Clinical management of chronic kidney disease

1. How do you recognize progressive kidney failure?

Progressive kidney failure is recognized by an increasing serum creatinine over time. However, some patients may have a normal creatinine early in the course of their chronic kidney disease (CKD). Individuals with an abnormal urinary sediment (e.g., proteinuria or hematuria) or abnormal pathology on a kidney biopsy are at risk for progressive kidney failure.

Because serum creatinine is a reflection of muscle mass, a person with low muscle mass can have CKD despite a creatinine in the normal range. Conversely, patients with larger muscle mass may have an abnormally elevated creatinine despite normal kidney function. For these reasons, calculating an estimated glomerular filtration rate (eGFR) is the recommended way to assess kidney function (see chapter on Glomerular Filtration Rate). These equations should not be used in acute kidney injury because the calculations assume a stable serum creatinine.

2. How do you monitor the rate of loss of kidney function?

Kidney function is monitored with serum creatinine (or eGFR correlates as outlined previously) and urinalysis. A certain degree of fluctuation in serum creatinine can be expected and is usually related to changes in volume status, medications, and diet. Creatinine values should be viewed over time to judge progression of CKD.

Creatinine-based GFR-estimating equations are less accurate in elderly patients and lead to overdiagnosis of CKD, particularly in those patients with higher eGFR. Directly measuring creatinine clearance or using creatinine in combination with cystatin C–based eGFR equations can be used to further assess kidney function in older patients if a definitive diagnosis of CKD is required (e.g., a potential kidney donor).

A rise in urine protein excretion (or a failure to decrease urine protein excretion following treatment) is also an indicator of disease activity and progression of kidney disease. Therapy should be aimed at reducing proteinuria to slow the progression of kidney disease. This can be done by treating the underlying disease, if possible, or using inhibitors of the renin angiotensin system (such as angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] but not in combination) to decrease proteinuria.

3. What are the risk factors, diseases, and complications that should be considered in the management of patients with progressive kidney failure?

See Box 24.1 .

4. What is the blood pressure (BP) goal for a person with progressive kidney failure?

Although guidelines such as Joint National Committee (JNC) 8 relaxed BP goals compared with prior treatment recommendations, there has been evidence from studies published subsequent to these guidelines supporting a more aggressive approach to BP management.

The Systolic Blood Pressure Intervention Trial (SPRINT) was a prospective randomized controlled trial that was enriched with CKD patients (although without significant proteinuria) that assigned patients to a systolic BP goal of less than 120 mm Hg (intensive treatment) or less than 140 mm Hg (standard treatment). BP was measured differently from typical office BPs, using a device that can average multiple consecutive readings with the patient resting alone in a room. A mean of three consecutive BPs was used as the visit BP.

Overall, participants assigned to the intensive treatment group, as compared with those assigned to the standard treatment group, had a 25% lower relative risk (RR) of major cardiovascular events, with consistent results across subgroups defined according to age, sex, race, medical history, and baseline BP. In addition, the intensive treatment group had a 27% lower RR of death from any cause. SPRINT was the first randomized controlled trial (RCT) to demonstrate a benefit in lower BP goals (i.e., systolic <140). Of note, the method of BP assessment in the trial is rarely used in clinical practice.

In an earlier RCT, the African American Study of Kidney Disease and Hypertension, African Americans with hypertension and CKD were randomly assigned one of two mean arterial pressure goals: 102 to 107 mm Hg or 92 mm Hg or less. Achieved BP averaged 128/78 mm Hg in the lower BP group and 141/85 mm Hg in the usual BP group. The mean change in GFR over the 4 years of the study did not differ significantly between arms (–2.21 vs. –1.95 mL/min per 1.73 m ² per year, in the lower and usual BP arms, respectively; P = .24).

To address BP targets in diabetic patients, the Action to Control Cardiovascular Risk in Diabetes blood pressure (ACCORD BP) trial randomly assigned 4733 patients with type 2 diabetes who had cardiovascular disease or at least two additional risk factors for cardiovascular disease to either intensive therapy (goal systolic BP less than 120 mm Hg) or standard therapy (goal systolic BP less than 140 mm Hg). There was no significant difference in the annual rate of the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes between the intensive versus standard therapy groups. There was an increase in drug side effects, including hypotension (2.4% vs. 1.4%), syncope (2.3% vs. 1.7%), and acute kidney injury (4.1% vs. 2.5%), in the intensive therapy group versus standard therapy group. Both SPRINT and ACCORD used the same BP targets, with different patient populations (ACCORD was diabetes only and SPRINT used patients at high cardiovascular disease (CVD) risk but excluded diabetes) and had different results. Of note, SPRINT had twice the number of patients as ACCORD did.

Given conflicting data, current treatment goals are systolic <130 and diastolic <80 for CKD with proteinuria. Kidney Disease: Improving Global Outcomes (KDIGO) currently recommends a goal BP of systolic <140 and diastolic <90 for nonproteinuric CKD patients.

5. What are the preferred antihypertensive medications for a patient with progressive kidney failure?

Multiple studies suggest that in CKD, particularly with increased urine protein excretion, an ACE inhibitor or ARB is the preferred antihypertensive medications (and perhaps direct renin inhibitors if ACE inhibitors or ARBs are not tolerated). For a patient with proteinuria, BP reduction and urine protein excretion should be goals of therapy and used to titrate doses of either of these medication classes upward. Studies of ACE inhibitors and ARBs in patients with diabetes, human immunodeficiency virus (HIV)-associated nephropathy, and multiple other glomerular diseases demonstrate a benefit from the use of these agents in slowing the progression of kidney disease independent of their BP effects.

Due to their effects on glomerular hemodynamics, patients treated with ACE inhibitors and ARBs should have their serum creatinine and potassium levels monitored. Side effects include hyperkalemia and acute kidney injury (AKI). Late-onset kidney failure from angiotensin blockade has been described. A study of older patients who had significant worsening of creatinine with angiotensin blockade (>25% increase in serum creatinine) found that once angiotensin blockade was stopped, most showed improvement or stabilization in kidney function. Whether these changes represent a transient hemodynamic effect or true progression of their underlying CKD needs further investigation.

6. What studies have demonstrated that BP control slows the progression of CKD?

Multiple observational studies show that individuals with lower BPs have better overall kidney outcomes and slower progression to ultimate kidney failure. However, it is important to demonstrate this effect through a randomized clinical trial looking at kidney end points with different BP goals. For instance, if patients are randomized to a higher versus lower BP, do the patients in the lower BP group have slower progression to kidney failure? The answer to this question is, No. In large studies including the Modification of Diet in Renal Disease (MDRD) study, African American Study of Kidney Disease and Hypertension (AASK), Ramipril Efficacy in Nephropathy-2 (REIN-2) Study as well as in SPRINT, lower BP goals failed to slow the progression of kidney failure. This was confirmed in a 2016 meta-analysis of 613,815 patients and 123 studies.

Every 10-mm Hg reduction in systolic BP significantly reduced the risk of major cardiovascular disease events (RR 0.80, 95% CI 0.77 to 0.83), coronary heart disease (RR 0.83, 95% CI 0.78 to 0.88), stroke (RR 0.73, 95% CI 0.68 to 0.77), and heart failure (RR 0.72, 95% CI 0.67 to 0.78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (RR 0.87, 95% CI 0.84 to 0.91). However, the effect on kidney failure was not significant (RR 0.95, 95% CI 0.84 to 1.07).

At this time, we do not have compelling evidence that lowering BP preserves kidney function, but given its powerful effect at modulating risk of stroke, heart disease, and total mortality, this should not dissuade from careful and thoughtful BP management.