Abstract
Abstract. The Ramipril Efficacy in Nephropathy Core and Follow-Up Study found that ≥36 mo of continued ramipril therapy decreased substantially the risk of end-stage renal failure (ESRF) in patients with chronic nephropathies and a urinary protein excretion rate ≥3 g/24 h. This study investigates the time-dependent changes in GFR in these patients and in control subjects who were randomized to conventional therapy during the Core period and switched to ramipril during the Follow-Up study. Analyses included 150 patients (continued ramipril: n = 74; switched to ramipril: n = 76) who had at least three GFR measurements (including baseline) during the whole observation period and a subgroup of 43 patients (continued ramipril: n = 26; switched to ramipril: n = 17) who had at least six GFR measurements, including at least three on the Core and at least three on the Follow-Up study. Ramipril (1.25 to 5 mg/d) and conventional therapy were targeted at achieving a diastolic BP below 90 mmHg. The main efficacy variables were GFR and ESRF (need for dialysis). Analysis was by intention to treat. Throughout the study, the mean ± SEM rate of GFR decline (ΔGFR) was significantly lower in patients continued on ramipril compared to those switched to ramipril (0.51 ± 0.09 versus 0.76 ± 0.10 ml/min per 1.73 m2 per mo, P < 0.03). In patients on continued ramipril who had at least six GFR measured—but not in control subjects—ΔGFR progressively improved with time and, in the cohort with the longest follow-up, decreased from (in ml/min per 1.73 m2 per mo): 0.16 ± 0.12 (at 18 mo) to 0.10 ± 0.05 (at 60 mo). This rate was about 10-fold slower compared to patients on conventional therapy during the REIN Core study. Analyses of the individual slopes found that at the end of the follow-up, 10 of 26 patients on continued ramipril therapy had a positive ΔGFR and another 10 patients had an improvement of ΔGFR while on ramipril therapy. ΔGFR significantly improved in parallel with a significant reduction in proteinuria. Changes in ΔGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups. Baseline characteristics and changes in systolic and diastolic BP and 24-h urine urea and sodium excretion were comparable. The present results offer evidence that in chronic nephropathies, the tendency of GFR to decline with time can be effectively halted, even in patients with remarkably severe disease.
The Ramipril Efficacy in Nephropathy (REIN) study was a randomized, double-blind, placebo-controlled trial designed to test whether glomerular protein traffic and its modification by an angiotensin-converting enzyme (ACE) inhibitor influenced renal disease progression in 352 patients with chronic nondiabetic nephropathies (1, 2). A prestratification strategy recognized two levels of proteinuria (>1 but <3 g/24 h, and ≥3 g/24 h) in patients randomly assigned the ramipril or conventional antihypertensive therapy. Treatments were targeted to the same level of BP control. The REIN Core study (2) found that in patients with proteinuria of 3 g or more per 24 h, who were fast progressors, ramipril safely decreased the rate of GFR decline (ΔGFR) and reduced by half the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF). These effects were accompanied by a substantial lowering of the urinary protein excretion rate, which exceeded that expected from the degree of BP reduction. At the end of the REIN Core study, patients with proteinuria of 3 g or more per 24 h, who either continued on ramipril or were shifted to ramipril, entered the REIN Follow-Up study (3). ΔGFR and risk of progression to ESRF (i.e., need of dialysis) were main efficacy variables. In the REIN Follow-Up study, ramipril slowed the rate of GFR decline and limited progression to ESRF even better than in the REIN Core study, both in the overall study population and separately in patients originally randomized to ramipril or conventional therapy (3). The novel finding of the Follow-Up study was that GFR almost stabilized in patients originally randomized to ramipril who continued with the active drug for more than 36 mo (3).
In the present study, we sought to investigate the determinants of ACE inhibition-induced time-dependent reduction of progression of chronic renal diseases.
Materials and Methods
The design of the REIN study has been described in detail elsewhere (1, 3). After completion of the Core study, all patients in the ≥3 g proteinuria stratum were asked to enter the REIN Follow-Up study. Every patient gave informed consent before entering the study.
The main objective was to compare the following factors in the two groups of patients originally randomized to ramipril or placebo plus conventional antihypertensive therapy: (1) ΔGFR and incidence of ESRF during the overall (Core and Follow-Up) study period; and (2) time-dependent changes in ΔGFR and predicted time to ESRF.
Patients and Study Design
Study participants included all of the 166 patients in stratum 2 of the REIN study (Figure 1). After completion of the Core study, patients originally randomized to ramipril were asked to continue on ramipril therapy with the same daily dose. Patients originally randomized to placebo plus conventional antihypertensive therapy were asked to start ramipril therapy after the first visit of the Follow-Up study. The first dose of the study drug (1.25 mg/d) and that of the increment dosages (i.e., 2.5 or 5 mg/d) were given in the hospital, and patients were monitored for 4 h after study drug ingestion. The dose of the study drug was titrated upward every 2 wk, and the dose of other antihypertensives were progressively reduced to avoid symptomatic hypotension. Patients without previous antihypertensive therapy were maintained on the lowest dose unless upward titration was required to maintain the target BP. In each patient, the general goal was to adjust the ramipril dose to maintain the target BP with the minimum dose of concomitant antihypertensive agents. ACE inhibitors or angiotensin II receptor antagonists could not be added to the study drug throughout the entire study period.
Ramipril Efficacy in Nephropathy Core and Follow-Up study profile.
Each patient was examined by a physician at randomization, every month during the first 3 mo, and every 3 mo therafter until completion of the Core and Follow-Up study. Additional visits were performed at the time of each increase in the study drug and when patients were switched from placebo to ramipril treatment. At each examination, BP and heart rate were measured in the sitting, lying, and standing position in the morning before the ingestion of the drug, and serum creatinine and electrolyte concentrations were determined. BP was also monitored from 8 a.m. to noon in all patients at the time of each GFR measurement. The GFR and other serum biochemical values (uric acid, glucose, cholesterol, triglycerides, liver enzymes, and bilirubin) and a complete blood count were evaluated, as well as 24-h urinary protein, sodium, and urea excretion, at baseline and every 6 mo thereafter. Patients originally randomized to the placebo had an additional GFR measurement 3 mo after the initial visit of the Core study to detect acute changes in GFR associated with the introduction of ramipril treatment. All of the patients were advised to limit their sodium intake and to eat 0.6 to 0.8 g/kg per d of protein per kilogram of body weight per day. No change in the diet was introduced subsequently during the study. Dietary compliance was assessed by evaluating 24-h urinary sodium and urea excretion rates.
Outcome Measures
Main outcome measures were incidence of ESRF (i.e., need of dialysis) and ΔGFR during the overall (Core and Follow-Up) study period. GFR was determined centrally (Mario Negri Institute for Pharmacological Research, Bergamo) as described previously (4). For ΔGFR estimation, a minimum of three GFR measurements (including baseline) was required. Analyses were performed on an intention to treat basis in all randomized patients retained in their assigned group regardless of their adherence to the treatment regimen.
Statistical Analyses
A sample size of 282 patients was estimated to power the study (1-β: 0.80, t test) to detect as statistically significant (α = 0.05, two-tailed test) a 25% difference in ΔGFR (from 0.29 ml/min per 1.73 m2 to 0.21 ml/min per 1.73 m2) during the Core study between patients originally randomized to ramipril or placebo (1, 2). Three hundred fifty-two patients had to be recruited to account for a predicted 20% dropout rate.
Data were analyzed on an intention to treat basis. Dichotomous and polychotomous baseline characteristics were compared by Fisher exact test; continuous baseline characteristics were compared with Wilcoxon rank-sum tests. Analyses on the decline in GFR were carried out in all patients who had three or more renal function determinations during the overall (Core and Follow-Up) study period and in the subgroup of patients who had at least six GFR measurements, of which at least three were obtained during the Core (including baseline) and three during the Follow-Up study. A single slope linear model was used. GFR slopes were compared by Wilcoxon rank-sum test (5) between the two treatment groups. Distribution testing for normality was performed using the Shapiro-Wilk test (5). To avoid potential bias due to premature withdrawal for reasons related to the response variable (i.e., ESRF), GFR slopes at different time intervals were evaluated in five cohorts of patients with identical follow-up periods (i.e., ≥36, ≥42, ≥48, ≥54, and ≥60 mo) considered separately within the two groups either on continued ramipril or originally on conventional treatment and switched to ramipril during the Follow-Up study.
To identify changes in ΔGFR by a two-phase linear regression (6, 7), we adapted to GFR measurements a program (7) originally implemented for the reciprocal of serum creatinine concentration. Preliminary analyses were done on the mean values of the available GFR at particular time points, and a breakpoint on these values was fitted retrospectively. To assess the improvement over a single straight line, an F test was then calculated (7). Further analyses were performed on single patient data to identify changes in individual ΔGFR. Linear trends were evaluated and described by Microsoft Excel.
ΔGFR, systolic and diastolic BP, 24-h urinary protein, urea, and sodium excretion rates after the breakpoint were evaluated by analysis of covariance adjusting for pre-breakpoint values.
The analyses were performed with Statistical Analysis System software (version 6.11). A P value <0.05 was taken to indicate statistical significance. All statistical tests were two-sided. Data are given as mean ± SD, unless otherwise stated.
Results
Patients
All of the 166 patients assigned to stratum 2 at baseline evaluation were considered for event analyses during the Core and Follow-Up study. Their baseline characteristics have been given elsewhere (2). The 78 randomized to ramipril had a follow-up of 27 ± 18 mo (range, 1 to 74), and the 88 randomized to placebo plus conventional antihypertensive therapy had a follow-up of 24 ± 19 mo (range, 1 to 72).
Of the 166 patients, 150 (74 randomized to ramipril and 76 to placebo plus conventional treatment) had at least three GFR evaluations (including baseline) during the entire study period. Main baseline characteristics were comparable in the two treatment groups (Tables 1 and 2) and, overall, were comparable to baseline characteristics of patients with less than three GFR measures who were not included in the analysis (data not shown). The overall follow-up was 28 ± 18 mo (range, 4 to 74) and 28 ± 19 mo (range, 3 to 72) in ramipril and conventionally treated patients, respectively. Of these, 43 patients (26 randomized to ramipril and 17 to placebo plus conventional treatment) had at least six GFR measurements. Previous studies found that in these patients ΔGFR remarkably and significantly decreased from the Core to the Follow-Up study not only, as expected, in those originally randomized to conventional treatment and switched to ramipril during the follow-up, but also, surprisingly enough, in those on continued ramipril since randomization (3). These patients had comparable baseline clinical characteristics and similar types of glomerular diseases (Table 3). The mean ± SD follow-up was 44 ± 17 mo (range, 25 to 74) and 45 ± 16 mo (range, 11 to 72) in patients randomized to ramipril or placebo plus conventional treatment, respectively. The number of GFR measures was 10 ± 3 (range, 6 to 13) and 10 ± 2 (range, 6 to 13) in patients randomized to ramipril or placebo plus conventional treatment, respectively.
Clinical characteristics at time of randomization of patients with baseline urinary protein excretion rate ≥3 g/d and at least three GFR measurements including baseline
Diagnosis of renal disease in the 150 patients with at least three GFR determinations (including baseline)
Diagnosis of renal disease in the 43 patients with at least six GFR determinations (including at least three GFR in the Core and at least three GFR in the Follow-Up study)
During the Follow-Up study, most of the patients were on ramipril (5 mg/d), and the dose was comparable in patients on continued ramipril and in those originally on placebo plus conventional treatment and then switched to ramipril.
Renal Survival during the Overall Study Period
Overall kidney survival during the Core and Follow-Up study was significantly higher in patients on continued ramipril compared to patients originally on placebo and switched to ramipril during the Follow-Up study. Eight months after the analyses of the REIN Follow-Up study were completed (3), no additional patients on continued ramipril progressed to ESRF, whereas two patients switched to ramipril during the Follow-Up study developed ESRF. After 36 mo of continued ramipril treatment had been completed, there were no further ESRF events (Figure 2). Incidence and relative risk (95% confidence intervals) of ESRF in the two groups during the overall study period, in the Core and Follow-Up study separately, and after 36 mo of treatment are shown in Figure 2.
Incidence of end-stage renal failure (ESRF) (percentage of patients with events) in the continued ramipril and switched to ramipril group, and relative risk (95% confidence intervals) of events between the two groups during the Core and Follow-Up studies separately, after at least 36 mo of treatment, and during the overall (Core and Follow-Up) study period.
Renal Function during the Overall Study Period
During the overall study period, ΔGFR (mean ± SEM) was significantly lower in patients on continued ramipril treatment compared to patients switched to ramipril during the Follow-Up study (0.51 ± 0.09 versus 0.76 ± 0.10 ml/min per 1.73 m2 per mo, P < 0.03). However, after an initial decline, GFR showed a trend to stabilize and then to increase after approximately 36 mo from randomization in patients on continued ramipril therapy, but not in those switched to ramipril only during the follow-up. Since this finding could be flawed by heterogeneous follow-up in the two groups and censoring of patients progressing to ESRF, the analysis was restricted to the 43 patients with six or more GFR (at least three in the Core and at least three in the Follow-Up study) who in a previous report (3) were found to have a slower ΔGFR during the Follow-Up than during the Core study. Again, in patients on continued ramipril therapy, the GFR had an initial trend to progressively decrease; however, approximately 36 mo after randomization, it progressively increased up to the last available follow-up point (Figure 3). In patients originally on placebo, the GFR progressively declined over time during the entire period of study, but the decline tended to progressively slow down and the GFR stabilized during the last year of follow-up (Figure 3). Actually, the breakpoint analysis found that in patients on continued ramipril therapy, changes in GFR over time were better described by two different regression lines from month 0 to month 36 and from month 36 to the study end (F test for improvement over single straight line: P < 0.01). The two curves showed opposite time-dependent changes in GFR, with GFR progressively decreasing up to month 36 and progressively increasing thereafter (Figure 3). In contrast, the same analysis failed to detect a breakpoint in time-dependent changes in GFR in patients originally on placebo and later switched to ramipril only during the Follow-Up study (Figure 3). Actually, the analysis found that in these patients the changes in GFR were better described by a single regression line showing a constant decline over time (Figure 3).
GFR time-dependent changes over time during the overall (Core and Follow-Up) study period in the 43 patients on continued ramipril (n = 26, Left Panel) and switched to ramipril (n = 17, Right Panel) who had at least three GFR measurements (including baseline) during the Core study and at least three GFR measurements during the Follow-Up study. First degree equations describing the curves interpolating the GFR values over time are given in both panels. In patients on continued ramipril, the breakpoint analysis found that GFR time-dependent changes could not be described by one single first degree equation, but rather by two different equations (Left Panel) from randomization to 36 mo and from 36 to 54 mo, respectively. Y1 and Y2 equations describe the interpolating curves before and after the breakpoint, respectively. For switched to ramipril patients (Right Panel), percentages of GFR measurements while on ramipril therapy at different times are given.
The time-dependent improvement in GFR was not dependent on censoring of patients with ESRF, since none of these patients on continued ramipril therapy progressed to renal failure during the study. However, since a confounding effect of different follow-up periods in the two treatment groups could not be ruled out with certainty, to further address the possibility of a true GFR improvement we evaluated ΔGFR time-dependent changes in the two groups in different cohorts of patients with homogeneous follow-up (Figure 4). Overall, all of the cohorts of patients on continued ramipril therapy had slower ΔGFR compared to the cohorts of patients switched to ramipril during follow-up. More important, ΔGFR (mean ± SEM) progressively improved (from 0.32 ± 0.09 ml/min per 1.73 m2 to 0.10 ± 0.05 ml/min per 1.73 m2 per mo) in the cohorts with progressively increasing follow-up (from 18 to 60 mo) among patients on continued ramipril therapy, but not among those originally on placebo plus conventional treatment (Figure 4). ΔGFR tended to improve progressively for each increase in length of the follow-up period (from 18 to 60 mo) within each cohort of patients on continued ramipril therapy, but not in the corresponding cohorts of patients originally on placebo plus conventional treatment (Figure 5). Of note, patients on continued ramipril therapy for at least 60 mo had a ΔGFR about ten-fold slower compared to patients on placebo plus conventional treatment during the REIN Core study (0.10 ml/min per 1.73 m2 versus 0.88 ml/min per 1.73 m2 per mo), despite comparable baseline characteristics.
GFR slopes at different time intervals from randomization in the 43 patients on continued ramipril (n = 26, Left Panel) and switched to ramipril (n = 17, Right Panel) who had at least three GFR measurements (including baseline) during the Core study and at least three GFR measurements during the Follow-Up study. For switched to ramipril patients (Right Panel), percentages of GFR measurements while on ramipril therapy at different times are given.
GFR slopes at different time intervals from randomization in cohorts of patients with different follow-up periods (from ≥18 to ≥60 mo) on continued ramipril (Top Row) or switched to ramipril (Bottom Row) who had at least three GFR measurements (including baseline) during the Core study and at least three GFR measurements during the Follow-Up study.
To further investigate the nature of the time-dependent improvement in ΔGFR, we looked for a breakpoint in the individual GFR slopes of patients on continued ramipril therapy and found that after the breakpoint, 10 of the 26 patients in the continued ramipril cohort had a positive ΔGFR and 10 additional patients had an improvement of ΔGFR while on ramipril therapy (Figure 6). Of note, after the breakpoint, ΔGFR significantly improved in parallel with a significant reduction in proteinuria in patients with a positive ΔGFR, but not in those who still did not reach a positive ΔGFR (Figure 7). In both subgroups, BP control and 24-h urinary urea and sodium excretion were comparable before and after the breakpoint. The analysis of covariance found that changes in ΔGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups even after correction for pre-breakpoint values. In contrast, changes in systolic and diastolic BP and 24-h urinary urea and sodium excretion were comparable (Figure 7). Distribution of underlying renal diseases (Table 4) and baseline characteristics of the two subgroups (data not shown) were comparable as well.
(Top Panel) Individual GFR slopes in 10 patients with positive ΔGFR including seven patients whose ΔGFR became positive after randomization (solid lines) and three patients whose ΔGFR was positive since randomization (dashed lines). (Bottom Panel) Individual GFR slopes in 16 patients still without positive ΔGFR, including 10 and six patients whose ΔGFR improved (solid lines) or did not improve (dashed lines) after the breakpoint, respectively.
Pre- and post-breakpoint ΔGFR and 24-h urinary protein excretion rate in patients with (left panel) or without (right panel) positive ΔGFR after the breakpoint. Systolic and diastolic blood pressure and 24-h urinary urea and sodium excretion rates are given below.
Diagnosis of renal disease in the 10 patients with positive ΔGFR and in the 16 patients without a positive ΔGFR on continued ramipril therapy and with ΔGFR during the Core and the Follow-Up study
On the basis of the last available GFR and of the actual mean (95% confidence intervals) ΔGFR measured during the Core and the Follow-Up study, time to ESRF (i.e., to GFR = 10 ml/min per 1.73 m2) could be predicted in each individual patient on continued ramipril therapy or switched to ramipril during the Follow-Up study. Data in the 43 patients with at least six GFR measurements (at least three during the Core and at least three during the Follow-up Study) during the overall observation period are given in Figure 8. Of note, if the breakpoint analysis shown in Figure 6 was used to describe time-dependent changes in individual ΔGFR, the 10 patients on continued ramipril therapy who had positive ΔGFR were predicted to never progress to ESRF. Moreover, even in 10 additional patients with an improving, but still not positive, ΔGFR, the improvement in ΔGFR after the breakpoint was such that ESRF was delayed from a median of 35.1 mo (interquartile range, 17.8 to 70.3) to a median of 84.4 mo (interquartile range, 60.1 to 223.4).
Predicted time to ESRF (GFR = 10 ml/min per 1.73 m2) in the 43 patients on continued ramipril (n = 26) and switched to ramipril (n = 17) who had at least three GFR measurements (including baseline) during the Core study and at least three GFR measurements during the Follow-Up study. Time to ESRF is predicted on the basis of the last available GFR and mean and 95% confidence intervals of ΔGFR measured during the overall (Core and Follow-Up) study period and during the Core and Follow-Up study separately.
Discussion
The present study demonstrates the ability of long-term ACE inhibition to effectively prevent progression to ESRF in some patients with chronic proteinuric nephropathies.
We have reported elsewhere that patients with chronic proteinuric nephropathies originally on ramipril and still on active treatment at 36 mo of follow-up failed to progress to ESRF during the study period compared to 23% of those originally randomized to conventional treatment and switched to ramipril in the Follow-Up study (3).
In the former group, in parallel with the decreasing frequency of ESRF, the slope describing the time-dependent changes in GFR progressively flattened. GFR actually stabilized after 36 mo of continued ramipril therapy, then increased thereafter to the last available follow-up. A similar trend was found in the subgroup of patients with at least three GFR measurements during the Core and at least three GFR measurements during the Follow-Up study (3). In these patients with a relatively homogeneous follow-up, a two-phase model described changes in GFR with time better than a linear slope. This suggested that the late improvement did not simply reflect selection bias or random fluctuations, but rather depended on a real modification of renal function during the course of the disease.
This finding was consistent with evidence that within each follow-up cohort, the slope describing a decline in ΔGFR in a time-dependent manner was eliminated in patients on continued ramipril therapy, but not in those switched to ramipril during follow-up. Actually, in patients on continued ramipril for at least 60 mo, ΔGFR progressively improved to a level of about 1 ml/min per 1.73 m2 of GFR decline per year, a rate that was 10-fold less than in patients with comparable renal dysfunction given conventional treatment (2). This rate of decline in GFR in fact approximates the physiologic, age-related loss of GFR with time observed in subjects with no evidence of renal disease. Because of such a remarkable slowing in the decline in GFR, the predicted time to ESRF was delayed approximately 10-fold in this group compared to control subjects, when a linear model was applied to properly describe ΔGFR.
Of interest, analysis of the slopes in individual patients revealed that after the breakpoint, 10 patients on continued ramipril therapy had a positive ΔGFR, and were therefore predicted to never progress to ESRF, and an additional 10 patients, among those with a negative ΔGFR, had an improvement in their slopes to such an extent that their ESRF was quite possibly delayed by about 5 yr. The different course of ΔGFR was definitely not dependent on selection bias since the underlying renal diseases and baseline patient characteristics were comparable between the two groups with positive or negative ΔGFR. Of extreme interest, moreover, the level of proteinuria after the breakpoint was significantly lower than before the breakpoint in patients with positive ΔGFR and when compared to those still without positive ΔGFR, despite comparable follow-up BP control and dietary compliance.
The present analysis provides evidence that the tendency of GFR to decline with time in chronic nephropathies can be effectively halted in some patients. The clinical relevance of these findings rests on data that patients recruited in the present study were selected for having a rather severe disease, which resulted in a study population expected to rapidly progress to ESRF if untreated (2, 3, 8, 9). The effect of long-term ACE inhibition we have observed cannot be attributed to a less severe disease in patients on continued ramipril therapy, since the underlying renal disease process, severity of hypertension, proteinuria, and all other potential predictors of outcome were comparable in the two treatment groups at study entry, nor can the above effect be explained by early loss of more severe cases among patients on continued ramipril since, during follow-up, ESRF events were remarkably less on ramipril compared with conventional therapy. If patients remaining free of dialysis were the ones selected for having a lower tendency to progress, renal function stabilization should have been more frequent in the conventional group due to the higher incidence of early progression to ESRF. In fact, the opposite was true. Similarly, better final GFR on ramipril by no means reflected early loss of fast progressors, since the decline in GFR was instead remarkably faster on conventional therapy.
Different degrees of BP control could not account for the differences in progression of renal disease in the two treatment groups. Actually and remarkably enough, during the Follow-Up study the BP was lower on conventional therapy than on continued ramipril treatment (3). Despite lower BP, patients on conventional treatment continued to have faster disease progression. This further corroborates the evidence of a time-dependent effect of continued ACE inhibition, which exceeds even the potential loss of efficacy related to a less effective BP reduction. On the other hand, findings that patients with positive ΔGFR had their proteinuria reduced much more than patients still without positive ΔGFR suggested that improved GFR in the former group might reflect a substantial healing of tubular injury due to less protein overload (10).
Other studies in diabetes suggests that long-term ACE inhibition therapy can achieve disease remission in humans. Lewis and coworkers (11, 12) found that eight type 1 diabetic patients with overt nephropathy and heavy, nephrotic-range proteinuria had their renal function stabilized and proteinuria reduced to subclinical ranges by continued long-term ACE inhibition therapy and intensified BP control. Preliminary studies in experimental animals also found that early ACE inhibition therapy may revert some of the glomerular and tubulointerstitial changes of remnant kidney nephropathy and in parallel sustain structural rearrangements aimed to increase the glomerular filtering surface by glomerular capillary neoformation (13).
Thus, both experimental and clinical data strongly suggest that remission is now an achievable goal in some patients with chronic renal disease. However, the current lag time between treatment start and remission is such that a substantial proportion of patients still progress to ESRF before their renal function begins to stabilize. Thus, future studies should specifically address the use of drug combination strategies (14) capable of accelerating the time to remission to maximize renoprotection and effectively avoid progression for the majority of patients with proteinuric nephropathies.
Appendix
Contributors (number in parentheses is the number of patients available at each center for complete GFR analyses): R. Pisoni, L. Mosconi, T. Bertani, Ospedali Riuniti, Bergamo (n = 17); E. Oliva, C. Zoccali, Centro di Fisiologia Clinica del CNR, Reggio Calabria (n = 7); G. Toti, S. Sisca, Q. Maggiore, USL Zona 10H, Bagno a Ripoli (n = 6); N. Bossini, B. F. Viola, F. Scolari, R. Maiorca, Spedali Civili, Brescia (n = 5); L. Moscarelli, R. Piperno, A. Rosati, M. Salvadori, Ospedale Regionale “Careggi-Monna Tessa,” Firenze (n = 4); A. Mazzi, G. Garini, A. Borghetti, Istituto di Clinica Medica, Parma (n = 2); E. Pignone, R. Boero, A. Quarello, Ospedale Zonale Giovanni Bosco, Torino (n = 1); D. Dissegna, A. Brendolan, G. La Greca, Ospedale S. Bortolo, Vicenza (n = 1).
Monitoring, Laboratory Measurements, and Analyses: G. Gherardi, N. Grigis, L. Tammuzzo, F. Arnoldi, I. Ciocca, A. Roggeri, S. Ferrari, L. Del Priore, D. Cattaneo, and F. Gaspari (Istituto di Ricerche Farmacologiche Mario Negri).
Acknowledgments
Acknowledgment
We are grateful to the “Comitato 30 Ore per la Vita” for supporting this study.
Footnotes
↵ a See Appendix for participating investigators and affiliated organizations.
Dr. Richard Glassock served as a Guest Editor and participated in the supervision of the review and final disposition of this manuscript.
American Society of Nephrology
- © 1999 American Society of Nephrology
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