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.
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 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 (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.
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 (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.
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.
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.
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.
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.
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.
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.
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