Chronic Kidney Disease

Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN

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 m2 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 angiotensinconverting 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 1999-2004. 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 1990-2001.

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 m2; 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 60year-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 24-hour 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 m2. 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 m2.[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 doubleblind, 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. A study by Plantinga et al found that a great number of individuals with chronic kidney disease may be unaware of their disease and thus may be at risk for further kidney injury through use of NSAIDs. Those who knew of their chronic kidney disease were less likely to use NSAIDs, suggesting that primary care physicians should be involved in communication regarding the risks of NSAID.[12] 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.[13]

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.[14] 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.[15] 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.[16] 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 for Nutrition 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 . [17]

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.[18]

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.
View full drug information 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.
View full drug information

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.
View full drug information 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.
View full drug information 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).
View full drug information 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.
View full drug information 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.
View full drug information 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.
View full drug information 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.
View full drug information 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.

View full drug information 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.
View full drug information 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).
View full drug information Iron sucrose (Venofer)

Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) in patients receiving long-term 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.
View full drug information Ferric gluconate (Ferrlecit, Nulecit)

Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme systems, allowing transportation of oxygen via hemoglobin.
View full drug information 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.

View full drug information 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.

Azotemia

Author: Moro O Salifu, MD, MPH, FACP; Chief Editor: Vecihi Batuman, MD, FACP, FASN

Background
Azotemia is an elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) levels, as depicted in the following graph.

The graph shows the relationship of the glomerular filtration rate (GFR) to steady-state serum creatinine and blood urea nitrogen (BUN) levels. As shown in this figure, in early renal disease, substantial decline in GFR may lead to only a slight elevation in serum creatinine. Elevation in serum creatinine is apparent only when the GFR falls to about 70 mL/min.

Each human kidney contains approximately 1 million functional units, called nephrons, which are primarily involved in urine formation. Urine formation ensures that the body eliminates the

final products of metabolic activities and excess water in an attempt to maintain a constant internal environment (homeostasis). Urine formation by each nephron involves 3 main processes, as follows: filtration at the glomerular level, selective reabsorption from the filtrate passing along the renal tubules, and secretion by the cells of the tubules into this filtrate. Perturbation of any of these processes impairs the kidney's excretory function, resulting in azotemia. The quantity of glomerular filtrate produced each minute by all nephrons in both kidneys is referred to as the glomerular filtration rate (GFR). Average GFR is about 125 mL/min (10% less for women) or 180 L/d. About 99% (178 L/d) is reabsorbed, and the rest (2 L/d) is excreted.
Measuring renal function

Radionuclide assessment of GFR is the criterion standard for measuring kidney function. However, because it is expensive and not widely available, serum creatinine concentration and creatinine clearance (CrCl) more commonly are used to estimate GFR. An inverse relationship between serum creatinine and GFR exists. However, the serum creatinine and CrCl are not sensitive measures of kidney damage for 2 reasons. First, substantial renal damage can take place before any decrease in GFR occurs. Second, substantial decline in GFR may lead to only slight elevation in serum creatinine, as seen in the image above. An elevation in serum creatinine is apparent only when the GFR falls to about 60-70 mL/min. This is due to compensatory hypertrophy and hyperfiltration of the remaining healthy nephrons. Because creatinine normally is filtered as well as secreted into the renal tubules, the CrCl may cause the GFR to be substantially overestimated, especially as kidney failure progresses because of maximal tubular excretion. More accurate determinations of GFR require the use of inulin clearance or a radiolabeled compound, such as iothalamate. In practice, precise knowledge of the GFR is not required, and disease process usually can be monitored by the estimated GFR (eGFR) using different methods, as shown below. The CrCl is best calculated by obtaining a 24-hour collection for creatinine and volume and then using the following formula: CrCl (mL/min) = U/P X V where U is the 24-hour creatinine in mg/dL, P is the serum creatinine in mg/dL, and V is the 24-hour volume/1440 (number of min in 24 h). Using the 24-hour creatinine in grams and the serum creatinine in milligrams, CrCl (mL/min) = creatinine [g/d]/serum creatinine [mg/dL]) X 70. An adequate 24-hour collection usually reflects a creatinine generation of 15-20 mg/kg in women and 20-25 mg/kg in men. When 24-hour creatinine is measured, the adequacy of the collection must be established prior to calculation of the creatinine clearance. Alternatively, a bedside formula (Cockroft and Gault) using the patient's serum creatinine, age, and lean weight (in kg) can be used to estimate the GFR, as follows: CrCl (mL/min) = (140 age) X weight (kg) / (72 X serum creatinine) in mg/dL (X 0.85 for women).

Another formula was derived from data collected in a large study called the Modification of Diet in Renal Disease (MDRD). This formula is known as the MDRD formula, or the Levey formula. It is now widely accepted as more accurate than the Cockroft and Gault formula and is an alternative to radioisotope clearance. Because serum creatinine levels alone cannot detect earlier stages of chronic kidney disease (CKD), the MDRD formula also takes into account the patient's age and race. Although more accurate, it is much more difficult to calculate manually. However, software for estimating GFR by the MDRD formula is available for most pocket digital assistants (PDA) and can be found on the Internet. Delanaye et al have argued that the MDRD formula is not applicable to all persons, such as healthy individuals and patients who are anorectic or obese.[1] It has therefore been argued that the formula should be applied with caution.

Pathophysiology
There are 3 pathophysiologic states in azotemia, as follows: prerenal azotemia, intrarenal azotemia, and postrenal azotemia.
Prerenal azotemia

Prerenal azotemia refers to elevation in BUN and creatinine levels because of problems in the systemic circulation that decrease flow to the kidneys. In prerenal azotemia, decrease in renal flow stimulates salt and water retention to restore volume and pressure. When volume or pressure is decreased, the baroreceptor reflexes located in the aortic arch and carotid sinuses are activated. This leads to sympathetic nerve activation, resulting in renal afferent arteriolar vasoconstriction and renin secretion through 1 -receptors. Constriction of the afferent arterioles causes a decrease in the intraglomerular pressure, reducing GFR proportionally. Renin converts angiotensin I to angiotensin II, which, in turn, stimulates aldosterone release. Increased aldosterone levels results in salt and water absorption in the distal collecting tubule. A decrease in volume or pressure is a nonosmotic stimulus for antidiuretic hormone production in the hypothalamus, which exerts its effect in the medullary collecting duct for water reabsorption. Through unknown mechanisms, activation of the sympathetic nervous system leads to enhanced proximal tubular reabsorption of salt and water, as well as BUN, creatinine, calcium, uric acid, and bicarbonate. The net result of these 4 mechanisms of salt and water retention is decreased output and decreased urinary excretion of sodium (< 20 mEq/L).
Intrarenal azotemia

Intrarenal azotemia, also known as acute renal failure (ARF), renal-renal azotemia, and acute kidney injury (AKI), refers to elevation in BUN and creatinine levels because of problems in the kidney itself. There are several definitions, including a rise in serum creatinine levels of about 30% from baseline or a sudden decline in output below 500 mL/d. If output is preserved, it is called nonoliguric ARF. If output falls below 500 mL/d, it is called oliguric ARF. Any form of ARF may be so severe to virtually stop formation, a condition called anuria (< 100 mL/d).

The most common causes of nonoliguric ARF are acute tubular necrosis (ATN), aminoglycoside nephrotoxicity, lithium toxicity, or cisplatin nephrotoxicity. Tubular damage is less severe than in oliguric ARF. Normal output in nonoliguric ARF does not reflect normal GFR. Patients may still make 1440 mL/d of urine even when the GFR falls to about 1 mL/min because of decreased tubular reabsorption. Some studies indicate that nonoliguric forms of ARF are associated with less morbidity and mortality than oliguric ARF. Uncontrolled studies also suggest that volume expansion, potent diuretic agents, and renal vasodilators can convert oliguric to nonoliguric ARF if administered early. The pathophysiology of acute oliguric or nonoliguric ARF depends on the anatomical location of the injury. In ATN, epithelial damage leads to functional decline in the ability of the tubules to reabsorb salt, water, and other electrolytes. Excretion of acid and potassium also is impaired. In more severe ATN, the tubular lumen is filled with epithelial casts, causing intraluminal obstruction, resulting in the decline of GFR. Acute interstitial nephritis is characterized by inflammation and edema, resulting in azotemia, hematuria, sterile pyuria, white cell casts with variable eosinophiluria, proteinuria, and hyaline casts. The net effect is a loss of urinary concentrating ability, with low osmolality (usually < 500 mOsm/L), low specific gravity (< 1.015), high urinary sodium (>40 mEq/L), and occasionally, hyperkalemia and renal tubular acidosis. However, in the presence of a superimposed prerenal azotemia, the specific gravity, osmolality, and sodium may be misleading. Glomerulonephritis or vasculitis is suggested by the presence of hematuria, red cells, white cells, granular and cellular casts, and a variable degree of proteinuria. Nephrotic syndrome usually is not associated with active inflammation and often presents as proteinuria greater than 3.5 g/24 h. Glomerular diseases may reduce GFR due to changes in basement membrane permeability and because of stimulation of the renin-aldosterone axis. Glomerular diseases often manifest as nephrotic or nephric syndrome. In nephrotic syndrome, the urinary sediment is inactive, and there is gross proteinuria (>3.5 g/d), hypoalbuminemia, hyperlipidemia, and edema. Azotemia and hypertension are uncommon initially, but their presence may indicate advanced disease. Some patients with nephrotic syndrome may present with ARF. Impairment of capillary circulation in the kidney due to edema (nephrosarca) and tubular obstruction from protein casts have been proposed as potential mechanisms for the development of ARF in patients with nephrotic syndrome. In nephritic syndrome, the urinary sediment is active with white or red cell casts, granular casts, and azotemia. Proteinuria is less obvious, but increased salt and water retention in glomerulonephritis can lead to hypertension, edema formation, decreased output, low urinary excretion of sodium, and increased specific gravity. Acute vascular diseases include vasculitis syndromes, malignant hypertension, scleroderma renal crisis, and thromboembolic disease, all of which cause renal hypoperfusion and ischemia leading to azotemia. Chronic vascular diseases are due to hypertensive benign nephrosclerosis, which has

not been conclusively associated with end-stage renal disease and ischemic renal disease from bilateral renal artery stenosis.[2] In bilateral renal artery stenosis, maintenance of adequate intraglomerular pressure for filtration greatly depends on efferent arteriolar vasoconstriction. Azotemia sets in when angiotensinconverting enzyme (ACE) inhibitors or angiotensin type 2 receptor blockers cause efferent arteriolar dilatation, thereby decreasing intraglomerular pressure and filtration. Therefore, converting enzyme inhibitors and receptor blockers are contraindicated in bilateral renal artery stenosis. In addition to accumulation of urea creatinine and other waste products, a substantial reduction in GFR in CKD results in decreased production of erythropoietin (causing anemia) and vitamin D-3 (causing hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy); reduction in acid, potassium, salt, and water excretion (causing acidosis, hyperkalemia, hypertension, and edema); and platelet dysfunction, which leads to increased bleeding tendencies. The syndrome associated with the signs and symptoms of accumulation of toxic waste products (uremic toxins) is termed uremia and often occurs at a GFR of about 10 mL/min. Some of the uremic toxins (ie, urea, creatinine, phenols, guanidines) have been identified, but none has been found responsible for all the manifestations of uremia.
Postrenal azotemia

Postrenal azotemia refers to elevation in BUN and creatinine levels because of obstruction in the collecting system. Obstruction to flow leads to a reversal of Starling forces responsible for glomerular filtration. Progressive bilateral obstruction causes hydronephrosis with an increase in the Bowman capsular hydrostatic pressure and tubular blockage resulting in progressive decline and ultimate cessation in glomerular filtration, azotemia, acidosis, fluid overload, and hyperkalemia. Unilateral obstruction rarely causes azotemia. With relief of complete ureteral obstruction within 48 hours of onset, there is evidence that relatively complete recovery of GFR can be achieved within a week, while little or no further recovery occurs after 12 weeks. Complete or prolonged partial obstruction can lead to tubular atrophy and irreversible renal fibrosis. Hydronephrosis may be absent if obstruction is mild or acute or if the collecting system is encased by retroperitoneal tumor or fibrosis.

Epidemiology
Frequency United States

Considerable variability exists in reports about the incidence of hospital or community-acquired ARF. In one report, community-acquired ARF occurred in about 1% of all hospital admissions.

Overall, ARF occurs in about 5% of all hospital admissions. However, differences exist in ARF occurring in the intensive care unit (about 15%) and in the coronary care unit (about 4%). In CKD, progressive azotemia leading to end-stage renal disease requiring dialysis or kidney transplantation occurs in a number of chronic diseases with frequencies for diabetes (36%), hypertension (24%), glomerulonephritis (15%), cystic kidney disease (4%), uncertain (5%), and all other known miscellaneous renal disorders (15%).
International

A report from Madrid evaluated 748 cases of ARF at 13 tertiary hospital centers. The most frequent causes were ATN (45%); prerenal (21%); acute or chronic renal failure, mostly due to ATN and prerenal disease (13%); urinary tract obstruction (10%); glomerulonephritis or vasculitis (4%); acute interstitial nephritis (2%); and atheroemboli (1%). Etiologies of CKD differ around the world. Diabetic nephropathy as a cause of CKD is on the rise in developed and developing countries.
Mortality/Morbidity

Prognosis in ARF generally is poor and depends on the severity of the underlying disease and the number of failed organs. While mortality rate in simple ARF without other underlying disease is 7-23%, the mortality in the patient in the intensive care unit on mechanical ventilation is as high as 80%. The prognosis of patients with CKD depends on the etiology of the failure. Patients with diabetic kidney disease, hypertensive nephrosclerosis, and ischemic nephropathy (ie, large-vessel arterial occlusive disease) tend to have progressive azotemia resulting in end-stage renal disease. Different types of glomerulonephritis have major differences in prognosis, with some being quite benign and rarely progressing to end-stage renal disease, whereas others have rapid progression to end-stage renal disease within months. About 50% of patients with polycystic kidney disease progress to end-stage renal disease by the fifth or sixth decade of life.

Race

In the 2008 annual report of the United States Renal Data System (USRDS), more than 500,000 patients with end-stage renal disease were receiving dialysis or a kidney transplant in the United States. Racial distribution was reported as Asian/Pacific Islander (4.7%), black (32.0%), white (61.0%), American Indian (1.3%), and other/unknown (0.6%).
Sex

Of the patients reported in the 2008 annual report of the USRDS, male frequency is 56.0% and female frequency is 44.0%.

Age

Of the patients reported in the 2008 annual report of the USRDS, frequencies for patients aged 019 years is 1.5%; aged 20-44 years, 19.1%; aged 45-64 years, 44.0%; aged 65-74 years, 19.6%; and older than 75 years, 15.7%.

History
It is necessary to quickly establish if azotemia is acute or chronic and whether it is due to prerenal, intrarenal, or postrenal causes. This is vital in initiating treatment and in preventing progression. Clinical evaluation requires a thorough history, physical examination, and specific laboratory tests. Tests include serologies, urinalysis, and, if indicated, radiologic studies and kidney biopsy.

Prerenal azotemia: History of diarrhea, vomiting, profound heat exhaustion, excessive sweat loss, concurrent illness that impairs patient's ability to eat and drink adequately, hemorrhage, liver disease, congestive heart failure, and polyuria (eg, caused by lithium intoxication, diuretics, diabetes, diabetes insipidus) Intrarenal azotemia o History of nocturia, polyuria, proteinuria, shock, and edema o Personal or family history of congenital or systemic diseases, especially diabetes, hypertension, systemic lupus erythematosus, other collagen vascular diseases, hepatitis B (HBV), hepatitis C (HCV), syphilis, multiple myeloma, and AIDS o Detailed medication history (looking for nephrotoxic medications, especially antibiotics, NSAIDs, ACE inhibitors, diuretics, and herbal remedies), chemical exposure, and intravenous drug abuse (exposure to HIV, HBV, and HCV infections) Postrenal azotemia: Renal colic, dysuria, frequency, hesitancy, urgency incontinence, pelvic malignancy or irradiation, and benign prostatic hypertrophy

Physical
Physical examination should be detailed but focused on signs of high diagnostic yield.

Prerenal azotemia: Look for tachycardia; orthostatic hypotension (systolic BP drop of >20 mm Hg, diastolic BP drop of >10 mm Hg or more from the supine to standing position); hypotension; signs of dehydration, including dry mucous membranes, loss of skin turgor, and loss of axillary sweat; and signs of congestive heart failure or hepatic insufficiency. Intrarenal azotemia: Look for hypertension and its end organ effects, such as hypertensive retinopathy and left ventricular hypertrophy (apical impulse displaced lateral to midclavicular line), rash, joint swelling or tenderness, needle tracks, hearing abnormality, palpable kidneys, abdominal bruits, pericardial rub, and asterixis. The latter 2 signs are suggestive of uremia. The presence of uremic pericarditis requires immediate dialysis. Postrenal azotemia: A palpable bladder that is dull to percussion and a rectal or pelvic mass on digital examination is suggestive of postrenal azotemia (obstruction).

Causes
Causes are broadly classified as prerenal, intrarenal, and postrenal.

Prerenal azotemia o Prerenal azotemia occurs as a result of impaired renal blood flow or decreased perfusion resulting from decreased blood volume, decreased cardiac output (congestive heart failure), decreased systemic vascular resistance, decreased effective arterial volume from sepsis or hepatorenal syndrome, and renal artery abnormalities. o It may be superimposed on a background of chronic renal failure. o Iatrogenic causes of prerenal azotemia, such as excessive diuresis and treatment with ACE inhibitors, should be ruled out. Intrarenal azotemia o Intrarenal azotemia occurs as a result of injury to the glomeruli, tubules, interstitium, or small vessels. o It may be acute oliguric, acute nonoliguric, or chronic. o The presence of systemic disease, nocturia, proteinuria, loss of urinary concentrating ability (low urine specific gravity), anemia, and hypocalcemia are suggestive of chronic intrarenal azotemia. Postrenal azotemia o Postrenal azotemia occurs when an obstruction to urine flow is present. o It is observed in bilateral ureteral obstruction from tumors or stones, retroperitoneal fibrosis, neurogenic bladder, and bladder neck obstruction from prostatic hypertrophy or carcinoma and posterior urethral valves. o It may be superimposed on a background of chronic renal failure.

Differentials

Acute Tubular Necrosis Chronic Renal Failure Glomerulonephritis, Acute Glomerulonephritis, Chronic Nephritis, Interstitial Obstructed Megaureter Uremia

Laboratory Studies
Obtain CBC count, biochemical profile, urinalysis, and urine electrolytes for the initial evaluation. In addition to establishing the presence of systemic disease, clues for the origin of azotemia may emerge from these tests. Diagnostic indices commonly used to differentiate prerenal from intrarenal or postrenal azotemia are summarized in the image below.

Diagnostic Images in Azotemia: Although these indices are helpful, it is not necessary to perform all these tests on a particular patient. Comparison should always be made with the patients baseline values to identify trends consistent with increase or decrease in effective circulating volume. It should be noted that use of some of these indices may be limited in certain clinical conditions, such as in anemia (hematocrit), hypocalcemia (serum calcium), decreased mucle mass (serum creatinine), liver disease (BUN, total protein, albumin), poor nutritional state (BUN, total protein, albumin) and use of diuretics (urine Na). FEUrea and FELi appear to be better in assessing prerenal status in patients on diuretics.

Prerenal azotemia o In prerenal azotemia, hemoconcentration results in elevation of hematocrit, total protein/albumin, calcium, bicarbonate, and uric acid from their baselines. o Oliguria (urine volume is < 500 mL/d), anuria (< 100 mL/d), high urine specific gravity (>1.015), normal urinary sediment, and low urinary sodium (< 20 fractional excretion of sodium [FENa] < 1.0%) are seen. o When volume depletion is predominant, exaggerated proximal tubular reabsorption results in azotemia, hypernatremia, elevated levels of calcium, uric acid, and bicarbonate, while hemoconcentration results in the elevation of total protein, albumin, and hematocrit levels from their baselines. When hypoperfusion due to decreased cardiac output or effective arterial volume is present, patients exhibit edema,

hyponatremia, and hypoalbuminemia. The hematocrit, calcium, uric acid, and bicarbonate levels vary widely in this category. These patients often are critically ill. o The FENa has traditionally been used to differentiate prerenal azotemia from ATN. An FENa below 1% is suggestive of a prerenal cause (eg, volume depletion), while an FENa above 2% is suggestive of ATN. Since the FENa is based on the fact that sodium reabsorption is enhanced in the setting of volume depletion, active use of diuretics may elevate the FENa even when volume depletion is present. The fractional excretion of urea or fractional excretion of urea nitrogen (FEUrea), or the fractional excretion of uric acid (FEUA), are the alternatives, because urea and uric acid excretion are not influenced by diuretics. An FEUrea of less than 35% or an FEUA of less than 25% is suggestive of a prerenal etiology of ARF, while an FEUrea of more than 50% or an FEUA above 25% suggests ATN.[3] Intrarenal azotemia o Anemia, thrombocytopenia, hypocalcemia, and high anion gap metabolic acidosis may suggest intrarenal azotemia. o Low urine specific gravity (< 1.015), active urinary sediment (see Pathophysiology), high urinary sodium (>40 mEq/L), FENa (>5%), plasma BUNcreatinine ratio (< 20), and low urine osmolality may suggest intrarenal azotemia. o For patients with long-standing CKD, a renal sonogram usually shows small, contracted kidneys. Some causes of CKD can be associated with normal or large-sized kidneys, such as HIV nephropathy, diabetes, and renal amyloidosis. The renal sonogram usually is diagnostic for patients with polycystic kidney disease. In patients with active urinary sediment, progressive azotemia, proteinuria, and/or normal-sized kidneys on sonogram, a renal biopsy should be considered. Consultation with a nephrologist is imperative in all such patients. Postrenal azotemia o Urinary indices in postrenal azotemia due to complete bilateral obstruction are usually nondiagnostic. The prima facie finding here is anuria and, occasionally, hypertension. Urine output still may be present if overflow (in bladder outlet obstruction) or partial ureteral obstruction is present. o A Foley catheter should be inserted as part of the initial evaluation to rule out obstruction below the bladder outlet. Unilateral ureteral obstruction rarely leads to azotemia; it occurs acutely (due to obstruction from calculi, papillary necrosis, or hematoma), producing renal colic, or may be chronic and asymptomatic, producing hydronephrosis. o Bilateral partial obstruction may be associated with azotemia in the presence of normal urine output. When patients are subjected to maneuvers that increase urinary flow (eg, diuretic renogram, perfusion pressure flow studies), they may exhibit an increase in size or pressure of the collecting system or experience pain. o In addition to azotemia, polyuria due to loss of concentrating ability and type 1 renal tubular acidosis, with hyperkalemia, hypercalcemia from metastatic pelvic tumor, and elevated prostate-specific antigen (PSA), may be clues to postrenal azotemia. Hydronephrosis in the absence of hydroureter may be seen in early (< 3 d) obstruction, retroperitoneal process, or partial obstruction. Renal sonogram is the test of choice to rule out obstructive uropathy. If renal sonogram is equivocal, a Lasix washout scan, as discussed below in Imaging Studies, should be performed.

Imaging Studies

Plain film of abdomen o If symptoms suggest nephrolithiasis, a plain film of the abdomen is performed to screen for presence of a radiopaque stone. o Calcium-containing, struvite, and cystine stones can be identified, but radiolucent ones, such as uric acid stones, will be missed. Renal sonogram is the most commonly used renal imaging study because of its ease of use and broad application for the following: o Renal sonogram can determine renal size, which is important when considering renal biopsy. Small kidneys (< 9 cm) may be suggestive of scarring from advanced renal disease, whereas normal or large kidneys with smooth contours may indicate a potentially reversible process. o It can differentiate cystic lesions from solid lesions. o It is a test of choice for diagnosing urinary tract obstruction. o Renal sonogram can detect kidney stones. Doppler renal ultrasonography can be used to evaluate renal vascular flow (eg, renal vein thrombosis, renal infarction, renal artery stenosis). Intravenous pyelogram o The risk of contrast nephrotoxicity should be weighed against the benefits of making a diagnosis that will not change management. o Intravenous pyelogram can provide detailed information concerning calyceal anatomy and the size and shape of the kidney. o It is extremely useful for detecting renal stones. o It is the preferred technique in the evaluation and diagnosis of certain structural disorders, such as chronic pyelonephritis, medullary sponge kidney, and papillary necrosis. o It can provide data on the degree of obstruction. Computed tomography (CT) scanning[4] is complementary to ultrasonography, especially when the diagnosis is uncertain. Contrast nephrotoxicity should be weighed against the benefits. CT scanning does the following: o It can be used to distinguish (in most cases) neoplastic lesions from simple cyst and is the criterion standard for radiologic diagnosis of renal stone disease, including radiolucent stones. o It can be used to evaluate and stage renal cell carcinoma and to diagnose renal vein thrombosis. It can diagnose polycystic kidney disease with higher sensitivity than ultrasonography, particularly in younger patients. Magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) o MRI or MRA is used only when CT scanning and ultrasonography are nondiagnostic. o They are the criterion standard for diagnosis of renal vein thrombosis. o They are used in the evaluation of renal cell carcinoma and renal artery stenosis or vasculitis. Renal arteriography o The availability of procedures not requiring contrast material (ie, sonography, MRI, MRA) and the risk of contracting contrast nephrotoxicity have reduced use of this test. o Renal arteriography is used in polyarteritis nodosa and renal artery stenosis to demonstrate multiple aneurysms and/or stenoses.

Renal venography o Risk of contrast nephrotoxicity is present. o Renal venography is the criterion standard for diagnosis of renal vein thrombosis. Radionuclide studies 99m o Technetium dimercaptosuccinic acid ( Tc DMSA) distributes heavily within the renal parenchyma at first pass and so is best for detecting renal parenchymal scarring. 99m o Technetium diethylenetriamine pentaacetic acid ( Tc DTPA) is heavily filtered at first pass and therefore is best for qualitative assessment of renal function (filtration, and excretion). Because it is heavily filtered, it is most sensitive in detecting urine leaks after renal transplant. For the same reason, it is also used concomitantly with Lasix washout scan (see below) for assessing functional obstruction of the collecting system. o Mercaptoacetyltriglycine (MAG3) scan is evenly distributed at first pass in the kidney and so is best for qualitative assessment of perfusion, filtration, and excretion. It is the preferred test after renal transplantation, to assess the 3 aspects of function. It can be used to detect urine leaks or functional obstruction with Lasix, although99m Tc DTPA scan remains the test of choice for these conditions. Voiding cystourethrogram can be performed with a radionuclide study, to detect vesicoureteral reflux. Retrograde or anterograde pyelography o This test has limited use because of the availability of sonography. o It may be used in patients with a high index of suspicion for hydronephrosis for whom sonogram results are normal, such as in retroperitoneal fibrosis. Lasix washout scan 99m o The 2 agents used in performing Lasix washout renal scans are Tc DTPA and MAG3. o Usually, the renal scan is performed first. Then, if needed, the Lasix washout is performed after the radionuclide has accumulated in the collecting system. Lasix is used as a part of the renogram to separate nonobstructive hydronephrosis from obstructive hydronephrosis. If there is no obstruction, flow induced by Lasix and containing little or no radionuclide will fill the collecting system, washing out urine that contains radionuclide from the system. However, in the presence of obstruction, the radionuclide is not washed out as quickly. o The half life or clearance of the radioisotope is plotted on a curve. A half life of less than 10 minutes is considered normal, of greater than 20 minutes is considered obstruction, and of between 10-20 minutes is subject to further interpretation. o Conditions that can make it difficult to interpret the Lasix washout curve include a megaureter or pelvis that accepts a large bolus of urine and poor renal function. In patients with a megaureter, it can be difficult to determine when the renal pelvis is full, and, in patients with renal disease, Lasix onset of action may be prolonged. To overcome the problem of poor renal function or relative hypovolemia if a patient has been fasting, the patient should be well hydrated with IV fluids prior to the study. o The test also is operator dependent, as the Lasix should be administered when it is thought that the renal pelvis is full. A full bladder also delays washout of isotope. Therefore, the patient's bladder needs to be catheterized before the study can be performed.

Procedures

Renal biopsy is indicated when glomerulonephritis, vasculitis, and, occasionally, interstitial nephritis are suspected to establish correct diagnosis and to guide therapy. The following are common indications for renal biopsy: o Isolated glomerular proteinuria or hematuria o Nephrotic syndrome o Acute nephritic syndrome o Unexplained acute or subacute renal failure Percutaneous renal biopsy complications o Severe bleeding causing hypotension occurs in 1-2% of patients. o Bleeding requiring transfusion occurs in about 0.1-0.3% of patients. Bleeding complications can be minimized by data obtained from tests for bleeding time, prothrombin time, partial thromboplastin time, and platelet count. NSAIDs should be stopped at least 1 week prior to a scheduled elective biopsy. Patients on Coumadin should be started on heparin at least 3 days prior to renal biopsy. Patients on heparin for other reasons should be stopped for at least 1 day. Percutaneous renal biopsy contraindications o Contraindications include uncorrectable bleeding diathesis, small kidneys, severe hypertension, multiple bilateral cysts or renal tumor, hydronephrosis, active renal or perirenal infection, and uncooperative patient. o Percutaneous biopsy may be performed in selected patients with a solitary kidney because of the generally low risk of bleeding. Open renal biopsy may be performed if a percutaneous attempt either is unsuccessful or contraindicated and if the benefits of diagnosis outweigh the risks. When percutaneous biopsy is contraindicated but a diagnosis is necessary, a transvenous transjugular renal core biopsy can be performed.[5] With this approach, bleeding occurs intravascularly, thereby reducing the risk of hematoma.

Medical Care

Prerenal azotemia o If volume depletion is due to free water loss, the serum sodium is often greater than 10 mEq/L. The amount of fluid replacement in liters (free water deficit) can be estimated from serum sodium (patients Na-140/140 X 0.5 X weight in kg). The free water deficit should be administered intravenously over 2-8 hours and should consist of hypotonic solutions, such as 0.5% NaCl or D5W. Alert patients should be encouraged to drink free water as much as tolerated; otherwise, free water can be administered via a nasogastric tube. Serum sodium should be measured every 6-8 hours, and fluid replacement should be adjusted to avoid a precipitous decline. The rate of decrease in serum sodium should be no more than 0.7 mEq/h (17 mEq/24 h) to avoid brain edema. Volume depletion due to blood loss requires IV saline and transfusion to maintain pressure (as well as interventions to halt further loss).

Diarrhea often causes isotonic volume loss requiring replacement with normal saline. Normal anion gap metabolic acidosis occurring with diarrhea requires bicarbonate in 0.5% normal saline infusion. o Diuretic induced volume depletion, especially in the elderly, manifests as dehydration, hyponatremia,[6] and, occasionally, hypokalemia. The treatment of choice is normal saline infusion and correction of hypokalemia. o Decreased cardiac output requires optimizing cardiac performance by careful use of diuretics, an ACE inhibitor, beta-blockers, nitrates, positive inotropic agents (including dobutamine), and, when indicated, specific therapy for the cause of impaired cardiac function. When ACE inhibitors are contraindicated because of hyperkalemia, the combination of nitrates and hydralazine offers an alternative. As these patients tend to have risk factors for macrovascular disease, the diagnosis of ischemic nephropathy or atheroembolic disease should be entertained when renal function continues to worsen despite optimization of cardiac function. o Decreased effective arterial volume due to systemic shunting can result from sepsis or liver failure (hepatorenal syndrome [HRS]). These patients often pose a management problem because of severe edema, hyponatremia, and hypoalbuminemia. Decreased oncotic pressure and increased vascular permeability, as well as exaggerated salt and water retention, shift the Starling forces toward formation of interstitial fluid. Effective treatment of sepsis with the appropriate antibiotics and hypotension with dopamine and norepinephrine is mandated. Crystalloid replacement can be tried, but it often leads to more edema. o For the severely hypoalbuminemic patient, salt-poor albumin infusion can be undertaken, but there is no conclusive evidence of benefit. Adequate nutrition and effective treatment of sepsis may improve oncotic pressure and normalize vascular permeability, thereby decreasing the systemic shunting. The net result is improved renal perfusion, decreased salt and water retention, improved output, and edema. In the HRS, the average survival is 1-2 weeks; however, there is evidence that the kidneys will recover with early liver transplantation. Occasionally, renal function is advanced, requiring replacement therapy. Intrarenal azotemia o Acute renal failure (acute kidney injury) Ischemic or nephrotoxic ATN The initial approach is to restore pressure (with fluid replacement) and to withdraw nephrotoxic drugs. If oliguria persists, albumin in combination with high-dose furosemide should be tried. The use of albumin in this context allows more Lasix to be bound to albumin for delivery to the organic anion transporter in the kidney, thereby allowing more Lasix to enter the tubule than would otherwise enter it. The administration of albumin in this setting is not for volume expansion. Although this approach is widely used, there is no supporting evidence for it. Other approaches that have no conclusive benefit include renal dose dopamine and synthetic atrial natriuretic peptide. The renal failure phase usually lasts 7-21 days if the primary insult can be corrected. Postischemic polyuria can be seen in the recovery phase and represents an attempt to excrete excess water and solute. Saline may be replaced (75% of output) as maintenance fluid because of salt wasting during this

phase. Hypokalemia may result from the saline diuresis. However, matching the hourly output with intravenous replacement is not recommended. Recovery is marked by the return of BUN and creatinine levels to near baseline values. Acute interstitial nephritis: Management is by withdrawal of the offending nephrotoxin, avoidance of further nephrotoxic exposure, and dehydration. The creatinine level begins to improve within 3-5 days. Renal biopsy may be indicated if renal failure is severe or azotemia is not improving. Once the diagnosis is confirmed, a trial of oral prednisone (starting at 1 mg/kg/d and tapering over 6 wk) or intravenous pulse methylprednisolone (1 g for 3 d) in severe cases can be considered. If the patient is a poor candidate for biopsy but the diagnosis is strongly suspected, therapy should be started. Radiocontrast-induced azotemia: This becomes evident 3-5 days after exposure. It is best prevented with adequate hydration with half-normal saline at 1 mL/kg/h 12 hours prior to administration of contrast and the use of smaller amounts of contrast. Clearly explain the risks of such procedures to the patient. The benefits of N -acetylcysteine and sodium bicarbonate are still being debated.[7, 8, 9] Until further evidence is derived from clinical trials, there are no contraindications for using these agents to help prevent contrast-induced nephropathy. o Chronic kidney disease It is important that patients with CKD be referred early to a nephrologist for the management of complications and for the transition to renal replacement therapy (ie, hemodialysis, peritoneal dialysis, renal transplantation). There is some evidence that early referral of patients with CKD improves short-term outcome. Disease progression can be slowed by various maneuvers, such as aggressive control of diabetes, hypertension, and proteinuria, and dietary protein and phosphate restriction, as well as specific therapies for some of the glomerular diseases, such as lupus. Anemia, hyperphosphatemia, acidosis, and hypocalcemia should be aggressively managed prior to renal replacement therapy. Postrenal azotemia o Relief of the obstruction is the mainstay of therapy. o In anuria, bladder catheterization is mandatory to rule out bladder neck obstruction, whereas in progressive azotemia, catheterization should be done after the patient has voided to determine the postvoid residual volume. A postvoid residual volume of 100 mL or more is suggestive of obstructive uropathy, and the cause should be further investigated.

Surgical Care

Unilateral or bilateral percutaneous nephrostomy o If hydronephrosis is due to ureteral obstruction, unilateral or bilateral stents or percutaneous nephrostomy is performed. Recovery of renal function takes 7-10 days, but renal function may be severely impaired, requiring dialysis until such time that partial recovery is adequate for withdrawal of dialysis.

Up to 500-1000 mL/min of postobstructive polyuria can be seen with relief of obstruction, which is appropriate and represents an attempt to excrete the excess fluid during the period of obstruction. Because of salt wasting during this phase, dehydration and hypokalemia are likely. Thus, two thirds of the urine output should be replaced with half-normal saline and potassium chloride if hypokalemic. Close monitoring is indicated to prevent hypotension and prerenal azotemia. Matching the hourly urine output with intravenous fluids is not recommended since excess water retention during the period of obstruction cannot be lost if hourly urine output is matched.

Medication Summary
The goals of therapy are to increase renal perfusion and to maintain urine output. Specific therapy for various systemic conditions affecting the kidney is discussed in other articles.[10]

Diuretics
Class Summary

To induce urine output in ATN, treat edema and hypertension. These drugs increase urine excretion by inhibiting sodium and chloride reabsorption at different sites in the nephron.
View full drug information Furosemide (Lasix)

Drug of choice as a diuretic. Inhibits sodium chloride reabsorption in the thick ascending limb of the loop of Henle.
View full drug information Metolazone (Mykrox, Zaroxolyn)

Adjunct to furosemide in severe edematous states or when furosemide alone does not achieve adequate diuresis. Increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. Metolazone may be more effective in impaired renal function.

Adrenergic agents
Class Summary

These agents stimulate vasodilation of the renal vasculature and enhance perfusion.
View full drug information Dopamine (Intropin)

Above a critical dose (renal dose), this drug becomes a potent vasoconstrictor. Renal dose dopamine is used widely, but benefit has not been established clearly.

Plasma volume expanders

Class Summary

Increase plasma oncotic pressure and mobilize fluid from the interstitial space into the intravascular space in hypoalbuminemic patients. Enhance delivery of furosemide to distal tubule.
View full drug information Albumin (Albuminar, Albumisol, Albunex, Albutein)

Supplied as a 5% solution in 250 mL or 25% in 50 mL. Preference is based on whether patient requires additional fluid replacement. Not used for nutritional supplementation; thus, attempts should be made to improve patient's nutrition.

Corticosteroids
Class Summary

Potent anti-inflammatory agent and immunosuppressant. Suppresses humoral and cellular response to tissue injury, thereby reducing inflammation.
View full drug information Prednisone (Sterapred)

Used commonly for many forms of glomerulonephritis and interstitial nephritis