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40th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Francisco, California / November 2-5, 2007

Nephrologists have to deal with patients who have persistent proteinuria and who are already being treated with optimized doses of an ACE inhibitor, angiotensin receptor blocker (ARB) or both. Further reduction in residual proteinuria is required to slow down the progression of kidney disease, and specialists are seeking an alternative therapy to help better protect kidneys. Findings from SMART (Supra Maximal Atacand Renal Trial) were presented here for the first time by Dr. Ellen Burgess, Professor of Medicine, Division of Nephrology, University of Calgary, Alberta. The primary objective of SMART was to determine the effects of high-dose candesartan on the overall reduction in proteinuria from baseline. The secondary objective was its effect on renal function and blood pressure (BP).

SMART enrolled 346 hypertensive patients with a minimum six-month history of proteinuria in excess of 1 g/24 h. Upon enrolment, patients were treated with candesartan 16 mg for a period of eight weeks. Of the 346 patients, 269 with persistent proteinuria at eight weeks were eligible for a double-blind randomization to 16 mg or a carefully uptitrated dose of either 64 mg/day or 128 mg/day for 30 weeks. Patients in the two latter groups were compared to the 16-mg active control population.

At randomization, the median urinary protein excretion rate was 2.66 g/24 h and median estimated glomerular filtration rate (eGFR) was 49.9 mL/min/1.73 m2. Mean baseline BP was 132.5/77.5 mm Hg while median serum creatinine was 130 µmol/L and median serum potassium was 4.5 mmol/L. As Dr. Burgess emphasized, patients with a serum potassium in excess of 5.5 mmol/L were excluded from the study. Approximately one-third of patients had primary glomerular disease, some 12% had hypertensive nephrosclerosis and just over half had diabetic nephropathy.

At final assessment 30 weeks later, there was a mean 33% reduction in urinary protein excretion in the intent-to-treat population given 128 mg (including everyone who had at least one dose of the active treatment) compared with the 16-mg group (P<0.0001).

In the per-protocol analysis (all doses taken for 30 weeks), there was a 44.3% mean reduction in proteinuria, again relative to the 16-mg group (P<0.0001). A non-significant 16.9% greater reduction in urinary protein excretion was also seen in the 64-mg group vs. the 16-mg group (Table 1).

Table 1. SMART: Mean Reduction in Urinary Excretion

“Systolic BP was not different between the three groups at randomization or at study completion,” Dr. Burgess reported, “and similarly, for diastolic BP, there were no significant differences across the three groups at randomization or at study end point.”

As anticipated, serum creatinine rose modestly during the study but increases were not significantly different across the three groups. Most importantly, however, serum potassium “remained comfortably within normal limits” throughout the 30-week trial and was not significantly different across the three groups, either at randomization or at study end point. The incidence of other adverses events was not significantly different across the three dosage groups either.

Analysis of Findings from SMART

According to Dr. Paul René de Cotret, Associate Professor of Medicine, Université Laval, Quebec City, Quebec, and member of the SMART steering committee, nephrologists have long assumed that antihypertensive doses of either ARBs or ACE inhibitors would suffice to protect the kidney and decrease proteinuria.

“There was no logic behind this, but this is what we’ve been assuming all along,” he indicated. As experts analyze the findings more carefully, it is obvious that blockade of the renin-angiotensin-aldosterone system (RAAS) with either therapeutic class is far from complete, given that optimal doses of both therapeutic classes, even when used together, do not prevent kidney disease from deteriorating into end-stage renal failure (ESRF). As it turns out, blocking the RAAS within tissues probably requires much higher doses of an ARB or an ACE inhibitor than those approved for BP lowering.

This is especially true in the kidney, Dr. René de Cotret added, where it is harder for any agent to penetrate and where there is vastly more angiotensin II to block than there is in the circulation. At least based on SMART findings, the kidneys may well be a “prototypic tissue” and serve as a harbinger of what else may be possible to achieve in other end-organ tissues, including the blood vessels and the myocardium, using the same ultra-high-dose strategy. “It is at least plausible that what we saw in the kidney with ultra-high-dose candesartan may also be the case in the myocardium, and at least it questions the dogma that we should be using antihypertensive doses for end-organ protection,” he told delegates.

In the meantime, physicians need to be cautious about extrapolating findings from SMART, as they have not necessarily been replicated in other ultra-high-dose ARB studies.

In the Rossing et al. study (Kidney Int 2005;68:1190-8), the renoprotective effects of ultra-high-dose irbesartan were evaluated, as reflected by short-term changes in albuminuria in type 2 diabetes patients with microalbuminuria.

At 300 mg q.d., 600 mg q.d. and 900 mg q.d., each dose of irbesartan significantly reduced the urinary albumin excretion rate from baseline but the 900-mg ultra-high-dose only lowered urinary albumin excretion by an additional 15% compared with the 300-mg dose, as Dr. René de Cotret pointed out. Similarly, reductions in urinary protein excretion with ultra-high-dose valsartan vs. antihypertensive doses of the same agent in the DROP study (Diovan Reduction of Proteinuria) were not as pronounced as reductions in proteinuria seen with ultra-high-dose candesartan in SMART.

Comparable Urinary Excretion

In the DROP study, 391 patients with type 2 diabetes and a urinary albumin excretion rate of 20 to 700 µg/min received 160 mg valsartan for the first four weeks, then were randomized to remain on standard-dose valsartan or to receive either 320 mg or 640 mg for an additional 26 weeks. Comparable reductions in urinary albumin excretion from baseline were seen in all groups at week 4, prior to randomization. By the end of the trial at week 30, there was a 49% reduction in urinary albumin excretion in the 640-mg dose group vs. a 51% reduction in the 320-mg group and a 25% reduction in the 160-mg group.

Urinary albumin excretion rates were normalized in 24% of patients in the 640-mg group vs. only 12% in the 160-mg group. Dr. René de Cotret stressed that SMART data should not extrapolated to other ARBs. He also emphasized that physicians need to be cautious about proceeding with ultra-high-dose candesartan in general and avoid using it altogether in patients with a baseline serum potassium in excess of 5 mmol/L.

“We also need to increase the dose of candesartan in a step-wise way, as we did in SMART, every two weeks, and check serum creatinine and potassium as we are inching upwards,” he added. Nevertheless, with the reductions in proteinuria observed in SMART, “we would predict that this [ultra-high-dose] will attenuate renal damage,” he indicated. SMART steering committee member Dr. Norman Muirhead, Professor of Medicine, University of Western Ontario, London, agreed with Dr. René de Cotret that it is “pretty obvious” that renal protection is far from complete, based on studies in which the ACE inhibitors or the ARBs have been used to modify the RAAS, as patients still progress and develop ESRF.

“At least part of the reason for this is because they have residual proteinuria,” he explained, “and finding strategies to lower proteinuria further is important to us all.” Even though prevention of fibrosis is the “Holy Grail” of end-organ protection in kidney patients—and even though no clinical studies have shown treatment can prevent fibrosis from occurring—“we would anticipate that improvement in proteinuria would translate into benefit in terms of fibrosis [prevention],” Dr. Muirhead stated.

He concurred with Dr. Burgess in affirming that the changes in urinary protein seen with an ultra-high-dose in SMART were achieved “largely independent of any changes in BP,” as changes in BP seen during the 30-week trial were small and not significant enough to explain the large reduction in proteinuria in the ultra-high-dose group. Dr. Muirhead also deemed it was important to mention that there was already a significant reduction in urinary protein during the run-in phase of the SMART study, where on 16 mg, many patients fell below their inclusion criteria of ³1 g/day.

“We deliberately selected study patients who had persistent proteinuria despite being on a decent dose of candesartan and that is what is unique about this study—these patients were well-treated, on an ACE inhibitor, an ARB or both, and at the end of eight weeks, they still had at least one gram of protein a day. This makes the ability of [the ultra-high-dose] to reduce proteinuria that much more remarkable because they were so well treated,” explained Dr. Muirhead. SMART clearly sets the stage for further and longer-term study with hard clinical end points, as it still remains to be demonstrated that further reductions in proteinuria made possible with ultra-high-dose candesartan do indeed benefit the kidney and significantly slows down disease progression.

For the moment, results from SMART “are something we’ve been waiting for, as we’ve been looking for evidence to see if we can do something with residual proteinuria, and this is the first really solid information that we’ve had that will help us better address this problem,” indicated Dr. Muirhead.

Other Study Findings

SMART investigator Dr. Sheldon Tobe, Associate Professor of Medicine, University of Toronto, also pointed out that most of the studies up until SMART have involved patients with lower amounts of albumin in the urine, including the Rossing study with irbesartan and the DROP study with valsartan.

In both of these trials, investigators reported what Dr. Tobe felt were quite “minor differences” in reductions in urinary albumin excretion between ultra-high-dose ARB therapy and standard antihypertensive doses.

Earlier trials in kidney disease in which two different ARBs were also used, including IDNT (Irbesartan Diabetic Nephropathy Trial) and RENAAL (Reduction of End Points in NIDDM with the Angiotensin II Antagonist Losartan Study), also showed how patients with significant proteinuria ended up in terms of on-treatment proteinuria was determined by the degree of progression with kidney disease. These results augur well for patients similar to those treated in SMART with ultra-high-dose ARB.

More recently, the Renoprotection of Optimal Antiproteinuric Doses (ROAD) study by Hou et al. (J Am Soc Nephrol 2007;18:1889-98) confirmed that optimal antiproteinuria doses of both an ACE inhibitor and an ARB significantly reduced the primary composite end point consisting of a doubling of the serum creatinine, end-stage renal disease or death. In ROAD, a total of 360 patients with chronic kidney disease and proteinuria but without diabetes were assigned to conventional doses of either benazepril (ACE inhibitor) or losartan (ARB) or to uptitration of either agent to achieve optimal antiproteinuric effects.

At a median follow-up of 3.7 years, 17.9% of patients assigned to the optimal antiproteinuric dose of benazepril had reached the primary composite end point, compared with 31.3% of those in the conventional dosage group (P=0.025). Likewise, 15.5% of patients who received optimal antiproteinuric dosages of losartan also reached the primary end point, compared with 29.5% in the conventional dosage group (P=0.022). Use of optimal antiproteinuric doses also reduced decline in renal function by 60% in the benazepril arm and by 55% in the losartan arm, as assessed by creatinine clearance. Both optimal doses were associated with a slowing in the decline of eGRF compared with conventional doses as well.

Reassuringly, there were no significant differences in the overall incidence of major adverse events between any of the treatment groups.

As investigators concluded, ROAD was the first study to demonstrate that significant uptitration of both benazepril and losartan provided further benefit not only on reductions in proteinuria but also on renal hard end points compared with conventional doses.

Based on these reductions, “we can say that from the ROAD study, reductions in proteinuria were associated with a very great reduction in end points,” Dr. Tobe observed. “So with SMART, we have a new paradigm of therapy, which is that we now know we can go to these very high doses of therapy and make a difference for our patients.”

Summary

Landmark trials are not commonplace in medicine and when they occur, they exert a significant influence on clinical decision-making. SMART needs to be taken further, with longer-term follow-up and hard clinical end points that demonstrate how further reductions in persistent proteinuria protect the kidney better than conventional doses of the same ARB. Until that study is carried out, physicians have excellent surrogate outcome data indicating that they can, in fact, reduce proteinuria with ultra-high-dose candesartan to a significantly greater extent than they can with optimized antihypertensive doses, and that such reductions, based on all available evidence to date, will very likely provide greater end-organ protection than is possible with lower-dose therapy. Whether the same strategy will provide greater end-organ protection in other organs also remains to be shown, but the paradigm has clearly shifted to one of optimized end-organ protection from optimized BP control for the potential benefit of all patients with kidney disease.