Progression to irreversible renal parenchymal damage and end-stage renal disease is the final common pathway of chronic proteinuric nephropathies and is relatively independent of the type of initial insult [1]. In animals, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that are intended to sustain renal function but may be detrimental in the long term [2,3]. High glomerular capillary pressure impairs glomerular permeability to proteins, which are then filtered in excessive quantities and reach the lumen of the proximal tubule [4].

In the past the amount of proteins found in the urine, taken as an indicator of the underlying abnormality in glomerular permeability, was considered by most nephrologists simply as a marker of the severity of renal lesions. Today the results of many studies indicate that proteins filtered through the glomerular capillary may have intrinsic renal toxicity, which together with other independent risk factors such as hypertension, can play a contributory role in the progression of renal damage [1,5]. Indeed, the secondary process of reabsorption of filtered proteins can contribute substantially to renal interstitial injury by activating intracellular events, including up-regulation of vasoactive and inflammatory genes. The corresponding molecules formed in excessive amounts by the renal tubules cause an interstitial inflammatory reaction that normally precedes renal scarring and correlates with declining renal function [1] (Figure 1).



Figure 1. Schematic representation of the mechanisms by which alterations in glomerular perm-selective properties to proteins may lead to tubulointerstitial injury and renal scarring.

Baseline urinary protein excretion rate is a predictor of renal disease progression

Results of clinical studies and clinicopathological correlations in patients with various forms of progressive proteinuric nephropathies indicate that the observation made in experimental models are relevant to understand human disease [1]. In a recent longitudinal study in 274 patients with non-diabetic chronic nephropathies and clinical proteinuri a [6] we found that, independently of the nature of the underlying disease, baseline urinary protein excretion rate is the best single predictor of renal disease progression. In particular, the higher the urinary protein excretion values the faster the subsequent decline in GFR and, even more important, the quicker the progression to ESRD (Figure 2).



Figure 2. Percentage risk of progression of nephropathy (combined end point of doubling of baseline serum creatinine or end-stage renal disease (ESRD) according to baseline urinary protein excretion in proteinuric nondiabetic patients of the REIN core study.


Thus patients with baseline urinary protein excretion <2.5 g/24 hours had a low rate of GFR decline and kidney failure over the subsequent three years of follow-up. On the other hand, patients with nephrotic range proteinuria (>4.3 g/24 hours) lost more than 10 ml/min/1.73 sqm of GFR per years with >50% kidney failure at three years. Along the same line are the results from the Modification of Diet in Renal Disease (MDRD) trial in 840 patients with nondiabetic renal disease showing that a rapid decline in GFR correlated directly with baseline proteinuria and was independent of diet or blood pressure control [7].

That baseline proteinuria predicts ESRD also derives indirectly from the analysis of the results of the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) trial [8], the largest study ever performed on ACE inhibition therapy in renal disease progression in humans. This study recruited patients with a variety of renal diseases, mainly non-diabetic, the majority of whom, however, had no measurable proteinuria. Predictably, only few patients reached the end point of doubling of baseline serum creatinine or ESRD, reinforcing the concept of a relationship between baseline urinary protein excretion values and subsequent progression to renal failure. Among a series of base-line tests, measurement of urinary protein excretion was a strong predictor of renal outcome also in patients with type I diabetes mellitus and nephropathy [9].

Moreover, in nephroangiosclerosis [10] and diabetic nephropathy [11] the onset of de novo proteinuria after a number of years of stable renal function indicated subsequent renal function decline. Evidence is also available that in patients with chronic nephropathies, the ratio of protein to creatinine concentration in a single morning urine specimen correlated with 24-hour urinary protein excretion and predicted the rate of decline in the glomerular filtration rate and the progression to end-stage renal disease better than measurement of 24-hour urinary protein excretion [12].

Pharmacologic manipulations that reduce urinary protein excretion in humans also limit progressive decline in renal function. Antihypertensive drugs have been used in humans to slow progression of renal disease in diabetic as well as non-diabetic glomerulopathies. ACE inhibitors, for the same level of blood pressure control, are more renoprotective than other antihypertensives also used in human nephropathies, and this appears to be linked to their property of lowering urinary proteins to a greater extent than conventional drugs [13].

Lewis and coworkers [14] found that patients with insulin-dependent diabetes mellitus given captopril had a lower incidence of doubling of serum creatinine than those on conventional therapy over 4 years of follow-up. Systemic blood pressure reduction was comparable in the two groups, while urinary protein actually decreased with captopril, but were higher than baselinein the conventional treatment group [15]. Also the AIPRI study [8], found a lower risk of doubling baseline serum creatinine in patients on ACE inhibitor with benazepril than on conventional therapy, but a difference in systolic/diastolic blood pressure between the two treatments left open the question of whether the renoprotective effect of the active drug was related to its antiproteinuric property or to better pressure control.

Analysis of the Ramipril Efficacy in Nephropathy (REIN) study [16], on the other hand, supports the concept that the renal protection conferred by ACE inhibitors exceeds the agents' antihypertensive effect. The REIN study was a randomized, double-blind, placebo-controlled trial designed to test whether glomerular protein traffic and its modification by an ACE inhibitor (ramipril) influenced renal disease progression in 352 patients with chronic non-diabetic nephropathies. A pre-stratification strategy recognized two levels of proteinuria (>1 but <3g/24h) and >3 gr/24h) in patients randomly assigned the ramipril or conventional antihypertensive therapy. Treatment were targeted to the same level of blood pressure control (DBP <90 mm Hg). The REIN core study found that in patients with proteinuria of 3 gr or more per 24h, who were fast progressors, ramipril safely decreased the rate of GFR decline and reduced by half the combined risk of doubling serum creatinine or ESRD. These effects were accompanied by a substantial lowering of the urinary protein excretion rate, which exceeded that expected from the degree of blood pressure reduction, indicating that the renoprotection is linked to reduction of protein traffic.

At the end of the REIN core study, patients with proteinuria of 3 gr or more per 24h, who either continued on ramipril or were shifted to ramipril, entered the REIN follow-up study. The results of the REIN follow-up study [17] indicated that ramipril slowed the rate of GFR decline and limited progression to ESRD even better than in the REIN core study, both in patients originally randomized to ramipril or conventional therapy (Figure 3).






Figure 3. Kidney survival in patients continued on or switched to ramipril during the whole (core and follow-up) study period of the REIN trial.


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 months, indicating that if the treatment period is long enough the ACE inhibitor can reverse the tendency of GFR to decline.

Other than predicting faster progression of the nephropathy, baseline urinary proteins can be used as a marker to identify patients who may benefit most from putative renoprotective treatments. In the MDRD trial, patients with higher baseline proteinuria were those who had their rate of GFR decline more remarkably decreased by tight blood pressure control [7]. Similarly, in the Lewis trial [14], diabetics with more advanced nephropathy, who conceivably had more severe proteinuria, were those whose progression to ESRD was more effectively delayed by ACE inhibition. In line with this are data of the AIPRI study showing that in nondiabetic renal disease virtually all of the renoprotective effects of ACE inhibition were confined to patients with more than 3 gr urinary protein excretion rate per day at baseline [8].

In the REIN study, among patients with urinary protein excretion rate >3gr/24h, the higher the level of baseline proteinuria, the greater the beneficial effect of ramipril both in slowing the GFR decline and in reducing the risk of ESRD [16]. More recently we also found that in nondiabetic nephropathies ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria [18]. Indeed, in patients of REIN stratum 1 (baseline proteinuria of less than 3 g/d) ramipril halved the risk of progression to ESRF and to persistent nephrotic range proteinuria, a strong predictor of rapidly declining GFR.

Recent evidence also suggests that long-term ACE inhibition therapy can achieve renal disease remission in humans. Thus more recent results from the whole REIN study (core and follow-up) documented that in chronic nephropathies, the tendency of GFR decline with time can be not only halted but also reverted, even in patients with remarkably severe disease [19]. Analyses of the individual slopes found that at the end of the follow-up, 10 of the 26 patients on continued ramipril therapy had a positive D GFR, and another 10 patients had an improvement of D GFR while on ramipril therapy. D GFR improved in parallel with a significant reduction on proteinuria. This is in agreement with data of Lewis and coworkers [20] showing that 8 type I 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 blood pressure control.

However, the current lag time between treatment start and remission is such that a substantial proportion of patients still progress to ESRD before their renal function begins to stabilize. The goal for the future should be to investigate strategies for limiting the number of patients progressing to ESRD during the initial period of 36 months. To achieve this goal, a possible strategy rely on a low sodium diet in addition to the pharmacological blockade of the renin-angiotensin system with ACE inhibitors.

Evidence is indeed available that in patients with chronic nephropathies lisinopril treatment associated with low salt diet provided a higher antiproteinuric effect than that achieved with the same ACE inhibitor but on a high salt diet regimen. An additional approach may be to specifically target treatment with ACE inhibitors to minimize the urinary protein excretion rate. We evaluated the effect of different dosage of ramipril from a minimum of 5 mg/d to a maximum of 20 mg/d (4 times the recommended maximum dosage) on the level of proteinuria. Although there was no additional effect on blood pressure with higher dosages, there was a further reduction in urinary protein excretion rates suggesting that the use of blood pressure alone to titrate dosage may result in failure to achieve the maximum renoprotective effect.

Conclusion

We have now compelling clinical evidence of the renoprotective effects of ACE inhibitors in patients with diabetic and nondiabetic chronic proteinuric renal disease. The REIN core study showed that, at comparable levels of blood pressure control, ACE inhibitors are more effective than conventional antihypertensive therapy in reducing proteinuria, slowing GFR decline, and limiting progression to ESRD.

Finally, in the follow-up phase of the REIN study we observed that prolonged (>36 months) ACE inhibition therapy may arrest the decline in GFR and eliminate the need for dialysis in such patients (disease remission). In a small number of patients with the longest follow-up there was even a small increase in GFR over time (possibly signifying regression of disease).

The future goal should be to reduce the time required to induce this remission of disease, thereby maximizing the preservation of renal function.

References