Samuel A. Levine Professor of Medicine, Harvard Medical School, Director Emeritus, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts

Correspondence: Barry M. Brenner, M.D., Renal Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: Bbrenner@partners.org

These comments were delivered upon receiving the inaugural AMGEN International Prize at the World Congress of Nephrology in Berlin, Germany, June 9, 2003.

I am extremely pleased to be named the first recipient of the AMGEN International Prize and express my appreciation to the International Society of Nephrology and to AMGEN, Inc. for this high honor. Please be assured that the prize recognizes the efforts of many devoted colleagues to whom I am indebted and delighted to cite in the references to follow. To place our studies on renoprotection in its proper context, let me remind you that when we began our studies in the 1970s, much of the effort in nephrology was concerned with improving the effectiveness of renal replacement therapies for patients with otherwise fatal end-stage renal disease (ESRD). At that time, we fortuitously gained access to a strain of rats with glomeruli situated on the renal cortical surface, accessible to direct study by new microtechniques developed in our laboratory¹. We were therefore in the unique position to address the following questions: What are the precise hemodynamic forces and biophysical properties that govern glomerular capillary function in health? How are these elements modified by renal injury? Do these modifications contribute to the relentless progression of renal disease? If so, can they be reversed so as to prevent or retard the development of ESRD?

When glomerular filtration rate (GFR) in humans falls below about half of normal, further loss of function often ensues, even when the original disease becomes inactive. In response to reduced renal mass, surviving nephrons undergo adaptations in structure and function that raise single-nephron GFR to meet excretory demands. In our initial study², we found that the glomerular hemodynamic adaptations responsible for increased single-nephron GFR actually proved to initiate and perpetuate glomerular injury following partial nephrectomy, suggesting that similar events may occur when nephrons are lost through disease. In addition to the detrimental effects of acquired nephron loss^3,4, we have also argued that inborn deficits in total nephron number in association with low birth weight contribute to hypertension and progressive glomerular injury in adult life^5,6, an hypothesis now confirmed in several recent reports^7,8,9.

The most unfavorable glomerular hemodynamic adaptation to congenital deficits or focal nephron obliteration by disease is elevated glomerular capillary pressure, which ultimately leads to glomerular scarring and nephron dropout. Among a variety of measures that slow progression of experimental renal disease, alleviation of glomerular capillary hypertension has been found to be the common denominator. Meyer, Hostetter and I, working with the partial nephrectomy model³, and Zatz, Meyer, Rennke, and I¹⁰, with the streptozotocin diabetes model, showed that dietary protein restriction reduces glomerular pressure and ameliorates renal structural injury. Glomerular capillary hypertension is maintained largely by angiotensin-dependent mechanisms, via increased systemic blood pressure and efferent arteriolar vasoconstriction¹¹. In addition to their potent systemic antihypertensive actions, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are highly effective in controlling glomerular capillary hypertension and thereby in retarding disease progression. In rats with partial renal ablation, Anderson, Rennke, and I observed that ACE inhibitors reduced the glomerular capillary pressure gradient, P, and slowed renal disease progression, as reflected by less proteinuria and glomerulosclerosis, whereas, with a combination of hydralazine, reserpine, and hydrochlorothiazide, despite equivalent systemic blood pressure lowering, glomerular hypertension persisted and disease progression continued unabated¹². Subsequent studies by my group and others consistently demonstrated renal protection with inhibitors of the renin-angiotensin system (RAS) in a variety of experimental models of renal injury¹³.

Thus, angiotensin II emerged as a central mediator of the glomerular hemodynamic changes associated with progressive renal injury. It soon became apparent that several nonhemodynamic effects of angiotensin II are also important in mediating renal disease progression. These include oxidant and aldosterone-induced injury, increased filtration of plasma proteins, and coordinated nuclear factor-kappa B (NF-B)–induced up-regulation of cytokines, chemokines, transforming growth factor- (TGF-), connective tissue growth factor (CTGF), and chemotactic and cell adhesion molecule expression, all of which in turn give rise to mesangial cell proliferation, increased synthesis of extracellular matrix proteins, stimulation of plasminogen activation inhibitor-1 production by endothelial and vascular smooth muscle cells, and macrophage activation and infiltration^14,15,16,17. Together, these factors promote focal and global glomerulosclerosis and tubulointerstitial fibrosis, culminating in further nephron loss and a vicious cycle or final common pathway of progressive renal damage Figure 1.

Figure 1.

Final common pathway for progression of chronic renal disease. Angiotensin II (ANG II) promotes injury in at least five separate steps in the cycle. Abbreviations are: PG_C, glomerular capillary pressure; SNGFR, single-nephron glomerular filtration rate (GFR); GS, glomerulosclerosis; TIF, tubulointerstitial fibrosis; FSGS, focal segmental glomerulosclerosis; NF-B, nuclear factor-kappaB; PAI-1, plasminogen activation inhibitor-1; TGF-, transforming growth factor-; CTGF, connective tissue growth factor; CAMs, cell adhesion molecules.

Full figure and legend (46K)

I will now review the key clinical trials that have emanated from these studies in experimental animals. Our initial studies in the partial nephrectomy model showing that dietary protein restriction abrogates the adaptive rise in glomerular pressure and slows the tendency to renal disease progression helped motivate the National Institutes of Health Modification of Diet in Renal Disease (NIH-MDRD) trial. Although the overall study results reported by Klahr et al¹⁸ were ambiguous, subsequent subgroup analyses by Levey et al^19,20 provided clear evidence of benefit from dietary protein restriction. Furthermore, a meta-analysis of ten randomized, controlled studies of the effects of protein restriction on the progression of diabetic and nondiabetic renal disease by Pedrini et al²¹ determined that the overall relative risk of renal failure or death was indeed reduced with protein restriction, as compared with nonrestricted protein intake.

With regard to pharmacologic approaches, our studies in rodents, showing that control of glomerular capillary hypertension with ACE inhibitors retards the development of glomerular lesions of experimental diabetic nephropathy²², soon motivated a number of clinical trials. Results of several small clinical studies performed to assess the effects of antihypertensive treatment in general, and ACE inhibitors in particular, on the rate of progression of diabetic nephropathy appeared to show a favorable response to therapy. However, none was sufficiently robust statistically to establish benefit conclusively. These shortcomings were resolved by the clinical trial entitled "The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy" performed by the Collaborative Study Group led by Dr. Edmund Lewis²³. A total of 407 patients with type 1 diabetes and proteinuria (>500 mg/day) were randomized to receive either the ACE inhibitor, captopril, or placebo. If needed, blood pressure was managed independently of the experimental treatment, using agents other than ACE inhibitors or calcium channel blockers. Captopril treatment was associated with a 50% reduction in the combined risk of ESRD or death. These results yielded solid clinical proof of the concept that ACE inhibitors provide effective retardation of nephropathy, in this case due to type 1 diabetes, and led to the first federally approved treatment in the United States for slowing the progression of kidney disease.

It must be noted, however, that most diabetic patients who develop ESRD suffer from type 2 diabetes, reflecting its approximately 20-fold greater prevalence over type 1 diabetes. Type 2 diabetic patients develop glomerular hyperfiltration, proteinuria, and progressive declines in GFR, much as in type 1 diabetes and with essentially the same time course. Most renal protection studies with ACE inhibitors demonstrated significant reduction in proteinuria but failed to address the hard end point of ESRD, as these trials generally enrolled patients at relatively early stages of diabetic nephropathy and their durations were usually 2 years or less.

Since 1995, ARBs have also been available to inhibit the RAS, by blocking angiotensin II subtype 1 (AT₁) receptors. Thus, whereas ACE inhibitors depress ACE-dependent angiotensin II production, ARBs block the effects of angiotensin II from any source at the receptor level. Despite these differences in mechanisms of action, experimental studies reveal that ACE inhibitors and ARBs produce similar improvements in glomerular hemodynamics and afford equivalent renoprotection in a variety of experimental models of kidney disease¹³.

Two large, recently completed, prospective, multicenter, randomized clinical trials showed that interruption of the RAS with ARBs in type 2 diabetic patients with overt nephropathy delays the progression of renal disease. The Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) evaluated the effects of the ARB, irbesartan, on renal and cardiovascular morbidity and mortality versus the effects of conventional therapy (placebo group) or the calcium channel blocker, amlodipine, in 1715 subjects²⁴. The primary composite end point of the study was the time to a first event, namely, doubling of baseline serum creatinine, ESRD, or death from any cause. For subjects receiving irbesartan, the adjusted relative risk of reaching the primary composite end point was 20% lower than for those receiving placebo and 23% lower than for those receiving amlodipine. There was no significant difference between placebo and amlodipine for the primary composite end point. The relative risk of ESRD in the irbesartan group was 17% lower that that in the placebo group and 24% lower than that in the amlodipine group, but these differences did not achieve statistical significance. Secondary cardiovascular outcomes also failed to show significant differences among the various arms of the IDNT study. Proteinuria was reduced an average of 33% in the irbesartan arm, compared with 6% and 10% in the amlodipine and placebo arms, respectively. The more favorable renal outcomes in the irbesartan group were in excess of effects directly attributable to blood pressure control.

The Reduction of End Points in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study was also undertaken to determine whether the ARB, losartan, reduces the number of patients with type 2 diabetes who experience a doubling of serum creatinine, ESRD or death, as compared with placebo-treated subjects²⁵. The primary and secondary end points of the study were similar to those in the IDNT study, but treatment was of longer average duration in the RENAAL study (3.4 vs. 2.6 years). In RENAAL, 1513 subjects were randomized to receive either losartan or placebo once daily on a background of conventional antihypertensive therapy, excluding ACE inhibitors or other ARBs. Losartan treatment significantly reduced the risk of the primary composite end point by 16% relative to placebo. Losartan lowered the risk of doubling of serum creatinine, the risk of reaching ESRD, and the combined risk of ESRD or death by 25%, 28%, and 20%, respectively, relative to placebo. RENAAL is thus the only study to date to specifically reduce the risk of ESRD in diabetes, in this case with losartan. Proteinuria declined by 35% in the losartan arm and increased slightly in the placebo group, and losartan slowed the estimated rate of loss of GFR by 18% relative to placebo. No significant difference was observed between the losartan and placebo arms for the secondary composite end point of cardiovascular morbidity or mortality, or for most of the cardiovascular components, although the losartan arm showed a significant reduction of 32% in the risk of a first hospitalization for heart failure. Once again, these consistent benefits of losartan in the RENAAL study were above and beyond effects that could be attributed to measured reductions in blood pressure.

Several studies investigated the potential of ACE inhibitors to afford renoprotection in nondiabetic forms of clinical renal disease. In the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) trial, Maschio et al²⁶ randomly assigned 583 patients with renal disease of diverse etiologies to treatment with benazepril or placebo. After 3 years of follow-up, the study found a 53% reduction with ACE inhibitor treatment in the combined risk of doubling of the baseline serum creatinine or need for dialysis. However, a significantly lower blood pressure among patients receiving ACE inhibitor versus placebo made it difficult to separate the beneficial effects of blood pressure reduction from any unique renoprotective effects of ACE inhibition.

In the more recent Ramipril Efficacy in Nephropathy (REIN) study²⁷, 352 patients with nondiabetic renal disease, randomly assigned to receive either ACE inhibitor or placebo, achieved similar control of blood pressure. Among patients with proteinuria of at least 3g/day at baseline, a significantly lower rate of decline of GFR was seen after 2 years in patients receiving the ACE inhibitor, ramipril (-0.44 vs. -0.81 mL/min/month with non-ACE conventional therapy). In the extension phase of the study²⁸, patients who initially received placebo were switched to ACE inhibitors, and those already on ACE inhibitors continued this treatment. Consistent with the findings in the first 2-year phase of the study, those switched from conventional therapy to ramipril treatment enjoyed a significant reduction in the rate of GFR decline, while patients continuing on the ACE inhibitor enjoyed a further reduction in the rate of GFR decline to levels similar to those associated with normal aging. Indeed, from 36 to 54 months of follow-up, no patients in the latter group reached ESRD, and a small number actually experienced a rise in GFR²⁹. Another 186 REIN study patients with less that 3 g/day of proteinuria at baseline also benefited from ramipril with reduced incidence of ESRD³⁰.

In the AIPRID data study, a recent patient-based meta-analysis of 1860 nondiabetic subjects from 11 randomized ACE inhibitor versus placebo-treatment trials, Jafar et al³¹ also concluded that ACE inhibitors are more effective that other antihypertensive treatment regimens in slowing renal disease progression and reducing proteinuria. Significantly lower values were seen with ACE inhibitors for several outcome measures, including level of proteinuria and incidence of ESRD. A similar conclusion emerged from the AASK trial in hypertensive African Americans³², in which ramipril proved more renoprotective that the comparator drugs, amlodipine or metoprolol.

In addition to the renoprotective effects of ACE inhibitor treatment, the recent Heart Outcomes Prevention Evaluation (HOPE)³³ and Losartan Intervention for End Point Reduction in Hypertension Study (LIFE)³⁴ trials reported substantial reductions in all-cause mortality, cardiac, and stroke events in patients receiving ramipril or losartan, respectively. Because cardiovascular disease is the single largest cause of morbidity and mortality among patients with even mild chronic kidney disease, the HOPE and LIFE trial data provide a further compelling argument for the use of drugs that interrupt the RAS in patients with kidney disease.

Large randomized clinical studies of the renoprotective effects of ARBs in nondiabetic kidney disease are still awaited, but preliminary data suggest that ARBs are likely to be as effective as ACE inhibitors. In small studies, ARBs and ACE inhibitors produced similar antihypertensive and antiproteinuric effects in patients with essential hypertension or chronic kidney disease. One important advantage of ARBs over ACE inhibitors is their more favorable side-effect profile, as ARBs are seldom associated with the cough that may occur in up to 40% of patients receiving ACE inhibitors. Finally, the differing effects of ACE inhibitors and ARBs on the RAS imply that in combination they may have additive or even synergistic effects, and early evidence appears to support this contention^{35,36,37,38,39}.

In the largest combination trial to date, the COOPERATE trial, involving 336 patients with nondiabetic renal disease treated for 3 years with maximally effective doses of the ACE inhibitor, trandolapril, or the ARB, losartan, alone or in combination, the combination clearly was more effective in reducing progression and urinary protein excretion than either drug alone³⁸.

Let's now take a moment and ask about other new and novel approaches that might enhance our efforts at renoprotection. I would like to comment upon a promising new drug class referred to as vasopeptidase inhibitors (VPIs). ACE and neutral endopeptidase (NEP) are mechanistically similar metallopeptidases. ACE cleaves two peptides from the decapeptide angiotensin I to form the vasoactive octapeptide, angiotensin II. ACE also degrades the vasodilator, bradykinin, to inactive metabolites. The chief substrates for NEP are the vasodilators, bradykinin, and atrial and brain natriuretic peptides. Thus, a single molecule capable of inhibiting these two metallopeptidases results in reduced angiotensin II–mediated vasoconstriction as well as enhanced vasodilation due to accumulation of bradykinin, atrial natriuretic peptide, and brain natriuretic peptide. Taal et al⁴⁰ recently evaluated one such dual ACE-NEP inhibitor, omapatrilat, in comparison to the ACE inhibitor, enalapril, in the rat partial nephrectomy model. Enalapril extended the time to high-grade proteinuria well beyond the time course seen in placebo-treated rats, whereas omapatrilat extended the period of renoprotection indefinitely, as we were forced by budgetary considerations to terminate the study at 1 year when renal injury was still less marked. Furthermore, the greater renoprotection with omapatrilat compared to enalapril was not because of better blood pressure control as systolic blood pressures were similarly well controlled in both treatment groups. We await with interest a suitable clinical renoprotection trial of this new drug class as our rat studies clearly predict that VPI will provide even greater renoprotection than ACE inhibition alone.

Based on the evidence reviewed, let me now propose what might be considered a reasonable comprehensive strategy for therapy of patients with chronic kidney disease Table 1. I think a strong case can be made for prescribing an ACE inhibitor, ARB, or both in any patient with kidney disease in doses sufficient to achieve two distinct goals, namely, to reduce proteinuria to less than 0.5 g/day, and to show, by at least twice yearly checks, that some reliable estimate that GFR is falling by no more than 2 mL/min/year. Beyond this effort, other adjunctive treatments should be prescribed to address the heightened risk of cardiovascular disease that exists in all patients with kidney disease. These include additional antihypertensive drugs as needed to achieve the Joint National Committee Seventh Report recommended blood pressure target of less than 130/80⁴¹. I also recommend moderate dietary protein and salt restriction, tight glycemic control in diabetics, statins, aspirin, erythropoietin, and measures to reduce calcium phosphorus product, excess body weight, tobacco use, and exposure to nephrotoxic drugs, including many herbal remedies and dietary supplements.

Table 1 - A comprehensive strategy for therapy in chronic kidney disease.

Full table

Clearly, this aggressive and comprehensive strategy will require substantial economic outlays from government or private insurers, as well as greater involvement of physicians and other health care professionals in overseeing attainment of treatment goals. But hopefully these added costs and efforts will translate into reduced morbidity and mortality from cardiovascular disease and fewer patients in need of expensive renal replacement therapy.

As we move forward with these efforts in regions with well-developed systems of medical care, let us also ask whether newer approaches are also needed in medically less advantaged societies where routine health screening, secondary and tertiary care facilities, and specialists in cardiovascular and renal medicine are lacking or in short supply. In such a setting, is it time to make available a once-a-day, low-cost cardiovascular and renoprotective pill, not unlike the all-purpose daily multivitamin so many of us now take? One such proposal might be an all-in-one clinically proven effective dose combination pill containing aspirin, lovastatin, and lisinopril, all now generic and therefore very low in cost. This combination pill, which I call ASTACE (for aspirin, statin, and ACE inhibitor), would be no larger than the daily multivitamin we now take. Clearly, government regulatory approvals would be required but I believe the time has come to consider this low-cost, universal approach to vital target organ protection. An even more ambitious proposal for a polypill containing folic acid and three antihypertensives (thiazide, ARB, and a calcium antagonist) together with low-dose aspirin and a statin has recently been advocated⁴².