238, p = 0.005).</p><p>Conclusions</p><p>Circulating bacterial DNA fragment level is a strong predictor of cardiovascular event, need of hospitalization, as well as the progressive change in arterial stiffness in new PD patients.</p></div

Baseline biochemical data and dialysis prescription.

<p>HDL, high density lipoprotein; LDL, low density lipoprotein; D/P, dialysate-to-plasma concentration ratio of creatinine; MTAC, mass transfer area coefficient; GFR, glomerular filtration rate; NPNA, normalized protein nitrogen appearance; FEBM, fat-free edema-free body mass by creatinine kinetics. Patients were divided to quartiles of plasma bacterial DNA. Quartile I had the lowest while quartile IV the highest plasma bacterial DNA level. Data are compared by one way analysis of variance (ANOVA).</p><p>Baseline biochemical data and dialysis prescription.</p

Comparison of (A) number of hospital admission; and (B) duration of hospitalization between quartiles of plasma bacterial DNA level.

<p>Quartile I had the lowest while quartile IV the highest plasma bacterial DNA level. (p < 0.0001 by Kruskal Wallis test for all comparisons between quartiles) (White box, hospitalization for all cause; hatched box, hospitalization for cardiovascular reasons.)</p

Cox proportional hazards model of composite cardiovascular end-point.

<p>AHR, adjusted hazard ratio; CI, confidence interval; MIS, malnutrition inflammation score; GFR, glomerular filtration rate.</p><p>Cox proportional hazards model of composite cardiovascular end-point.</p

Comparison of (A) carotid-radial; and (B) carotid-femoral pulse wave velocity (PWV) between quartiles of plasma bacterial DNA level.

<p>Quartile I had the lowest while quartile IV the highest plasma bacterial DNA level. P values depicted are computed by paired Student’s t test.</p

Independent predictors of hospitalization for cardiovascular reasons by log-linear model.

<p>CI, confidence interval; MIS, malnutrition inflammation score.</p><p>NB. e^COEF was the exponential coefficient indicating the relative number of hospital admission (per year) or duration of hospitalization (days per year of follow up) compared to the 2-fold lower of plasma bacterial DNA level (i.e. one extra threshold cycle of polymerase chain reaction), and 1 point less for MIS.</p><p>Independent predictors of hospitalization for cardiovascular reasons by log-linear model.</p

Kaplan-Meier plot of (A) event-free survival; and (B) cardiovascular disease-free survival (excluding congestive heart failure).

<p>Patients were divided to quartiles of plasma bacterial DNA. Quartile I had the lowest while quartile IV the highest plasma bacterial DNA level. Data are compared by the log rank test.</p

Baseline demographic and clinical data.

<p>PD, peritoneal dialysis; PCR, polymerase chain reaction. Patients were divided to quartiles of plasma bacterial DNA. Quartile I had the lowest while quartile IV the highest plasma bacterial DNA level. Note that a higher PCR cycle number indicates a lower level of bacterial DNA. Data are compared by Chi square test or one way analysis of variance (ANOVA) as appropriate.</p><p>Baseline demographic and clinical data.</p