Background
Acute renal failure (ARF) or acute kidney injury (AKI), as it is now referred to in the literature, is defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration). However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion. A rise in the BUN level can occur without renal injury, such as in GI or mucosal bleeding, steroid use, or protein loading, so a careful inventory must be taken before determining if a kidney injury is present.
Pathophysiology
AKI may occur in 3 clinical patterns, including the following: (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons; (2) in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, in general terms, AKI may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.
Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. Classifying AKI as oliguric or nonoliguric based on daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400 mL/d and has a worse prognosis, except in prerenal failure. Anuria is defined as a urine output of less than 100 mL/d and, if abrupt in onset, is suggestive of bilateral obstruction or catastrophic injury to both kidneys. Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy.
Prerenal AKIPrerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss from GI, renal, cutaneous (eg, burns), and internal or external hemorrhage can result in this syndrome. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). Special classes of medications that can induce prerenal AKI in volume-depleted states are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, with the use of radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), amphotereicin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney.Intrinsic AKI
Structural injury in the kidney is the hallmark of intrinsic AKI, and the most common form is acute tubular injury (ATN), either ischemic or cytotoxic. Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. The distal nephron may also be subjected to obstruction by desquamated cells and cellular debris. In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.
Many endogenous growth factors that participate in the process of regeneration have not been identified; however, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI. Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant.
Intrarenal vasoconstriction is the dominant mechanism for the reduced glomerular filtration rate (GFR) in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage and the macula densa is presented with increased chloride load.
Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function.A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because the accumulation of solute in the medulla depends on normal distal nephron function. Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg. Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). The pathologic correlation of RPGN is the presence of glomerular crescents (glomerular injury) on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI.Postrenal AKI
Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI.
If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors.
Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women.
Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.
Frequency
United States
Approximately 1% of patients admitted to hospitals have AKI at the time of admission, and the estimated incidence rate of AKI is 2-5% during hospitalization. Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated in their report that the appropriate nephrologist referral rate is approximately 70 cases per million population.1
Mortality/Morbidity
The mortality rate estimates vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. Increments of 0.3 mg/dL in serum creatinine have important prognostic significance.
Race
No racial predilection is recognized.
Read more HERE
Showing posts with label Nephrology. Show all posts
Showing posts with label Nephrology. Show all posts
Friday, 20 June 2008
Thursday, 19 June 2008
Syndrome of Inappropriate Secretion of Antidiuretic Hormone
Background
Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.
The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.
SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.
Pathophysiology
ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.
In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.
Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.
V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.
V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.
ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.
The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.
In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.
The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.
If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.
In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.
Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.
Frequency
United States
SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.
Mortality/Morbidity
The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.
In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.
Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.
The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.
SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.
Pathophysiology
ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.
In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.
Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.
V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.
V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.
ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.
The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.
In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.
The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.
If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.
In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.
Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.
Frequency
United States
SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.
Mortality/Morbidity
The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.
In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.
Wednesday, 18 June 2008
Azotemia
Background
Each human kidney contains approximately 1 million functional units, called nephrons, which are primarily involved in formation. 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, which is elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) levels.
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.
An inverse relationship between serum creatinine and GFR exists. However, the serum creatinine and CrCl are not sensitive measures of kidney damage for two reasons. First, substantial renal damage can take place before any decrease in GFR occurs. Second, a substantial decline in GFR may lead to only slight elevation in serum creatinine, as shown in Media file 1. 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 on most pocket digital assistants (PDA) or can be found on the Internet.
Pathophysiology
There are three 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 b1-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>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, as well as 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.
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 glomerulnephritis 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.
In bilateral renal artery stenosis, maintenance of adequate intraglomerular pressure for filtration greatly depends on efferent arteriolar vasoconstriction. Azotemia sets in when angiotensin-converting 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.
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 2006 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 (4.0%), black (33.0%), white (61.0%), American Indian (1.3%), and other/unknown (1.7%).
Sex
Of the patients reported in the 2006 annual report of the USRDS, male frequency is 56.0% and female frequency is 44.0%.
Age
Of the patients reported in the 2006 annual report of the USRDS, frequencies for patients aged 0-19 years is 1%; aged 20-44 years, 17.0%; aged 45-64 years, 41.0%; aged 65-74 years, 22.0%; and older than 75 years, 18.0%.
Read more HERE
Each human kidney contains approximately 1 million functional units, called nephrons, which are primarily involved in formation. 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, which is elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) levels.
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.
An inverse relationship between serum creatinine and GFR exists. However, the serum creatinine and CrCl are not sensitive measures of kidney damage for two reasons. First, substantial renal damage can take place before any decrease in GFR occurs. Second, a substantial decline in GFR may lead to only slight elevation in serum creatinine, as shown in Media file 1. 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 on most pocket digital assistants (PDA) or can be found on the Internet.
Pathophysiology
There are three 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 b1-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>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, as well as 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.
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 glomerulnephritis 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.
In bilateral renal artery stenosis, maintenance of adequate intraglomerular pressure for filtration greatly depends on efferent arteriolar vasoconstriction. Azotemia sets in when angiotensin-converting 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.
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 2006 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 (4.0%), black (33.0%), white (61.0%), American Indian (1.3%), and other/unknown (1.7%).
Sex
Of the patients reported in the 2006 annual report of the USRDS, male frequency is 56.0% and female frequency is 44.0%.
Age
Of the patients reported in the 2006 annual report of the USRDS, frequencies for patients aged 0-19 years is 1%; aged 20-44 years, 17.0%; aged 45-64 years, 41.0%; aged 65-74 years, 22.0%; and older than 75 years, 18.0%.
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