Managing advanced chronic kidney disease: A primary care guide
ABSTRACTChronic kidney disease (CKD) is a common disorder that requires close collaboration between the primary care physician and nephrologist. Most aspects of early CKD can be managed in the primary care setting with nephrology input. As the disease progresses, many aspects of care should be transitioned to the nephrologist, especially as the patient nears end-stage renal disease, when dialysis and transplantation must be addressed.
KEY POINTS
- Steps to stabilize renal function include blood pressure and diabetes control.
- Patients have a very high risk of cardiovascular disease, and one should try to reduce modifiable risk factors such as hypertension (which is also a risk factor for the progression of CKD) and hyperlipidemia.
- In addition to controlling blood pressure, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria, a risk factor for progression of CKD.
- Patients with CKD develop secondary hyperparathyroidism, hyperphosphatemia, and, in advanced CKD, hypocalcemia, all leading to disorders of bone mineral metabolism. Low vitamin D levels should be raised with supplements, and high phosphorus levels should be lowered with dietary restriction and phosphate binders.
Aggressive lipid management
Hyperlipidemia is a common risk factor for cardiovascular morbidity and mortality in CKD.21 However, until recently, all studies of outcomes of patients treated for hyperlipidemia excluded patients with CKD. Post hoc analyses of these studies 22–27 showed statins to be beneficial in primary and secondary cardiovascular prevention in patents with “normal” serum creatinine values but estimated GFR levels of 50 to 59 mL/min/1.73 m2.
The SHARP trial28 was the first prospective trial to study lipid-lowering therapy in patients with CKD. In this trial, patients with various stages of CKD, including advanced CKD, had fewer major vascular events if they received the combination of low-dose simvastatin (Zocor) and ezetimibe (Zetia). However, the evidence does not suggest that statin therapy slows the progression of CKD.28–31
Recommendation. Manage hyperlipidemia aggressively using statin therapy with or without ezetimibe, with a target low-density lipoprotein cholesterol level below 100 mg/dL.32
Manage other cardiovascular risk factors
Because hypertension and proteinuria are risk factors not only for cardiovascular disease but also for progression of CKD, they are discussed in the section below.
ATTEMPT TO PREVENT WORSENING OF RENAL FUNCTION
Medications to avoid
It is important to review a CKD patient’s medication list—prescription and over-the-counter drugs—to identify any that may contribute to a worsening of renal function. CKD patients need to be informed about avoiding medications such as nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and herbal supplements because they can cause further renal injury. In addition, other medications (eg, metformin) are contraindicated in CKD because of side effects that may occur in CKD.
Patients should be encouraged to discuss any changes in their medications, including over-the-counter products, with their primary care physicians.
Manage hypertension aggressively
Many patients with CKD also have hypertension,33,34 possibly because they have a higher frequency of underlying essential hypertension or because CKD often worsens preexisting hypertension. Moreover, uncontrolled hypertension is associated with a further decline in renal function.35,36
The ACCORD trial37 found no benefit in lowering systolic blood pressure to less than 120 mm Hg compared with less than 140 mm Hg in patients with diabetes mellitus. (The patients in this study did not necessarily have CKD.)
A meta-analysis38 of trials of antihypertensive treatment in patients with CKD found that the optimal target systolic blood pressure for decreasing the progression of CKD was 110 to 129 mm Hg. The relative risk of progression of renal dysfunction was:
- 1.83 (95% confidence interval [CI] 0.97–3.44) at 130 mm to 139 mm Hg, vs
- 3.14 (95% CI 1.64–5.99) at 160 mm Hg or higher.
There is also evidence that blood pressure control can be relaxed as patients age. While the exact age differs among published guidelines, the evidence supports a goal blood pressure of less than 150/90 mm Hg once a patient reaches the age of 70, regardless of CKD or proteinuria.
Recommendation. Current evidence suggests the following blood pressure goals in CKD patients:
- With diabetes mellitus or proteinuria: < 130/80 mm Hg
- Without proteinuria: < 140/90 mm Hg
- Age 70 and older: <150/90 mm Hg.39
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive drugs in patients with diabetes or proteinuria (see below).
Manage proteinuria
Proteinuria is also associated with progression of CKD. AASK,40 a study that included nondiabetic African American patients whose estimated GFRs were between 20 and 60 mL/min/1.73 m2, showed that higher levels of proteinuria were associated with a higher risk of decline in GFR and a higher risk of end-stage renal disease. Findings were similar to those in studies of other CKD populations.41–43 Proteinuria is also an independent risk factor for cardiovascular disease and death. Multiple large studies16,17,44,45 have found associations between higher levels of albumin excretion and risk of major cardiovascular events, cardiovascular death, and death from any cause in people with and without diabetes.
Reducing proteinuria has been shown to both slow progression of renal dysfunction and reduce the cardiovascular risk.44,45 In a substudy of the IDNT46 in patients with diabetic nephropathy, each 50% reduction in urinary protein excretion was associated with a 56% reduction in risk of progression of CKD. Similar effects have been shown in nondiabetic CKD patients.47
ACE inhibitors and ARBs are the preferred treatments for proteinuria in patients with CKD.48–50 Combination therapy with an ACE inhibitor and an ARB has been used,51–53 with a better response in proteinuria reduction. However, combination therapy with these drugs cannot currently be recommended, as the only prospective study of this regimen to date suggested worse renal and overall outcomes in patients at high cardiovascular risk.54 These drugs may also have renoprotective effects independent of their effects on blood pressure and proteinuria.38 Dietary salt restriction and diuretic therapy can further increase the efficacy of proteinuria reduction by ACE inhibitors or ARBs.55,56
On the other hand, stopping ACE inhibitors or ARBs may be beneficial as the patient nears end-stage renal disease. Ahmed et al57 demonstrated that stopping ACE inhibitors or ARBs in advanced stage 4 CKD (mean estimated GFR 16 mL/min/1.73 m2) was associated with improved GFR and delayed onset of renal replacement therapy. This improvement may be due to regaining the slight decrease in GFR that occurred when these medications were started.
Nondihydropyridine calcium channel blockers such as diltiazem (Cardizem) and verapamil (Calan) have also been shown to be useful for reducing proteinuria,58 whereas dihydropyridine calcium channel blockers such as amlodipine (Norvasc) and nifedipine (Procardia), when used without ACE inhibitors or ARBs, can worsen proteinuria.58,59
Correct metabolic acidosis
The kidneys play an important role in maintaining acid-base balance, keeping the blood from becoming too acidic both by reabsorbing bicarbonate filtered into the urine by the glomerulus and by excreting the daily acid load. Metabolic acidosis can develop when these functions break down at more advanced stages of CKD, most often when the estimated GFR declines to less than 20 mL/min/1.73 m2.
Bicarbonate levels of 22 mmol/L or less have been associated with a higher risk of worsening renal function.60 When such patients were treated with sodium bicarbonate to achieve a serum bicarbonate of at least 23 mmol/L, they had an 80% lower rate of progression to end-stage renal disease without any increase in edema, admission for congestive heart failure, or change in blood pressure.61
Susantitaphong et al62 reviewed six randomized trials of bicarbonate supplementation in CKD and found that it was associated with improved kidney function and a 79% lower rate of progression to end-stage renal disease.
The proposed mechanism behind this benefit lies in the increase in ammonia production that each surviving nephron must undertake to handle the daily acid load. The increased ammonia is thought to play a role in activating the alternative complement pathway,63 causing renal inflammation and injury.
Recommendation. Bicarbonate therapy should be used to maintain serum bicarbonate levels above 22 mmol/L in CKD.64
