Published: August 2010
Chronic kidney disease (CKD) is an important source of long-term morbidity and mortality. It has been estimated that CKD affects more than 20 million people in the United States. Given that most patients are asymptomatic until the disease has significantly progressed, they remain unaware of the condition. Thus, it is essential to have clinical practice guidelines aimed at early detection, evaluation, diagnosis, and treatment of this condition. This chapter reviews the medical management of patients with CKD, emphasizing measures aimed at slowing disease progression and treatment of its common complications. Methods used for estimating the level of renal function are presented elsewhere in this section (“ Kidney Function Assessment: Creatinine-Based Estimation Equations”).
CKD is an irreversible, progressive reduction in renal function. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines define CKD as sustained kidney damage indicated by the presence of structural or functional abnormalities (e.g., microalbuminuria/proteinuria, hematuria, histologic or imaging abnormalities), and/or reduced glomerular filtration rate (GFR) to less than 60 mL/min/1.73 m2 for at least 3 months. Based on GFR estimation, the National Kidney Foundation has classified CKD into five stages (Table 1).1
|Stage||Description||GFR (mL/min/1.73 m2) Action||Plan|
|1||Kidney damage with normal or elevated GFR||≥90||Diagnosis, treatment of underlying
condition and comorbidities, cardiovascular
disease risk reduction
|2||Kidney damage with mildly decreased GFR||60-89||Estimating progression|
|3||Moderately decreased GFR||30-59||Evaluating and treating complications|
|4||Severely decreased GFR||15-29||Preparation for renal replacement therapy|
|5||Kidney failure (ESRD)||<15 (or dialysis, transplantation)||Replacement therapy (dialysis or transplantation)|
ESRD, end-stage renal disease; GFR, glomerular filtration rate.
Adapted from the National Kidney Foundation: K/DOQI Clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-S266.
In addition to GFR estimation, the evaluation of all patients with suspected or confirmed CKD should include a urinalysis, with testing for proteinuria. In addition to being a marker of kidney damage, proteinuria is a strong predictor of increased risk of cardiovascular morbidity and mortality in patients with or without CKD. To quantify the level of proteinuria, rather than using a 24-hour urine collection, the determination of the protein-to-creatinine or albumin-to-creatinine ratio in a random urine specimen is recommended. Urinary ratios are also useful for monitoring changes in the degree of proteinuria in CKD patients.
Once the presence of CKD and the disease stage have been established, the K/DOQI recommends following a stage-specific clinical action plan (see Table 1). During stages 1 and 2, the focus should be on treating comorbid conditions, addressing reduction of cardiovascular risk factors. and instituting measures to slow the progression of kidney disease. During these early stages, aggressive blood pressure control is the mainstay of therapy. In stage 3, in addition to continuing with the measures described, the focus shifts to evaluating and treating complications of CKD, such as anemia and the effects of abnormal mineral metabolism on bone and overall health. By stage 4, preparations for renal replacement therapy (dialysis, transplantation, or both) should begin. When stage 5 is reached, or when symptoms of the uremic syndrome ensue, renal replacement therapy is started.
Given the progressive nature of most forms of CKD, with a continued decrease in the GFR over time, it is important to address factors known to contribute to loss of renal function. Primary renoprotective strategies for limiting the progression of CKD are presented in Table 2.
|Blood pressure control (mm Hg)||<130/80 if proteinuria <1 g/day; <125/75 if proteinuria >1 g/day||ACE inhibitors, ARBs, sodium, restriction, diuretics|
|Reduction in proteinuria||<0.5 g/day||ACE inhibitors, ARBs|
|Glycemic control||HgbA1c< 7%||Dietary counseling, oral hypoglycemic agents, insulin|
|Dietary protein restriction||0.6-0.8 g/kg/day||Dietary counseling|
|Lipid lowering||LDL <100 mg/dL||Dietary counseling, statins|
|Lifestyle modifications||Smoking cessation, achieving ideal body weight, regularly exercising||Counseling, exercise program|
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LDL, low-density lipoprotein.
The progression of CKD is strongly linked to hypertension control. A number of studies have shown that for diabetic and nondiabetic kidney disease, elevated blood pressure is associated with a faster decline in GFR. The Modification of Diet in Renal Disease (MDRD) study has shown that control of hypertension is even more important in patients with proteinuria higher than 1 g/day, because lowering blood pressure to a target of 125/75 mm Hg in these patients achieves a greater decrease in the rate of decline of GFR than in patients with less proteinuria.2 For patients with proteinuria higher than 3 g/day, the impact of blood pressure lowering was even greater. The MDRD study also showed that hypertensive African Americans have faster progression of CKD compared with their white counterparts. However, reduction of blood pressure to lower than 125/75 mm Hg reduced the rate of decline by 50% in this group.
The Ramipril Efficacy in Nephropathy (REIN) trial followed nondiabetic renal disease patients with proteinuria higher than 1 g/day. It demonstrated that patients being treated with an angiotensin-converting enzyme (ACE) inhibitor have more effective preservation of renal function at similar levels of blood pressure reduction. This effect was most profound in those patients with the highest levels of baseline proteinuria.
In the African American study of kidney disease (AASK), metoprolol, amlodipine, and ramipril were compared as first-line drugs in patients with nondiabetic nephropathy. Blood pressure control was similar among the three groups. However, only in the patients treated with ramipril were there significant reductions in rates of renal disease progression and in composite end points (22%-38% reduction in renal function, need for dialysis, or death).
These combined results support the hypothesis that reduction in systemic hypertension slows or prevents progression of proteinuric and nonproteinuric renal disease. Studies have shown that even treating isolated systolic hypertension in older patients slows the progression of CKD.
Most classes of antihypertensive medication can be used to treat patients with CKD because many of these trials required additional drugs to achieve their goals. However, it has also been shown that at similar degrees of blood pressure control, ACE inhibitors are more protective, particularly in proteinuric disease. In patients who cannot tolerate ACE inhibitors, an angiotensin receptor blocker (ARB) may reasonably be prescribed. In spite of these observations, the therapeutic goal of reducing the blood pressure to target, regardless of agent used, should not be sacrificed.
It is worth noting that CKD may alter some of the pharmacologic characteristics of multiple medications, including the antihypertensive medications. However, specific pharmacologic information is beyond the scope of this chapter.
Microalbuminuria and proteinuria are well-recognized prognostic factors for the development and progression of CKD. The MDRD study has shown that severe proteinuria (>3 g/day) is associated with a higher rate of decline in GFR. Other studies have shown that this holds true for the glomerular and nonglomerular forms of CKD. Interventions aimed at reducing proteinuria, including ACE inhibition and dietary modifications, have been shown to predict outcomes better in diabetic and nondiabetic CKD patients. Proposed mechanisms for the effects of proteinuria include initiation and progression of tubulointerstitial fibrosis and inflammation through toxicity from filtered compounds (e.g., transferrin-iron, albumin-bound fatty acids, inflammatory cytokines).
Extensive studies of chronic renal failure in animal models have shown that reduced dietary protein is associated with a reduction in glomerular hyperfiltration and slows the progression of renal disease. Although animal models of disease and treatment do not always apply to humans, a number of human studies in nondiabetic and diabetic renal disease have tested whether dietary protein restriction ameliorates the rate of progression of disease. The MDRD study was the largest controlled multicenter trial to compare usual protein intake (1 g/kg/day) with low (0.6 g/kg/day) and very low (0.28 g/kg/day) protein intake in nondiabetic patients.2 Although the primary outcome was inconclusive, several subanalyses have suggested that a prescribed dietary protein intake of 0.6 g/kg/day as compared with 1 g/kg/day reduces the rate of progression by about 28%, the same benefit seen in achieving the low blood pressure goal. A meta-analysis of five of the best studies of both diabetic and nondiabetic renal disease has suggested that a small reduction in rate of progression occurs with dietary protein restriction. In an analysis of the MDRD data, Locatelli and Del Vecchio have found that adherence to a low (0.6 g/kg/day) versus a usual (1 g/kg/d) protein diet for 9 years would delay the need for renal replacement therapy by approximately 1 year.3 The difficulty of achieving consistent dietary protein restriction, however, makes the application of this intervention unwieldy and prone to failure, especially in diabetic patients. Compliance in the MDRD was successful but required intensive regular interaction by dietitians.
Clinically proven strategies to slow the progression of nondiabetic renal disease include the following:
As GFR declines, a wide range of disorders develop, including fluid and electrolyte imbalances, such as volume overload, hyperkalemia, metabolic acidosis, and hyperphosphatemia4 ; hormonal imbalances leading to anemia and secondary hyperparathyroidism, which accompanies bone disease (renal osteodystrophy); and systemic dysfunction that develops in the uremic syndrome, such as neuropathy, anorexia, nausea, vomiting, fatigue, and malnutrition.
Given these considerations, every patient with CKD should undergo evaluation by a nutritionist. Box 1 shows typical dietary recommendations for CKD patients; specific recommendations should be modified based on the needs of the individual patient.5,6
|Box 1: Typical Dietary Recommendations for Chronic Kidney Disease Patients|
|Protein: 0.6-0.8 g/kg/day|
|Sodium: <2 g/day (<6 g/day of salt)|
|Potassium: 40-70 mEq/day|
|Phosphate: 600-800 mg/day|
|Calcium: 1400-1600 mg/day (not to exceed 2000 mg/day)|
|Free water (in excess of urine output): 1-1.5 L/day|
Sodium and intravascular volume balance are usually well maintained until the GFR falls below 15 mL/min/1.73 m2. This is caused by an increase in the fractional excretion of salt and water by the remaining nephrons. However, the ability to respond to rapid infusions of sodium with volume expansion will be reduced, even in patients with CKD stages 3 and 4, making them prone to fluid overload. The optimal level of daily salt intake varies from patient to patient. Less than 6 g/day of sodium chloride (<2 g/day of sodium) is the typical initial recommendation. Adjustments need to be made depending on the patient's volume status, aiming to achieve normotension and only trace pedal edema. Patients with a GFR below 20 mL/min/1.73 m2 in whom, despite sodium restriction, edema ensues, respond well to diuretic therapy, usually a loop diuretic. Given that the ability to concentrate or dilute the urine maximally becomes progressively impaired as GFR declines, patients with stage 4 or 5 CKD tend to be isosthenuric. Therefore, these patients are at risk for developing hypo- or hypernatremia caused by positive or negative water balance, respectively. Free water intake should be approximately equal to urine output plus an additional 1 to 1.5 L/day to account for insensible losses.
Renal potassium excretion is preserved at near-normal levels in patients with CKD as long as both the renin-angiotensin-aldosterone system (RAAS) and distal nephron flow are maintained. Therefore, hyperkalemia generally develops in oliguric patients with a GFR lower than 10 mL/min/1.73 m2 or in those who experience an additional alteration in potassium metabolism because of increased intake or from certain medications (e.g., ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs). See elsewhere in this section for further information (“ Hypokalemia and Hyperkalemia”).
Dietary restriction is the mainstay of management of chronic hyperkalemia in these patients (40-70 mEq/day). If it persists, the next step is the addition of a loop diuretic (more so if hypertension or volume overload is an issue) to promote kaliuresis by increasing sodium delivery to the distal nephron. If acidosis is present, sodium bicarbonate is helpful by increasing distal nephron sodium delivery, inducing kaliuresis, and promoting intracellular potassium shift. An additional alternative is the use of potassium-binding resins such as sodium polystyrene sulfonate (Kayexalate) combined with sorbitol to avoid constipation, at smaller doses than those typically used for the treatment of acute hyperkalemia, given daily or every other day.
The kidneys’ ability to regenerate bicarbonate consumed in buffering the daily net acid production diminishes as nephron mass decreases. This occurs because of reduced production of ammonia, decreased filtration of titratable acids (e.g., sulfates, phosphates, urates, hippurates), decreased proximal tubular bicarbonate reabsorption, and decreased renal tubular hydrogen ion secretion. The resultant metabolic acidosis is initially of the nonanion gap type but, as GFR declines, the anion gap widens—because of retained titratable acids—with the serum bicarbonate concentration tending to stabilize between 12 and 20 mEq/L. Buffering of excess hydrogen ions occurs in bone, contributing to the development of renal osteodystrophy (see later). Additionally, chronic acidosis leads to muscle protein breakdown and reduced albumin synthesis.
The goal of therapy is to maintain the serum bicarbonate concentration at or above 22 mEq/L to avoid the deleterious effects of acidosis on bone histology and protein catabolism. The first-line agent is sodium bicarbonate, 0.5 to 1 mEq/kg/day; a typical starting dosage is 650 mg three times daily. Sodium citrate, generally better tolerated than bicarbonate, should be restricted to patients who are not taking aluminum-containing phosphate binders because it enhances intestinal aluminum absorption.
As functional nephron mass declines, the fractional excretion of phosphate drops, leading to an increase in the serum phosphate level. This is accompanied by a reciprocal decrease in serum calcium concentration. These events lead to an increase in parathyroid hormone (PTH) release; this has a phosphaturic effect, resulting in the return of phosphate and calcium to normal levels. As GFR continues to decline, this cycle maintains serum calcium and phosphate concentrations within the normal ranges, at the expense of rising PTH levels. When further renal mass is lost and GFR drops below 30 mL/min/1.73 m2, despite the compensatory hyperphosphaturia, hyperphosphatemia becomes sustained.7
Parallel to this, as nephron mass decreases, the 1α-hydroxylation in the kidney of 25-hydroxyvitamin D [25-(OH)D] declines, leading to lower serum levels of 1,25-dihydroxyvitamin D [1,25-(OH2)D]. This lack of 1,25-(OH2)D contributes to the development of hypocalcemia, given its role of enhancing calcium absorption in the gut and enhancing PTH-mediated calcium release from bone. The combination of all these factors contributes to the development of secondary hyperparathyroidism and renal osteodystrophy.
The primary goals in the management of these abnormalities are maintaining phosphate levels within target range (2.7-4.6 mg/dL for CKD stages 3 and 4; 3.5 to 5.5 mg/dL for CKD stage 5 or end-stage renal disease, ESRD) and the calcium-phosphorus product at lower than 55 mg2/dL2.8 Treatment should begin with dietary phosphorus restriction to approximately 800 mg/day. In addition to dietary restriction, patients with a GFR of lower than 30 mL/min/1.73 m2 will generally need oral phosphate binders given with meals to decrease gut absorption of phosphate. These are available as calcium-containing or non–calcium-containing binders. The decision as to which class of binder to use initially is based on the starting phosphate level and the calcium-phosphorus product. When the serum phosphate level is higher than 7 mg/dL or the calcium-phosphorus product is higher than 63 mg2/dL2, the initial choice should be a non–calcium-containing binder.
Calcium-containing binders are available as calcium carbonate or calcium acetate (PhosLo); the latter is suggested as a more efficient binder. Calcium citrate is avoided in CKD patients because it markedly increases intestinal aluminum absorption. Because of the risk of vascular calcification, the aim is to maintain the total elemental calcium intake (including both dietary calcium intake and calcium-based phosphate binders) under 2000 mg/day. Among non–calcium-containing binders, current available options include sevelamer (Renagel), a cationic polymer that binds phosphate through ion exchange, and lanthanum carbonate (Fosrenol), a rare earth element. Aluminum hydroxide is an effective phosphate binder but can lead to osteomalacia and neurologic complications and should be limited to short-term use only.
Vitamin D or vitamin D analogues should be given to treat secondary hyperparathyroidism. The CKD stage-specific target levels of intact PTH are shown in Box 2. Once the PTH level is established, the next step is assessment of 25-(OH)D levels and replacement with vitamin D2 (ergocalciferol) if levels are lower than 30 ng/mL. If the intact PTH level is elevated and the serum 25-(OH)D level is higher than 30 ng/mL, treatment with an active form of vitamin D is indicated. Available options are calcitriol, alfacalcidol, or doxercalciferol. During vitamin D therapy, serum calcium and phosphorus levels need to be monitored closely to prevent hypercalcemia and hyperphosphatemia, aiming for levels lower than 10.2 mg/dL and lower than 4.6 mg/dL, respectively. Calcimimetics are agents that increase the sensitivity of the calcium-sensing receptor in the parathyroid gland to calcium. The only available medication in this category is cinacalcet (Sensipar), which can be used if elevated serum phosphorus or calcium levels limit the use of vitamin D analogues.
|Box 2: Target Parathyroid Hormone Ranges for Chronic Kidney Disease Patients|
|Stage 3: 35-70 pg/mL|
|Stage 4: 70-110 pg/mL|
|Stage 5: 150-300 pg/mL|
Anemia is almost a universal finding in patients with stages 3 to 5 CKD, and its presence should be sought for when the estimated GFR is lower than 60 mL/min/1.73 m2. The anemia of CKD is typically normochromic and normocytic and is caused primarily by a decrease in erythropoietin production relative to the degree of anemia. This relative erythropoietin deficiency renders erythropoietin levels not useful for the evaluation of this population, which should begin when the hemoglobin level is lower than 12 g/dL in women and lower than 13.5 g/dL in men.
Before the initiation of erythropoietin replacement, nonrenal causes of anemia need to be excluded. The workup typically includes determination of red blood cell indices, absolute reticulocyte count, serum iron level, total iron binding capacity, percentage transferrin saturation, serum ferritin level, and white blood cell count and differential, platelet count, and testing for occult blood in the stool. Depending on clinical suspicion, laboratory findings, or both, a more extensive workup may be indicated, including serum vitamin B12 levels, intact PTH level, serum or urine protein electrophoresis, hemolysis panel, and possibly referral to a hematologist. If no alternative cause for the anemia is found, therapy with erythropoietin-stimulating agents (ESAs) is initiated usually at a nephrologist's office. The potential proven benefits of ESA therapy are reduction in the need for transfusions and of anemia-induced symptoms, with enhanced quality of life. Many observational studies have suggested that treating anemia with ESA improves overall and cardiovascular mortality in CKD. However, there are no randomized trials at present to confirm these observational findings.
There are currently two ESAs available in the United States, epoetin alfa and darbepoetin alfa. Both products are equally effective and mainly differ in their half-lives, so their interval dosing varies.
The target hemoglobin level for both predialysis CKD and end-stage renal disease (ESRD) patients should be 11 to 12 g/dL. Targeting hemoglobin to levels higher than 12 g/dL has been associated with adverse cardiovascular outcomes. The most common cause for suboptimal response to ESA therapy is iron deficiency. ESA-stimulated erythropoiesis is iron restrictive and requires the presence of adequate iron stores. Current K/DOQI guidelines suggest administering iron to maintain the transferrin saturation at or greater than 20%, and serum ferritin level higher than 100 ng/mL.9 This is typically achieved by oral iron supplementation, with a daily dosage of approximately 200 mg of elemental iron (ferrous sulfate, 325 mg three times daily). Oral iron absorption is best when given without food, typically in between meals. However, this form of therapy is not always well tolerated because of gastrointestinal side effects. Intravenous iron is typically reserved for patients already on dialysis, although it may be used in predialysis CKD patients not achieving targeted iron parameters. In addition to iron deficiency, other causes of poor response to ESA therapy include the presence of an underlying inflammatory state, uremia, hyperparathyroidism, and malignancy.
CKD carries a significant burden of morbidity and mortality. Care of patients with CKD requires a multifaceted approach, with focus on close monitoring of GFR and aggressive institution of measures aimed at slowing progression of the disease. Addressing the comorbidities that accompany CKD (e.g., hypertension, diabetes, hyperlipidemia) should occur early in the course of the disease (stages 1 to 3 CKD). These initial measures are best instituted by the primary care provider, with assistance from the nephrologist, if needed, for developing a clinical action plan. As the disease progresses, the roles of the nephrologist widen, including determining the cause of CKD, initiating disease-specific therapies to treat or further slow down progression, diagnosing and treating CKD-related complications and, in the advanced stages, preparing the patient for renal replacement therapy.
The strongest evidence for the importance of referral to a nephrologist is for patients with CKD stages 4 and 5 (GFR <30 mL/min/1.73 m2). Late referral (less than 3 months before initiation of renal replacement therapy) is associated with an increased mortality rate after starting dialysis. At this point, patients are better served by comanagement between the primary care provider and nephrologist. During this phase, special attention should be given to patient education regarding renal replacement therapy (e.g., hemodialysis, peritoneal dialysis, transplantation), and timely creation of vascular access for those opting for hemodialysis. For those who qualify for kidney transplantation, donor evaluation for preemptive transplantation should begin.