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 because 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.
Renal fractional clearances of albumin, IgG, IgG4, PA and SA were estimated from ambulatory 24-h urine samples in 12 subjects with normo-albuminuria (UAE 4 3-17 micrograms/min), six with micro-albuminuria (UAE: 14736-200 micrograms/min), and 20 with macro-albuminuria (UAE: 2301 608-13611 micrograms/min).
Macro-albuminuria is associated with a reduced IgG/IgG4 and PA/SA, whereas micro-albuminuria 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 macro-albuminuria. 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.
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. 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.
Optimal albuminuria reduction is considered essential to halting chronic kidney disease (CKD) progression. Both vitamin D receptor activator (VDRA) treatment and dietary sodium restriction potentiate ...the efficacy of renin-angiotensin-aldosterone-system (RAAS) blockade to reduce albuminuria. The ViRTUE study addresses whether a VDRA in combination with dietary sodium restriction provides further albuminuria reduction in non-diabetic CKD patients on top of RAAS blockade. The ViRTUE study is an investigator-initiated, prospective, multi-centre, randomized, double-blind (paricalcitol versus placebo), placebo-controlled trial targeting stage 1-3 CKD patients with residual albuminuria of >300 mg/day due to non-diabetic glomerular disease, despite angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. During run-in, all subjects switched to standardized RAAS blockade (ramipril 10 mg/day) and blood pressure titrated to <140/90 mmHg according to a standardized protocol. Eligible patients are subsequently enrolled and undergo four consecutive study periods in random order of 8 weeks each: (i) paricalcitol (2 µg/day) combined with a liberal sodium diet (∼200 mmol Na(+)/day, i.e. mean sodium intake in the general population), (ii) paricalcitol (2 µg/day) combined with dietary sodium restriction (target: 50 mmol Na(+)/day), (iii) placebo combined with a liberal sodium diet and (iv) placebo combined with dietary sodium restriction. Data are collected at the end of each study period. The primary outcome is 24-h urinary albumin excretion. Secondary study outcomes are blood pressure, renal function (estimated glomerular filtration rate), plasma renin activity and, in a sub-population (N = 9), renal haemodynamics (measured glomerular filtration rate and effective renal plasma flow). A sample size of 50 patients provides 90% power to detect a 23% reduction in albuminuria, assuming a 25% dropout rate. Further reduction of residual albuminuria by combination of VDRA treatment and sodium restriction during single-agent RAAS-blockade will justify long-term studies on cardiorenal outcomes and safety.
NTR2898 (Dutch trial register).
In glomerular disease proteinuria usually has a circadian pattern with maximum excretion during the day. Blockade of the renin-angiotensin system (RAS) results in a 50% reduction of proteinuria as ...measured in 24-h urine collections. We questioned whether anti-proteinuric treatment by blockade of the RAS is as effective during the day as during the night.
We analysed data from two intervention studies on proteinuria in patients with non-diabetic renal disease. In the first study, six hospitalized patients (proteinuria 5.8 +/- 2.9 g/day) were treated with the renin-inhibitor remikiren 600 mg o.d. during 8 days. In the second study eight ambulant patients (proteinuria 7.5 +/- 2.7 g/day) were treated during 6 weeks with the ACE-inhibitor trandolapril 4 mg o.d. Urine was collected in a day- and in a night-time portion.
Daytime proteinuria declined from 0.29 +/- 0.15 to 0.22 +/- 0.11 g/h (P < 0.05) during remikiren and from 0.33 +/- 0.14 to 0.16 +/- 0.08 g/h (P < 0.05) during trandolapril. Night-time proteinuria, however, was not significantly reduced from 0.23 +/- 0.11 to 0.19 +/- 0.11 g/h during remikiren and from 0.29 +/- 0.17 to 0.20 +/- 0.12 g/h during trandolapril. Both interventions effectively lowered blood pressure during the day as well as the night.
In both studies relative nocturnal therapy resistance to the antiproteinuric effect of RAS blockade was found, despite 24-h efficacy of blood pressure effect. This may have clinical relevance because it contributes to rest-proteinuria and thus may affect long term renal function outcome. It may be worthwhile to explore alternative therapeutic regimens to improve the nocturnal antiproteinuric response.
Pregnancy may be followed by a postpartum acceleration of renal function loss in patients with renal disease. We retrospectively analyzed the effects of pregnancy on progressive renal function ...decline, and the risk factors for an acceleration, in a group of 19 renal disease patients with 30 pregnancies and a group of 31 patients who did not become pregnant after onset of glomerular disease. The rate of renal function loss was calculated for each patient by linear regression on reciprocal serum creatinine values over 11 years' follow-up. Multiple regression analysis showed that both pregnancy (P = 0.03) and initial proteinuria (P = 0.005) were independently related with the rate of renal function loss. Such a relation could not be observed with histologic diagnosis, and initial age, renal function, blood pressure, and serum albumin. Further analysis showed that 10 of 30 pregnancies are followed by a predefined acceleration of renal function loss. These pregnancies were preceded and complicated by a higher proteinuria (4.1 v 1.7 g/d, P < 0.005; and 3.6 v 2.1 g/d, P < 0.05, respectively) compared with the other 20 pregnancies that are not followed by such an acceleration. In conclusion, patients with primary glomerular disease complicated by substantial proteinuria are at risk for acceleration of renal function decline after pregnancy.
Fractional dextran clearances have been extensively used to study glomerular size selectivity. We report on an analysis of different laboratory procedures involved in measuring fractional dextran ...clearances. The deproteinization of plasma samples by 20% trichloroacetic acid (TCA) revealed a protein contamination of 0.2% ± 0.3%, whereas both 5% TCA and zinc sulfate deproteinization revealed a significantly higher remaining sample protein content (2.5% ± 0.4% and 3.4% ± 0.1%, respectively). Only zinc sulfate revealed incomplete deproteinization of urine samples (0.6% ± 0.2%). Dextran recovery in plasma and urine supernatants was significantly lower after 5% TCA and zinc sulfate deproteinization when compared with 20% TCA deproteinization. Gel permeation chromatography (GPC) and high-performance liquid chromatography (HPLC) showed a variance of calibration smaller than 5% over 1 year. The use of 3 different sets of standard dextrans revealed significant differences in calibration. GPC and HPLC followed by anthrone assay showed a comparable variance in dextran concentration in plasma, from 3 to 6 nm (14% to 25%), whereas the variance in urine was lower for the GPC and anthrone assay, especially from 5.4 to 6 nm (23% to 43% versus 50% to 78%). HPLC and online refractometry showed the lowest variance of dextran concentration in plasma, from 3 to 6 nm (<4%), and in urine, from 3 to 5.2 nm (<7%), whereas it showed a higher variance in urine, from 5.4 to 6 nm, in comparison with GPC and HPLC with the anthrone assay. The GPC and anthrone assay revealed higher fractional dextran clearances in comparison with the HPLC and anthrone assay in healthy subjects (3 to 5.4 nm) as well as in patients with nondiabetic proteinuria (4.2 to 5.8 nm), and lower clearances in patients from 3 to 3.4 nm. The HPLC and anthrone assay revealed higher clearances in comparison with HPLC and online refractometry in healthy subjects (3.6 to 5.4 nm) and in patients (3.6 to 5.2 nm). The GPC and anthrone assay revealed characteristic differences in fractional dextran clearances between healthy subjects and patients. The HPLC and anthrone assay showed no significant differences between both groups, whereas HPLC and online refractometry showed only an increased clearance of dextrans from 4.6 to 5.2 nm in patients. Fractional clearances of dextran 5.6 nm as estimated by all 3 dextran assays were not significantly related to the fractional immunoglobulin G clearance or the immunoglobulin-to-albumin clearance index in our patients. Quantitative and qualitative differences in fractional dextran clearances may be induced by differences in laboratory procedures. We recommend sample preparation by 20% TCA deproteinization, frequent calibration with 1 set of dextran standards with low polydispersity, size-exclusion chromatography by GPC, and dextran detection by anthrone assay for optimal measurement of fractional dextran clearances. Even with such an approach, however, the variability in the measurement remains extremely high in the important range of dextrans greater than 5 nm.
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