Chapter 22. Slowing the Progression of Chronic Kidney Disease

• Estimated glomerular filtration rate (GFR) <60 mL/minute/1.73 m2.
• Proteinuria or hematuria.
• Hypertension.
• Focal and segmental sclerosis and tubulointerstitial fibrosis on renal biopsy.

End-stage renal disease (ESRD) represents a major challenge to health care providers around the globe. It is estimated that in 2001 there were approximately 1.1 million people receiving dialysis worldwide and this number is projected to rise by 7% per year to over 2 million by 2010. The financial costs of dialysis provision are considerable and projected worldwide expenditure on dialysis treatment for the decade 2000–2010 is expected to exceed US$ 1 trillion. Whereas chronic dialysis does prolong life in ESRD, it is associated with an annual mortality of approximately 20%, representing a survival rate worse that many common forms of cancer. Renal transplantation does offer improved survival and quality of life, but the majority of patients are not medically suitable for transplantation and a universal shortage of donor organs continues to restrict the number of transplants performed.

Against this background it is critical to appreciate that the majority of cases of ESRD result from the slow progression of chronic kidney disease (CKD) over many months or years. There is therefore an opportunity to intervene in the course of CKD to slow the rate of decline in renal function and thereby reduce the number of patients requiring renal replacement therapy. In this chapter we review the mechanisms that contribute to CKD progression as well as clinical aspects and interventions that are effective in slowing the rate of decline in renal function.

CKD should be viewed as a clinicopathologic syndrome (defined above) that ensues after renal injury resulting from a wide range of kidney pathologies. This suggests that the progressive decline in renal function that is characteristic of CKD results from a common set of mechanisms that is largely independent of the initiating renal pathology. Intensive research over the past three decades has identified several interacting mechanisms that together produce a vicious cycle of progressive nephron loss resulting in ESRD (Figure 22–1).

Glomerular Hemodynamic Factors

Studies in animal models of CKD reported that when the nephron number was severely reduced by surgical ablation, marked hemodynamic changes were observed in the remaining glomeruli, characterized by a substantial increase in the filtration rate of each glomerulus (single nephron glomerular filtration rate, SNGFR) that resulted in part from an increase in glomerular capillary hydraulic pressure (Pgc). Whereas these adaptations initially allowed partial compensation for nephron loss, further studies indicated that they were associated with structural injury to glomerular cells and subsequent glomerulosclerosis. In subsequent experiments, treatment with an angiotensin-converting enzyme inhibitor (ACEI) normalized Pgc without abrogating the adaptive increase in SNGFR and prevented glomerulosclerosis, suggesting that increased Pgc (also termed glomerular capillary hypertension) was the hemodynamic factor most likely responsible for glomerular injury. These observations suggested that adaptive hemodynamic changes in glomeruli after substantial nephron loss result in further glomerular damage and nephron loss, thereby establishing a vicious cycle of progressive renal injury.

Angiotensin II

Angiotensin II is a potent vasoconstrictor peptide that has been identified as an important mediator of the glomerular hemodynamic adaptations observed after nephron loss. Whereas systemic levels of angiotensin II are normal or decreased in CKD, experimental studies have confirmed that intrarenal angiotensin II levels are elevated. Additionally, recent research has identified multiple nonhemodynamic effects of angiotensin II that may contribute to progressive renal injury. These include effects on glomerular permeability resulting in exacerbation of proteinuria, plasminogen activator inhibitor-1 production by endothelial and vascular smooth muscle cells, mesangial cell proliferation and transforming growth factor (TGF)-β expression, macrophage activation, and adrenal production of aldosterone, recently identified as a mediator of renal fibrosis. Taken together, it is clear that angiotensin II plays a central role in the pathogenesis of progressive renal injury through multiple hemodynamic and nonhemodynamic mechanisms. Inhibition of the production or actions of angiotensin II therefore represents a single intervention that may abrogate many of these mechanisms and would be expected to be effective in slowing the progression of CKD.

Proteinuria

Proteinuria is usually a result of disordered permselectivity of the glomerular filtration barrier and is therefore the hallmark of glomerulopathy as well as a marker of disease severity. Additionally, research over the past decade has produced evidence that the presence of abnormal amounts of plasma proteins in glomerular ultrafiltrate may contribute directly to further renal damage. In the normal kidney small amounts of low-molecular-weight proteins are present in the tubular fluid and are reabsorbed by proximal tubule cells. In vitro experiments have found that culturing renal tubule cells in the presence of high concentrations of plasma proteins induces expression of a range of proinflammatory cytokines. Moreover, in animal models of renal disease this enhanced expression is evident on the basolateral aspect of tubule cells. It therefore seems likely that these proinflammatory molecules are secreted into the peritubular interstitium where they contribute to the development of interstitial inflammation and fibrosis. Thus, proteinuria provides a mechanistic link between glomerular and tubulointerstitial pathology. Further experimental evidence indicates that abnormally filtered plasma proteins also accumulate within podocytes where they may contribute to glomerular injury.

CKD results from a wide range of renal pathologies, many of which occur sporadically; it is therefore difficult to devise an effective strategy for primary prevention of CKD. One important exception to this principle, however, is diabetic nephropathy, the most common cause of CKD in many developed countries. In this case the “at-risk” population may be readily identified and at least two interventions have been shown to reduce the incidence of diabetic nephropathy. Following the landmark Diabetes Control and Complications Trial (DCCT) it became clear that the level of glycemic control is critical in determining the risk of microvascular complications, including nephropathy. Among patients in the intensive diabetic control group, significantly lower hemoglobin A1C (HbA1C) levels versus conventional therapy (7.2% versus 9.1%) were associated with a 34% reduction in the risk of developing microalbuminuria. Second, treatment with an ACEI may reduce the risk of developing microalbuminuria. One small study found some beneficial effect (absolute risk reduction of 12.5%) of ACEI treatment among normotensive, normoalbuminuric patients with type 2 diabetes and recently a large randomized trial (BENEDICT) that included 1204 patients with type 2 diabetes and hypertension reported a significantly lower incidence of microalbuminuria among patients treated with trandolapril (6.0%) or trandolapril plus verapamil (5.7%) versus those treated with verapamil (11.9%) or placebo (10%). Thus tight glycemic control (HbA1C <7%) and treatment of hypertension with an ACEI should be regarded as essential interventions for preventing nephropathy in patients with diabetes.

For other forms of CKD the most critical factor for improving outcomes is early detection to allow intervention with measures that slow the rate of decline in renal function. Appropriate tests for CKD screening will vary according to circumstances and available resources. As most forms of CKD are associated with urinary abnormalities, the simplest form of detection is urinalysis with standard urinary dipsticks. Some forms of CKD may not cause urinary abnormalities and screening should therefore also include an estimate of renal function based on a measurement of serum creatinine. Diagnostic tests and further investigations are discussed in more detail below.

As CKD is relatively uncommon in the general population, it would be expensive and inefficient to screen entire populations. On the other hand, epidemiologic studies indicate that substantial numbers of patients have undiagnosed CKD. Focused screening of “at-risk” patients would therefore increase the detection of early stage CKD and facilitate early intervention to preserve renal function. Factors that place patients at risk for CKD vary in different countries, but general categories of patients who should be considered for screening are listed in Table 22–1. The optimal interval for screening remains to be determined but annual screening in high-risk groups is recommended.

Symptoms and Signs

CKD is often asymptomatic until moderate to severe renal failure has developed. Nocturia due to a failure of urine-concentrating mechanisms may be an early symptom of CKD, but this is often attributed to prostatism and rarely prompts patients to seek medical attention. If severe proteinuria is present, peripheral edema may be the first symptom to develop. Patients with advanced renal failure may present with malaise, breathlessness, pruritis, loss of appetite, nausea, and vomiting.

Similarly, abnormal clinical signs are often lacking in patients with CKD. Hypertension is almost universally present and is often the first detectable sign. It is thus critical that all patients with newly diagnosed hypertension be screened for CKD. Peripheral edema may be present in patients with severe proteinuria or more advanced renal failure. Clinical pallor due to anemia may be observed in patients with CKD stage 3–5. Most (but not all) patients with CKD have urinary abnormalities detectable with standard dipstick testing. Proteinuria is the hallmark of CKD and may be accompanied by hematuria.

Laboratory Findings

Laboratory investigations are essential for the diagnosis of CKD. As discussed previously, the diagnosis rests on the detection of urinary abnormalities (usually proteinuria) and impaired renal function.

Assessment of Proteinuria

The measurement of protein or albumin concentration in a 24-hour urine collection represents the most accurate method for assessment of proteinuria, but clinical utility is limited by inconvenience to patients and variable success in achieving a complete collection. Whereas protein or albumin concentration in a random urine specimen is of limited use due to variations in urine osmolality, the urine protein or albumin-to-creatinine ratio provides a reliable measure of proteinuria. Moreover, the urinary protein-to-creatinine ratio expressed in milligrams/milligram correlates closely with 24-hour urinary protein excretion expressed in grams/day and is thus convenient for patients as well as being easy to interpret. Some authorities prefer to use the albumin-to-creatinine ratio. Due to diurnal variations in the urinary protein excretion rate the assessment should be performed on an early morning specimen of urine.

Assessment of Renal Function

Determining the optimal method for the assessment of GFR depends upon finding a method with the best compromise between accuracy and reproducibility as well as patient convenience. Radioisotope clearance studies represent the most accurate method, but these require a hospital attendance of several hours as well as some radiation exposure and are therefore not suitable for serial monitoring of renal function. Creatinine clearance studies based on 24-hour urine collections were widely used until recently, but are inconvenient for patients and results may be significantly affected by undercollections or overcollections of urine. These difficulties prompted the development of a variety of formulas for estimating GFR based on serum creatinine concentration. Comparison with radioisotope clearance studies has shown that a four-variable equation [GFR = 1.86.3 × (Pcr in mg/dL)−1.154 × (age)−0.203 × 1.212 (if black) × 0.742 (if female)] derived from the Modification of Diet in Renal Disease (MDRD) Study provides the most accurate estimate of GFR and is more accurate than creatinine clearance. Variations in the creatinine assays used by different laboratories have been overcome by the use of standardised assays and a modified MDRD formula. Many laboratories now report an estimated GFR with each creatinine result. It should be noted, however, that the MDRD formula was derived from the data of patients known to have CKD. It therefore tends to underestimate GFR in patients with normal serum creatinine values. Thus, patients with moderately reduced estimated GFR (>60 mL/minute/1.73 m2) may not necessarily have CKD. On the other hand, normal estimated GFR does not necessarily exclude CKD as increases in single nephron GFR may compensate for nephron loss in the early stages. It is therefore critical that urinalysis remain a part of the screening process. Finally it should be noted that the four-variable equation does not account for body size and may not be reliable at extremes of body habitus. Further validation is required in ethnic groups other than African-American.

Special Examinations

Patients with CKD should be investigated to establish a specific diagnosis and to identify possible etiologic factors. This is important to facilitate the use of disease-specific therapies to limit the initial renal insult and reduce the risk of progressive renal injury. A detailed description of the diagnostic approach to specific renal diseases is beyond the scope of this chapter and is discussed in other sections of this book. Additionally, cardiovascular risk should be assessed with a fasting lipid profile and electrocardiograph.

A progressive decline in renal function and the risk of developing ESRD are the obvious complications of CKD that form the focus of this chapter. It should be noted, however, that CKD is associated with a marked increase in the risk of cardiovascular disease that in many patients exceeds the risk of ESRD. Additional complications of CKD include anemia, renal osteodystrophy, and malnutrition.

Nonpharmacology

Modification of Lifestyle

Patients with CKD should be encouraged to adopt a healthy lifestyle to reduce their cardiovascular risk. Whereas large randomized trials of lifestyle modification in CKD have not been conducted, there is evidence that some of the measures recommended may also slow the rate of CKD progression. If overweight, patients should be encouraged to lose weight as obesity per se is associated with glomerular hyperfiltration and proteinuria. Dietary salt should be restricted to assist with blood pressure control, particularly in patients prescribed an ACEI or angiotensin receptor blocker (ARB). Physical exercise should be encouraged and swimming in particular may reduce proteinuria. Smoking cessation is critical for cardiovascular risk reduction; in addition, there is growing evidence that smoking is associated with worse outcomes in diabetic and nondiabetic CKD.

Dietary Protein Restriction

The role of dietary protein restriction in renoprotective strategies remains controversial. Whereas experimental studies reported clear renoprotective benefits in animals assigned to a low protein diet, these findings have not been duplicated in humans. In the largest clinical trial to investigate this issue, the MDRD Study, the conclusion was to recommend protein restriction of 0.6 g/kg/day for patients with GFR <25 mL/minute/1.73 m2. Two meta-analyses also support a role for dietary protein restriction. However, it is not clear whether these benefits accrue to patients who are already receiving optimal ACEI or ARB treatment and there are concerns regarding the risk of malnutrition. A recent consensus statement from the International Society of Nephrology recommends dietary protein restriction to 0.8 g/kg/day in all patients and consideration of further restriction to 0.6 g/kg/day if renal function continues to decline or proteinuria persists despite ACI or ARB treatment.

Pharmacology

Control of Hypertension

The treatment of hypertension remains fundamental to therapeutic interventions for slowing the progression of CKD. Early clinical studies found that even modest reductions in blood pressure result in substantial attenuation of the rate of decline in renal function. These observations raise two important questions: What level of blood pressure control is required for optimal preservation of renal function? What antihypertensive drugs afford the most effective renoprotection?

Level of Blood Pressure Control

It is increasingly being recognized that lower therapeutic goals for blood pressure reduction are associated with better outcomes with respect to cardiovascular disease. Two large prospective randomized studies have sought to examine this issue in patients with CKD but unfortunately have failed to provide clear answers. Despite the equivocal results of randomized studies, other evidence supports the notion that lower blood pressure targets are associated with slower rates of decline in GFR. Analysis of data from nine long-term clinical trials involving patients with diabetic and nondiabetic forms of CKD found lower rates of GFR decline among patients with lower blood pressure. The extent of consensus on this point is reflected by the fact that several professional bodies including the American Diabetes Association, National Kidney Foundation, Joint National Committee on Prevention, Detection and Treatment of High Blood Pressure, and the International Society of Nephrology now recommend that blood pressure should be lowered to <130/80 mm Hg in all patients with CKD. It should be noted that aggressive treatment of hypertension may be associated with an increased risk of hypotension in patients with autonomic neuropathy, labile blood pressure, or arteriosclerosis (resulting in decreased vascular compliance), all of which were excluded from the MDRD Study.

Choice of Antihypertensive Drug

Whereas some studies, including the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, have found no differences in outcomes between different classes of antihypertensive agents among hypertensive patients, other evidence shows that when the hypertension is associated with CKD, some drugs may produce specific benefits or adverse effects. As discussed in detail below, ACEIs and ARBs afford significant renoprotective benefit beyond that attributable to their antihypertensive effects and should be regarded as first-line therapy in patients with CKD unless contraindicated. Diuretics are generally not effective as monotherapy in patients with renal failure, but may produce a substantial additional decrease in blood pressure if added to ACEI or ARB therapy. However, nondihydropyridine calcium channel blockers (CCB) may produce undesirable effects in patients with CKD. We therefore recommend that in patients with CKD, non-dihydropyridine CCB should be used only in combination with an ACEI or ARB.

Inhibition of the Renin–Angiotensin System

Several randomized prospective trials published over the past two decades have established a firm evidence base to support the use of ACEI or ARB therapy as the single most effective intervention for slowing the rate of progression of CKD.

Diabetic Nephropathy

Diabetic nephropathy is the most common underlying cause of end-stage renal failure in many developed countries and is projected to increase worldwide over the next two decades. This topic is comprehensively discussed in Chapter 54 and here we will review only specific aspects relevant to the treatment of CKD. Whereas the pathogenesis of diabetic nephropathy is similar in type 1 and type 2 diabetes, the populations affected by these two forms of diabetes are quite distinct and have different associated comorbidities. Therapeutic trials have therefore included either one or the other and are reviewed separately.

Microalbuminuria

Microalbuminuria (urinary albumin excretion of 30–300 mg/day) represents the earliest manifestation of diabetic nephropathy and identifies patients at risk for developing overt nephropathy as well as a progressive decline in renal function. Among patients with type 1 diabetes, several small trials have shown benefits from treatment with an ACEI. A meta-analysis that combined the results of 12 such studies (689 patients) found that ACEI treatment was associated with a significant reduction in the risk of progression to overt nephropathy (odds ratio 0.38) and three times the incidence of complete normalization of the microalbuminuria. Among patients with type 2 diabetes, several studies have reported a reduction in microalbuminuria or a decrease in the number of patients progressing from microalbuminuria to overt nephropathy (risk reduction 24–67%) with ACEI treatment. Importantly, subgroup analysis in the HOPE Study also reported cardiovascular benefits associated with ACEI treatment. Among patients with type 2 diabetes treated with an ACEI, there was a 25% reduction in the combined primary endpoint of myocardial infarction, stroke, or cardiovascular death. However, one relatively large study found no renoprotective benefit of ACEI over β-blocker treatment among patients with hypertensive type 2 diabetes with normoalbuminuria or microalbuminuria.

Two studies have reported a clear benefit associated with ARB treatment of microalbuminuria in patients with type 2 diabetes. Among 590 patients randomized to irbesartan treatment (at 300 or 150 mg/day) versus placebo there was a significant, dose-dependent reduction in the incidence of overt proteinuria (5.2% versus 9.7% versus 14.9%). In a similar study 332 patients were randomized to treatment with valsartan or amlodipine and doses were adjusted to achieve equivalent blood pressure control. Valsartan treatment was associated with significantly lower levels of albuminuria and more patients receiving valsartan reverted to normoalbuminuria (29.9% versus 14.5%).

The benefits observed with ACEI or ARB treatment suggest that there may be additional benefit with combination ACEI and ARB therapy. In the candesartan and lisinopril microalbuminuria (CALM) study 199 hypertensive patients with type 2 diabetes with microalbuminuria were randomized first to ACEI or ARB therapy and then, after 12 weeks, to combination therapy or continued monotherapy. Whereas combination therapy afforded greater reductions in blood pressure and, to some extent, albuminuria than continued monotherapy, the study was only of 24 weeks duration and did not examine the relative incidence of overt nephropathy in different groups.

In summary, there is evidence that ACEI treatment decreases the risk of overt nephropathy associated with microalbuminuria in type 1 and 2 diabetes and that ARB treatment has a similar effect in type 2 diabetes. Importantly, the irbesartan study found a substantial dose-dependent effect and treatment should therefore be escalated to the maximum recommended dose. At present there are insufficient data to support the use of combination ACEI and ARB therapy in patients with microalbuminuria. Finally, the HOPE Study findings provide important evidence that ACEI treatment also reduces cardiovascular risk in patients with diabetes with microalbuminuria.

Overt Diabetic Nephropathy

Evidence of the benefit of ACEI treatment in patients with type 1 diabetes and overt nephropathy was provided by a landmark study that was the first large trial to show renoprotection attributable to ACEI treatment in human CKD. Four hundred and nine patients with proteinuria >0.5 g/day and serum creatinine <2.5 mg/dL were randomized to either captopril or placebo treatment. Additional antihypertensive treatment was added as required to achieve a blood pressure goal of <140/90 mm Hg. After a median follow-up of 3 years, captopril treatment was associated with a 48% reduction in the risk of a doubling of serum creatinine and a 50% reduction in the incidence of the combined endpoint of death, dialysis, and renal transplantation. Blood pressure control was similar in the two groups, implying that the additional renoprotection was not due only to the antihypertensive effects of captopril.

Among patients with type 2 diabetes with overt nephropathy evidence for the use of ACEI treatment is less clear, with only one study reporting benefit. However, two large randomized studies have reported renoprotective effects with ARB therapy. In summary, available data provide good evidence for renoprotective efficacy with ACEI treatment in patients with overt nephropathy and type 1 diabetes as well as ARB treatment in type 2 diabetes. There are currently no data from large long-term studies regarding the use of combination ACEI and ARB therapy in overt diabetic nephropathy.

Nondiabetic CKD

The clear benefits of ACEI treatment in diabetic nephropathy prompted further trials to examine potential renoprotective effects in nondiabetic patients with CKD. In the REIN Study, 352 patients with nondiabetic CKD were randomized to treatment with ACEI, ramipril, or placebo. Other antihypertensive drugs were added to achieve a diastolic blood pressure of <90 mm Hg in both groups. Among patients with pretreatment proteinuria of ≥3 g/day, the study was stopped prematurely after an interim analysis found a significantly slower rate of decline in GFR in patients receiving ramipril (0.53 versus 0.88 mL/minute/month). Further analysis showed a significant reduction in the risk of the combined endpoint of a doubling of serum creatinine or ESRD in the ramipril group (risk ratio = 1.91 for the placebo group). Among patients with pretreatment proteinuria of 1–3 g/day, ramipril treatment also significantly reduced the incidence of ESRD (relative risk for placebo group = 2.72), particularly among those with a GFR of <45 mL/minute at baseline. Similarly in the AASK Study, African-American patients randomized to treatment with ramipril evidenced a lower incidence of the composite outcome (reduction in GFR by 50% or more, ESRD, or death) than those receiving amlodipine or metoprolol (risk reduction 38% and 22%, respectively). This is an important observation because ACEIs are often not prescribed in African-American patients due to decreased antihypertensive efficacy, a problem that can readily be overcome by combination with a diuretic. One randomised study has confirmed that ACEI treatment slows CKD progression even in patients with advanced CKD. The findings of these studies were confirmed by a meta-analysis of 11 studies of nondiabetic CKD that included 1860 patients. ACEI treatment was associated with greater reductions in blood pressure and proteinuria than other antihypertensive treatments, but even after statistical adjustment for these factors, ACEI treatment afforded a lower risk of reaching ESRD (relative risk = 0.69; CI 0.51–0.94). Few studies have examined the benefits of ACEI treatment in patients with a single form of nondiabetic CKD. In one such study of 44 patients with IgA nephropathy and >0.5 g/day of proteinuria, ACEI treatment was associated with a reduction in proteinuria and a significantly lower incidence of the primary endpoint, a 50% increase in serum creatinine concentration.

One large randomized study has examined the role of combination ACEI and ARB therapy in nondiabetic CKD. This trial was halted prematurely after an interim analysis revealed a substantial difference in outcomes, such that combination therapy was associated with significantly greater reductions in proteinuria (−75.6% versus −42.1% and −44.3%) and a lower incidence of the primary endpoint, doubling of serum creatinine or ESRD (hazard ratio 0.4 versus monotherapy groups). Close matching of blood pressure between the groups ensured that these benefits could be attributed specifically to combination therapy. There were no significant differences in outcomes between the monotherapy groups. Thus, although this study was not designed to compare ACEI and ARB monotherapy, it does provide some evidence that they provide similar renoprotection in nondiabetic CKD.

In summary, there is now clear evidence that ACEI treatment affords renoprotection in patients with nondiabetic CKD and proteinuria. There are no data from large randomized studies regarding ARB monotherapy in nondiabetic CKD, but the COOPERATE study results suggest that ARB treatment is associated with renoprotection similar to ACEI treatment. Finally, the COOPERATE Study reported significant additional renoprotection with combination ACEI and ARB therapy. Further studies are required to clarify the role of combination therapy, but pending these we recommend that it should be considered when therapeutic goals for blood pressure control or reduction of proteinuria are not achieved with monotherapy.

Angiotensin-Converting Enzyme Inhibitors versus Angiotensin Receptor Blockers

Whereas ACEI and ARB both inhibit the renin–angiotensin system, they act on different elements of the system and may not necessarily produce equivalent therapeutic effects. ACEIs inhibit angiotensin-converting enzyme (ACE) and therefore block conversion of the inactive peptide angiotensin I to the potent vasoconstrictor angiotensin II. Additionally, ACE catalyzes the breakdown of bradykinin and thus ACEI treatment is associated with elevated bradykinin levels that may mediate some of its effects. However, ARBs bind to and inhibit the angiotensin subtype 1 receptor. Loss of feedback inhibition results in elevated angiotensin II levels that may exert effects via other subtypes of angiotensin receptor. Despite these considerations, experimental studies of CKD have generally found no differences in the efficacy of ACEI versus ARB treatment. Few clinical trials have directly compared the renoprotective effects of ACEI and ARB in CKD patients. Nevetheless, available data suggest that ACEI and ARB treatments probably do afford similar renoprotection.

Randomized trials have shown ACEI treatment to be renoprotective in type 1 diabetes with microalbuminuria or overt nephropathy and type 2 diabetes with microalbuminuria as well as in nondiabetic CKD. However, ARB treatment has proven renoprotective effects in type 2 diabetes with microalbuminuria or overt nephropathy. Despite the lack of specific data, an ARB should be considered as alternative therapy in patients who are ACEI intolerant, most often due to a cough that may affect up to 20%.

Direct Renin Inhibitors

Direct renin inhibitors (DRI) represent novel treatments for inhibiting the RAS. One randomised trial of aliskerin, the first DRI in clinical use, reported additional albuminuria reduction when aliskerin was combined with ARB therapy in patients with type 2 diabetes and diabetic nephropathy.

Safety Considerations

Despite the proven renoprotective benefits of ACEI and ARB treatment, some physicians remain reluctant to prescribe them in patients with CKD due to concerns about their potential adverse effects in patients with renal failure. The two principal areas of concern are hyperkalemia and exacerbation of renal failure, but the risk of each can be minimized by the application of simple precautions.

Hyperkalemia

In large randomized trials of ACEI or ARB treatment in CKD, the risk of hyperkalemia is reported to be low and resulted in discontinuation of therapy in only 0–4% of patients. A higher risk can be anticipated in patients with more advanced renal failure and in diabetic nephropathy. The mainstay of prevention is comprehensive counseling to reduce dietary potassium intake and avoidance of potassium supplements as well as potassium-sparing diuretics. Serum potassium should be measured prior to initiation of therapy and again 3–5 days after the first dose as well as after any dose increase.

Exacerbation of Renal Failure

As discussed above, ACEI and ARB treatment results in lowering of glomerular capillary hydraulic pressure and can therefore be expected to produce an initial reduction in GFR, evidenced by a rise in serum creatinine. Analysis of data from 12 randomized trials found that, paradoxically, the extent of the reduction in renal function associated with the initiation of ACEI treatment was inversely correlated with the subsequent rate of decline in renal function over time. Thus an initial increase in serum creatinine should not prompt the discontinuation of ACEI or ARB treatment, provided the increase is not progressive and is less than 30% over the first 2 months. We recommend that serum creatinine should be monitored 3–5 days after initiation of ACEI treatment and after each dose increase. Additional measures that may reduce the risk of a decline in renal function include ensuring adequate hydration, omitting or reducing diuretic treatment for 1 or 2 days prior to starting the ACEI or ARB, avoidance of nonsteroidal anti-inflammatory drugs, and starting ACEI or ARB treatment at a low dose. ACEI and ARB treatments are contraindicated in patients with bilateral renal artery stenosis and should be used with caution in patients with extensive vascular disease who may have undiagnosed renovascular disease.

Reduction of Proteinuria

Evidence that abnormal urinary excretion of protein may contribute directly to progressive renal injury has focused attention on the relationship between renal outcomes and proteinuria. It has been recognized for many years that the extent of proteinuria is a marker of disease severity and in several studies, baseline proteinuria showed a positive correlation with the subsequent rate of decline in GFR. Recent analyses have found that residual proteinuria on therapy is also a powerful predictor of outcomes. The importance of residual proteinuria has been confirmed by a meta-analysis of data from 1860 patients with nondiabetic CKD that found a 5.56-fold increase in the risk of reaching a combined endpoint of doubling of serum creatinine or onset of ESRD for each 1.0 g/day increase in extent of proteinuria after initiation of treatment. One randomised trial has confirmed that titrating ACEI or ARB treatment to the maximum antiproteinuric dose affords greater renoprotection than standard doses. Thus proteinuria is regarded as an independent, modifiable risk factor for CKD progression and a clinically useful surrogate marker of the success of renoprotective interventions. Moreover, albuminuria is also predictive of cardiovascular risk and in the RENAAL Study each 50% reduction in albuminuria over the first 6 months was associated with an 18% reduction in cardiovascular risk as well as a 27% reduction in the risk of heart failure. Based on these data we recommend that treatment with ACEI or ARB should be escalated until proteinuria is reduced to <1 g/day and combination ACEI and ARB therapy should be considered if this goal is not achieved. Even lower proteinuria goals of <0.3 g/day have been recommended, but data regarding the optimal target for proteinuria reduction are currently lacking.

Treatment of Dyslipemia

Dyslipemia characterized by elevated triglyceride-rich lipoproteins and reduced high-density lipoprotein (HDL) cholesterol is commonly associated with CKD and probably contributes to the attendant increased cardiovascular risk. Moreover, experimental evidence suggests that lipid abnormalities may also contribute to progressive renal injury. In several animal models, treatment of hyperlipidemia has been associated with attenuation of CKD progression. To date only small prospective studies have been conducted in humans. A meta-analysis of 13 such studies reported a significantly slower rate of GFR decline among CKD patients receiving lipid-lowering therapy. Several large randomized trials are underway to test the hypothesis that treatment of dyslipemias contributes to renoprotection and results should be available within 2–3 years. Until these data are published it is possible to recommend active treatment of dyslipemias on the basis of cardiovascular risk alone. It should be noted that standard cardiovascular risk estimates probably underestimate the risk in CKD patients, who were excluded from the studies used to derive the estimates. Thresholds and targets for treatment as well as the relative efficacy of different drugs all remain to be determined. The Kidney Disease Outcome Quality Initiative (K/DOQI) Guidelines currently recommend that patients with CKD stage 1–4 should be considered to be in the highest cardiovascular risk group and managed according to guidelines published by the National Cholesterol Education Program. Low-density lipoprotein (LDL) cholesterol should be reduced to <100 mg/dL and additional treatment should be considered if triglyceride levels are >200 mg/dL.

Treatment of Anemia

Anemia due to decreased renal production of erythropoietin is a common complication of CKD and may have a major impact on patients' quality of life. Replacement therapy with recombinant human erythropoietin allows correction of the anemia and results in improvement in quality of life as well as a decrease in hospital admissions. Additionally, correction of anemia may contribute to slowing the rate of GFR decline in CKD. Analysis of data from the RENAAL Study found that baseline hemoglobin was a significant predictor of the subsequent development of ESRD such that each 1 g/dL decrease in hemoglobin was associated with an 11% increase in the risk of ESRD. Moreover, one randomized study that included 88 patients with nondiabetic CKD has shown that early treatment (started when hemoglobin <11.6 g/dL) with erythropoietin alpha was associated with a 60% reduction in the risk of doubling serum creatinine, ESRD, or death versus delayed treatment (started when hemoglobin <9.0 g/dL). It should be noted, however, that ACEI and ARB treatments were discontinued prior to entry into this trial and it is therefore not clear whether these benefits would occur in patients receiving ACEIs or ARBs. On the other hand, the CREATE trial reported more rapid progression to ESRD among CKD patients receiving erythropoietin treatment and randomised to a target haemoglobin of 13.0–15.0 g/dL versus those randomised to a target haemoglobin of 10.5–11.5 g/dL. There are insufficient data available at present to allow recommendations regarding thresholds for treatment or therapeutic goals. K/DOQI currently recommends treatment to achieve a hemoglobin of 11.0–12.0 g/dL in CKD patients not requiring dialysis.

Glycemic Control

As discussed above, there is good evidence that tight glycemic control reduces the risk of developing microalbuminuria in patients with type 1 and type 2 diabetes. Among patients who already have microalbuminuria data are conflicting with some but not all studies reporting a lower risk of progression to proteinuria in patients with better glycemic control. In patients with established diabetic nephropathy there are no data regarding the effect of glycemic control. Nevertheless, a study that found regression of early diabetic nephropathy lesions after pancreatic transplantation suggests that improved glycemic control does confer renoprotective benefit. Moreover, patients with diabetes with nephropathy remain at risk for other microvascular complications and tight glycemic control (HbA1C <7%) should therefore remain a treatment goal. It should be noted however that in some patients, attempts to achieve tight glycemic control may be associated with adverse consequences. In the ACCORD trial patients with type 2 diabetes randomised to a low target HBA1C of <6.0% evidenced increased mortality.

Clinical trials have identified several interventions that are effective in slowing the rate of GFR decline in CKD. Whereas each affords benefit, none is able to arrest progression of CKD in the majority of patients. Thus, many will still progress to ESRD, albeit at a slower rate. Factors shown to be predictive of a worse prognosis include severity of proteinuria, serum creatinine, serum albumin, and hemoglobin. In light of these data it seems logical to combine effective interventions directed at different aspects of CKD progression into a comprehensive strategy for maximizing renoprotection. One study has shown that application of intensive combination therapy in patients with type 2 diabetes and microalbuminuria was associated with a 53% reduction in risk of cardiovascular disease and an approximately 60% reduction in risk of microvascular complications. Additionally, it is helpful to apply the concept of “remission” to CKD such that treatment is escalated until the major manifestations of CKD have been brought under control. The interventions that comprise such a strategy and therapeutic goals that define remission are summarized in Table 22–2. It should be noted that the treatments and tests required for monitoring are relatively inexpensive and are widely available. Application of this approach should therefore be possible across a wide range of healthcare systems and may substantially reduce the number of patients dependent on renal replacement therapy worldwide. Achieving this goal is arguably the greatest challenge facing nephrologists today.

• Kidney Disease Improving Global Outcomes: www.kdigo.org. Provides links to several major national and international treatment guidelines.
• National Kidney Foundation: www.kidney.org/professionals/kdoqi/guidelines. Provides access to all K/DOQI treatment guidelines as well as updates. The Web site also offers online calculation of estimated GFR and CKD stage-specific treatment plans. Many features are available for downloading.