Halting the Progression of Chronic Nephropathy

Halting the Progression of Chronic Nephropathy J Am Soc Nephrol 13: S190 S195, 2002 RUTH C. CAMPBELL,* PIERO RUGGENENTI,* and GIUSEPPE REMUZZI* *Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Unit of Nephrology, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo Italy; and Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Abstract. The incidence of end-stage renal disease (ESRD) is increasing worldwide. In the United States alone, there were 372,000 patients requiring renal replacement therapy in the year 2000 and is expected to rise to 650,000 by the year 2010. The trends in Europe and Japan are forecasted to follow a similar path. These increases represent a significant burden to countries worldwide; not only due to the financial costs of providing ESRD care, but also because of lost productivity and significant morbidity and mortality for the affected patients. There is clearly a pressing need for the aggressive identification and early treatment of patients with nephropathy to prevent progression to ESRD. Research in the last 25 yr has made great advances in the understanding of the progression of chronic renal disease in diabetic and nondiabetic proteinuric nephropathy. There are now effective treatment options that can slow the progression of chronic nephropathies in many individuals, and ongoing research has raised the tantalizing prospect of the reversal of renal disease progression. Pathophysiology of Progressive Nephropathies Experimental data from animal models have shown that there are a wide variety of glomerular insults that result in a common pathway of increased glomerular hypertension, systemic hypertension, glomerular permeability, and proteinuria. These diverse pathologies appear to incite a vicious cycle of injury and inflammation, resulting in a similar pattern of progressive nephropathy, in which glomerular injury leads to proteinuria, interstitial inflammation, and ultimately, scarring (1). Glomerular Hypertension Brenner and coworkers (2) established the importance of glomerular hypertension and hyperfiltration in response to nephron loss in the 1980s. After nephron loss, the remaining nephrons develop glomerular capillary hypertension and the single-nephron GFR increases (hyperfiltration). These changes are thought to be adaptive in that they help to initially maintain the overall GFR. However, they have negative long-term effects and ultimately lead to renal insufficiency and ESRD. Interventions that reduce glomerular capillary hypertension, such as blockade of the renin angiotensin system (RAS) (3,4) or a low-protein diet (2), slow the progression of chronic nephropathy in experimental forms of nephropathy. Inhibition of the RAS, either through the reduction in production of angiotensin II (angiotensin-converting enzyme inhibitors [ACE-I]) or by blocking the action of angiotensin II at the Correspondence to Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11-24125 Bergamo, Italy. Phone: 39-035 319 888; Fax: 39-035 319 331; E-mail: gremuzzi@marionegri.it 1046-6673/1300-0190 Journal of the American Society of Nephrology Copyright 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000032522.29672.0A AT-R1 receptor level (angiotensin receptor antagonist [ARA]), is particularly effective at preventing renal injury. The benefit seen with these drugs is beyond that which would be expected from their antihypertensive effects. Compared with a non ACE-I regimen that achieved equivalent systemic BP control, captopril better reduced glomerular hypertension and renal injury (4). Glomerular hyperfiltration is also important in the development of diabetic nephropathy, although it is not preceded by nephron loss. In animal models, a period of hyperfiltration presages the appearance of albuminuria and hypertension (5). Aggressive control of blood glucose to normal levels can prevent the development of glomerular hyperfiltration (6). Treatment with ACE-I in models of diabetic nephropathy is also effective; it normalizes glomerular pressures and prevents the development of microalbuminuria and prevents renal injury (7). The benefits of RAS blockade, however, for both diabetic and nondiabetic chronic nephropathy may not be solely due to changes in glomerular hypertension. Angiotensin II also has potent proinflammatory effects that are independent of its hemodynamic effects. It can cause hypertrophy and hyperplasia of mesangial cells in culture and also stimulates the production of a number of cytokines involved in inflammation and matrix deposition, such as transforming growth factor (TGF- ) and plasminogen activator inhibitor (PAI) (8). TGF-, in turn, is an important regulator of inflammation and can increase production of nuclear factor- B (NF- B), RANTES, monocyte chemoattractant protein-1 (MCP-1), and insulin-like growth factor (9). Treatment with ACE-I helps to prevent the expression of these cytokines and may be an important component of ACE-I therapy (9). Proteinuria Glomerular hypertension in both diabetic and nondiabetic chronic nephropathies leads to increased glomerular perme-

J Am Soc Nephrol 13: S190 S195, 2002 Chronic Nephropathy S191 ability and excessive protein filtration. The protein ultrafiltrates are toxic to the proximal tubules, resulting in tubular damage, interstitial inflammation, and scarring (1). The degree of proteinuria correlates with the magnitude of renal damage in experimental models, and proteinuria reduction helps to preserve renal function (1). Proteins in the urine are normally absorbed by endocytosis in the proximal tubules. During periods of heavy proteinuria, the filtered proteins accumulate in lysosomes in the proximal tubular cells, causing cell disruption and injury (10,11). Proteins may also incite a toxic response through stimulation of the expression of proinflammatory cytokines. Cultured proximal tubule cells that are exposed to albumin, transferrin, or IgG produce increased amount of endothelin -1 (ET-1), a powerful vasoconstrictor that also contributes to inflammation and fibrosis (12). Exposure to albumin or transferrin also increase the production of MCP-1, which, in proximal tubule cell cultures that maintain polarity, is preferentially excreted into the basolateral compartment, suggesting a possible mechanism for inflammatory infiltrates in vivo (13). These findings have been echoed in both immune (Heyman nephritis) and non-immune (5/6 nephrectomy) models of nephropathy, in which albumin, immunoglobulins, and complement localize to proximal tubules that later develop inflammatory infiltrates (14). ET-1 expression is also increased, and the degree of expression correlates with the rate of progression (15). Treatment with ACE-I, which decreases the filtered proteins, also decreases the production of these inflammatory cytokines and preserves renal function (16). Lastly, the proteins themselves, such as complement, may be directly toxic to the proximal tubules and incite injury. In a subtotal nephrectomy model of renal insufficiency, C3 staining was associated with the appearance of interstitial infiltrates. Treatment with ACE-I, which lowered proteinuria, also decreased C3 staining (17). Data from Clinical Trials BP Control Systemic hypertension is a strong marker of progression in humans. The Multiple Risk Factor Intervention Trial (MRFIT) documented that elevated BP was a strong and independent risk factor for the development of end-stage renal disease (ESRD) (18) in men. Reduction of BP is associated with a reduction in the development of ESRD. In the Modification of Diet in Renal Disease (MDRD) study, patients with greater than1gofprotein/24 h who were randomized to a mean arterial target of 92 mmhg had a greater reduction in proteinuria and a slower rate of loss of GFR than patients randomized to a mean arterial pressure of 107 mmhg (19). Hypertension is also an important risk factor in the progression of diabetic nephropathy. In type 1 diabetes, systemic hypertension often appears just before or with the appearance of microalbuminuria (20). Patients with type 1 and 2 diabetes have a more rapid decline in GFR at higher levels of BP (21,22). A clear reduction in the incidence of macrovascular and microvascular end points was also documented in the UKPDS trial that compared tight BP control with either captopril or atenolol (defined as 150/85) versus usual, although a large part of the reduction of microvascular complications was due to a reduction in retinal photocoagulation (23). However, Parving et al. (24) found that tight BP control was associated with remission of type 1 diabetic nephropathy, and Weidman et al. (25) found a strong relation between the degree of BP reduction and reduction in proteinuria in diabetic nephropathy. But is it possible to go too low? There has been concern about a possible J-point effect, that is, a low-bp goal that is associated with adverse outcomes (26,27). A meta-analysis showed that a systolic BP of less than 100 mmhg was associated with an increased risk of doubling of serum creatinine or doubling of ESRD (28). However, a J-point has not been found in all studies. The Hypertension Optimal Treatment (HOT) (29) study demonstrated that the lowest cardiovascular mortality and fewest major events occurred at pressures of 139/86 and 138/83. Diabetic patients benefited from even tighter control: those randomized to the treatment goal of a diastolic of less than 80 mmhg had even fewer cardiovascular outcomes. There were not a greater number of adverse events in the lower target group and there was no evidence of a J-point effect. The ABCD (30) trial compared two BP targets of 132/75 and 138/85 in diabetic patients and did not find that the lower goal was associated with more adverse outcomes. However, neither did it find a greater benefit to the lower goal, although the authors noted that a potential benefit might not have been seen because of the relatively short study duration. Parving et al. (31) did not find a threshold effect for the systolic BP on preserving GFR in type I diabetics and saw no evidence of a J-point effect. Based on these results, the MDRD recommendation for a target BP of 125/75 for patients with greater than 1 g of proteinuria appears to be safe. Achieving this goal may be difficult for some patients and will mostly likely require more than one drug. In the UKPDS study, 29% of the patients in the tight BP groups, whose average pressure was 144/83 (captopril) and 143/81(atenolol), required three or more antihypertensive drugs to achieve this target (23). The greater number of pills required may be a challenge to both physicians and patients regarding compliance. The awareness that one drug will not be sufficient for adequate BP control has also shifted the focus of research in this area. The question becomes not which one drug is the best, but which combination of drugs is the best. Inhibitors of the RAS ACE-I are highly effective in reducing proteinuria in nondiabetic nephropathy and slowing progression to ESRD. Their effect on slowing loss of GFR is tightly linked to their antiproteinuric effect. The Ramipril Efficacy in Nephropathy (REIN) trial provided definitive evidence that an ACE-I (ramipril) compared with conventional antihypertensive therapy more effectively slowed the rate of GFR at equivalent levels of BP control. The trial was divided into two levels on the basis of degree of baseline proteinuria (stratum 1, 1 to 3 g/24 h; stratum 2, 3 g/24 h). The stratum 2 arm was stopped early because of greater efficacy of ramipril on preserving GFR (mean decline in monthly GFR 0.53 ml/min versus 0.88 ml/ min for placebo). The ramipril group showed a slower rate of

S192 Journal of the American Society of Nephrology J Am Soc Nephrol 13: S190 S195, 2002 loss of GFR and a greater decrease in proteinuria (55% for ramipril versus no reduction for placebo). The reduction in proteinuria was inversely related to the reduction in GFR (32). The investigators also found that this effect was seen across degrees of renal insufficiency and that patients in the lowest tertile of GFR (10 to 30 ml/min) also benefited from treatment with ACE-I without a significant increase in the risk of hyperkalemia (33). RAS inhibition is effective in treating type 1 and type 2 diabetic nephropathy. ACE-I reduce the risk of progression of overt type 1 diabetic nephropathy to ESRD and in type 1 patients with microalbuminuria to overt nephropathy (34). The evidence that inhibition of the RAS was superior to conventional antihypertensive therapy in type 2 diabetic patients was less clear until recently. It is important to consider type 2 diabetic nephropathy separately from type 1, as there are significant differences between the two. Both type 1 and 2 diabetic nephropathies are characterized by the appearance of microalbuminuria, which leads to overt proteinuria and progressive loss of GFR (20). However, a series of renal biopsies type 2 diabetic patients with proteinuria revealed that a significant proportion of these patients had glomerular lesions other than the classic lesions associated with type 1 diabetic nephropathy (35,36). ACE-I, which improve glomerular permeability in type I diabetic patients as assessed by dextran clearances, do not do so in type 2 patients (37). Furthermore, the superior effect of blockade of the RAS has been difficult to prove. The UKPDS study did not show a difference in the outcome of either macrovessel or microvessel disease for patients treated with either captorpril or atenolol to a goal pressure of 150/80 (23). Two recent studies demonstrate that ARA are superior to conventional therapy (38) and amlopidine in slowing the progression of overt nephropathy (39). The RENAAL study (38) compared the effect of losartan compared with conventional therapy without RAS inhibitors in 1513 patients with type 2 diabetic nephropathy using a combined primary composite end point of the time to doubling of the serum creatinine, progression to ESRD, or death. Fewer patients in the losartan group reached the composite end point (43.5%) compared with placebo (47.1%), resulting in 16% risk reduction. Most of the reduction in the primary end point was due to renal components: 21.6% of losartan patients experienced a doubling in the serum creatinine compared with 26% of placebo, and 19.6% progressed to ESRD compared with 25.5% of patients receiving placebo. The Irbesartan Diabetic Nephropathy Trial (IDNT) (39) compared the effect of ARA to the effect of a dihydropyridine calcium channel blocker or of standard antihypertensive therapy in 1715 type 2 hypertensive patients. The primary end point was the same as that of RENAAL: doubling of the serum creatinine, progression to ESRD, or death. The irbesartan group had a lower rate of progression to the primary end point (32.6%) compared with amlodipine (41.1%) or placebo (39%). The beneficial effect remained even after correction for the difference in BP between the treatment groups and placebo. The irbesartan group also had a 33% reduction in proteinuria compared with 6% for amlodipine and 10% for placebo. Another recent trial examined the efficacy of two different doses irbesartan (150 mg versus 300 mg) compared with placebo to prevent the progression of diabetic nephropathy in 590 type 2 diabetic patients with hypertension, microalbuminuria, and serum creatinine 1.5 mg/dl (40). Fewer patients in the high-dose group developed nephropathy (10) compared with the lower-dose irbesartan group (19) and the placebo group (30). The combination of irbesartan groups achieved greater BP control than the placebo group, but after adjusting for differences in BP, the beneficial effects of irbesartan persisted. All three of these trials were performed with ARA and not ACE-I. This has raised the question as to whether or not such beneficial results in type 2 diabetic patients would be seen with ACE-I as well. Unfortunately, for the reasons elegantly outlined by Hostetter (41), a large head-to-head comparison of ACE-I and ARA is unlikely to be made. The choice between an ARA and an ACE-I is made more difficult by the results of the MICRO-HOPE (42) trial, in which ramipril reduced the risk of myocardial infarction, stroke, or cardiovascular death by 26% after 2 yr. Perhaps the more interesting question is whether or not the combination of ACE-I and ARA is more effective than either drug alone. In diabetic nephropathy, there are small studies with conflicting results (43,44). The issue needs further study for both diabetic and nondiabetic nephropathy. Low-Protein Diet A low-protein diet in animal models of chronic nephropathy consistently shows a protective effect. It has been more difficult to document this effect in humans, and it is the subject of some controversy. Low-protein diets may delay dialysis either through a reduction in uremic symptoms or through a specific renal protective effect; the exact mechanism is unclear. Several studies have suggested that a low-protein diet slows the progression to ESRD (45), but a meta-analysis of 13 randomized and 11 nonrandomized trials found that there was only a small benefit in the randomized trials (46). The MDRD study, the largest study to address this issue to date, found that a lowprotein diet of 0.58 g of protein/kg body weight per day compared with a usual intake of 1.3 g of protein/kg body weight per day in patients with a GFR of 25 to 55 ml/min per 1.73 m 2 body surface area produced only a modest improvement in the rate of loss of GFR (47). Additionally, patients with more severe renal impairment (GFR 25 ml/min per 1.73 m 2 body surface area) did not benefit from a very low-protein diet consisting of 0.28 kg protein/kg body weight per day compared with the low-protein diet (47). The study has received a number of criticisms of its design (45), and a secondary analysis suggested that there may be a stronger effect of protein restriction in patients with a GFR 25 ml/min per 1.73 m 2 body surface area (48). There is concern that a low-protein diet may lead to malnutrition; however, both the low-protein diet and very low-protein diets, as supervised by a qualified dietitian, were well tolerated in the MDRD study (47). Although it seems reasonable to advise a carefully monitored low-protein diet of 0.6 g/kg per 1.73 m 2 body surface area for patients with GFR 25 ml/min per 1.73 m 2 body surface area, it is difficult

J Am Soc Nephrol 13: S190 S195, 2002 Chronic Nephropathy S193 to say how effective it is in slowing the progression to ESRD. Further study is needed. Lipid Control Increased total and LDL cholesterol and reduced HDL cholesterol are well-know risk factors for cardiac disease, and there is evidence that they might contribute to the progression of nephropathy as well (49,50). Triglycerides have also been identified as a risk factor in the progression of type 2 diabetic nephropathy (51). Parving and coworkers (52), in their cohort of 301 type 1 diabetic patients, found that elevated serum cholesterol was an independent risk factor for progression in type 1 diabetic nephropathy. The optimal intervention, however, for hyperlipidemia in renal disease is unknown and requires further study. Glucose Control Aggressive glycemic control is helpful in halting the progression to microalbuminuria in type 1 diabetic patients. Both type 1 (53) and type 2 diabetic patients have been shown to benefit from intensified glucose control for primary prevention and for slowing progression of microalbuminuria (54). It has been more difficult to establish that intensified glucose control is helpful in treating overt nephropathy, perhaps due to the limited length of study design (31). However, most authorities recommend intensified glucose control as a strategy to slow microvascular and macrovascular complications. Smoking Smoking accelerates loss of GFR in patients with type 1 or type 2 diabetic nephropathy and in patients with nondiabetic chronic nephropathies (55). Patients should be counseled to stop smoking. New Approaches Aldosterone Inhibition. There is experimental data that suggests that aldosterone may also be important in progressive nephropathy (56). In experimental hypertensive nephrosclerosis, treatment with Aldactone is effective in preventing scarring and loss of renal function (57), and infusion of aldosterone with concomitant ACE-I effectively negates the protection provided by ACE-I (58). Spironolactone had been extensively studied for the treatment of congestive heart failure. The Randomized Aldactone Evaluation Study (RALES) (59), which compared the effect of spironolactone to placebo in addition to standard therapy consisting of ACE-I, loop diuretic, and digoxin was stopped early because of a 30% reduction in all-cause mortality in the spironolactone group. A relatively low dose of 25 mg was used, and the effect was independent of the antihypertensive effect. Spironolactone was also well tolerated, with a small but significant rise in serum potassium. These data raise the question of whether aldosterone alone or in combination with other agents that inhibit the RAS would be effective for the treatment of progressive nephropathy. Of concern is the potential for life-threatening hyperkalemia, particularly in patients with advanced renal insufficiency, or a predisposition to hyperkalemia, such as type 2 diabetics with type 4 renal tubular acidosis. The safety and efficacy of aldosterone inhibitors in the treatment of proteinuric renal disease remains to be defined. Vasopeptidase Inhibitors. Vasopeptidase inhibitors are a relatively new class of cardiovascular agents that inhibit both angiotensin-converting enzyme and neutral endopeptidase (NEP), the enzyme responsible for the degradation of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, adrenomedullin, urodilatin, and bradykinin (60). These peptides contribute to vasodilatation and natriuresis as well as causing a decrease in the activities of the reninangiotensin and sympathetic nervous systems (60). The combination of ACE and NEP inhibition is highly effective as antihypertensive therapy and for the treatment of heart failure (60). There is less available research on the efficacy of these agents for the treatment of chronic nephropathies. Animal data suggest that they afford the same renoprotection as treatment with ACE-I (61), or perhaps more (62), so but there is little human data regarding this point. Unfortunately, these agents are also associated with angioedema (60), which can be lifethreatening. The extent of this risk is currently being further evaluated, and their role in the treatment of proteinuria renal disease is promising but still unclear. Multi-Drug Approaches. Further examination of the RENAAL and IDNT data reveals that although these trials resulted in a significant reduction in adverse renal events, 43.5% of patients taking losartan (38) and 32.6% taking irbesartan (39) still reached a primary end point. More effective strategies are called for in the treatment of type 2 diabetic nephropathy. Parving et al. (31) have found that an intensive, multi-pronged approach to the treatment of diabetic microalbuminuria, which includes BP control, inhibition of the RAS, glucose control, and lipid control, is more effective than standard approaches. In a small trial at our center, such an approach with diabetic and nondiabetic nephropathy has been successful. We have instituted a remission clinic for patients with nephrotic range proteinuria ( 3 g/24 h) despite the use of maximally recommended ACE-I doses. We use a standard approach consisting of a low-salt diet, the addition of an ARA or nondihydropyridine calcium channel blocker to ACE-I, aggressive BP control, and the use of HMGCoA reductase inhibitors for dyslipidemia. Nine of 13 patients, who had not previously responded to maximal doses of ACE-I, admitted to the clinic achieved remission of proteinuria ( 1 g/24 h) and had stable renal function after 3 to 24 mo (63). These preliminary data suggest that such an approach is effective for the treatment of nephropathy and need confirmation in larger clinical trials. There are now effective methods for treating diabetic and nondiabetic chronic nephropathy. Aggressive BP control, reduction of proteinuria, use of agents that block the RAS, and careful attention to metabolic and lifestyle issues (smoking) result in slower loss of GFR and remission for some patients. Unfortunately, not all patients respond equally to these measures. In the REIN trial, men with the ID or II ACE genotype did not respond to treatment with an ACE-I and thus failed to benefit from the renal protective benefits of these drugs (64). Further research is needed to identify new strategies to obtain

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