Determination of albuminuria can be done using timed urine samples (Table 28-4).
Typically, a 24-hour collection period termed albumin excretion rate (AER) is used,
although a timed sample collected overnight may be more reliable because albumin
excretion can vary throughout the day and with postural changes (i.e., orthostatic
albumin in a timed collection, this method corrects for variations in hydration status
and may be more accurate because protein excretion is normalized to glomerular
filtration. The albumin and creatinine concentrations in the urine are measured from a
spot urine sample, preferably from first morning urine sample, because it correlates
best with 24-hour albumin excretion. If a first morning urine
sample is not available, a random sample is acceptable. Factors associated with
albuminuria, such as ingestion of a high-protein meal and vigorous exercise, must be
considered when evaluating urinary albumin. Measuring urinary protein after
exercise will result in a falsely elevated urine protein level as a consequence of an
increase in the membrane permeability of the glomeruli to protein and a saturation of
the tubular reabsorption process of filtered protein. To minimize this risk, it is
recommended to wait approximately 4 hours after exercise to test for proteinuria.
Screening for albuminuria can also be done using urine dipstick testing of a spot
urine sample. Reagent strips are available from several commercial vendors and
differ with regard to the specified testing procedure and the sensitivity and
specificity for detecting albuminuria. Patients with a positive dipstick screening test
should have a subsequent quantitative assessment of the ACR to confirm proteinuria.
The KDIGO Guidelines for Evaluation and Management of CKD provide criteria for
albuminuria categories (Table 28-4).
COMPLICATIONS OF CHRONIC KIDNEY DISEASE
Complications specific to CKD begin to develop as kidney disease progresses, most
often when patients reach CKD 3 (eGFR <60 mL/minute/1.73 m2
complications include fluid and electrolyte abnormalities, metabolic acidosis,
anemia, MND, cardiovascular complications, and poor nutritional status. Often, these
complications go unrecognized or are inadequately managed during the earlier stages
of CKD, leading to poor outcomes by the time a patient is in need of dialysis therapy.
Hypoalbuminemia and anemia were identified in more than 50% of a population of
patients new to dialysis therapy, and these findings were associated with a decreased
37 Late referral to a nephrologist to manage CKD and its associated
complications has also been associated with increased mortality in the ESRD
37 The KDIGO guidelines recommend referral of patients to a nephrologist
in any of the following circumstances: AKI or an abrupt fall in GFR, a GFR <30
, persistent albuminuria (ACR ≥ 300 mg/g), progression of CKD,
hereditary kidney disease, CKD with resistant hypertension on four or more
antihypertensive agents, and in all patients in whom the risk of progression to CKD
5D (CKD category 5 receiving dialysis) in the next year is estimated at 10% to 20%
1 These and similar reports underscore the need for early and aggressive
therapy to manage complications of CKD. Complications of CKD will be presented
in more detail throughout this chapter, and complications associated with dialysis
therapy are discussed in Chapter 30, Renal Dialysis.
Appropriate management of CKD includes measures to slow progression of the
disease and regular evaluation of kidney function to assess changes in disease
severity and to monitor therapy. This includes aggressive strategies to manage the
disorders that cause kidney disease or are known to accelerate the disease process,
such as diabetes mellitus, hypertension, high protein intake, and dyslipidemias (see
Chapter 8, Dyslipidemias, Atherosclerosis, and Coronary Heart Disease; Chapter 9,
Essential Hypertension; and Chapter 53, Diabetes Mellitus).
Proteinuria is a significant predictor of ESRD in patients with CKD.
protein ingestion are associated with a rise in eGFR, possibly as a result of structural
changes of the glomerulus and changes in renal plasma flow with an increased
40 Evidence such as this has led to the investigation of methods to reduce
the degree of proteinuria. In addition to controlling the primary causes of kidney
dietary protein restriction has been evaluated as a strategy for reducing proteinuria
and delaying progression of kidney disease.
A number of studies have investigated the effect of protein restriction on disease
progression with varying results.
40–42 These conflicting conclusions may be
attributable to differences in study design, patient populations, methods to assess
kidney function, degrees of protein restriction, and dietary compliance. The MDRD
study evaluated the effects of protein restriction and strict BP control on the
progression of kidney disease. There was no difference in renal function
deterioration comparing patients who received a normal protein diet (1.3 g/kg/day)
with those receiving a low-protein (0.58 g/kg/day) diet.
receiving a low-protein diet (0.58 g/kg/day) compared with those receiving a very
low-protein diet (0.28 g/kg/day plus keto and amino acid supplementation) had a
faster decline in renal function. A secondary analysis of the MDRD study, which
accounted for dietary compliance, suggested that patients with severe kidney disease
) could benefit from protein restriction of 0.6
44 However, a follow-up analysis of the MDRD study found no significant
KDIGO Guidelines for Evaluation and Management of CKD currently recommend
lowering protein intake to 0.8 g/kg/day while avoiding high protein intake (i.e.,
>1.3g/kg/day) in adults at risk for progression.
1 Avoiding excessive accumulation of
uremic toxins, loss of lean body mass, and malnutrition are benefits of appropriate
dietary protein restrictions. The potential benefits of protein restriction in patients
with CKD must be weighed against the potential adverse effect on overall nutritional
status. Malnutrition is prevalent in patients with CKD starting dialysis and is a
predictor of mortality in this population.
Antihypertensive therapy prevents kidney damage and slows the rate of progression
of CKD in both diabetic and nondiabetic patients.
In addition, the added benefit of
reduced cardiovascular mortality further supports the use of antihypertensive therapy
in patients at risk for progressive CKD. Despite what is known about the beneficial
effects of BP control in patients with CKD, rates of hypertension control in the
predialysis population remain suboptimal.
The 2014 Evidence-Based Guideline for the Management of High Blood Pressure
in Adults (commonly referred to as JNC-8) and the KDIGO/Management of Blood
Pressure in Chronic Kidney Disease Guideline recommends is a BP less than 140/90
46,47 Controversy exists as to the optimal BP target in CKD patients
with albuminuria (>30 mg in 24 hours or equivalent). The KDIGO guidelines
recommend a BP target of ≤130/80 mm Hg in CKD patients with albuminuria (>30
mg in 24 hours or equivalent) while JNC-8 suggest a target of 140/90 mm Hg for
patients with albuminuria. Evidence for further reduction of BP in patients with
albuminuria stems mostly from ancillary analysis of larger trials. Results from the
MDRD study showed that further lowering of BP to less than 125/75 mm Hg (or a
mean arterial pressure <92 mm Hg) was more beneficial than usual BP control in
patients with higher rates of urinary protein excretion (>1 g protein/day).
effects of more aggressive BP control on progression of kidney disease were also
studied in the African American Study of Kidney Disease and Hypertension (AASK)
49 African Americans aged 18 to 70 years with hypertensive kidney disease
) were included in this study. A post hoc analysis of
that patients with proteinuria greater than 1 g/day assigned to the low BP target had
50 Clearly, BP control is important to delay progression
of kidney disease, and with the expanding data supporting more aggressive BP
lowering in patients with more severe proteinuria, the importance of BP control in
this patient population is pivotal in slowing progression of CKD. In light of the
concerns with the presence of albuminuria, a target of <140/90 mm Hg is reasonable
in the CKD patient with albuminuria.
Among the available classes of antihypertensive agents, ACE inhibitors (ACEIs;
e.g., enalapril, captopril, lisinopril) and ARBs (e.g., losartan, irbesartan,
candesartan) may afford additional benefits in preserving kidney function. As a
result, ACEIs and ARBs are most commonly recommended as first-line treatment
options for hypertension in those with CKD, those at risk for CKD (e.g., diabetics),
and those with albuminuria by the KDIGO hypertension guidelines.
decreased eGFR, angiotensin II primarily causes compensatory vasoconstriction of
the efferent arteriole, thereby increasing glomerular capillary pressure (PGC) and
eGFR (Fig. 28-1). This effect is beneficial in conditions of acute renal failure;
however, sustained increases in PGC cause hypertrophy of individual nephrons and
progressive kidney disease. ACEI and ARB therapy prevent the chronic increase in
glomerular pressure mediated by angiotensin II. Benefits of ACEIs have been
demonstrated in patients with diabetes with some degree of proteinuria, suggesting
that ACEI use be considered in this population regardless of BP.
diabetes, ACEIs have been shown to reduce BP, decrease proteinuria, and slow the
progression of kidney disease when compared with other agents. An initial and mild
decrease in eGFR is expected with ACEI therapy; therefore, an increase in SCr of
30% within the first 2 months of therapy is acceptable.
failure, and severe hyperkalemia are reasons to consider discontinuing therapy (also
see Chapter 14, Heart Failure).
Angiotensin II receptor blockers offer similar benefits to ACEIs on the basis of
their ability to decrease efferent arteriolar resistance by blockade of the angiotensin
) receptor. In patients with type 2 diabetes mellitus, losartan decreased
the incidence of a doubling of SCr by 25% and of ESRD by 28% when compared
with placebo after a mean of 3.4 years of therapy.
52 Similar effects were observed in
the Irbesartan Diabetic Nephropathy Trial (IDNT), with a 23% decreased risk of
ESRD observed in patients treated with irbesartan.
In both studies, these beneficial
effects were independent of reduction in BP. Reduction in the degree of proteinuria
has also been demonstrated with candesartan and valsartan.
with an ARB and ACEI increases the progression to ESRD, hyperkalemia events,
and acute kidney injury risk and should be avoided.
Aliskiren is the only available direct renin inhibitor. Its use as monotherapy is
unclear and combination with ACEI or ARBs should be avoided.
been associated with reduction in GFR and filtration fraction in patients receiving
optimal heart failure therapy.
Calcium-channel blockers have been considered for preventing progression of
kidney disease owing to their effects on renal hemodynamics and cytoprotective and
antiproliferative properties (prevention of mesangial expansion and renal scarring).
Nondihydropyridine agents (e.g., diltiazem and verapamil) have been beneficial in
reducing proteinuria when compared with dihydropyridines (e.g., amlodipine), which
have been found to worsen proteinuria.
59,60 Dihydropyridine calcium-channel
blockers have the effect of increasing albuminuria and should not be used alone in
patients with proteinuria, but can be used safely in combination with an ACEI or
ARB. Combination therapy with an ACEI and nondihydropyridine agents has resulted
in greater reductions in proteinuria in patients with diabetes than with either agent
alone, suggesting that it may be rational to use multiple agents in this population.
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