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Background: Non-dihydropyridine calcium antagonists such as verapamil are equally effective in reducing proteinuria as ACE inhibitors in hypertensive patients with diabetic nephropathy. To date it is unknown whether verapamil elucidates such an antiproteinuric capacity in non-diabetic renal disease., Methods: We performed a double-blind, placebo-controlled, random cross-over study which compared the antiproteinuric effect of 6 weeks treatment with verapamil SR (360 mg) to that of the ACE inhibitor trandolapril (4 mg), and their fixed combination vera/tran (180 mg verapamil SR and 2 mg trandolapril) in 11 non-diabetic patients with proteinuria of 6.6 (5.1-8.8) g/day, a creatinine clearance of 87 (74-106) ml/min, and a 24-h blood pressure of 136/85 (126/76-157/96) mmHg at baseline., Results: Twenty-four-hour mean arterial pressure did not change during verapamil, whereas both trandolapril and vera/tran induced a significant reduction in MAP. Verapamil showed no significant effects on renal haemodynamics. Trandolapril and vera/tran did not significantly change GFR, but ERPF increased and FF decreased during both treatments (P<0.05). The antiproteinuric response of verapamil was significantly less compared to that of trandolapril and vera/tran (-12% (-17/-1) vs -51% (-56/-25) and -41% (-50/-19) respectively). The blood pressure and antiproteinuric response during verapamil tended to be greater in hypertensive patients than in normotensive patients, although this difference was not significant. Baseline blood pressure was related to the change in blood pressure during verapamil (r = -0.70; P < 0.02)., Conclusions: The antiproteinuric and antihypertensive response of verapamil is less than that of the ACE inhibitor trandolapril in patients with non-diabetic renal disease. In contrast to the antiproteinuric response of trandolapril, the antiproteinuric reponse of verapamil seems to be completely dependent from effective blood pressure reduction. The fixed combination of verapamil and ACE inhibition at half doses has similar effects as ACE inhibition at full dose.

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.

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 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., Methods: 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: 147[36-200] micrograms/min), and 20 with macro-albuminuria (UAE: 2301 [608-13611] micrograms/min)., Results: 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., 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.

Whether ACE inhibitors (ACEi) differ from other antihypertensives in their efficacy to lower proteinuria is controversial. We therefore performed a meta-analysis of articles on this subject. The secondary objective in our meta-analysis was to study whether there is any difference between diabetic and non-diabetic patients in antiproteinuric response to blood pressure reduction. To identify all articles we performed a computer search using the bibliographic databases. To minimize publication bias, only trials in which a direct comparison was made between an ACEi and another antihypertensive were included. Studies performed both in diabetic and in non-diabetic patients were eligible. Included were 41 studies, comprising 1124 patients, of which 558 had non-diabetic renal disease. The mean antiproteinuric effect of ACEi was significantly greater than that of their comparator drugs: -39.9% (95% confidence interval: -42.8 to 36.8%) versus -17.0% (-19.0 to -15.1%) respectively (difference 24% (19.5 to 28.6%)). The blood-pressure-lowering effect was equal: -12.0% (-12.8 to -11.2%) versus -11.4% (-11.7 to -11.1%) respectively (difference -0.8% (-1.8 to 0.2%)). Thus it may be concluded that ACEIs confer an antiproteinuric effect beyond that attributable to their blood-pressure-lowering effect. A wide interstudy variation in antiproteinuric response to non-ACEI antihypertensives was observed. Multiple variable regression analysis was performed to assess which factors may explain this heterogeneity. From the comparator drugs, the class was of no importance: calcium-channel antagonists (CCA), beta-blockers, and a rest group of other drug types showed a similar response. Patient characteristics such as initial GFR and blood pressure partly explained the variation in response, but most of it appeared dependent on the blood pressure reduction achieved. Furthermore the type of CCA is of importance, with nifedipine having the least effect. A significantly greater antiproteinuric effect of 'non-ACEI' antihypertensives was found in diabetic patients compared to non-diabetics. However, this coincided with a greater blood pressure reduction in diabetics. Adjusted for differences in blood pressure control, diabetics showed even a slightly lesser antiproteinuric response to non-ACEI antihypertensive compared to non-diabetics.

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.