In individuals with chronic kidney disease, progression is documented either by increasing levels of serum creatinine or falling levels of the glomerular filtration rate (GFR), as estimated by measured creatinine clearance or by creatinine clearance formulas.

Currently, chronic kidney disease is defined by:

1. Kidney damage for >3 months defined by structural or functional abnormalities, with or without decreased GFR, and manifested by either:
   • Pathologic abnormalities, or
   • Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities on imaging tests
2. GFR <60 mL/min for >3 months, with or without kidney damage.¹

The prevalence of chronic kidney disease in the United States population is rising significantly. A 1998 report of the National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994 estimated that 6.2 million individuals over age 12 years had reduced kidney function, defined as a serum creatinine concentration of >1.5 mg/dL; 2.5 million had serum creatinine >1.7 mg/dL; and 800,000 had a serum creatinine of >2.0 mg/dL. Further, these data showed a higher prevalence of abnormal creatinine levels in older compared with younger individuals, in non-Hispanic blacks compared with whites or Mexican-Americans, and in men compared with women.² In 1998, 86,000 patients began treatment for end-stage renal disease (ESRD), and in that same year there were more than 300,000 prevalent cases of ESRD. By 2010, these numbers are projected to be 172,667 incident and 661,330 prevalent cases of ESRD.³ In particular, renal disease in diabetes mellitus is a disproportion of the rising prevalence and incidence of new cases of progressive kidney disease in the United States.

Historically, progressive kidney injury has been thought to occur from disease or insults that produce both an initial and a continuing injury to the kidney, such as polycystic renal disease and severe lupus nephritis. Recently, it has become abundantly clear that progressive renal disease more often results from a combination of initial disease insult or injury followed by the maladaptive renal response to that insult (eg, idiopathic focal segmental glomerulosclerosis, severe hypertensive renal injury, surgical removal or absence of >51% of functioning renal tissue), coupled with the adverse effect of systemic hypertension. Most renal diseases cause an initial injury that results in loss of functioning nephrons. This loss causes intrarenal changes in glomerular hemodynamics, brought about by stimulation of intrarenal vasoactive hormones (eg, angiotensin II/aldosterone, prostaglandin E₂ [PGE₂]), which causes preferential efferent glomerular arteriolar constriction that results in hyperfiltration and stimulation of cytokines (eg, transforming growth factor-beta [TGF-ß₁]). All of these can produce further relentless injury and scarring to the remaining nephrons. In addition, most renal diseases are accompanied by systemic hypertension and proteinuria, both of which are thought to contribute to this ongoing maladaptive intrarenal response. In contrast, diabetic renal disease begins, not with loss of nephrons, but with glomerular hyperfiltration and cytokine stimulation, and then progresses to nephron loss and glomerular sclerosis. The following diagram depicts some of these intrarenal factors known to contribute to progressive renal injury (Figure 1).

The sheer scope and cost of this medical problem demands vigorous attempts at intervention. Based on the growing knowledge of factors contributing to progressive renal disease, several clinical studies have tested clinical interventions that might prevent or slow the rate of progression.

Dietary Protein Restriction and Control of Hypercholesterolemia and Hyperuricemia

Extensive study of chronic renal failure in animal models has shown that reduced dietary protein is associated with a reduction in glomerular hyperfiltration and slows the progression of renal disease. Although animal models of disease and treatment do not always apply to humans, there are now more than 35 human studies in nondiabetic renal disease and more than 15 studies in diabetic renal disease to test whether dietary protein restriction ameliorates the rate of progression of disease.⁴ The Modification of Diet in Renal Disease study⁵ (MDRD) was the largest controlled multicenter trial to compare usual protein intake (1 g/kg/d) with low (0.6 g/kg/d) and very low (0.28 g/kg/d) protein intake in nondiabetic patients. Although the primary outcome was inconclusive, several subanalyses suggested that a prescribed dietary protein intake of 0.6 g/kg/d as compared with 1 g/kg/d reduced the rate of progression by about 28%, the same benefit that was seen from achieving the low blood-pressure goal.⁶ A meta-analysis of five of the best studies of both diabetic and nondiabetic renal disease suggests that a small reduction in rate of progression occurs with dietary protein restriction. In an analysis of the MDRD data, Locatelli and Del Vecchio⁷ found that adherence to a low (0.6 g/kg/d) versus a usual (1g/kg/d) protein diet for 9 years would delay the need for renal replacement therapy by approximately 1 year. The difficulty of achieving consistent dietary protein restriction, however, makes the application of this intervention unwieldy and prone to failure, especially in diabetic patients. In fact, a dietary protein prescription of 0.6 g/kg/d resulted in an achieved protein intake of 0.7 to 0.75 g/kg/d and was not associated with any adverse nutritional outcome. Compliance in the MDRD was successful but required intensive, regular interaction by dieticians.

Experimental studies in animals have suggested that lipid-lowering agents such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have favorable effects on several processes known to participate in progressive nephropathy.⁸

• HMG-CoA reductase inhibitors inhibit the proliferation of mesangial, vascular smooth muscle cells and tubular epithelial cells to various mitogenic stimuli.
• They also reduce the release of cytokines from macrophages.
• They have slowed the rate of renal disease progression in a 1 and 5/6 rat ablation model of progressive nephropathy.

However, to date, no human clinical trial has shown benefit from lipid lowering in the progression of renal disease. In many patients with renal disease, there are other reasons (coronary disease, atherosclerosis) why lipid-lowering treatment should be prescribed.

In humans, there has been an association between hyperuricemia, hypertension, and renal failure. Many have come to doubt that there is a chronic renal disease caused by hyperuricemia.⁹ In animals, deposition of uric acid in the kidney causes severe interstitial nephritis. However, no clinical controlled trials have been conducted on the value of treating hyperuricemia in the prevention of renal disease. Some of the suggestive evidence for a role for uric acid in renal disease is the subject of a recent review.¹⁰

Blood Pressure Reduction and
Angiotensin-Converting Enzyme
Inhibitors in Nondiabetic Kidney Diseases

Systemic hypertension is associated with progression of renal disease. The mechanism is partially explained as follows: when diseases cause glomerular injury and loss, hyperfiltration ensues in the remaining glomeruli. The hyperfiltering state results from an afferent arteriolar dilation and efferent arteriolar constriction (Figure 1). Such a glomerulus is vulnerable to the adverse effects of systemic hypertension because the systemic pressure directly affects the glomerular structures. This, in turn, causes further glomerular injury.

The MDRD study⁵ was also designed to compare the effect of blood pressure control on progression of renal failure in two groups: a usual-blood-pressure group (mean arterial pressure [MAP] <107 mm Hg) and low blood pressure group (MAP <92 mm Hg) The MDRD demonstrated only a 4-mm Hg difference between the groups at the conclusion of the study. Nevertheless, the low-blood-pressure group had a significant reduction in the rate of renal failure progression. This benefit was most profound in the patients with urinary protein excretion >1 g/d, except for patients with autosomal dominant polycystic kidney disease (ADPKD).

A study of 24 patients with ADPKD compared the effects of amlodipine versus enalapril.¹¹ During 5 years of follow-up, both drugs produced similar reductions in blood pressure, but only enalapril was associated with a sustained reduction in urinary albumin excretion. Whether such interventions will translate into improved renal survival in ADPKD remains to be proven.

Two studies^12,13 that included more than 700 patients with nondiabetic renal disease showed that lowering systemic blood pressure with angiotensin-converting enzyme (ACE) inhibitors or sustained-release nifedipine reduced the rate of progression of renal failure, especially in patients with proteinuria >1 g/d. The Ramipril Efficacy in Nephropathy (REIN) trial^14,15 followed 352 patients with proteinuria >1 g/24 hr. These patients were randomized to ramipril or placebo plus conventional antihypertensive medications to lower the diastolic blood pressure to <90 mm Hg. The results demonstrated that, after a median of 31 months of follow-up and at similar levels of blood pressure reduction, the ACE inhibitor was more effective in preserving renal function. This effect was most profound in those patients with the highest levels of baseline proteinuria.

In the recently reported African-American study of kidney disease (AASK),¹⁶ metoprolol, amlodipine, and ramipril were compared as first-line drugs in patients with nondiabetic nephropathy. Blood pressure control was similar among the three groups. However, only in the patients treated with ramipril was there a significant reduction in rates of renal disease progression and in composite end points (22-38% reduction in renal function, need for dialysis, or death).

Jafar et al¹⁷ performed a meta-analysis of 1,860 patients in 11 randomized trials of patients with nondiabetic proteinuric renal disease. They found that the greatest progression of renal disease is found in those patients with the highest level of proteinuria. In turn, they also noted that the antiproteinuric effect of ACE inhibitors was greatest in those patients with the highest level of proteinuria. Reduction in proteinuria was associated with reduced progression.

These combined results support the belief that reduction in systemic hypertension slows or prevents progression of proteinuric renal disease. They also show that at similar degrees of blood pressure control, ACE inhibitors are more protective than amlodipine. This suggests that preventing progression of nondiabetic renal disease requires more than lowering blood pressure. It appears that ACE inhibitors slow progression not only by reduction of systemic blood pressure but also by direct intrarenal effects that include favorable change in glomerular hemodynamics and reduction of angiotensin-mediated fibrosis. In patients who cannot tolerate ACE inhibitors, the AT₁ receptor antagonists may reasonably be prescribed, but there are no trials in nondiabetic patients showing the same benefit from this substitution.

Blood Pressure Reduction, ACE inhibition, and Angiotensin Receptor Blocker (ARB) Therapy in Diabetic Kidney Disease

Glomerular hyperfiltration is frequently present in both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients before there is clinical evidence of proteinuria or kidney disease. The rat model of diabetes mellitus has shown that interruption of the angiotensin effect in the kidney, control of blood pressure, and careful glycemic control can all reduce or prevent the development of overt diabetic nephropathy.

Several clinical studies in humans have now shown that the following interventions significantly affect the course of diabetic renal disease:

• In the Diabetes Control and Complications Trial (DCCT),¹⁸ tight versus usual glycemic control in type 1 diabetic patients was shown to significantly reduce the development of microalbuminuria and to lessen the likelihood that microalbuminuria would transform to overt nephropathy.
• Lewis et al¹⁹ studied the effect of captopril versus placebo in type 1 diabetic patients who had overt diabetic nephropathy. Although blood pressure control was comparable, the captopril group had a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the two groups. This finding suggests that the benefit seen with ACE inhibition is due to an effect beyond that attributable to blood pressure control alone.
• Lewis et al,²⁰ showed in 126 type 1 diabetic patients who had nephropathy and azotemia that treating blood pressure to a MAP goal of 92 mm Hg versus 107 mm Hg was associated with greater reductions in proteinuria and favorable stabilization of renal function.
• In normotensive type 2 diabetic patients with normal renal function and microalbuminuria, Ravid et al²¹ showed that use of ACE inhibition results in stabilization of the serum creatinine and prevention of overt nephropathy. They also showed that ACE inhibition prevents progression of renal disease in previously untreated type 2 diabetic patients with proteinuria and mild azotemia. The study by Ravid et al²² of 156 type 2 diabetic patients with normal renal function and no albuminuria also demonstrated that enalapril treatment was associated with reduction in the development of microalbuminuria-the earliest clinical manifestation of diabetic nephropathy.
• In recent trials of type 2 diabetes mellitus with azotemic kidney disease, adding losartan²³ or irbesartan²⁴ to the treatment regimen reduced the progression of the renal disease independent of blood pressure effect. Parving et al²⁵ compared irbesartan with placebo in type 2 diabetic patients who had microalbuminemia and normal kidney function. Irbesartan delayed progression of nephropathy independent of blood pressure control.

The Possible Role of Cytokine Control

The observation that ACE inhibitors reduce renal injury in diabetic and nondiabetic patients even in the absence of hypertension or proteinuria raises questions of what other pathophysiologic mechanisms might be operative. In this regard, several animal models of progressive renal disease in which tissue fibrosis is a prominent pathologic feature are known to be accompanied by increased levels of TGF-ß₁ activity in the renal and systemic circulation.^26,27 Humans with biopsy-proven diabetic renal disease were found to have very high levels of TGF-ß.²⁴ Further, TGF-ß mRNA levels were found to be elevated early in diabetic nephropathy and to correlate with hemoglobin A_1C levels. ^28,29

Several investigators have shown that angiotensin stimulates TGF-ß and that suppression of the renin-angiotensin system is associated with reduced tissue levels of TGF-ß.^30,31 These observations imply that it is reasonable to expect that ACE inhibitors or AT₁ receptor blockers (ARBs) might produce beneficial effects by suppressing TGF-ß. In that respect, in the Collaborative Study Captopril Trial,³² TGF-ß levels in serum were measured at baseline and at 6 months of treatment with either placebo or captopril. Captopril treatment significantly lowered the TGF-ß levels at 6 months, and the degree of reduction at 6 months was associated with greater preservation of GFR at 2 years of follow-up.

Reducing Proteinuria

Most progressive renal diseases are accompanied by proteinuria. In general, the greater the proteinuria, the more likely the disease will progress. Many have considered the proteinuria as simply a marker for significant renal injury. Recent studies, however, suggest that the proteinuria itself may contribute to the pathologic injury^33,34 and is a modifiable risk factor.¹⁷

Glomerular injury results in increased permeability of the glomerular basement membrane for plasma proteins, some of which are ingested by proximal tubular cells. When proximal tubular cells ingest filtered protein, an inflammatory response is initiated, which contributes to the interstitial scarring. In rats with 1-5/6 nephrectomy Romero et al,³⁵ Abbate, et al,³⁶ and Remuzzi, et al³⁷ have shown that lisinopril and mycophenolate significantly reduce the proteinuria-induced inflammatory injury and that both agents combined have the most significant effect on suppression of the inflammatory injury. Such information suggests that whenever a therapy reduces proteinuria, there is likely to be a further benefit beyond that which would normally accompany blood pressure reduction or alteration of glomerular hemodynamics. Based upon these observations, treatments given to prevent progression of renal disease should be monitored not only by measuring blood pressure, glucose control, or serum creatinine, but also by measuring the effect of such treatment on the degree of proteinuria.

The Role of Other Antihypertensives
in Preventing Progression

Bakris et al³⁸ performed a comparison of verapamil or diltiazem versus lisinopril versus atenolol in 52 type 2 diabetic patients who had nephropathy and hypertension. Each of the three classes of drugs produced the same blood pressure reduction. Lisinopril and nondihydropyridine calcium channel blockers, in contrast to atenolol, reduced both rate of renal disease progression and degree of proteinuria. Since reduction of proteinuria in diabetic nephropathy seems to be a marker for beneficial effect, it appears that when an ACE inhibitor or AT₁ receptor blocker cannot be used or must be supplemented, a nondihydropyridine calcium channel blocker is an appropriate addition.

Russo et al³⁹ compared the short-term effect of an ACE inhibitor and an ARB alone and combined in eight patients with IgA nephropathy. Both drugs alone significantly reduced proteinuria, and the two agents together caused a greater reduction in proteinuria than either drug did alone.

Special Considerations

Worsening Renal Function Associated
With ACE or ARB Treatment
Because of the importance of the angiotensin effect on glomerular filtration in patients with kidney disease and impaired renal function, many patients will have further reduction of GFR when treated with ACE inhibitors or AT₁ receptor blockers. This has led many to question whether such treatment is appropriate or safe in individuals with mild to moderate azotemia. Ahmed⁴⁰ recently reviewed 12 randomized trials in which ACE inhibitor or ARB therapy was used in patients with preexisting renal insufficiency, with or without diabetes or heart failure. These patients had a baseline serum creatinine of 1.7 mg/dL and achieved blood pressure goals. With treatment, the serum creatinine rose about 25% above baseline by 4 weeks, and did not rise further unless the patient was also exposed to volume depletion from diuretics or gastroenteritis or had taken nonsteroidal anti-inflammatory agents. Despite this rise in serum creatinine, these patients still experienced risk reduction in their rate of renal failure progression after 2 or more years of follow-up.

Relation Between Renal Insufficiency
and Cardiovascular Events
Several studies have shown that microalbuminuria itself as well as renal insufficiency of even mild degrees are independent risk factors for cardiovascular morbidity and mortality. In the Heart Outcomes and Prevention Evaluation (HOPE) study⁴¹, 980 patients with mild renal insufficiency (serum creatinine >1.4 mg/dL) and 8,307 patients with normal renal function were studied for cardiovascular outcomes and the benefits of ACE inhibition treatment. This study showed that in patients with preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril treatment reduced cardiovascular risk in both groups without increasing adverse effects.

The Role of Isolated Systolic Hypertension
In Progressive Kidney Disease
In an analysis of 2,181 patients enrolled in the placebo arm of the Systolic Hypertension in the Elderly Program (SHEP), a decline in kidney function (defined as an increase in serum creatinine >0.4 mg/dL over 5 years of follow-up) most strongly correlated with systolic blood pressure.⁴² This further confirms the importance of lowering even isolated systolic blood pressure.

Clinically proven strategies to slow progression of nondiabetic renal disease include:

1. Blood pressure reduction to <130/80 whenever possible, and nondihydropyridine calcium channel blockers as additional therapy or as substitutes if ACE inhibitors are not tolerated;
2. Dietary protein restriction (0.6 to 0.8 g/kg/d) is reasonable for patients who are willing to follow dietary restrictions.

Clinically proven strategies especially for diabetic patients:

1. Glycemic control to achieve a hemoglobin A_1C of <7% to 8%;
2. Use of ACE inhibitors in any type 1 diabetic patient with kidney disease, even in the absence of hypertension;
3. Use of ARB therapy in type 2 diabetic patients who have kidney disease with or without azotemia or hypertension.

Caveats
All azotemic patients with preexisting vascular disease or diabetes combined with additional cardiovascular risk factors should be treated with ACE inhibition to reduce future cardiovascular events and to delay progression of renal disease.

In patients with mild to moderate azotemia, ACE inhibition and ARB therapy may be associated with up to a 25% further increase in serum creatinine within 4 weeks of initiation of therapy. This, however, will still be associated with reduction in rate of renal disease progression.

In type 2 diabetes, large clinical trials have not tested whether ACE inhibitors will have the same protective benefit on progression of renal disease as does ARB therapy.

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