β-Blockers may offer benefits in the treatment of diabetic nephropathy as
demonstrated by the United Kingdom Prospective Diabetes Study, which showed
similar effects of atenolol and captopril on decreasing the incidence of albuminuria
61 β-Blockers offer several benefits to CKD patients such as
attenuation of excessive sympathetic output and reduction in sudden cardiac death
62,63 β-Blocker selection should take into account the
dialyzability of the drug and/or the risk for drug accumulation.
Low HDL levels, impaired HDL function, higher percentages of oxidized LDL
(highly atherogenic LDL molecules), and elevated lipoprotein(a) (highly atherogenic
lipoproteins) levels are characteristic alterations of dyslipidemia in CKD that vary
65 Similar to the general population, very high cholesterol
and elevated non-HDL lipoprotein cholesterol have been associated with increased
hospitalizations and CVD mortality in CKD. A meta-analysis of trials have
demonstrated an association of statin use with decreased proteinuria and uncertainty
66 Despite uncertainty of therapy with regard to delaying
CKD progression, dyslipidemia should be treated in the kidney disease population.
Abnormal lipid metabolism is present in these patients, which predisposes them to
the development of atherosclerotic disease. Although the potential for elevated
cholesterol profiles in CKD suggests a beneficial role for lipid-lowering therapies in
CKD, a varying cardiovascular pathology (e.g., vascular calcification, sympathetic
overactivity) in CKD limits the role of lipid-lowering therapies (i.e., statins) across
) and efferent arteriolar constriction (mediated primarily by angiotensin II) occur within remaining
The KDIGO Clinical Practice Guidelines for Lipid Management in CKD released
guidance for the management of dyslipidemia. Similar to the general population,
statin therapy is recommended irrespective of baseline LDL cholesterol levels in
non-dialysis–dependent CKD patients.
67 For CKD patients ≥50 years and not on
dialysis, KDIGO recommends treatment with a statin or statin/ezetimibe combination.
CKD patients aged 18 to 49 years with additional CVD risk factors such as known
coronary disease (MI or coronary revascularization), diabetes, prior ischemic stroke,
or estimated 10-year coronary heart disease risk >10% are recommended to initiate
statin therapy. A strategy of “fire-and-forget” is suggested for statin therapy where
measurement of LDL cholesterol is avoided unless results would alter management.
However, recent commentary of the KDIGO guidelines suggest measuring lipids 6
weeks to 3 months after initiation of a statin in order to identify patients with an
inadequate response to moderate-intensity statins and who require dose titration as a
reasonable approach to lipid monitoring.
The Study of Heart and Renal Protection (SHARP) assessed the effect of lowering
LDL cholesterol in 9,270 CKD patients with ezetimibe 10 mg daily and simvastatin
20 mg daily or matching dummy placebo tablets for an average of 5 years. Mean
; 3,023 (33%) were on dialysis and 2,094 (23%)
had diabetes. Key outcomes were reductions in major atherosclerotic events and
kidney disease progression. SHARP results showed a 25% risk reduction in major
atherosclerotic events. However, there was no effect on the progression of kidney
69 The significance found with the combined primary outcome was most
likely driven by significant reductions in non-hemorrhagic stroke and coronary
revascularization. Although the study was not powered to detect differences within
subgroups, subgroup analysis did not find a statistically significant benefit in patients
The cardiovascular benefits of statin use observed in the general population have
not consistently been demonstrated in the dialysis populations, possibly owing to the
multifactorial pathogenic process of CVD in those with kidney disease (e.g., the
presence of vascular calcification).
65 KDIGO lipid guidelines recommend against
treatment with a statin in CKD 5D patients unless initiated prior to the start of
The Die Deutsche Diabetes Dialyse Studie (4D) and AURORA are two large
multicenter, double blind, placebo-controlled, randomized controlled trials that
examined the effects of lowering the level of LDL-C on cardiovascular events and
mortality with atorvastatin or rosuvastatin, respectively. Both studies with a
combined patient population of greater than 4,000 demonstrated significant
reductions in LDL cholesterol levels; however, neither produced statistically
significant reductions in the primary outcome measure. The results of these studies
along with the negative effects in dialysis patients from the SHARP study have
largely driven KDIGO recommendations to avoid initiating statin therapy in dialysis
KDIGO recommend that statins be prescribed in preference to fibrates. Fibrates
should be used cautiously in patients with CKD; all agents in this class are
metabolized by the kidney and are eliminated primarily via the kidney, which may
lead to an increased risk of rhabdomyolysis. However, fibric acid derivatives may
be considered in patients presenting with very high triglycerides (>1,000 mg/dL).
Gemfibrozil is cautioned in mild to moderate kidney dysfunction and not
recommended in severe kidney impairment.
END-STAGE RENAL DISEASE (CHRONIC
During CKD 4 and 5, patients may develop the more severe signs and symptoms
associated with advanced kidney disease, often referred to as uremic syndrome. The
manifestations and metabolic consequences of advanced kidney disease are listed in
Table 28-7. These manifestations certainly may develop in the earlier stages of CKD,
underscoring the importance of early intervention, but they become more prominent
as the disease worsens. The pathogenesis of these disorders has been attributed, in
part, to the accumulation of uremic toxins. The search for uremic toxins has led to the
identification of nitrogenous compounds that are consistently observed in the serum
of patients with kidney disease. A cause and effect relationship between these
compounds and the clinical manifestations of uremia has not been clearly
Metabolic Effects of Progressive Kidney Disease
Calcium–phosphorous imbalances
Altered carbohydrate metabolism
Hypophyseal-gonadal dysfunction
Fluid, Electrolyte, and Acid–Base Effects
Muscular irritability and cramps (i.e., restless legs syndrome)
As ESRD becomes inevitable, the appropriate dialysis modality must be selected on
the basis of patient preference and options for vascular access for HD or peritoneal
access for PD. Early planning for dialysis therapy and timely initiation may lower
patient morbidity and mortality. (Indications for dialysis and considerations in
selection of modality are discussed in Chapter 30, Renal Dialysis.) Kidney
transplantation is an option for all patients with ESRD without specified
contraindications if a suitable organ match is available (see Chapter 34, Kidney and
Pharmacotherapy in patients with ESRD requires interventions to manage comorbid
conditions and secondary complications of CKD. The extent of medication use,
including medications administered during dialysis therapy, contributes to the
potential for drug interactions, adverse reactions, and nonadherence to therapy.
effect of decreased kidney function on absorption, distribution, metabolism, and
elimination of pharmacologic agents, in addition to the contribution of dialysis to
drug removal, further complicates pharmacotherapy in this population (see Chapter
31, Dosing of Drugs in Renal Failure). Appropriate pharmacotherapeutic
management includes choice of rational agents based on the indication, a regular
comprehensive review of all medications, and frequent reevaluation to adjust
regimens relative to kidney function.
G.B.’s abnormal values for SCr, BUN, serum potassium, magnesium, phosphate, uric
acid, CO2 content, hemoglobin, are all consistent with kidney disease and its
associated complications. Assuming relatively stable kidney function (i.e., no acute
changes in kidney function), her eGFR is approximately 21 mL/minute/1.73 m2 based
on the MDRD equation, placing her in CKD category 4 (eGFR 15–29
). As the eGFR declines to the degree observed in G.B., normal
regulation of fluids and electrolytes is impaired. Elevations in SCr, BUN, sodium,
potassium, magnesium, phosphate, and uric acid as well as signs of fluid
accumulation are observed. G.B.’s serum potassium is slightly elevated and the risk
of hyperkalemia increases with CKD.
73 The substantial degree of proteinuria
observed in G.B. is consistent with advanced glomerular damage. Volume overload
from continued intake and decreased sodium and water excretion leads to weight
gain, hypertension, and edema. Metabolic acidosis results from impaired synthesis of
ammonia by the kidney, which normally buffers hydrogen ions and facilitates acid
excretion. Anemia associated with CKD is caused primarily by decreased EPO
production by the kidneys, but it also can be caused by shortened half-life of RBCs
from uremia, and iron deficiency. G.B.’s recent onset of nausea and malaise may be a
consequence of the accumulation of uremic toxins (azotemia) from the decline in
past 6 months. The workup reveals the following pertinent laboratory values:
Random blood glucose, 289 mg/dL
a 10-lb weight gain. Additional laboratory studies show the following results:
Hematologic studies show the following results:
White blood cell (WBC) count, 9,600/μL
diagnosis of advanced kidney disease?
CASE 28-1, QUESTION 2: What is the cause of G.B.’s advanced kidney disease?
Given G.B.’s presentation, her kidney disease is most likely caused by diabetic
nephropathy from her 20-year history of type 2 diabetes mellitus. Poor compliance
with regular appointments, elevated glucose concentration and hemoglobin A1c
albuminuria serve as the primary cause. Diabetic nephropathy rarely develops
within the first 10 years after the onset of type 1 diabetes; however, 5% to 20% of
patients with type 2 diabetes have some degree of albuminuria at diagnosis. The
annual incidence is greatest after approximately 20 years’ duration of diabetes and
declines thereafter. G.B. fits this pattern in that she has diabetic nephropathy after a
20-year history of diabetes, although her nephropathy was likely evident several
years previously. African Americans, Native Americans, and Hispanics have an
increased risk of developing ESRD from diabetes relative to whites.
Diabetic nephropathy is a microvascular complication of diabetes resulting in
albuminuria, hemodynamic changes in kidney microcirculation, glomerular structural
changes, and a progressive decline in kidney function. Diabetic nephropathy
develops in approximately one-third of all patients with type 1 and type 2 diabetes.
Because type 2 diabetes is more prevalent, these patients account for most diabetic
patients starting dialysis. With the increased prevalence of diabetes and the increase
in life expectancy of this population, it is likely that diabetic nephropathy will remain
the leading cause of ESRD in the United States. Whereas most research has focused
on the pathophysiology, prevention, and treatment of diabetic nephropathy in type 1
diabetes, it is reasonable to extrapolate available evidence on prevention of diabetic
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