Chronic Kidney Disease and Its Complications
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Prim Care See other articles in PMC that cite the published article.
Go to:
Abstract
article-meta
Chronic kidney disease (CKD) is a complex disease impacting more than twenty million individuals in the United States. Progression of CKD is associated with a number of serious complications, including increased incidence of cardiovascular disease, hyperlipidemia, anemia and metabolic bone disease. CKD patients should be assessed for the presence of these complications and receive optimal treatment to reduce their morbidity and mortality. A multidisciplinary approach is required to accomplish this goal.
Keywords: chronic kidney disease, cardiovascular disease, metabolic bone disease, anemia, hyperlipidemia, nutrition
Go to:
Introduction
Chronic kidney disease (CKD) is recognized as a major health problem affecting approximately 13% of the United States population 1. Numbers of prevalent CKD patients will continue to rise, reflecting the growing elderly population and increasing numbers of patients with diabetes and hypertension. As numbers of CKD patients increase, primary care practitioners will be confronted with management of the complex medical problems unique to patients with chronic renal impairment. As well documented in the literature, the nephrologist rarely manages the medical needs of CKD patients until renal replacement therapy is required. In this chapter we will define CKD staging and discuss five complications associated with CKD: anemia, hyperlipidemia, nutrition, osteodystrophy, and cardiovascular risk.
Go to:
CKD Classification/Staging
CKD is defined as the presence of kidney damage, manifested by abnormal albumin excretion or decreased kidney function, quantified by measured or estimated glomerular filtration rate (GFR), that persists for more than three months2;3. Although creatinine clearances can be calculated from urine creatinine concentration measured in a 24 hour urine collection and a concomitant serum creatinine concentration, a more practical approach in the office is to estimate GFR (estimated GFR or eGFR) from the serum creatinine concentration, using either the Cockcroft-Gault or the Modification of Diet in Renal Disease (MDRD) Study estimating equations. Web based tools are available for both estimating equations (MDRD eGFR: http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm; Cockcroft-Gault eGFR: http://www.mdcalc.com/cockcroftgault). Both complications and likelihood of progression to end-stage renal disease requiring renal replacement therapy are more likely to occur in patients with severe CKD. In addition, early intervention will more commonly reduce serious CKD sequelae and slow CKD progression. To facilitate assessment of CKD severity and, the National Kidney Foundation developed criteria, as part of its Kidney Disease Outcomes Quality Initiative (NKF KDOQI™), stratify CKD patients4: - list-behavior=unordered prefix-word= mark-type=disc
- Stage 1: normal eGFR ≥ 90 mL/min per 1.73 m2 and persistent albuminuria
- Stage 2: eGFR between 60 to 89 mL/min per 1.73 m2
- Stage 3: eGFR between 30 to 59 mL/min per 1.73 m2
- Stage 4: eGFR between 15 to 29 mL/min per 1.73 m2
- Stage 5: eGFR of < 15 mL/min per 1.73 m2 or end-stage renal disease
The prevalence of these stages of CKD in the US population is as follows: 1.8% for stage 1, 3.2% for stage 2, 7.7% for stage 3 and 0.35 % for stages 4 and 5. Patients with stage 3 or 4 disease progress to end stage renal disease or stage 5 at a rate of 1.5% per year. Stage 1 or 2 CKD patients progress to more advanced stages at approximately 0.5% per year 5. In addition, the NKF KDOQI provides evidence-based, clinical practice guidelines for all stages of chronic kidney disease to optimize management of related complications. Twelve sets of guidelines have been published and are available on the NKF web site (http://www.kidney.org/professionals/KDOQI/). Each of the complications discussed in this article is addressed by the NKF KDOQI guidelines. Go to:
Chronic kidney disease-associated anemia
Anemia is defined as a reduction in one or more of the major red blood cell measurements; hemoglobin concentration, hematocrit, or red blood cell count. The World Health Organization defines anemia as a hemoglobin level less than 13 g/dL in men and post-menopausal women, and less than 12 g/dL in pre-menopausal women6. The NKF defines anemia as a hemoglobin of less than 13.5 g/dL in men and less than 12.0 g/dL in women 7.
A normochromic, normocytic anemia usually accompanies progressive CKD 8, and the overall prevalence of CKD-associated anemia is approximately 50% 9. Although anemia may be diagnosed in patients at any stage of CKD, there is a strong correlation between the prevalence of anemia and the severity of CKD. One quarter of stage 1 CKD patients, half of those stratified to CKD stages 2, 3, and 4 and three quarters of CKD patients starting dialysis suffer from anemia10. Therefore, primary care providers play an important role in diagnosing and managing anemia in CKD patients.
While anemia in CKD can result from multiple mechanisms (iron, folate, or vitamin B12 deficiency; gastrointestinal bleeding; severe hyperparathyroidism, systemic inflammation, and shortened red blood cell survival), decreased erythropoietin synthesis is the most important and specific etiology causing CKD-associated anemia. Erythropoietin is a glycoprotein secreted by the kidney interstitial fibroblasts11 and is essential for the growth and differentiation of red blood cells in the bone marrow. In CKD, tubular atrophy generates tubulointerstitial fibrosis, which compromises renal erythropoietin synthetic capacity and results in anemia.
The anemia of CKD increases morbidity and mortality from cardiovascular complications (angina, left ventricular hypertrophy (LVH) and worsening heart failure)8, which may lead to further deterioration of renal function and the establishment of a vicious cycle termed the “cardiorenal anemia syndrome”. The presence LVH is associated with decreased survival of patients on dialysis. In fact, end stage renal disease patients with LVH have a 30% lower five-year survival rate than individuals lacking LVH 12. In addition, anemia is an independent predictor of death in stable coronary artery disease patients with CKD 13.
The anemia of CKD is treated via recombinant human erythropoietin (epo). This intervention has replaced transfusions as the mainstay of treatment and improved the survival of anemic CKD patients 14. The target level of Hgb in patients with CKD has changed as more studies have been reported. Normalization of hemoglobin levels is no longer considered the goal of therapy since these target levels have been associated with higher mortality15. The CHOIR trial studied the outcomes of anemia treatment in over 1400 CKD patients (MDRD eGFR between 15 to 50 mL/min per 1.73 m2), who had a hemoglobin < 11 g/dL at entry. Enrolled subjects were randomly assigned to epo therapy treatment protocols designed to achieve a target hemoglobin levels of either 13.5 (n=715) or 11.3 g/dL (n= 717). The study was terminated prematurely due to higher mortality rates and adverse events in the group with higher targeted Hgb levels.16 Consequently, the United States Food and Drug Administration (FDA) issued an alert recommending a target Hgb level between 11 and 12 g/dL in CKD patients, although more data will be needed to determine the optimal Hgb level to maximize quality of life and reduce excess mortality from anemia-related complications. In summary, despite the clear benefit from treatment of anemia on morbidity and morality in CKD patients, a significant proportion of anemic CKD patients do not receive adequate treatment prior to dialysis to achieve current FDA recommended targets17, and half of all CKD patients with anemia do not receive treatment with erythropoietin18. The precise target level for Hgb has not been definitively determined but following FDA recommendations is prudent.
Go to:
CKD-associated Mineral and Bone Disorders
The term “CKD-associated mineral and bone disorders” comprises abnormalities in bone and mineral metabolism and/or extra-skeletal calcification secondary to CKD pathophysiology 19;20. Renal osteodystrophy is the spectrum of histological changes, which occur in bone architecture of patients with CKD. The kidney is the primary site for phosphate excretion and 1-α-hydroxylation of vitamin D. CKD patients develop hyperphosphatemia as a result of inadequate 1, 25 dihydroxy-vitamin D levels that reflect reduced synthesis from parenchymal scarring. In addition, renal phosphate excretion is reduced. Together both processes cause, serum calcium levels to fall resulting in increased secretion of parathyroid hormone (secondary hyperparathyroidism). Parathyroid hormone has a phosphaturic effect. It also increases the calcium levels by increasing bone resorption and promoting 1-α-hydroxylation of 25-hydroxy vitamin D synthesized by the liver (limited effect because of reduced kidney reserve from scarring). Rising phosphorus levels are almost universally observed in stage 3 CKD patients. However, secondary hyperparathyroidism often begins to distort bone architecture earlier before serum phosphorus is noted to be abnormal, indicating that phosphate binder therapy needs to be initiated when eGFRs have declined below 50 mL/min per 1.73 m2.
Changes in bone architecture can be caused by either a high bone turnover state or a low bone turnover state. Four types of bone phenotypes (renal osteodystrophy) can be diagnosed in CKD patients: osteitis fibrosa cystica (high bone turnover with secondary hyperparathyroidism), osteomalacia (low bone turnover and inadequate mineralization, primarily related to diminished vitamin D synthesis), adynamic bone disorder (low bone turnover from excessive suppression of the parathyroid glands), and mixed osteodystrophy (with elements of both high and low bone turnover). The predominant type of renal osteodystrophy and CKD-mineral and bone disorder differs between pre-dialysis and end stage renal disease patients. In pre-dialysis patients, high bone turnover bone disease is most prevalent. In contrast, low bone turnover predominates in dialysis patients. Patients with low turnover disease represent the majority of cases of renal osteodystrophy 21. The cause of this prevalent bone phenotype results from oversuppression of parathyroid hormone and high calcium dialysate concentrations 22. Acidosis, the suppressive effect of phosphate retention on renal synthesis of 1, 25 dihydroxy-vitamin D synthesis, and absence of the physiologic inhibitory effect of vitamin D on parathormone secretion are also minor factors that contribute to the low turnover bone disease in CKD patients 23
CKD-associated mineral bone disorders significantly increase mortality in CKD patients. In fact, hyperphosphatemia is one of the most important risk factors associated with cardiovascular disease in CKD patients 24. The exact mechanism underlying this association remains unclear. It is believed to be related to hyperparathyroidism 25 and vascular calcification, which results from high phosphorus levels 26. Use of calcium based binders and excessive vitamin D therapy 27 may also contribute to the vascular calcification and its attendant cardiovascular mortality. Patients on hemodialysis who have a plasma phosphorus level above the K/DOQI guideline target levels have a 40% higher mortality rate when compared to those having target levels 28.
The principle goal of the treatment of CKD-associated bone and mineral disorders is phosphorous level reduction 1. Initial treatment restricts dietary phosphorus intake when phosphate or parathyroid hormone levels begin to rise. According to K/DOQI guidelines http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm), serum phosphorus levels should be maintained between 2.7 and 4.6 mg/dL in patients with stages 3 and 4 CKD, and between 3.5 and 5.5 mg/dL in individuals with stage 5 CKD. Different classes of phosphate binders can be used to accomplish this goal. For chronic therapy, calcium-based formulations for management of CKD-associated hyperphosphatemia are the most widely used clas of phosphate binders and have supplanted aluminum-based phosphate binders since aluminum-associated toxicities have been recognized. However, calcium-based phosphate binders can induce hypercalcemia, which increases the tissue calcium deposition, especially in the presence of hyperphosphatemia. If indicated (e.g., a CKD patient with hypercalemia), short term usage of aluminum-based phosphate binders remains appropriate, although alternative calcium-free, phosphate have been developed, such as the nonabsorbable agent sevelamer. This agent has the advantage of lacking calcium or aluminum. In addition to phosphate binders, several other classes of drugs have been developed to manage CKD-associated mineral disorder. Given the reduced 1-hydroxylation of vitamin D by the failing kidney, vitamin D and its related compounds may be needed to raise the serum calcium concentration sufficiently to suppress parathyroid hormone secretion. Patients can also be given calcimimetics, agents which increase the calcium sensitivity of the calcium-sensing receptor expressed by the parathyroid gland, down-regulating parathyroid hormone secretion and reducing hyperplasia of the parathyroid gland. The KDOQI guidelines provide specific management recommendations for use these agents and the interested reader is referred to the web link provided above for details.
Go to:
Cardiovascular Risk
The increased cardiovascular risk associated with end stage renal disease has been well established, and estimated cardiovascular mortality rates are ten to one hundred fold higher among dialysis patients than age- and sex-matched individuals in the general population.29 The cardiovascular risk associated with renal impairment increases earlier in the course of kidney disease progression than was initially hypothesized. More specifically, there is evidence that even mild to moderate degrees of renal impairment are associated with increased cardiovascular risk. Many traditional cardiovascular risk factors, documented in the general population, contribute to cardiovascular risk in CKD patients. In fact, many Framingham risk factors are more prevalent among individuals with CKD than those with normal renal function. In addition, non-traditional risk factors, specific to CKD patients, also contribute to the burden of cardiovascular disease (discussed below).
Hypertension is a traditional cardiovascular risk factor which contributes to the cardiovascular risk associated with CKD. Szcech and colleagues demonstrated that patients with hypertension are at increased risk for new or recurrent cardiovascular events in individuals with stage 2–3 CKD 30. Systolic blood pressure is more strongly associated with cardiovascular death in dialysis patients than either pulse or diastolic pressure 31. However, a U-shaped relationship exist between systolic blood pressure and mortality in which high or low systolic blood pressures appear to be associated with increased mortality rates in stage 5 CKD patients. Low systolic pressures may identify a sicker group of patients rather than being an etiology for excess mortality. KDOQI guidelines recommend target blood pressure less than 130/85 mm Hg for all patients with kidney disease and less than 125/75 mmHg for patients with urinary protein excretion greater than 1g/24h. Detailed treatment recommendations are beyond the scope of this review. Given the renal protective effects of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, this class of agents are optimal first-line agents in patients with proteinuric (> 1 gm/24h), progressive diabetic and nondiabetic renal disease.
Diabetes is associated with adverse outcomes in all stages of CKD 32. Moreover, lower fasting plasma glucose and /or glycated hemoglobin levels are associated with lower risk of all cause mortality and reduced cardiovascular death of borderline significance in patients with moderate to severe renal impairment. The presence of left ventricular hypertrophy (LVH), a complication which increases in relation to progressively lower levels of eGFR, is also a cardiovascular risk determinant in CKD patients. Anemia and hypertension, are two CKD associated complications hypothesized to play a role in the development of LVH 12. In a prospective cohort of 2,423 patients with stage 3–4 CKD, investigators noted an independent risk of LVH for the composite endpoint of myocardial infarction and fatal coronary heart disease. Patients were followed over a period of 102 months. In adjusted analysis, LVH was associated with increased risk for composite and cardiac outcomes hazard ratio (HR 1.67; 95% CI 1.34 to 2. 07).Tobacco use is also associated with increased mortality and incidence of heart failure among patients with stage 5 CKD 33.
Several cardiovascular risk factors associated with CKD are unique to patients with this disease (non-traditional risk factors). Anemia, which has been discussed above, is a risk factor for adverse cardiovascular outcomes in CKD patients. Abnormal serum phosphate levels, calcium-phosphate ion product, and parathyroid hormone levels are independent cardiovascular risk factors in the setting of stage 5 CKD 34. Higher calcium–phosphate products and the cumulative dose of oral calcium-based phosphate binders correlate with the extent and progression of arterial calcification in dialysis 35 and stage 3 or 4 CKD patients Interestingly, serum phosphate levels were associated with increased rates of death and myocardial infarction in patients with stage 3 or 4 CKD36, 37. This suggests that arterial calcification results in clinical morbidity and mortality in this patient population. Poorly controlled metabolic bone disease contributes to vascular calcification, which promotes arteriolosclerosis and increases vascular wall stiffness. Aortic stiffness is an independent predictor of total and cardiovascular mortality, CAD, and fatal stroke in patients with hypertension. One study of 96 patients, aged 18–70 with a creatinine clearances ranging from 15–90 ml/min per 1.73m2, found coronary calcification in 64%, and severe calcification present in 23% patients 38.
Inflammation is a non-traditional risk factor believed to play a role in mediating cardiovascular risk in CKD. Markers of inflammation are often elevated in CKD patients and are predictive of cardiovascular risk in this population. Some, but not all studies, have found serum C-reative protein (CRP) levels predicts cardiovascular outcomes in CKD patients. Menon et al. analyzed samples obtained from Modification of Diet in Renal Disease study patients (all had stage 3, 4 or 5 CKD at enrollment), measuring CRP concentration and analyzing its relationship to long-term outcomes 39. With a 10 year median follow-up period, all-cause mortality was 20% and cardiovascular mortality was 10%. High CRP was an independent predictor of all cause and cardiovascular mortality after investigators adjusted for confounding variables. The authors concluded that elevated CRP is useful for predicting outcomes in CKD patients.
Proteinuria, a hallmark of renal impairment, is associated with an increased risk for cardiovascular disease and early cardiovascular mortality in patients with and without diabetes and hypertension 40;41. This association was first demonstrated by the Framingham Heart Study investigators. More recently, Gerstein et al. in a cohort of more than 9000 individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial noted an increased relative risk in the primary aggregate outcome of myocardial infarction, stroke and cardiovascular death in microalbuminuric (urine albumin excretion 30 mg/ 24hr) subjects with and without diabetes (1.97 and 1.61 respectively). The risk associated with the presence of microalbuminuria increased progressively with increasing absolute levels of microalbuminuria 42.
CKD patients are more likely to develop congestive heart failure (CHF). Bibbins et al evaluated the association between CKD and new-onset CHF in African and Caucasians Americans 43. In the study, enrollees were stratified by cystatin C- and serum creatinine-based measurements of renal function. Investigators noted that risk for developing CHF correlated with the degree of renal impairment. A meta analysis (16 studies, which included 80,098 hospitalized and non hospitalized patients with CHF) evaluated the prevalence and mortality risk associated with the presence of CKD in patients with CHF 44. The eGFR was < 90ml/min in 63% of patients included in the analysis. Approximately 30% of these patients were found to have moderate to severe renal impairment. In 11 of the 16 studies reporting all-cause mortality rates for follow up ≥ 1 year (range 1–11.7 years), 26% of patients without renal impairment, 42% with any renal impairment and 51% with moderate to severe impairment died. A combined unadjusted mortality risk of RR= 1.48, 95% CI 1.45 to 1.52, P < 0.001 was noted in patients with any renal impairment and RR = 1.81, 95% CI 1.76 TO 1.86, P < 0.001 in patients with moderate to severe impairment. The authors concluded that renal impairment confers a clinically significant risk for excess mortality in patients with heart failure and the magnitude of the increased mortality risk is comparable to that associated with traditional prognostic indicators in heart failure such as ejection fraction.
Progression of CKD is associated with a number of serious health complications, including increased incidence of cardiovascular disease (Figure 1). Treating both traditional and non-traditional cardiovascular risk factors in individuals with CKD involves a multidisciplinary approach to care. Involvement of nurses, dieticians, educators and surgeons increases optimization of care. Controlling blood pressure control using KDOQI guidelines (BP goal <130/85, <125/75 with proteinuria, <130/85 in the setting of diabetes), use of ACE inhibitor and/or angiotensin receptor blockers to reduce proteinuria, titrating insulin and statin therapy to achieve appropriate glycated hemoglobin and serum cholesterol levels (<100 mg/dL), respectively will reduce cardiovascular risk and prevent or slow the progression of kidney failure. Additional randomized trials are needed to establish treatment goals for cardioprotective therapies in this population of patients. fig ft0fig mode=article f1
caption a4 Interplay of processes secondary to chronic kidney disease leading to cardiovascular disease and death. Red arrows: Pathogenetic pathways; black arrow: Feedback loop; kidney disease worsened by heart failure |
Go to:
Dyslipidemia
Dyslipidemia is a major risk factor for cardiovascular morbidity and mortality and is common among patients with CKD. Lipid profiles vary widely in these patients, reflecting the level of kidney function and the degree of proteinuria 45. In general, the prevalence of hyperlipidemia increases as renal function declines, with the degree of hypertriglyceridemia and elevation of LDL cholesterol being proportional to the severity of renal impairment.
Several factors contribute to the development dyslipidemia associated with chronic renal impairment. Patients with CKD have a reduction in the activity of lipoprotein lipase and hepatic triglyceride lipase. This interferes with uptake of triglyceride-rich, apolipoproteinB-containing lipoproteins by the liver and in peripheral tissue, yielding increased circulation of these atherogenic lipoproteins. Hypercholesterolemia in nephrotic syndrome is thought to be due to increased production and decreased catabolism of lipoproteins. The degree of lipoprotein abnormality is roughly proportional to the amount of proteinuria and inversely proportional to serum albumin levels. However, infusions of albumin or dextran both normalize lipoprotein concentrations, suggesting that oncotic pressure changes rather than hypoalbuminemia signals increased lipoprotein synthesis by the liver. Additional data supporting this hypothesis is derived from in-vitro experiments demonstrating direct stimulation of increased hepatic apolipoprotein-B gene transcription in cells exposed to reduced oncotic pressure 46. Studies also suggest that hyperparathyroidism and the accumulation of calcium in pancreatic islet cells likely contribute to dyslipidemia of CKD as well 47.
Clinical trials in the general population have demonstrated that coronary heart disease mortality decreases proportional to LDL-cholesterol level reduction. Evidence for benefit of statins in reducing cardiovascular risk (i.e., composite outcomes) in CKD patients is less definitive. Recently, the largest clinical trial of statins in patients with stage 5 CKD (4D trial) was conducted in Germany, In this study, atorvastatin did not to reduce death from fatal stroke, nonfatal myocardial infarction, or nonfatal stroke in 200 patients with diabetes and stage 5 CKD 48. The results of the Study of Heart and Renal Protection (SHARP) will be available in 2008 and should provide further insight into the role of cholesterol lowering therapy in reducing cardiovascular events in kidney disease patients. SHARP is a prospective, randomized trial in which 9,000 patients with CKD and 3,000 dialysis patients without coronary artery disease have been enrolled to assess the effects of lowering LDL-cholesterol with the combination of simvastatin and ezetimibe, with the primary outcome measure being the time to a first “major vascular event” defined as non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or an arterial revascularization procedure.
A relationship between total cholesterol levels and coronary heart disease (CHD) mortality as the primary outcome also has not been clearly established. In fact, several observational studies of stage 5 kidney disease patients suggest that lower total cholesterol levels are associated with higher mortality rate. For example, in a recent 10 -year prospective study the importance of total cholesterol levels on mortality was evaluated in 1,167 stage 5 kidney disease patients 49. Hypercholesterolemia (total cholesterol levels >200) was associated with increased all cause mortality rate. Further studies are needed to evaluate whether low cholesterol identifies a subgroup of more severely ill patients or whether inflammation and /or malnutrition were confounding variables in these studies.
A complete fasting lipid profile with assessment of total, LDL and HDL cholesterol and triglyceride levels should be included in the evaluation of patients with CKD and hyperlipidemia. Individuals with elevated cholesterol or other forms of hyperlipidemia should undergo evaluation for secondary dyslipidemias before initiation of lipid lowering therapy 50. KDOQI guidelines recommend that all stages of CKD be considered a CHD-risk equivalent. Thus, patients with CKD are viewed as being in the highest risk group for CHD and LDL-cholesterol levels should be lowered below 100 mg/dl (2. 6 mmol /L). CKD patients may achieve LDL goals via implementation of lifestyle modification (dietary modification with dietitian consultation, increased physical activity, moderate alcohol intake, and smoking cessation). All adults with CKD should be evaluated for lipid abnormalities. In CKD patients with nephrotic syndrome the primary goal is induce remission of the disease 51. When this is not possible any reduction in urinary protein excretion will be beneficial. In addition, nephrotic patients with elevated lipid levels should be treated with a lipid lowering diet, which may aid in reducing total cholesterol and LDL cholesterol levels.
Specific K/DOQI guidelines on the management of hyperlipidemia include:
- list-behavior=enumerated prefix-word= mark-type=decimal
- For patients with LDL cholesterol levels between 100 and 129 mg/dL (2.57 to 3.34mmol /L) lifestyle changes may be the initial therapy. If target LDL levels are not achieved (LDL < 100 mg/dL [2.57 mmol/L]), low-dose statin therapy can be instituted.
- For patients with LDL ≥ 130 mg/dL (3.36 mmol/L), lifestyle changes alone are likely to be ineffective. Statins can used as initial therapy and the dose titrated to achieve target LDL < 100 mg/dL (2.57 mmol/L).
- For patients with TG ≥ 200 mg/dL (3.36 mmol/L), the goal is to achieve non-HDL cholesterol ≤ 130 mg/dL. Initial treatment comprises lifestyle changes plus a low dose statin which is increased as needed to achieve target levels.
In summary, patients with CKD have a higher burden of dyslipidemia in comparison to the general population and are at increased risk for cardiovascular morbidity and mortality. This disproportionate cardiovascular disease burden places CKD patients in the highest risk category, as defined by the Adult Treatment Panel III (ATPIII) treatment guidelines. Identification of these patients and intervention via lifestyle and /or pharmacologic therapy is a sound, initial clinical approach. Ongoing randomized trials will provide more definitive data on the risk and benefits of lipid lowering therapy in this population of patients.
Go to:
Nutritional Issues
As patients progress through the stages of CKD, nutritional requirements are altered and metabolism of protein, water, salt, potassium, and phosphorous are affected 52. These changes lead to ineffective energy generation despite adequate intake of protein and carbohydrate substrates. In more extreme manifestations, these alterations in nutrient utilization cause “uremic malnutrition,” a syndrome that is distinct from malnutrition caused by inadequate nutrient intake. Both inadequate nutrient intake and ineffective nutrient utilization can contribute to nutritional disorders in CKD patients and we will not distinguish between these etiologies in our discussion. The association between uremic malnutrition and outcomes in the early stages of CKD has not been investigated. However, there is adequate evidence to suggest that a poor predialysis, nutritional status increases patient morbidity and mortality after initiation of renal replacement therapy 53. Maintenance of neutral nitrogen balance is important for preservation of nutritional health in patients with chronic renal impairment. Treatment goals in this setting should be to establish and maintain optimal nutritional status, minimize uremic symptoms and signs as renal impairment declines, and to establish a nutritional plan that is acceptable to the patient. To accomplish these goals, involvement of a dietician in the care of these patients is often necessary.
The ability of the generalist to assess nutritional status in the setting of CKD is important in addressing the nutritional needs of individuals with CKD. Several nutritional markers can be used to assess nutritional status. Serum albumin is the most extensively studied nutritional marker in all patient populations due to its easy availability and strong association with hospitalization and risk of death 54. Low levels of serum albumin are highly predictive of poor clinical outcomes in all stages of CKD, and therefore, serum albumin is considered a reliable marker of general clinical status 55. Clinical guidelines recommend maintenance of a value of 4.0 g/dL or greater for serum albumin in stage 5 CKD patients 56. Non-nutritional causes of hypoalbuminemia, such as tissue injury, hepatic disease, gastrointestinal disorders, and volume overload, can affect the specificity of this marker 57. Moreover, given the fact that serum albumin is a negative acute-phase reactant, its levels decrease in response to inflammatory stimuli such as burns, infection, or trauma 58. Serum prealbumin is a sensitive marker for assessing subtle changes in visceral protein stores given its low body pool and fairly rapid turnover of 2–3 days. Levels less than 30 mg/dL suggest protein depletion.59 Low serum creatinine concentrations are associated with poor clinical outcome in maintenance of stage 5 CKD. Patients with serum creatinine concentration less than 10 mg/dL should be evaluated for muscle wasting due to poor nutrition. Serum cholesterol concentration is an independent predictor of mortality in chronic dialysis patients, and low levels can suggest low dietary and energy intake. Serum cholesterol concentrations less than 150 mg/dL also warrant careful evaluation of nutritional status. Utilization of Subjective Global Assessment (SGA) as a nutritional assessment tool for various stages of CKD is growing in both clinical and research settings 60. Studies have demonstrated that SGA can adequately assess nutritional status in the setting of peritoneal and hemodialysis.61
Prevention and treatment are as important as identifying inadequate nutritional status in CKD patients. Therapy varies with the severity of CKD and no single treatment approach will alleviate the adverse consequences associated with uremic malnutrition. 62 In cases in which low protein and energy intake (as noted in patients on unrestricted diets), a dietary protein intake of less than .75 g/kg/d is an early warning sign for the development of uremic malnutrition. For many CKD patients, poor nutrition may warrant initiation of hemodialysis or be an indication for transplant. Several studies have suggested better outcomes with early initiation of hemodialysis in this setting. Additional signs that suggest need for early hemodialysis initiation include: energy intake less than 20 kcal/kg/d, serum albumin concentration of less than 4.0 g/dL, and decrements in other nutritional indices such as transferrin, prealbumin, insulin growth factor-1, and lean body mass. Alternative interventions may be necessary in cases when dietary counseling alone fail to optimize dietary intake. Enteral delivery of nutrition may be necessary, including oral protein, amino acid and/or energy supplements; feeding through nasogastric tubes or percutaneous endoscopic gastroscopy or jejunostomy tubes or institution of intradialytic parental nutrition. Evidence supporting these approaches is limited however. Only a few studies evaluating the efficacy of oral nutrition supplementation in stage 5 CKD patients have been published. For example, Eustace et al , found that oral amino acid supplementation improved serum albumin concentration in CKD 5 patients 63. Caglar and colleagues noted that intradialytic oral nutritional supplementation improved several nutritional parameters in a subgroup of malnourished stage 5 CKD patients 64. However, the role of supplemental enteral nutrition in patients with advanced CKD or in dialysis patients remains controversial, and a primary care provided should consider expert consultation before initiating any of these therapies
In conclusion, uremic malnutrition is very prevalent in CKD patients, and several studies have established a correlation between malnutrition and poor clinical outcome. Management of nutrition in CKD and dialysis patients can be difficult and involvement of dieticians with experience in the treatment of kidney disease patients is recommended.
Go to:
Summary
Patients with CKD present several complex management issues to health care providers. The staging system introduced in 2002 by the National Kidney Foundation is a significant accomplishment, which stratifies patients according to disease severity. In addition, the K/DOQI guidelines are an excellent tool for management of CKD and dialysis patients and recommend treatments according to disease stage. These interventions may reduce morbidity and mortality in these patients. With early identification and treatment of anemia, renal osteodystrophy, uremic malnutrition, hyperlipidemia and cardiovascular disease, primary care physicians and nephrologists together are making significant strides toward extending and improving the lives of patients with chronic renal disease. Table 1 briefly summarizes current treatment and preventive measures. table ft1table-wrap mode=article t1
| caption a4 Mainstay of Treatment in Chronic Kidney Disease Complications |
Go to:
Footnotes
back/fn-group
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Go to:
Reference List
1. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. Jama-Journal of the American Medical Association. 2007;298:2038–2047. [PubMed] 2. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am.J.Kidney Dis. 2006;47:S11–S145. [PubMed] 3. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int. 2005;67:2089–2100. [PubMed] 4. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. American Journal of Kidney Diseases. 2003;41:1–12. [PubMed] 5. Hsu CY, Vittinghoff E, Lin F, et al. The incidence of end-stage renal disease is increasing faster than the prevalence of chronic renal insufficiency. Ann.Intern.Med. 2004;141:95–101. [PubMed] 6. World Health Organization. Nutritional anaemias: Report of a WHO scientific group. 1968. [PubMed] 7. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am.J.Kidney Dis. 2006;47:S11–S145. [PubMed] 8. Besarab A, Levin A. Defining a renal anemia management period. Am.J.Kidney Dis. 2000;36:S13–S23. [PubMed] 9. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney disease. Curr.Med.Res.Opin. 2004;20:1501–1510. [PubMed] 10. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney disease. Curr.Med.Res.Opin. 2004;20:1501–1510. [PubMed] 11. Ratcliffe PJ. Molecular biology of erythropoietin. Kidney Int. 1993;44:887–904. [PubMed] 12. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. American Journal of Kidney Diseases. 1996;27:347–354. [PubMed] 13. Muzzarelli S, Pfisterer M. Anemia as independent predictor of major events in elderly patients with chronic angina. Am.Heart J. 2006;152:991–996. [PubMed] 14. Fink J, Blahut S, Reddy M, et al. Use of erythropoietin before the initiation of dialysis and its impact on mortality. Am.J.Kidney Dis. 2001;37:348–355. [PubMed] 15. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N.Engl.J.Med. 1998;339:584–590. [PubMed] 16. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N.Engl.J.Med. 2006;355:2085–2098. [PubMed] 17. Silverberg D. Outcomes of anaemia management in renal insufficiency and cardiac disease. Nephrol.Dial.Transplant. 2003;18 Suppl 2:ii7–ii12. [PubMed] 18. Dowling TC. Prevalence, etiology, and consequences of anemia and clinical and economic benefits of anemia correction in patients with chronic kidney disease: an overview. Am.J.Health Syst.Pharm. 2007;64:S3–S7. [PubMed] 19. Moe S, Drueke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int. 2006;69:1945–1953. [PubMed] 20. Gal-Moscovici A, Sprague SM. Bone health in chronic kidney disease-mineral and bone disease. Adv.Chronic.Kidney Dis. 2007;14:27–36. [PubMed] 21. Joy MS, Karagiannis PC, Peyerl FW. Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J.Manag.Care Pharm. 2007;13:397–411. [PubMed] 22. Hruska KA, Teitelbaum SL. Renal osteodystrophy. N.Engl.J.Med. 1995;333:166–174. [PubMed] 23. Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis revisited. Am.J.Kidney Dis. 1995;25:663–679. [PubMed] 24. Lee GH, Benner D, Regidor DL, et al. Impact of kidney bone disease and its management on survival of patients on dialysis. J.Ren Nutr. 2007;17:38–44. [PubMed] 25. El-Kishawi AM, El-Nahas AM. Renal osteodystrophy: review of the disease and its treatment. Saudi.J.Kidney Dis.Transpl. 2006;17:373–382. [PubMed] 26. Hutchison JA. Vascular calcification in dialysis patients. Prilozi. 2007;28:215–224. [PubMed] 27. Moe SM. Vascular calcification and renal osteodystrophy relationship in chronic kidney disease. Eur.J.Clin.Invest. 2006;36 Suppl 2:51–62. [PubMed] 28. Noordzij M, Korevaar JC, Boeschoten EW, et al. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients. Am.J.Kidney Dis. 2005;46:925–932. [PubMed] 29. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. American Journal of Kidney Diseases. 1998;32:S112–S119. [PubMed] 30. Muntner P, He J, Astor BC, et al. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: Results from the atherosclerosis risk in communities study. Journal of the American Society of Nephrology. 2005;16:529–538. [PubMed] 31. Port FK, Hulbert-Shearon TE, Wolfe RA, et al. Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients. American Journal of Kidney Diseases. 1999;33:507–517. [PubMed] 32. Tonelli M, Keech A, Shepherd J, et al. Effect of pravastatin in people with diabetes and chronic kidney disease. Journal of the American Society of Nephrology. 2005;16:3748–3754. [PubMed] 33. Combe C, McCullough KP, Asano Y, et al. Kidney Disease Outcomes Quality Initiative (K/DOQI) and the Dialysis Outcomes and Practice Patterns Study (DOPPS): Nutrition guidelines, indicators, and practices. American Journal of Kidney Diseases. 2004;44:S39–S46. [PubMed] 34. Block GA, Hulbert-Shearon TE, Levin NW, et al. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. American Journal of Kidney Diseases. 1998;31:607–617. [PubMed] 35. Goodman WG, London G, Amann K, et al. Vascular calcification in chronic kidney disease. American Journal of Kidney Diseases. 2004;43:572–579. [PubMed] 36. Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. Journal of the American Society of Nephrology. 2005;16:520–528. [PubMed] 37. Kramer H, Toto R, Peshock R, et al. Association between chronic kidney disease and coronary artery calcification: The Dallas Heart Study. Journal of the American Society of Nephrology. 2005;16:507–513. [PubMed] 38. Tomiyama C, Higa A, Dalboni MA, et al. The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients. Nephrology Dialysis Transplantation. 2006;21:2464–2471. [PubMed] 39. Menon V, Sarnak MJ. The epidemiology of chronic kidney disease stages 1 to 4 and cardiovascular disease: A high-risk combination. American Journal of Kidney Diseases. 2005;45:223–232. [PubMed] 40. Hoehner CM, Greenlund KJ, Rith-Najarian S, et al. Association of the insulin resistance syndrome and microalbuminuria among nondiabetic Native Americans. The Inter-Tribal Heart Project. Journal of the American Society of Nephrology. 2002;13 [PubMed] 41. Wachtell K, Olsen MH, Dahlof B, et al. Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE Study. Journal of Hypertension. 2002;20:405–412. [PubMed] 42. Gerstein HC, Mann JFE, Yi QL, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. Jama-Journal of the American Medical Association. 2001;286:421–426. [PubMed] 43. Bibbins-Domingo K, Chertow GM, Fried LF, et al. Renal function and heart failure risk in older black and white individuals - The health, aging, and body composition study. Archives of Internal Medicine. 2006;166:1396–1402. [PubMed] 44. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure - Systematic review and meta-analysis. Journal of the American College of Cardiology. 2006;47:1987–1996. [PubMed] 45. Kasiske BL. Hyperlipidemia in patients with chronic renal disease. American Journal of Kidney Diseases. 1998;32:S142–S156. [PubMed] 46. Yamauchi A, Fukuhara Y, Yamamoto S, et al. Oncotic Pressure Regulates Gene Transcriptions of Albumin and Apolipoprotein-B in Cultured Rat Hepatoma-Cells. American Journal of Physiology. 1992;263:C397–C404. [PubMed] 47. Arnadottir M, NilssonEhle P. Has parathyroid hormone any influence on lipid metabolism in chronic renal failure? Nephrology Dialysis Transplantation. 1995;10:2381–2382. [PubMed] 48. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N.Engl.J.Med. 2005;353:238–248. [PubMed] 49. Iseki K, Yamazato M, Tozawa M, et al. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney International. 2002;61:1887–1893. [PubMed] 50. Eknoyan G, Levin A, Levin N. K/DOQ1 clinical practice guidelines for managing dyslipidemias in chronic kidney disease. American Journal of Kidney Diseases. 2003;41:S6–S91.
51. Cleeman JI, Grundy SM, Becker D, et al. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) Jama-Journal of the American Medical Association. 2001;285:2486–2497. [PubMed] 52. Appel GB, Blum CB, Chien S, et al. The Hyperlipidemia of the Nephrotic Syndrome - Relation to Plasma-Albumin Concentration, Oncotic Pressure, and Viscosity. New England Journal of Medicine. 1985;312:1544–1548. [PubMed] 53. Khan IH, Catto GRD, Edward N, et al. Death During the First 90 Days of Dialysis - A Case-Control Study. American Journal of Kidney Diseases. 1995;25:276–280. [PubMed] 54. Herrmann FR, Safran C, Levkoff SE, et al. Serum-Albumin Level on Admission As A Predictor of Death, Length of Stay, and Readmission. Archives of Internal Medicine. 1992;152:125–130. [PubMed] 55. Owen WF, Lew NL, Liu Y, et al. The Urea Reduction Ratio and Serum-Albumin Concentration As Predictors of Mortality in Patients Undergoing Hemodialysis. New England Journal of Medicine. 1993;329:1001–1006. [PubMed] 56. [Anon]: National Kidney Foundation releases K/DOQI nutrition guidelines for dialysis patients. Dialysis & Transplantation. 2000;29:264.
57. Fleck A, Hawker F, Wallace PI, et al. Increased Vascular-Permeability - A Major Cause of Hypoalbuminemia in Disease and Injury. Lancet. 1985;1:781–784. [PubMed] 58. Ballmer PE, Ballmerhofer K, Repond F, et al. Acute Suppression of Albumin Synthesis in Systemic Inflammatory Disease - An Individually Graded Response of Rat Hepatocytes. Journal of Histochemistry & Cytochemistry. 1992;40:201–206. [PubMed] 59. Sreedhara R, Avram MM, Blanco M, et al. Prealbumin is the best nutritional predictor of survival in hemodialysis and peritoneal dialysis. American Journal of Kidney Diseases. 1996;28:937–942. [PubMed] 60. Dumler F. Use of bioelectric impedance analysis and dual-energy X-ray absorptiometry for monitoring the nutrition status of dialysis patients. Asaio Journal. 1997;43:256–260. [PubMed] 61. Davies SJ, Phillips L, Griffiths AM, et al. Analysis of the effects of increasing delivered dialysis treatment to malnourished peritoneal dialysis patients. Kidney International. 2000;57:1743–1754. [PubMed] 62. Hakim RM, Lazarus JM. Initiation of Dialysis. Journal of the American Society of Nephrology. 1995;6:1319–1328. [PubMed] 63. Eustace JA, Coresh J, Kutchey C, et al. Randomized double-blind trial of oral essential amino acids for dialysis-associated hypoalbuminemia. Kidney International. 2000;57:2527–2538. [PubMed] 64. Caglar K, Fedje L, Dimmitt R, et al. Therapeutic effects of oral nutritional supplementation during hemodialysis. Kidney International. 2002;62:1054–1059. [PubMed] 
