Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels

Abstract Background Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria. Methods We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75–95) ml/min, proteinuria 3.2 (2.5–4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na+/day) and low (89 ± 8 mmol Na+/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median. Results Lower CrCl was correlated with higher PAC during placebo as well as during ARB (β = −1.213, P = 0.008 and β = −1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median. Conclusions In CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction. The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675)

Measurement of glomerular charge selectivity in non-diabetic renal disease

Background. Until now, the renal clearance index of IgG to IgG4 (IgG/IgG4) as well as pancreatic to salivary amylase (PA/SA) were separately used as parameters of renal charge selectivity in diabetic and non-diabetic albuminuria. The suitability of the IgG index may be questioned becuase urinary loss of IgG rather reflects a size selective defect. In contrast, the amylase index seems more appropriate to reflect renal charge selectivity because its molecular size is comparable to albumin. We questioned whether IgG/IgG4 and PA/SA reflect renal charge selectivity in a comparable way in subjects with non-diabetic albuminuria over a wide range. Methods. Renal fractional clearances of albumin, IgG, IgG4, PA and SA were estimated from ambulatory 24-h urine samples in 12 subjects with normoalbuminuria (UAE 4 [3-17] mu g/min), six with microalbuminuria (UAE: 147 [36-200] mu g/min), and 20 with macro-albuminuria (UAE: 2301 [608-13611] mu g/min). Results. Macro-albuminuria is associated with a IgG/IgG4 and PA/SA, whereas microalbuminuria is only associated with a reduced IgG/IgG4 compared to normo-albuminuria. A reduction of IgG/IgG4 (r = -0.75, P <0.001) and PA/SA (r = -0.52, P <0.001) correlates with an increased albuminuria. In addition, IgG/IgG4 correlates with PA/SA in the total population (r = 0.49, P <0.01). IgG/IgG4 (r = 0.51, P <0.05) correlates with the size selective index IgG/albumin in an opposite way to PA/SA (r = -0.52, P <0.05) in 20 subjects with macroalbuminuria. Multiple regression analysis revealed IgG clearance to be the variable which contributes to the variance of albuminuria clearance for the greater part in our population. Conclusion. Both charge selective indices do not appear to correlate in micro-albuminuria. In addition. the presence of a size selective defect has a opposing effect on both charge selective indices. Although the reduction of IgG/IgG4 and PA/SA with increasing albuminuria suggests a progressive charge selective defect, albuminuria in our population is almost entirely explained by urinary loss of IgG. These data seriously question whether either one or both charge selective indices IgG/IgG4 and PA/SA do specifically reflect glomerular charge selectivity

Blood pressure reduction initiates the antiproteinuric effect of ACE inhibition

Blood pressure reduction initiates the antiproteinuric effect of ACE inhibition. Several observations question the role of blood pressure and renal hemodynamic changes in the long-term antiproteinuric effect of ACE inhibition. To differentiate blood pressure and renal effects in the initial antiproteinuric response, the placebo-controlled acute effects of the ACE inhibitor enalaprilat (10mg i.v.) on blood pressure, renal hemodynamics, and proteinuria were compared with those of nitroprusside in nine patients with non-diabetic proteinuria. In addition, we studied whether an exogenous angiotensin II infusion reverse the initial enalaprilat-induced antiproteinuric response. Enalaprilat and nitroprusside reduced MAP by -11.3 ± 2.4% and -14.1 ± 2.3%, respectively, whereas only enalaprilat showed renal hemodynamic effects, reflected by an increase in ERPF of 18.4 ± 5.4% and a decrease in FF of -17.1 ± 2.6%. Despite the contrasting renal hemodynamic profiles, enalaprilat (-10.6 ± 4.8%) and nitroprusside (-12.8 ± 5.1%) equally decreased proteinuria. Exogenous infusion of angiotensin II completely reversed the blood pressure reduction and renal efferent vasodilatation induced by enalaprilat. Proteinuria also increased by 13.1 ± 7.8% to placebo level, albeit statistically non-significant. We conclude that the initial antiproteinuric effect of ACE inhibition appears to be mediated by blood pressure reduction and does not require its specific renal hemodynamic effect. Further studies should clarify whether the renal efferent vasodilatation during ACE inhibition is required to gradually induce renal structural changes that prevent the abundant passage of proteins