Taken from emedicine - medscape Background

Chronic kidney disease (CKD) is a worldwide public health problem. It is recognized as a common condition that is associated with an increased risk of cardiovascular disease and chronic renal failure (CRF). In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost (see Epidemiology). The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for 3 or more months. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time. In 2002, K/DOQI published its classification of the stages of chronic kidney disease, as follows: Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2) Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2) Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2) Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2) Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m 2 or dialysis) In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities on imaging studies, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease. The K/DOQI definition and classification of chronic kidney disease allow better communication among physicians and facilitate intervention at the different stages. Patients with chronic kidney disease stages 1-3 are generally asymptomatic; clinically manifestations typically appear in stages 4-5 (see Clinical). Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with chronic kidney disease. These may delay, or possibly halt, progression. The medical care of patients with chronic kidney disease (see Treatment) should focus on the following: Delaying or halting the progression of chronic k idney disease Treating the pathologic manifestations of chronic kidney disease Timely planning for long-term renal replacement therapy

Pathophysiology
Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. In the face of renal injury (regardless of the etiology), the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons, by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea and creatinine start to show significant increases only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will approximately double with a 50% reduction in GFR. A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass. The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has

been based on studies of five-sixths nephrectomized rats, which develop lesions identical to those observed in humans with chronic kidney disease. Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following: Systemic hypertension Acute insults from nephrotoxins or decreased perfusion Proteinuria Increased renal ammoniagenesis with interstitial injury Hyperlipidemia Hyperphosphatemia with calcium phosphate deposition Decreased levels of nitrous oxide Smoking

Hyperkalemia
The ability to maintain potassium (K) excretion at near-normal levels is generally maintained in chronic kidney disease as long as both aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with chronic kidney disease is increased potassium excretion in the GI tract, which also is under control of aldosterone. Therefore, hyperkalemia usually develops when the GFR falls to less than 20-25 mL/min because of the decreased ability of the kidneys to excrete potassium. It can be observed sooner in patients who ingest a potassium-rich diet or if serum aldosterone levels are low, such as in type IV renal tubular acidosis commonly observed in people with diabetes or with use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Hyperkalemia in chronic kidney disease can be aggravated by an extracellular shift of potassium, such as that occurs in the setting of acidemia or from lack of insulin. Hypokalemia is uncommon but can develop among patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, diarrhea, or diuretic use.

Metabolic acidosis
Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter is observed generally with chronic kidney disease stage 5 but with the anion gap generally not higher than 20 mEq/L. In chronic kidney disease, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid into the urine in the form of ammonium. In chronic kidney disease stage 5, accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in anion gap. Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to the following: Negative nitrogen balance Increased protein degradation Increased essential amino acid oxidation Reduced albumin synthesis Lack of adaptation to a low protein diet Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body mass, and muscle weakness. The mechanism for reducing protein may include effects on adenosine triphosphate (ATP)dependent ubiquitin proteasomes and increased activity of branched chain keto acid dehydrogenases. Metabolic acidosis is a factor in the development of renal osteodystrophy, as bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may interfere with vitamin D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia or low-turnover bone disease.

Salt and water handling abnormalities

Salt and water handling by the kidney is altered in chronic kidney disease. Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion. This generally becomes clinically manifest when the GFR falls to less than 10-15 mL/min, when compensatory mechanisms have become exhausted. As kidney function declines further, sodium retention and extracellular volume expansion lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a higher GFR, excess sodium and water intake could result in a similar picture if the ingested amounts of sodium and water exceed the available potential for compensatory excretion.

Anemia
Normochromic normocytic anemia principally develops from decreased renal synthesis of erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC) production. It starts early in the course of disease and becomes more severe as the GFR progressively decreases with the availability of less viable renal mass. No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding is increased from the uremia-induced platelet dysfunction. Other causes of anemia in chronic kidney disease include the following: Chronic blood loss Secondary hyperparathyroidism Inflammation Nutritional deficiency Accumulation of inhibitors of erythropoiesis

Bone disease
Renal bone disease is a common complication of chronic kidney disease. It results in both skeletal complications (eg, abnormality of bone turnover, mineralization, linear growth) and extraskeletal complications (eg, vascular or soft tissue calcification). Different types of bone disease occur with chronic kidney disease, as follows: High-turnover bone disease due to high parathyroid hormone (PTH) levels Low-turnover bone disease (adynamic bone disease) Defective mineralization (osteomalacia) Mixed disease Beta-2-microglobulin associated bone disease Chronic kidney diseasemineral and bone disorder (CKD-MBD) involves biochemical abnormalities, (ie, serum phosphorus, PTH, and vitamin D levels) related to bone metabolism. Secondary hyperparathyroidism develops in chronic kidney disease because of the following factors: Hyperphosphatemia Hypocalcemia Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or calcitriol) Intrinsic alteration in the parathyroid gland, which give rises to increased PTH secretion as well as increased parathyroid growth Skeletal resistance to PTH Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion. Phosphate retention begins in early chronic kidney disease; when the GFR falls, less phosphate is filtered and excreted, but serum levels do not rise initially because of increased PTH secretion, which increases

renal excretion. As the GFR falls toward chronic kidney disease stages 4-5, hyperphosphatemia develops from the inability of the kidneys to excrete the excess dietary intake. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min. Increased phosphate concentration also effects PTH concentration by its direct effect on parathyroid gland (posttranscriptional effect). Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels and possibly from calcium binding to elevated serum levels of phosphate. Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in chronic kidney disease, particularly in the more advanced stages, PTH secretion becomes maladaptive and the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate. If serum levels of PTH remain elevated, a high bone turnover lesion, known as osteitis fibrosa, develops. This is one of several bone lesions, which as a group are commonly known as renal osteodystrophy. These lesions develop in patients with severe chronic kidney disease and are common in those with ESRD. The prevalence of adynamic bone disease in the United States has increased, and it has been described before the initiation of dialysis in some cases. The pathogenesis of adynamic bone disease is not well defined, but several factors may contribute, including high calcium load, use of vitamin D sterols, increasing age, previous corticosteroid therapy, peritoneal dialysis, and increased level of N-terminally truncated PTH fragments. Low-turnover osteomalacia in the setting of chronic kidney disease is associated with aluminum accumulation. It is markedly less common than high-turnover bone disease. Dialysis-related amyloidosis from beta-2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years is another form of bone disease. It manifests with cysts at the ends of long bones.

Etiology
Causes of chronic kidney disease include the following: Vascular disease Glomerular disease (primary or secondary) Tubulointerstitial disease Urinary tract obstruction Vascular diseases that can cause chronic kidney disease include the following:

Renal artery stenosis Cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)positive vasculitides Antineutrophil cytoplasmic antibody (ANCA)negative vasculitides Atheroemboli Hypertensive nephrosclerosis Renal vein thrombosis Primary glomerular diseases include the following: Membranous nephropathy Immunoglobulin A (IgA) nephropathy Focal and segmental glomerulosclerosis (FSGS) Minimal change disease Membranoproliferative glomerulonephritis

Rapidly progressive (crescentic) glomerulonephritis Secondary causes of glomerular disease include the following: Diabetes mellitus Systemic lupus erythematosus Rheumatoid arthritis Mixed connective tissue disease Scleroderma Goodpasture syndrome Wegener granulomatosis Mixed cryoglobulinemia Postinfectious glomerulonephritis Endocarditis Hepatitis B and C Syphilis Human immunodeficiency virus (HIV) Parasitic infection Heroin use Gold Penicillamine Amyloidosis Light chain deposition disease Neoplasia Thrombotic thrombocytopenic purpura (TTP) Hemolytic-uremic syndrome (HUS) Henoch-Schnlein purpura Alport syndrome Reflux nephropathy Causes of tubulointerstitial disease include the following: Drugs (eg, sulfa, allopurinol) Infection (viral, bacterial, parasitic) Sjgren syndrome Chronic hypokalemia Chronic hypercalcemia Sarcoidosis Multiple myeloma cast nephropathy Heavy metals Radiation nephritis Polycystic kidneys Cystinosis Urinary tract obstruction may result from any of the following: Urolithiasis Benign prostatic hypertrophy Tumors Retroperitoneal fibrosis Urethral stricture Neurogenic bladder Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort, suggest that inflammation and hemostasis are antecedent pathways for chronic kidney disease.[1] This study used data from 1787 cases of chronic kidney disease that developed between 1987 and 2004.

After adjustments for various factors, such as demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction (MI), antihypertensive use, and alcohol use, the above study revealed that the risk for chronic kidney disease rose with increasing quartiles of white blood cell (WBC) count, fibrinogen, von Willebrand factor, and factor VIIIc. The investigators found a strong inverse association between serum albumin level and chronic kidney disease risk.

Epidemiology
In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. Kidney disease is the ninth leading cause of death in the United States. The Third National Health and Examination Survey (NHANES III) estimated that the prevalence of chronic kidney disease in adults in the United States was 11% (19.2 million): 3.3% (5.9 million) had stage 1, 3% (5.3 million) had stage 2, 4.3% (7.6 million) had stage 3, 0.2% (400,000) had stage 4, and 0.2% (300,000) had stage 5. The prevalence of chronic kidney disease stages 1-4 increased from 10% in 1988-1994 to 13.1% in 19992004. This increase is partially explained by the increase in the prevalence of diabetes and hypertension, the two most common causes of chronic kidney disease. Data from the United States Renal Data System (USRDS) indicated that the prevalence of chronic renal failure increased 104% between the years 19902001. According to the Third National Health and Nutrition Examination Survey, it was estimated that 6.2 million people (ie, 3% of the total US population) older than 12 years had a serum creatinine value above 1.5 mg/dL; 8 million people had a GFR of less than 60 mL/min, the majority of them being in the Medicare senior population (5.9 million people). Therefore, for the first time, the US Surgeon Generals latest 10-year national objectives for improving the health of all Americans, Healthy People 2020, contains a chapter focused on chronic kidney disease. For 2020, Healthy People lays out 14 goals and strategies to reduce the incidence, morbidity, mortality, and health costs of chronic kidney disease in the United States. Reducing renal failure will require additional public health efforts, including effective preventive strategies and early detection and treatment of chronic kidney disease. Because of the nonuniform definition of kidney disease prior to publication of the K/DOQI classification in 2002, among other factors, most patients with earlier stages of chronic kidney disease have not been recognized or adequately treated. The incidence rates of end-stage renal disease (ESRD) have increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, with the United States taking second place.

Racial demographics
Chronic kidney disease affects all races, but, in the United States, a significantly higher incidence of ESRD exists in blacks than in whites; the incidence rate for blacks is nearly 4 times that for whites. Choi et al found that rates of ESRD among black patients exceeded those among white patients at all levels of baseline estimated GFR (eGFR).[2]Similarly, mortality rates among black patients were equal to or higher than those among white patients at all levels of eGFR. Risk of ESRD among black patients was highest at an eGFR of 45-59 mL/min/1.73 m2 (hazard ratio, 3.08), as was the risk of mortality (hazard ratio, 1.32).

Sex- and age-related demographics

In NHANES III, the distribution of estimated GFRs for the chronic kidney disease stages was similar in both sexes. Nonetheless, the USRDS 2004 Annual Data Report reveals that the incident rate of ESRD cases is higher for males, with 409 per million population in 2002 compared with 276 for females.

Chronic kidney disease is found in persons of all ages. Nonetheless, in the United States, the highest incidence rate of ESRD occurs in patients older than 65 years. As per NHANES III data, the prevalence of chronic kidney disease was 37.8% among patients older than 70 years. A study of Israeli youth revealed that patients aged 16-25 years with persistent asymptomatic isolated microscopic hematuria had an increased risk of treated ESRD for 22 years; however, the absolute risk and incidence was slight. [3] Besides diabetes mellitus and hypertension, age is an independent major predictor of chronic kidney disease. The geriatric population is the most rapidly growing kidney failure (chronic kidney disease stage 5) population in the United States. The biologic process of aging initiates various structural and functional changes within the kidney. Renal mass progressively declines with advancing age. Glomerulosclerosis leads to a decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of as much as 30-50% by age 70 years. The GFR peaks during the third decade of life at approximately 120 mL/min/1.73 m 2; it shows an annual mean decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years. Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood from the afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomical and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow. Renal hemodynamic measurements in aged human and animals suggest that altered functional response of the renal vasculature may be an underlying factor in diminished renal blood flow and increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the elderly when compared to younger patients. However, the vasoconstrictor response to intrarenal angiotensin is identical in both young and older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may indicate that the aged kidney is in a state of vasodilatation to compensate for the underlying sclerotic damage. Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected. However, a wide variation in the rate of decline in the GFR is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction.

Prognosis
Patients with chronic kidney disease generally progress to ESRD. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventive measures, and on the individual patient. Timely initiation of chronic renal replacement therapy is imperative to prevent the uremic complications of chronic kidney disease that can lead to significant morbidity and death. Tangri et al developed and validated a model that uses routine laboratory results to predict progression from chronic kidney disease (stages 3-5) to kidney failure. The study showed that lower estimated GFR, higher albuminuria, younger age, and male sex pointed to a faster progression of kidney failure. Also, a lower serum albumin, calcium, and bicarbonate, and a higher serum phosphate can predict an elevated risk of kidney failure.[4] In the United States, the general hemodialysis and peritoneal dialysis populations have 2 hospital admissions per patient per year; patients who have a renal transplant have an average of 1 hospital admission per year. Additionally, patients with ESRD who undergo renal transplantation survive longer than those on chronic dialysis. The mortality rates associated with hemodialysis are striking and indicate that the life expectancy of patients entering into hemodialysis is markedly shortened. In 2003, over 69,000 dialysis patients enrolled in the ESRD program died (annual adjusted mortality rate of 210.7 per 1000 patient-years at risk for the dialysis population, which represents a 14% decrease since peaking at 244.5 per 1000 patient-years in 1988).

The highest mortality rate is within the first 6 months of initiating dialysis. Mortality then tends to improve over the next 6 months, before increasing gradually over the next 4 years. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%, and approximately 25% in patients with diabetes. At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a 60-year-old patient starting hemodialysis is closer to 4 years. Among patients with ESRD aged 65 years and older, mortality rates are 6 times higher than in the general population.[5] The most common cause of sudden death in patients with ESRD is hyperkalemia, which often follows missed dialysis or dietary indiscretion. The most common cause of death overall in the dialysis population is cardiovascular disease; cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population. The morbidity and mortality of dialysis patients is much higher in the United States compared with most other countries, which is probably a consequence of selection bias. Due to liberal criteria for receiving government-funded dialysis in the US and rationing (both medical and economic) in most other countries, US patients receiving dialysis are on the average older and sicker than those in other countries. In the NHANES III prevalence study, hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker of mortality in dialysis patients as well as in the general population) was independently associated with low bicarbonate as well as the inflammatory marker C-reactive protein. A study by Raphael et al suggests that higher serum bicarbonate levels are associated with better survival and renal outcomes in African Americans.[6] An elevated level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) has been linked with mortality in patients with ESRD. Isakova et al reported that elevated FGF-23 is also an independent risk factor for end-stage renal disease in patients who have fairly preserved kidney function (stages 2-4) and for mortality across the scope of chronic kidney disease.[7]

Reproductive issues
Female patients with advanced chronic kidney disease commonly develop menstrual irregularities; women with ESRD are typically amenorrheic and infertile. Pregnancy in chronic kidney disease can be associated with accelerated renal decline. In advanced chronic kidney disease and ESRD, pregnancy is associated with markedly decreased fetal survival.

Patient Education
Patients with chronic kidney disease should be educated about the following: Importance of compliance with secondary preventive measures Natural disease progression Prescribed medications (highlighting their potential benefits and adverse effects) Avoidance of nephrotoxins Diet Renal replacement modalities, including peritoneal dialysis, hemodialysis, and transplantation Permanent vascular access options for hemodialysis

History
Patients with chronic kidney disease stages 1-3 (glomerular filtration rate [GFR] >30 mL/min) are generally asymptomatic; they do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements. Generally, these disturbances become clinically manifest with chronic kidney disease stages 4-5 (GFR < 30 mL/min).

Uremic manifestations in patients with chronic kidney disease stage 5 are believed to be primarily secondary to an accumulation of toxins, the identity of which is generally not known. Metabolic acidosis in stage 5 may manifest as protein-energy malnutrition, loss of lean body mass, and muscle weakness. Altered salt and water handling by the kidney in chronic kidney disease can cause peripheral edema and, not uncommonly, pulmonary edema and hypertension. Anemia is associated with fatigue, reduced exercise capacity, impaired cognitive and immune function, and reduced quality of life. Anemia is also associated with the development of cardiovascular disease, the new onset of heart failure, or the development of more severe heart failure. Anemia is associated with increased cardiovascular mortality. Other manifestations of uremia in ESRD, many of which are more likely in patients who are inadequately dialyzed, include the following: Pericarditis - Can be complicated by cardiac tamponade, possibly resulting in death Encephalopathy - Can progress to coma and death Peripheral neuropathy Restless leg syndrome GI symptoms - Anorexia, nausea, vomiting, diarrhea Skin manifestations - Dry skin, pruritus, ecchymosis Fatigue, increased somnolence, failure to thrive Malnutrition Erectile dysfunction, decreased libido, amenorrhea Platelet dysfunction with tendency to bleeding

Physical Examination
The physical examination often is not very helpful. However, it may reveal findings characteristic of the condition that is underlying chronic kidney disease (eg, lupus, severe arteriosclerosis, hypertension) or complications of chronic kidney disease (eg, anemia, bleeding diathesis, pericarditis).

Screening for depression

Forty-five percent of patients with chronic kidney disease have depressive symptoms at dialysis therapy initiation, as assessed using self-report scales. However, these scales may emphasize somatic symptomsspecifically, sleep disturbance, fatigue, and anorexiathat can coexist with chronic disease symptoms. Hedayati et al reported that the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR[16]) and the Beck Depression Inventory (BDI) are effective screening tools and that scores of 10 and 11, respectively, were the best cutoff scores for identification of a major depressive episode in their study's patient population.[8] The study compared the BDI and QIDS-SR(16) with a gold-standard structured psychiatric interview in 272 patients with stage 2-5 chronic kidney disease who had not been treated with dialysis.

Diagnostic Considerations
Because of anatomic and physiologic changes, elderly patients with chronic kidney disease may behave differently, in terms of progression and response to pharmacologic treatment, than younger patients. A serum creatinine value of 1.2 mg/dL in a 70-kg, 25-year-old man represents an estimated glomerular filtration rate (eGFR) of 74 mL/min/1.73m2, but in a 70-kg, 80-year-old man, that same value represents an eGFR of 58 mL/min/1.73m2. Thus, in a 70-kg, 80-year-old man, what might appear to be only mild renal impairment with a serum creatinine of 2 mg/dL actually represents severe renal impairment when the eGFR is calculated to be 32 mL/min/1.73m2. Therefore, in elderly patients an eGFR must be determined, using a formula such as the Modification of Diet in Renal Disease (MDRD) equation, which includes age as a variable. This will allow appropriate

drug dosing adjustments to be made and nephrotoxins to be avoided in patients who have more extensive chronic kidney disease than would be suggested by the serum creatinine value alone.

Approach Considerations
Testing typically includes a complete blood count (CBC), basic metabolic panel, and urinalysis, with calculation of renal function. Serum phosphate, vitamin D, and intact parathyroid hormone (PTH) levels are obtained to look for evidence of renal bone disease. Renal ultrasound and other imaging studies may be indicated. Normochromic normocytic anemia is commonly seen in chronic kidney disease. Other underlying causes of anemia should be ruled out. The blood urea nitrogen (BUN) and creatinine levels will be elevated in patients with chronic kidney disease. Hyperkalemia or low bicarbonate levels may be present in patients with chronic kidney disease. Serum albumin levels may also be measured, as patients may have hypoalbuminemia due to urinary protein loss or malnutrition. A lipid profile should be performed in all patients with chronic kidney disease because of their increased risk of cardiovascular disease. In certain cases, the following tests may be ordered as part of the evaluation of patients with chronic kidney disease: Serum and urine protein electrophoresis - Screen for a monoclonal protein possibly representing multiple myeloma Antinuclear antibodies (ANA), double-stranded DNA antibody levels - Screen for systemic lupus erythematosus Serum complement levels - May be depressed with some glomerulonephritides Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA) levels - Helpful if positive in diagnosis of Wegener granulomatosis and polyarteritis nodosa Perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA) - Helpful if positive in diagnosis of microscopic polyangiitis Antiglomerular basement membrane (anti-GBM) antibodies - Highly suggestive of underlying Goodpasture syndrome Hepatitis B and C, HIV, Venereal Disease Research Laboratory (VDRL) serology - Conditions associated with some glomerulonephritides

Urinalysis
Dipstick proteinuria may suggest a glomerular or tubulointerstitial problem. The urine sediment finding of RBCs, RBC casts, suggests proliferative glomerulonephritis. Pyuria and/or WBC casts are suggestive of interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection. Although 24-hour urine collection for total protein and creatinine clearance (CrCl) can be performed, spot urine collection for total protein-to-creatinine ratio allows reliable approximation (extrapolation) of total 24hour urinary protein excretion. A value of greater than 2 g is considered to be within the glomerular range, and a value of greater than 3-3.5 g is within the nephrotic range; less than 2 is characteristic of tubulointerstitial problems.

Renal Function Formulas

The Cockcroft-Gault formula for estimating CrCl should be used routinely as a simple means to provide a reliable approximation of residual renal function in all patients with chronic kidney disease. The formulas are as follows: CrCl (male) = ([140-age] weight in kg)/(serum creatinine 72) CrCl (female) = CrCl (male) 0.85 Alternatively, the Modification of Diet in Renal Disease (MDRD) Study equation could be used to calculate the GFR. This equation does not require a patient's weight.[9]

However, MDRD underestimates measured GFR at levels >60 mL/min/1.73 m 2. Stevens et al found that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is more accurate than the MDRD Study equation overall and across most subgroups, and it can report eGFR 60 mL/min/1.73 m 2.[10]

Imaging Studies
Renal ultrasonography
Renal ultrasonography is useful to screen for hydronephrosis, which may not be observed in early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Small echogenic kidneys are observed in advanced renal failure. Kidneys usually are normal in size in advanced diabetic nephropathy, where affected kidneys initially are enlarged from hyperfiltration. Structural abnormalities, such as polycystic kidneys, also may be observed.

Radiography
A retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction exists despite a negative finding on renal ultrasonography. Intravenous pyelography is not commonly performed because of the potential for renal toxicity from the intravenous contrast; however, this procedure is often used to diagnose renal stones. Plain abdominal x-ray is particularly useful to look for radio-opaque stones or nephrocalcinosis. A voiding cystourethrogram (VCUG) is the criterion standard for diagnosis of vesicoureteral reflux

CT, MRI, and radionuclide scan

A computed tomography (CT) scan is useful to better define renal masses and cysts usually noted on ultrasound. Also, it is the most sensitive test for identifying renal stones. IV contrastenhanced CT scans should be avoided in patients with renal impairment to avoid acute renal failure; this risk significantly increases in patients with moderate-to-severe chronic kidney disease. Dehydration also markedly increases this risk. Magnetic resonance imaging (MRI) is very useful in patients who require a CT scan but who cannot receive intravenous contrast. It is reliable in the diagnosis of renal vein thrombosis, as are CT scan and renal venography. Magnetic resonance angiography also is becoming more useful for diagnosis of renal artery stenosis, although renal arteriography remains the criterion standard. A renal radionuclide scan is useful to screen for renal artery stenosis when performed with captopril administration; it also quantitates differential renal contribution to total GFR. However, radionuclide scans are unreliable in patients with a GFR of less than 30 mL/min.

Renal Biopsy
Percutaneous renal biopsy is performed most often with ultrasound guidance and the use of a mechanical gun. It generally is indicated when renal impairment and/or proteinuria approaching the nephrotic range are present and the diagnosis is unclear after appropriate other workup. It is not indicated when renal ultrasound reveals small echogenic kidneys on ultrasound because this finding represents severe scarring and chronic irreversible injury. The most common complication of this procedure is bleeding, which can be life threatening in a minority of occurrences. Surgical open renal biopsy can be considered when the risk of renal bleeding is felt to be great, occasionally with solitary kidneys, or when percutaneous biopsy is technically difficult to perform. Renal histology in chronic kidney disease reveals findings compatible with the underlying primary renal diagnosis and, generally, findings of segmental and globally sclerosed glomeruli and tubulointerstitial atrophy, often with tubulointerstitial mononuclear infiltrates.

Approach Considerations

Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with chronic kidney disease. These may delay, or possibly halt, progression. Early nephrologic referral is of extreme importance. The medical care of patients with chronic kidney disease should focus on the following: Delaying or halting the progression of chronic kidney disease Treating the pathologic manifestations of chronic kidney disease Timely planning for long-term renal replacement therapy Patients with chronic kidney disease acutely presenting with indications for dialytic therapy should be transferred to a hospital center where acute dialysis can be performed. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has issued 13 clinical practice guidelines for managing all stages of chronic kidney disease and related complications.

Delaying or Halting Progression of Chronic Kidney Disease

Treatment of the underlying condition if possible is indicated. Aggressive blood pressure control to target values per current guidelines is indicated. Systolic blood pressure control is considered more important and is also considered difficult to control in elderly patients with chronic kidney disease. Use angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as tolerated, with close monitoring for renal deterioration and for hyperkalemia (see the image below). Avoid these agents in advanced renal failure, bilateral renal artery stenosis [RAS], or RAS in a solitary kidney.

The tracing shows a wide QRS and very large T waves. In the setting of a minimally symptomatic patient with renal failure, this must be treated as hyperkalemia until the potassium level is not elevated. Hyperkalemia may be completely asymptomatic until a lethal arrhythmia occurs. Calcium salts are the most rapid acting of the agents used to treat hyperkalemia.

Data support the use of ACE inhibitors or ARBs in diabetic kidney disease with or without proteinuria. However, in nondiabetic kidney disease, these agents are effective in retarding the progression of disease among patients with proteinuria of less of than 500 mg/d. Aggressive glycemic control per the American Diabetes Association (ADA) recommendations (target HbA1C < 7%) is indicated. Although the Modification of Diet in Renal Disease (MDRD) Study failed to show the effect of protein restriction in retardation of the progression of kidney disease, a meta-analysis suggests a beneficial role for protein restriction. The National Kidney Foundation guidelines suggest that if a patient is started on protein restriction, the physician needs to closely monitor the patient's nutritional status. Predialysis low serum albumin is associated with a poor outcome among dialysis patients. A small trial (n=61) by Fishbane et al found that paricalcitol (Zemplar), a synthetic analog of calcitriol, can reduce protein excretion in patients with chronic kidney disease. [11] In this double-blind, randomized study, which compared paricalcitol, 1 mg/d, with placebo for 6 months, more patients in the paricalcitol group achieved a 10% reduction in proteinuria than did members of the control group (57.1% vs 25.9%, respectively). Treatment of hyperlipidemia to target levels per current guidelines is indicated. Avoidance of nephrotoxins, including IV radiocontrast, nonsteroidal anti-inflammatory agents (NSAIDs), and aminoglycosides is indicated.

Encourage smoking cessation, as smokers tend to reach end-stage renal disease (ESRD) earlier than nonsmokers. A large-population Norwegian study found that although smoking posed a great risk factor for the future onset of kidney failure, cessation decreased the risk, especially in men, who tended to be heavier smokers than women in this cross-section.[12]

Treating Pathologic Manifestations of Chronic Kidney Disease

The following should be addressed: Anemia with erythropoietin (Epogen) Hyperphosphatemia with dietary phosphate binders and dietary phosphate restriction Hypocalcemia with calcium supplements with or without calcitriol Hyperparathyroidism with calcitriol or vitamin D analogs Volume overload with loop diuretics or ultrafiltration Metabolic acidosis with oral alkali supplementation Uremic manifestations with long-term renal replacement therapy (hemodialysis, peritoneal dialysis, or renal transplantation) Cardiovascular complications With erythropoietin treatment, the goal is a hemoglobin level of 11-12 g/dL, as normalization of hemoglobin in patients with chronic kidney disease stages 4-5 has been associated with an increased risk of combined outcome. Before starting erythropoietin, iron stores should be checked. The aim is to keep iron saturation at 30-50% and ferritin at 200-500. London et al summarize the best evidence and the Kidney Disease Improving Global Outcomes (KDIGO) recommendations on how to manage chronic kidney diseasemineral and bone disorder.[13] The KDIGO guidelines are issued after weighing the quality and the depth of evidence, when available, and propose a common-sense approach to the evaluation and treatment of mineral and bone disorder in different stages of chronic kidney disease. The evidence for the benefits and risks of correcting metabolic acidosis is very limited, with no randomized controlled trials in patients not yet in end-stage renal disease (ESRD), none in children, and only 3 small trials in dialysis patients. These trials suggest that there may be some beneficial effects on both protein metabolism and bone metabolism, but the trials were underpowered to provide robust evidence. Experts recommend alkali therapy to maintain the serum bicarbonate concentration above 22 mEq/L. De Brito-Ashurst et al found that patients with chronic kidney disease who receive bicarbonate supplementation show a slower decline in renal function.[14] In this study, 134 adult patients with chronic kidney disease (ie, creatinine clearance [CrCl] 15-30 mL/min/1.73 m2 and serum bicarbonate 16-20 mmol/L) were randomly assigned to receive oral sodium bicarbonate supplementation or standard care for 2 years. A slower decline in CrCl was observed in the bicarbonate group than in the control group (1.88 vs 5.93 mL/min/1.73 m2). Patients in the bicarbonate group were also less likely to experience rapid disease progression than were members of the control group (9% vs 45%), and fewer patients who received bicarbonate supplementation developed ESRD (6.5% vs 33%). In addition to the benefits listed above, nutritional parameters improved with bicarbonate supplementation. Indications for renal replacement therapy include the following: Severe metabolic acidosis Hyperkalemia Pericarditis Encephalopathy Intractable volume overload Failure to thrive and malnutrition Peripheral neuropathy

Intractable gastrointestinal symptoms Glomerular filtration rate (GFR) less than 10 mL/min

Timely Planning for Long-Term Renal Replacement Therapy

Consider the following: Early education regarding natural disease progression, different dialytic modalities, renal transplantation, patient option to refuse or discontinue chronic dialysis Timely placement of permanent vascular access (arrange for surgical creation of primary arteriovenous fistula, if possible, and preferably at least 6 months in advance of anticipated date of dialysis) Timely elective peritoneal dialysis catheter insertion Timely referral for renal transplantation

Diet
Protein restriction early in chronic kidney disease as a means to delay a decline in the GFR is controversial; however, as the patient approaches chronic kidney disease stage 5, this strategy is recommended to delay the onset of uremic symptoms. Patients with chronic kidney disease who already are predisposed to becoming malnourished are at higher risk for malnutrition with overly aggressive protein restriction. Malnutrition is a well-established predictor of increased morbidity and mortality in the ESRD population and must be avoided if possible. A meta-analysis found that dietary salt reduction significantly reduced blood pressure in individuals with type 1 or type 2 diabetes.[15] These findings, along with other evidence relating salt intake to blood pressure and albuminuria in hypertensive and normotensive patients, make a strong case for a reduction in salt intake as a means of slowing the progression of diabetic nephropathy. The recommendation for the general population in public health guidelines is less than 5-6 g/d. Dietary salt reduction may help slow progression of kidney disease in both type 1 and type 2 diabetes. The following dietary restrictions may also be indicated: Phosphate restriction starting early in chronic kidney disease Potassium restriction Sodium and water restriction as needed to avoid volume overload The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has issued a Clinical Practice Guideline for Nutrition in Chronic Renal Failure, as well as a 2008 revision of recommendations forNutrition in Children with Chronic Kidney Disease. A randomized controlled trial by Slagman et al found that moderate dietary sodium reduction (approximately 2500 mg/day of Na+ or 6 g/d of NaCl) added to ACE inhibition compared with dual blockade (ACE inhibitor and angiotensin receptor blocker) was more effective in reducing both proteinuria and blood pressure in nondiabetic patients with modest chronic kidney disease. Furthermore, low-sodium diet added to dual therapy yielded additional reductions in both blood pressure and proteinuria, emphasizing the beneficial effect of dietary salt reduction in the management of nondiabetic patients . [16]

Consultations and Long-Term Monitoring

Consultations may include the following: Early nephrology referral (decreases morbidity and mortality) Renal dietitian Vascular surgery for permanent vascular access General surgery for peritoneal catheter placement Referral to renal transplant center Patients with chronic kidney disease should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up until initiation of chronic renal replacement therapy.

A multidisciplinary approach to care, including involvement of the nephrologist, primary care physician, renal dietitian, nurse, and social worker, should be initiated early in the course of chronic kidney disease, with close patient follow-up. Patients should be monitored for obstructive sleep apnea (OSA), which occurs with increased frequency in patients receiving dialysis. In addition, a Japanese study has shown a connection between OSA and nondialysis chronic kidney disease. Sakaguchi et al found a high incidence (65%) of OSA in patients with nondialysis chronic kidney disease, with about one third of those having moderate or severe OSA. The study also found that decreased GFR was associated with an increased risk of OSA.[17]

Medication Summary
In chronic kidney disease, doses and intervals of drugs that are excreted or metabolized renally should be adjusted accordingly for the residual glomerular filtration rate (GFR). Some drugs are contraindicated in moderate-to-severe renal impairment because of potentially serious effects from drug or metabolite accumulation. Routine consultation of the appropriate references should be undertaken when prescribing any new drug to a patient with chronic kidney disease. Hyperphosphatemia is treated with dietary phosphate binders and dietary phosphate restriction. Hypocalcemia is treated with calcium supplements and possibly calcitriol. Hyperparathyroidism is treated with calcitriol or vitamin D analogs.

Phosphate-Lowering Agents
Class Summary
Dietary phosphate binders promote the binding of phosphate, typically with calcium, to reduce hyperphosphatemia.
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Calcium acetate (PhosLo, Eliphos)

This agent is used for treatment of hyperphosphatemia in chronic kidney disease. It combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.
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Calcium carbonate (Caltrate, Oystercal, Oysco, Alcalak)

This agent is used for treatment of hyperphosphatemia or as a calcium supplement in chronic kidney disease. It successfully normalizes phosphate concentrations in patients with chronic kidney disease. Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces. It is marketed in a variety of dosage forms and is relatively inexpensive.
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Calcitriol (Rocaltrol, Calcijex, Vectical)

Calcitriol (1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3), the hormonally active form of vitamin D, is used to suppress parathyroid production and secretion in secondary hyperparathyroidism and for treatment of hypocalcemia in chronic kidney disease by increasing intestinal calcium absorption.
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Doxercalciferol (Hectorol)
Doxercalciferol is a vitamin D analog (1-alpha-hydroxyergocalciferol) that does not require activation by the kidneys. It is indicated for the treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD).
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Lanthanum carbonate (Fosrenol)

Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with end-stage renal disease. It directly binds dietary phosphorus in the upper GI tract, thereby inhibiting phosphorus absorption.
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Sevelamer (Renagel, Renvela)

Sevelamer is indicated for the reduction of serum phosphorus levels in patients with end-stage renal disease (ESRD). This agent binds dietary phosphate in the intestine, thus inhibiting its absorption. In patients on hemodialysis, sevelamer treatment results in fewer hypercalcemic episodes than calcium acetate treatment.
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Paricalcitol (Zemplar)
Paricalcitol is a synthetic analog of calcitriol that is used for treatment of secondary hyperparathyroidism in ESRD. It reduces parathyroid hormone levels, stimulates calcium and phosphorus absorption, and stimulates bone mineralization.

Growth Factors
Class Summary
Growth factors are used to treat anemia of chronic kidney disease by stimulating red blood cell (RBC) production.
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Epoetin alfa (Epogen, Procrit)

This agent stimulates division and differentiation of committed erythroid progenitor cells. It induces release of reticulocytes from the bone marrow into the blood stream.
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Darbepoetin (Aranesp)
Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production. Darbepoetin contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3 such chains. Darbepoetin has longer a half-life than epoetin alfa, and may be administered weekly or biweekly.

Iron Salts
Class Summary
Iron salts are nutritionally essential inorganic substances used to treat anemia.
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Ferrous sulfate (Feosol, Fer-In-Sol, Slow FE, Fer-iron, MyKidz Iron 10)
Ferrous sulfate is used as a building block for hemoglobin synthesis in patients with anemia of chronic kidney disease who are being treated with erythropoietin.
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Iron dextran (DexFerrum, InFed)

Iron dextran is used to treat microcytic, hypochromic anemia resulting from iron deficiency, and to replenish iron stores in individuals on erythropoietin therapy, when oral administration is infeasible or ineffective. A 0.5-mL (0.25 mL in children) test dose should be administered prior to starting therapy. This agent is available as 50 mg iron/mL (as dextran).

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Iron sucrose (Venofer)

Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) in patients receiving longterm hemodialysis. Iron deficiency in these patients is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the GI tract. There is a lower incidence of anaphylaxis with iron sucrose than with other parenteral iron products.
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Ferric gluconate (Ferrlecit, Nulecit)

Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme systems, allowing transportation of oxygen via hemoglobin.
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Ferumoxytol (Feraheme)
This agent is indicated for iron replacement in adults with chronic kidney disease who have iron deficiency anemia.

Calcimimetic Agents
Class Summary
These agents reduce parathyroid hormone levels.
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Cinacalcet (Sensipar)
Cinalcet directly lowers intact parathyroid hormone (iPTH) levels by increasing the sensitivity to extracellular calcium of calcium-sensing receptors on chief cells of the parathyroid gland. It also results in a concomitant decrease in serum calcium. It is indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.