Acute and chronic renal failure.

1. Causes of chronic renal failure (CRF).

Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are non-specific, and might include feeling generally unwell and experiencing areduced appetite

. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.

Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a lower glomerular filtration rateand as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction. Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is often called end stage renal disease (ESRD) or end stage renal failure (ESRF) and is synonymous with the now outdated terms chronic kidney failure (CKF) or chronic renal failure (CRF).

There has been a dramatic increase in the incidence of ESRD as well as a shift in the relative incidence of etiologies of CRD during the past two decades. Whereas glomerulonephritis was the leading cause of CRD in the past, diabetic and hypertensive nephropathy are now much more frequent underlying etiologies – diabetes, hypertension, glomerulonephritis, cystic disease. This may be a consequence of more effective prevention and treatment of glomerulonephritis or of diminished mortality from other causes among individuals with diabetes and hypertension. Greater overall longevity and diminished premature cardiovascular mortality have also increased the mean age of patients presenting with ESRD. Hypertension is a particularly common cause of CRD in the elderly, in whom chronic renal ischemia due to renovascular disease may be an underrecognized additional contribution to the pathophysiologic process. Many patients present at an advanced stage of CRD, precluding definitive determination of etiology.

Pic. 1. Chronic pyelonephritis, as reason of development of CRF.

2. Pathophysiology of CRF.

The pathophysiology of CRD involves initiating mechanisms specific to the underlying etiology as well as a set of progressive mechanisms that are a common consequence following long-term reduction of renal mass, irrespective of etiology. Such reduction of renal mass causes structural and functional hypertrophy of surviving nephrons. This compensatory hypertrophy is mediated by vasoactive molecules, cytokines, and growth factors and is due initially to adaptive hyperfiltration, in turn mediated by increases in glomerular capillary pressure and flow. Eventually, these short-term adaptations prove maladaptive, in that they predispose to sclerosis of the remaining viable nephron population. This final common pathway for inexorable attrition of residual nephron function may persist even after the initiating or underlying disease process has become inactive. Increased intrarenal activity of the renin-angiotensin axis appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis. These maladaptive long-term actions of renin-angiotensin axis activation are mediated in part through downstream growth factors such as transforming growth factor b. Interindividual variability in the risk and rate of CRD progression can be explained in part by variations in the genes encoding components of these and other pathways involved in glomerular and tubulointerstitial fibrosis and sclerosis.

The earliest stage common to all forms of CRD is a loss of renal reserve. When kidney function is entirely normal, glomerular filtration rate (GFR) can be augmented by 20 to 30% in response to the stimulus of a protein challenge. During the earliest stage of loss of renal reserve, basal GFR may be normal or even elevated (hyperfiltration), but the expected further rise in response to a protein challenge is attenuated. This early stage is particularly well documented in diabetic nephropathy. At this stage, the only clue may be at the level of laboratory measurements, which estimate GFR. The most commonly utilized laboratory measurements are the serum urea and creatinine concentrations. By the time serum urea and creatinine concentrations are even mildly elevated, substantial chronic nephron injury has already occurred.

As GFR declines to levels as low as 30% of normal, patients may remain asymptomatic with only biochemical evidence of the decline in GFR, i.e., rise in serum concentrations of urea and creatinine. However, careful scrutiny usually reveals early additional clinical and laboratory manifestations of renal insufficiency. These may include nocturia, mild anemia and loss of energy, decreasing appetite and early disturbances in nutritional status, and abnormalities in calcium and phosphorus metabolism (moderate renal insufficiency). As GFR falls to below 30% of normal, an increasing number and severity of uremic clinical manifestations and biochemical abnormalities supervene (severe renal insufficiency). At the stages of mild and moderate renal insufficiency, intercurrent clinical stress may compromise renal function still further, inducing signs and symptoms of overt uremia. Such intercurrent clinical conditions to which patients with CRD may be particularly susceptible include infection (urinary, respiratory, or gastrointestinal), poorly controlled hypertension, hyper- or hypovolemia, and drug or radiocontrast nephrotoxicity, among others. When GFR falls below 5 to 10% of normal (ESRD), continued survival without renal replacement therapy becomes impossible.

Pic. 2 Method of palpation| of kidneys

3. Clinical manifestations of the CRF.

3.1. Peculiarities of clinical manifestations of CRF according disease.

DIAGNOSTIC APPROACH

The most important initial step in the evaluation of a patient presenting de novo with biochemical or clinical evidence of renal failure is to distinguish CRD, which may be first coming to clinical attention, from true acute renal failure. The demonstration of evidence of chronic metabolic bone disease and anemia and the finding of bilaterally reduced kidney size by imaging studies strongly favor a long-standing process consistent with CRD. However, these findings do not rule out the superimposition of an acute and reversible exacerbating factor that has accelerated the decline in GFR. Having established that the patient suffers from CRD, in the early stages it is often possible to establish the underlying etiology. However, when the CRD process is quite advanced, then definitively establishing an underlying etiology becomes less feasible in many cases and also of less therapeutic significance. Age: CRF can be found in people of any age, from infants to the very old. Nonetheless, in the United States, the highest incidence of ESRD occurs in those older than 65 years. The elderly population also is the most rapidly growing ESRD population in the United States.

Note that after age 30 years progressive physiological glomerulosclerosis occurs, with GFR (and creatinine clearance [CrCl) falling linearly at a rate of approximately 8 cc/min/1.73 m²/y from a maximal GFR of 140 cc/min/1.73 m². Aging also results in concomitant progressive physiological decrease in muscle mass such that daily urinary creatinine excretion also decreases; this combination of factors results in constant serum creatinine values over time in a given individual, despite a decrease in CrCl (and GFR).

Therefore, a serum creatinine value of 0.8 mg/dL in a 70-kg, 25-year-old man versus one who is 80 years old represents a CrCl of 140 cc/min and 73 cc/min, respectively. What can appear as only mild renal impairment in an 80-year-old, 70-kg man with a pathologically elevated serum creatinine of 2.0 mg/dL actually represents severe renal impairment when the CrCl is calculated to be 29 cc/min. Therefore, a CrCl must be calculated simply by using the Cockcroft-Gault formula (see Other Tests) in elderly people so that appropriate drug dosing adjustments can be made and nephrotoxins can be avoided in patients who have more extensive CRF than would be suggested by the serum creatinine alone.

History: Patients whose renal adaptation maintains a GFR of 70-100 cc/min and those with CRI (GFR >30 cc/min) generally are entirely asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or endocrine/metabolic derangements. These disturbances generally become clinically manifest through the stages of CRF (GFR <30 cc/min) and ESRD (GFR <10 cc/min). Uremic manifestations in patients with ESRD are felt to be secondary to accumulation of toxins, the identity of which generally is not known.

• Hyperkalemia usually develops when GFR falls to less than 20-25 cc/min because of 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 and commonly observed with use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs). Hyperkalemia in CRF can be aggravated by extracellular shift of potassium, such as occurs in the setting of acidemia or from lack of insulin.

• Metabolic acidosis often is mixed, non–anion gap and anion gap, the latter observed generally with severe CRF that is approaching or at ESRD but with the anion gap generally not higher than 20 mEq/L. In CRF, 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 very advanced CRF, accumulation of phosphates, sulphates, and other organic anions are the cause of the small anion gap.

• Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion. This generally becomes clinically manifest when GFR falls to less than 10-15 cc/min, when compensatory mechanisms have become exhausted. Patients present with peripheral 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.

• 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 becomes more severe as 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.

• Secondary hyperparathyroidism develops because of hypocalcemia, decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or calcitriol), and hyperphosphatemia.

Calcium and calcitriol are primary feedback inhibitors, and the latter is a stimulus, to parathyroid hormone (PTH) synthesis and secretion.

Phosphate retention begins in early CRF; when 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 GFR falls into the moderate-to-severe stages of CRF, 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 cc/min.

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 CRF, 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 CRF and are common in those with ESRD. Osteomalacia and adynamic bone disease are the 2 other lesions observed. The former, observed primarily from aluminum accumulation, is markedly less common than the latter, whose etiology is unclear. Adynamic bone disease represents the predominant bone lesion in patients on chronic peritoneal dialysis and is increasing in frequency. Dialysis-related amyloidosis from beta2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years is another form of bone disease that manifests with cysts at the ends of long bones.

• Other manifestations of uremia in ESRD, many of which are more likely in patients who are inadequately dialyzed, include the following:

Pericarditis - Can complicate with 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: The physical examination often is not very helpful but may reveal findings characteristic of the condition underlying CRF (eg, lupus, severe arteriosclerosis, hypertension) or complications of CRF (eg, anemia, bleeding diathesis, pericarditis).

Causes:

• Vascular disease - 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

Picture

· Primary glomerular disease - Membranous nephropathy, immunoglobulin A (IgA) nephropathy, focal and segmental glomerulosclerosis (FSGS), minimal change disease, membranoproliferative glomerulonephritis, rapidly progressive (crescentic) glomerulonephritis

· Secondary glomerular disease - 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-Schönlein purpura, Alport syndrome, reflux nephropathy

· Tubulointerstitial disease - Drugs (eg, sulfa, allopurinol), infection (viral, bacterial, parasitic), Sjögren syndrome, chronic hypokalemia, chronic hypercalcemia, sarcoidosis, multiple myeloma cast nephropathy, heavy metals, radiation nephritis, cystinosis

· polycystic kidneys

Picture. US of polycystic kidneys

• Urinary tract obstruction - Urolithiasis, benign prostatic hypertrophy, tumors, retroperitoneal fibrosis, urethral stricture, neurogenic bladder
• Pyelonephrities

Lab Studies:

· Elevated serum urea and creatinine

· Hyperkalemia, low serum bicarbonate, hypocalcemia, hyperphosphatemia, hyponatremia (in ESRD with free-water excess)

· Hypoalbuminemia in patients who are nephrotic and/or malnourished

· Normochromic normocytic anemia - Other underlying causes of anemia should be ruled out.

· Urinalysis - Dipstick proteinuria may suggest glomerular or a tubulointerstitial problem.

· Urine sediment finding of RBCs, RBC casts, suggests proliferative glomerulonephritis. Pyuria or/and WBC casts are suggestive of interstitial nephritis (particularly if eosinophiluria is present) or urinary tract infection.

· 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 2.0 g is considered to be within glomerular range, and a value greater than 3.0-3.5 g is within the nephrotic range; less than 2.0 is characteristic of tubulointerstitial problems.

· Twenty-four–hour urine collection for total protein and CrCl

· Serum and urine protein electrophoresis to screen for a monoclonal protein possibly representing multiple myeloma

· Antinuclear antibodies (ANA), double-stranded DNA antibody levels to screen for systemic lupus erythematosus

· Serum complement levels - May be depressed with some glomerulonephritides

· C-ANCA and P-ANCA levels - Helpful if positive in diagnosis of Wegener granulomatosis and polyarteritis nodosa or microscopic polyangiitis, respectively

· Anti–glomerular 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

Imaging Studies:

· Plain abdominal x-ray - Particularly useful to look for radio-opaque stones or nephrocalcinosis

· Intravenous pyelogram - Not commonly used because of potential for intravenous contrast renal toxicity; often used to diagnose renal stones and pyeloectasia (shown below)

· Renal ultrasound - 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 a polycystic kidneys, also may be observed. This is a useful test to screen for hydronephrosis, which may not be observed in early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction exists despite a negative study finding.

· Renal radionuclide scan - Useful to screen for renal artery stenosis when performed with captopril administration but is unreliable for GFR of less than 30 cc/min; also quantitates differential renal contribution to total GFR

• CT scan - 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 contrast-enhanced 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 CRF. Dehydration also markedly increases this risk.

· 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.

· Voiding cystourethrogram (VCUG) - Criterion standard for diagnosis of vesicoureteral reflux

Other Tests:

· 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 CRF. The formulas are as follows:

o CrCl (male) = ([140-age] X weight in kg)/(serum creatinine X 72)

o CrCl (female) = CrCl (male) X 0.85

Procedures:

· Percutaneous renal biopsy currently 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 in the setting of small echogenic kidneys on ultrasound because these are severely scarred and represent 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.

Histologic Findings: Renal histology in CRF 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.

Medical Care: Medical care of the patients with CRF should focus on the following:

· Delaying or halting progression of CRF

Treatment of the underlying condition if possible

Aggressive blood pressure control to target value

Use of ACE inhibitors as tolerated, with close monitoring for renal deterioration and for hyperkalemia (avoid in advanced renal failure, bilateral renal artery stenosis [RAS], RAS in a solitary kidney)

Aggressive glycemic control in patients with diabetes

Protein restriction - Controversial

Treatment of hyperlipidemia

Avoidance of nephrotoxins - IV radiocontrast, nonsteroidal anti-inflammatory agents, aminoglycosides

· Treating pathologic manifestations of CRF

Anemia with erythropoietin

Hyperphosphatemia with dietary phosphate binders and dietary phosphate restriction

Hypocalcemia with calcium supplements +/- calcitriol

Hyperparathyroidism with calcitriol or vitamin D analogs

Volume overload with loop diuretics or ultrafiltration

Metabolic acidosis with oral alkali supplementation

Uremic manifestations with chronic renal replacement therapy (hemodialysis, peritoneal dialysis, or renal transplantation): Indications include severe metabolic acidosis, hyperkalemia, pericarditis, encephalopathy, intractable volume overload, failure to thrive and malnutrition, peripheral neuropathy, intractable gastrointestinal symptoms, and GFR less than 10 cc/min.

· Timely planning for chronic renal replacement therapy

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

ESTABLISHING THE ETIOLOGY

Of special importance in establishing the etiology of CRD are a history of hypertension; diabetes; systemic infectious, inflammatory, or metabolic diseases; exposure to drugs and toxins; and a family history of renal and urologic disease. Drugs of particular importance include analgesics (usage frequently underestimated or denied by the patient), NSAIDs, gold, penicillamine, antimicrobials, lithium, and ACE inhibitors. In evaluating the uremic syndrome, questions about appetite, diet, nausea, vomiting, hiccoughing, shortness of breath, edema, weight change, muscle cramps, bone pain, mental acuity, and activities of daily living are especially helpful.

Physical Examination. Particular attention should be paid to blood pressure, fundoscopy, precordial examination, examination of the abdomen for bruits and palpable renal masses, extremity examination for edema, and neurologic examination for the presence of asterixis, muscle weakness, and neuropathy. In addition, the evaluation of prostate size in men and potential pelvic masses in women should be undertaken by appropriate physical examination.

Laboratory Investigations. These should also focus on a search for clues to an underlying disease process and its continued activity. Therefore, if the history and physical examination warrant, immunologic tests for systemic lupus erythematosus and vasculitis might be considered. Serum and urinary protein electrophoresis should be undertaken in all patients over the age of 40 with unexplained CRD and anemia, to rule out paraproteinemia. Other tests to determine the severity and chronicity of the disease include serial measurements of serum creatinine and blood urea nitrogen, hemoglobin, calcium, phosphate, and alkaline phosphatase to assess metabolic bone disease. Urine analysis may be helpful in assessing the presence of ongoing activity of the underlying inflammatory or proteinuric disease process, and when indicated should be supplemented by a 24-h urine collection for quantifying protein excretion. The latter is particularly helpful in guiding management strategies aimed at ameliorating the progression of CRD. The presence of broad casts on examination of the urinary sediment is a nonspecific finding seen with all diverse etiologies and reflects chronic tubulointerstitial scarring and tubular atrophy with widened tubule diameter, usually signifying an advanced stage of CRD.

Imaging Studies. The most useful among these is renal sonography. An ultrasound examination of the kidneys verifies the presence of two symmetric kidneys, provides an estimate of kidney size, and rules out renal masses and obstructive uropathy. The documentation of symmetric small kidneys supports the diagnosis of progressive CRD with an irreversible component of scarring. The occurrence of normal kidney size suggests the possibility of an acute rather than chronic process. However, polycystic kidney disease, amyloidosis, and diabetes may lead to CRD with normal-sized or even enlarged kidneys. Documentation of asymmetric kidney size suggests either a unilateral developmental or urologic abnormality or chronic renovascular disease. In the latter case, a vascular imaging procedure, such as duplex Doppler sonography of the renal arteries, radionuclide scintigraphy, or magnetic resonance angiography should be considered. A computed tomographic scan without contrast may be useful in assessing kidney stone activity, in the appropriate clinical context. Voiding cystourethrography to rule out reflux may be indicated in some younger patients with a history of enuresis or with a family history of reflux. However, in most cases, by the time CRD is established, reflux has resolved; even if present, its repair may not stabilize renal function. In any case, imaging studies should avoid exposure to intravenous radiocontrast dye where possible because of its nephrotoxicity.

Differentiation of CRD from Acute Renal Failure The most classic constellation of laboratory and imaging findings that distinguishes progressive CRD from acute renal failure are bilaterally small (<8.5 cm) kidneys, anemia, hyperphosphatemia and hypocalcemia with elevated PTH levels, and a urinary sediment that is inactive or reveals proteinuria and broad casts. Furthermore, integration of a particular constellation of clinical, laboratory, and imaging findings based on the approach noted above strongly supports a particular presumed underlying etiologic disease process. For example, in a patient with insulin-dependent type 1 diabetes mellitus of 15 to 20 years' duration, diabetic retinopathy, and nephrotic-range albuminuria without hematuria, the diagnosis of diabetic nephropathy is likely. The diagnosis of chronic hypertensive nephrosclerosis requires a history of long-standing hypertension, in the absence of evidence for another renal disease process, and hence is usually a diagnosis of exclusion. Usually, proteinuria is mild to moderate (<3 g/d) and the urine sediment inactive. In many cases of presumed hypertensive nephrosclerosis, renovascular disease may not only be the cause of hypertension but also may cause ischemic renal damage. Bilateral renovascular ischemic disease may be a greatly underdiagnosed cause of CRD. This is of therapeutic significance from two points of view: (1) documentation of ischemic renal disease may prompt revascularization therapy in some patients, with occasional dramatic stabilization or improvement in renal function; and (2) renovascular ischemic disease is a contraindication to ACE inhibitor therapy in most cases. Analgesic-associated chronic tubulointerstitial nephropathy is also an underdiagnosed cause of CRD. Imaging studies, including computed tomography, often reveal pathognomonic features such as papillary calcification and necrosis. Under such circumstances, cessation of analgesic exposure may dramatically stabilize renal function.

Kidney Biopsy This procedure should be reserved for patients with near-normal kidney size, in whom a clear-cut diagnosis cannot be made by less invasive means, and when the possibility of a reversible underlying disease process remains tenable so that clarification of the underlying etiology may alter management. The extent of tubulointerstitial scarring on kidney biopsy generally provides the most reliable pathologic correlate indicating prognosis for continued deterioration toward ESRD. Contraindications to renal biopsy include bilateral small kidneys, polycystic kidney disease, uncontrolled hypertension, urinary tract or perinephric infection, bleeding diathesis, respiratory distress, and morbid obesity.

3.2. K+ disorder.

Potassium Homeostasis. When GFR is normal, the approximate daily filtered load of K+ is 700 mmol. The majority of this filtered load is reabsorbed in tubule segments prior to the cortical collecting tubule, and most of the K+ excreted in the final urine reflects events governing K+ handling at the level of the cortical collecting tubule and beyond. These factors include the flow of luminal fluid and the delivery and reabsorption of Na+, which generates the lumen-negative electromotive force for K+ secretion at the aldosterone-responsive distal nephron sites. In CRD, these factors may be well preserved, such that a decline in GFR is not necessarily accompanied by a concomitant and proportionate decline in urinary K+ excretion. In addition, K+ excretion in the gastrointestinal tract is augmented in patients with CRD. However, hyperkalemia may be precipitated in a number of clinical situations, including augmented dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, and following the exposure to a variety of medications that inhibit K+ entry into cells or K+ secretion in the distal nephron. Most commonly encountered medications in this regard are beta blockers, ACE inhibitors, K+-sparing diuretics (amiloride, triamterene, spironolactone), and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, certain etiologies of CRD may be associated with earlier and more severe disruption of K+ secretory mechanisms in the distal nephron, relative to the reduction in GFR. Most important are conditions associated with hyporeninemic hypoaldosteronism (e.g., diabetic nephropathy and certain forms of distal renal tubular acidosis).

Most commonly, clinically significant hyperkalemia does not occur until the GFR falls to below 10 mL/min or unless there is exposure to a K+ load, either endogenous (e.g., hemolysis, trauma, infection) or exogenous (e.g., administration of stored blood, K+-containing medications, K+-containing dietary salt substitute). In kidney transplant recipients, cyclosporine is another common cause of increased plasma K+ concentration. Hyperkalemia in CRD patients may also be induced by abrupt falls in plasma pH, since acidosis is associated with efflux of K+ from the intracellular to the extracellular fluid compartment.

Although total-body K+ is frequently reduced in CRD, hypokalemia is uncommon. The occurrence of hypokalemia usually reflects markedly reduced dietary K+ intake, in association with excessive diuretic therapy or gastrointestinal losses. Hypokalemia occurs as a result of primary renal K+ wasting in association with other solute transport abnormalities, as in Fanconi's syndrome, renal tubular acidosis, or other forms of hereditary or acquired tubulointerstitial diseases. However, even under these circumstances, as GFR declines, the tendency to hypokalemia diminishes and hyperkalemia may supervene. Accordingly, K+ supplementation and K+-sparing diuretics should be used with caution as GFR declines.

3.3. Calcium abnormalities.

Calcium. The total plasma Ca2+ concentration in patients with CRD is often significantly lower than normal. Patients with CRD tolerate the hypocalcemia quite well; rarely is a patient symptomatic from the decreased Ca2+ concentration. This may partly be due to the frequent concomitant acidosis, which offsets some of the neuromuscular effects of hypocalcemia. The hypocalcemia in CRD results from decreased intestinal absorption of Ca2+ due to vitamin D deficiency. Also, with the increasing serum PO43- level, Ca2+ phosphate is deposited in soft tissues and serum Ca2+ concentration (both total and ionized) declines. In addition, patients with CRD are resistant to the action of PTH. Hypocalcemia is a potent stimulus to PTH secretion and leads to hyperplasia of the parathyroid gland. Ca2+ binds to a specific Ca2+-sensing receptor protein located in the cell membrane. The Ca2+-sensing receptor is linked to several cytoplasmic messenger systems by one or more GTP-binding proteins. These signaling pathways are responsible for either enhanced or suppressed release of PTH during acute hypo- and hypercalcemia, respectively. Several studies have demonstrated the mRNA and protein expression of the Ca2+-sensing receptor to be reduced in primary (adenomas) and secondary hyperparathyroidism (hyperplasia) compared to the expression in normal parathyroid tissue. In secondary hyperparathyroidism, expression of the Ca2+-sensing receptor is often depressed in nodular areas compared with adjacent nonnodular hyperplasia. Thus, decreased Ca2+ receptor expression in hyperparathyroidism is compatible with a less efficient control of PTH synthesis and release, in response to varying plasma Ca2+ concentration.

During the initial phase of CRD, the elevated PTH levels may normalize serum levels of Ca2+, PO43-, and vitamin D. Therefore hypocalcemia, hyperphosphatemia, and reduced 1,25(OH)2D3 are observed only as CRD progresses. However, even at the earliest stages of CRD, the elevated PTH levels adversely affect bone metabolism, causing increased osteoclastic and osteoblastic activity (high-turnover bone disease). Additional detrimental factors include the chronic uremic acidosis, which inhibits osteoblastic bone formation and stimulates osteoclastic bone resorption.

3.4. Hematologic abnormalities.

Anemia of CRD. A normocytic, normochromic anemia is present in the majority of patients with CRD. It is usually observed when the GFR falls below 30 mL/min. When untreated, the anemia of CRD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, altered menstrual cycles, and impaired immune responsiveness. In addition, anemia may play a role in growth retardation in children. The primary cause of anemia in patients with CRD is insufficient production of EPO by the diseased kidneys. Additional factors include the following: iron deficiency, either related to or independent of blood loss from repeated laboratory testing, needle punctures, blood retention in the dialyzer and tubing, or gastrointestinal bleeding; severe hyperparathyroidism; acute and chronic inflammatory conditions; aluminum toxicity; folate deficiency; shortened red cell survival; hypothyroidism; and underlying hemoglobinopathies. These potential contributing factors should be considered and addressed.

Before 1989, the EPO-deficient condition characteristic of CRD could only be treated with blood transfusions and anabolic steroids, with limited success and substantial complications. The availability of recombinant human EPO, approved by the U.S. Food and Drug Administration in 1989, has been one of the most significant advances in the care of renal patients in the past decade. Considerable debate continues regarding the optimal target hematocrit in dialysis patients receiving EPO. Mortality and hospitalization studies support the National Kidney Foundation Dialysis Outcomes Quality Initiative target hematocrit range of 33 to 36% as providing the best associated outcomes. EPO can be administered either intravenously or subcutaneously. Most studies have shown that administering EPO by the subcutaneous route has a sparing effect, with the target hematocrit achieved at a lower EPO dose. Management Guidelines for the correction of anemia in CRD are as follows.

The iron status of the patient with CRD must be assessed, and adequate iron stores should be available before treatment with EPO is initiated. Iron supplementation is usually essential to ensure an adequate response to EPO in patients with CRD, because the demands for iron by the erythroid marrow frequently exceed the amount of iron that is immediately available for erythropoiesis (as measured by percent transferrin saturation) as well as iron stores (as measured by serum ferritin). In most cases, intravenous iron will be required to achieve and/or maintain adequate iron. However, excessive iron therapy may be associated with a number of complications, including hemosiderosis, accelerated atherosclerosis, increased susceptibility to infection, and possibly an increased propensity to the emergence of malignancies. In addition to iron, an adequate supply of the other major substrates and cofactors for erythrocyte production must be assured, especially vitamin B12 and folate. Anemia resistant to recommended doses of EPO in the face of adequate availability of iron and vitamin factors often suggests inadequate dialysis; uncontrolled hyperparathyroidism; aluminum toxicity; chronic blood loss or hemolysis; and associated hemoglobinopathy, malnutrition, chronic infection, multiple myeloma, or another malignancy. Blood transfusions may contribute to suppression of erythropoiesis in CRD; because they increase the risk of hepatitis, hemosiderosis, and transplant sensitization, they should be avoided unless the anemia fails to respond to EPO and the patient is symptomatic.

Abnormal Hemostasis. Abnormal hemostasis is common in CRD and is characterized by a tendency to abnormal bleeding and bruising. Bleeding from surgical wounds and spontaneous bleeding into the gastrointestinal tract, pericardial sac, or intracranial vault (in the form of subdural hematoma or intracerebral hemorrhage) are of greatest concern. Prolongation of bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption contribute to the clotting defects. The abnormality in platelet factor III correlates with increased plasma levels of guanidinosuccinic acid and can be corrected by dialysis. Prolongation of the bleeding time is common even in well-dialyzed patients. Abnormal bleeding times and coagulopathy in patients with renal failure may be reversed with desmopressin, cryoprecipitate, conjugated estrogens, and blood transfusions, as well as by the use of EPO.

Enhanced Susceptibility to Infection Changes in leukocyte formation and function in uremia lead to enhanced susceptibility to infection. Lymphocytopenia and atrophy of lymphoid structures occur, whereas neutrophil production is relatively unimpaired. Nevertheless, the function of all leukocyte cell types may be affected adversely by uremic serum. Alterations in monocyte, lymphocyte, and neutrophil function cause impairment of acute inflammatory responses, decreased delayed hypersensitivity, and altered late immune function.

3.5. Clinical manifestations of CRF.

CLINICAL AND LABORATORY MANIFESTATIONS OF CHRONIC RENAL FAILURE AND UREMIA

Uremia leads to disturbances in the function of every organ system. Chronic dialysis reduces the incidence and severity of these disturbances, so that, where modern medicine is practiced, the overt and florid manifestations of uremia have largely disappeared. Unfortunately, even optimal dialysis therapy is not a panacea, because some disturbances resulting from impaired renal function fail to respond fully, while others continue to progress.

CARDIOVASCULAR AND PULMONARY ABNORMALITIES

Congestive Heart Failure. Salt and water retention in uremia often result in congestive heart failure and/or pulmonary edema. A unique form of pulmonary congestion and edema may occur even in the absence of volume overload and is associated with normal or mildly elevated intracardiac and pulmonary capillary wedge pressures. This entity, characterized radiologically by peripheral vascular congestion giving rise to a "butterfly wing" distribution, is due to increased permeability of alveolar capillary membranes. This "low-pressure" pulmonary edema as well as cardiopulmonary abnormalities associated with circulatory overload usually respond promptly to vigorous dialysis.

Hypertension and Left Ventricular Hypertrophy. Hypertension is the most common complication of CRD and ESRD. When it is not found, the patient may have a salt-wasting form of renal disease (e.g., medullary cystic disease, chronic tubulointerstitial disease, or papillary necrosis), may be receiving antihypertensive therapy, or be volume-depleted, the last condition usually due to excessive gastrointestinal fluid losses or overzealous diuretic therapy. Since volume overload is the major cause of hypertension in uremia, the normotensive state can often be restored by appropriate use of diuretics in the predialysis patient or with aggressive ultrafiltration in dialysis patients. Nevertheless, because of hyperreninemia, some patients remain hypertensive despite rigorous salt and water restriction and ultrafiltration. Rarely, patients develop accelerated or malignant hypertension. Intravenous nitroprusside, labetolol, or more recently approved agents such as fenoldopam or urapidil, together with control of ECFV, generally controls such hypertension. Subsequently, such patients usually require more than one oral antihypertensive drug. Enalaprilat or other ACE inhibitors may also be considered, but in the face of bilateral renovascular disease they have the potential to further reduce GFR abruptly. Administration of erythropoietin (EPO) may raise blood pressure and increase the requirement for antihypertensive drugs. A high percentage of patients with CRD present with left ventricular hypertrophy or dilated cardiomyopathy. These are among the most ominous risk factors for excess cardiovascular morbidity and mortality in patients with CRD and ESRD and are thought to be related primarily to prolonged hypertension and ECFV overload. In addition, anemia and the surgical placement of an arteriovenous anastomosis for future or ongoing dialysis access may generate a high cardiac output state, which also intensifies the burden placed on the left ventricle.

Pericarditis. With the advent of early initiation of renal replacement therapy, pericarditis is now observed more often in underdialyzed patients than in patients with CRD in whom dialysis has not yet been initiated. Pericardial pain with respiratory accentuation, accompanied by a friction rub, are the hallmarks of uremic pericarditis. The finding of a multicomponent friction rub strongly supports the diagnosis. Furthermore, the usual occurrence of multiple cardiac murmurs, S3 and S4 heart sounds, and transmitted bruits from arteriovenous access devices may render precordial auscultation more challenging in this group of patients. Classic electrocardiographic abnormalities include PR-interval shortening and diffuse ST-segment elevation. Pericarditis may be accompanied by the accumulation of pericardial fluid, readily detected by echocardiography, sometimes leading to cardiac tamponade. Pericardial fluid in uremic pericarditis is more often hemorrhagic than in viral pericarditis.

There is a tendency for uremic patients to have less fever in response to infection, perhaps because of the effects of uremia on the hypothalamic temperature control center. Leukocyte function may also be impaired in patients with CRD because of coexisting acidosis, hyperglycemia, protein-calorie malnutrition, and serum and tissue hyperosmolarity (due to azotemia). In patients treated with hemodialysis, leukocyte function is disturbed because of the effects of the bioincompatibility of various dialysis membranes. Activation of cytokine and complement cascades likewise occurs when blood comes in contact with dialysis membranes. These substances in turn alter inflammatory and immune responses of the uremic patient. Mucosal barriers to infection may also be defective, and, in dialysis patients, vascular and peritoneal access devices are common portals of entry for pathogens, especially staphylococci. Glucocorticoids and immunosuppressive drugs used for various renal diseases and renal transplantation further increase the risk of infection.

NEUROMUSCULAR ABNORMALITIES

Subtle disturbances of central nervous system function, including inability to concentrate, drowsiness, and insomnia, are among the early symptoms of uremia. Mild behavioral changes, loss of memory, and errors in judgment soon follow and may be associated with neuromuscular irritability, including hiccoughs, cramps, and fasciculations/twitching of muscles. Asterixis, myoclonus, and chorea are common in terminal uremia, as are stupor, seizures, and coma. Peripheral neuropathy is also common in advanced CRD. Initially, sensory nerves are involved more than motor nerves, lower extremities more than upper, and distal portions of the extremities more than proximal. The "restless legs syndrome" is characterized by ill-defined sensations of discomfort in the feet and lower legs requiring frequent leg movement. If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including loss of deep tendon reflexes, weakness, peroneal nerve palsy (foot drop), and, eventually, flaccid quadriplegia. Accordingly, evidence of peripheral neuropathy is a firm indication for the initiation of dialysis or transplantation. Some of the central nervous system and neuromuscular complications of advanced uremia resolve with dialysis, although nonspecific electroencephalographic abnormalities may persist. Successful transplantation may reverse residual peripheral neuropathy.

Two types of neurologic disturbances are unique to patients on chronic dialysis. Dialysis dementia may occur in patients who have been on dialysis for many years and is characterized by speech dyspraxia, myoclonus, dementia, and eventually seizures and death. Aluminum intoxication is probably the major contributor to this syndrome, but other factors, such as viral infections, may play a role since not all patients with aluminum exposure develop the syndrome. Dialysis disequilibrium, which occurs during the first few dialyses in association with rapid reduction of blood urea levels, manifests clinically with nausea, vomiting, drowsiness, headache, and, rarely, seizures. The syndrome has been attributed to cerebral edema and increased intracranial pressure due to the rapid (dialysis-induced) shifts of omsolality and pH between extracellular and intracellular fluids. This complication can often be anticipated and prevented in patients who present with markedly elevated concentrations of plasma urea, by prescribing an initial dialysis regimen that produces slower solute removal.

GASTROINTESTINAL ABNORMALITIES

Anorexia, hiccoughs, nausea, and vomiting are common early manifestations of uremia. Protein restriction is useful in diminishing nausea and vomiting late in the course of renal failure. However, protein restriction should not be implemented in patients with early signs of protein-calorie malnutrition. Uremic fetor, a uriniferous odor to the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Mucosal ulcerations leading to blood loss can occur at any level of the gastrointestinal tract in the very late stages of CRD. Peptic ulcer disease is common in uremic patients. Whether this high incidence is related to altered gastric acidity, enhanced colonization by Helicobacter pylori, or hypersecretion of gastrin is unknown. Patients with CRD, particularly those with polycystic kidney disease, have an increased incidence of diverticulosis. Pancreatitis and angiodysplasia of the large bowel with chronic bleeding have been noted more commonly in dialysis patients. Hepatitis B antigenemia was very common in the past, but it is much less so now because of the implementation of universal precautions, the use of hepatitis B vaccine, and the diminished need for blood transfusions resulting from the introduction of EPO. There is a higher incidence of hepatitis C virus infection in patients treated with chronic hemodialysis. Unlike hepatitis B, this infection is most often persistent. Although it does not seem to cause significant liver disease in most patients, it is a definite concern in patients who subsequently undergo transplantation and immunosuppression, in whom the incidence of active chronic hepatitis and cirrhosis is considerably higher than in those without hepatitis C infection.

ENDOCRINE-METABOLIC DISTURBANCES

Disturbances in parathyroid function, protein-calorie and lipid metabolism, and overall nutritional abnormalities of uremia have already been considered.

Glucose metabolism is impaired, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. Fasting blood glucose is usually normal or only slightly elevated, and the mild glucose intolerance related to uremia per se, when present, does not require specific therapy. Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects, both in the fasting and post-prandial states. However, the response to insulin and glucose utilization is impaired in CRD. Many renal hypoglycemic drugs require dose reduction in renal failure, and some, such as metformin, are contraindicated when GFR has diminished by more than approximately 25 to 50%.

In women, estrogen levels are low, and amenorrhea and inability to carry pregnancies to term are common manifestations of uremia. When GFR has declined by approximately 30%, pregnancy may hasten the progression of CRD. In women with ESRD, the reappearance of menses is a sign of efficient renal replacement therapy and is a frequent occurrence after an adequate chronic dialysis regimen has been established. Successful pregnancies are rare. In men with CRD, including those receiving chronic dialysis, impotence, oligospermia, and germinal cell dysplasia are common, as are reduced plasma testosterone levels. Like growth, sexual maturation is often impaired in adolescent children with CRD, even among those treated with chronic dialysis. Many of these abnormalities improve or reverse with successful renal transplantation.

DERMATOLOGIC ABNORMALITIES

The skin may show evidence of anemia (pallor), defective hemostasis (ecchymoses and hematomas), calcium deposition and secondary hyperparathyroidism (pruritus, excoriations), dehydration (poor skin turgor, dry mucous membranes), and the general cutaneous consequences of protein-calorie malnutrition. A sallow, yellow cast may reflect the combined influences of anemia and retention of a variety of pigmented metabolites, or urochromes. The gray to bronze discoloration of the skin related to transfusional hemochromatosis has now become uncommon with the availability and usage of EPO. In advanced uremia, the concentration of urea in sweat may be so high that, after evaporation, a fine white powder can be found on the skin surfaceѕso-called uremic (urea) frost. Although many of these cutaneous abnormalities improve with dialysis, uremic pruritus often remains a problem. The first lines of management are to rule out unrelated skin disorders, to adjust the dialysis prescription so as to ensure adequacy of dialysis, and to control PO43-concentration with avoidance of an elevated Ca2+-PO43- product. Occasionally, pruritus remains refractory to these measures and to other nonspecific systemic and topical therapies. The latter has itself been reported to improve pruritus. Skin necrosis can occur as part of the calciphylaxis syndrome, which also includes subcutaneous, vascular, joint, and visceral calcification in patients with poorly controlled calcium-phosphate product.

4. Treatment of the CRF.

4.1.1. Dietotherapy.

Protein Restriction in CRD. In contrast to fat and carbohydrates, protein in excess of the daily requirement is not stored but is degraded to form urea and other nitrogenous wastes, which are principally excreted by the kidney. In addition, protein-rich foods contain hydrogen ions, PO43-, sulfates, and other inorganic ions that are also eliminated by the kidney. Therefore, when patients with CRD consume excessive dietary protein, nitrogenous wastes and inorganic ions accumulate, resulting in the clinical and metabolic disturbances characteristic of uremia. Restricting dietary protein can ameliorate many uremic symptoms and may slow the actual rate of nephron injury. The effectiveness of protein restriction in slowing the progression of CRD has been evaluated in a number of controlled clinical trials. The Modification of Diet in Renal Disease (MDRD) Study was the most extensive trial devoted to this question, but it nevertheless yielded an ambiguous result, although positive trends emerged when it ended after an average follow-up of only 2.2 years. In a separate study of patients with insulin-dependent diabetic nephropathy, protein restriction was shown to slow progression significantly in one well-controlled study. Two meta-analyses of studies of the effects of protein restriction on progression concluded that low-protein diets slow progression of both diabetic and nondiabetic renal disease.

It is crucial that protein restriction be carried out in the context of an overall dietary program that optimizes nutritional status and avoids malnutrition, especially as patients near dialysis or transplantation. Measurements of urinary nitrogen appearance, anthropometric and biochemical measurements, as well as dietary consultation are mandatory to preempt malnutrition. Among the most readily available and useful indices of malnutrition are plasma concentrations of albumin (<3.8 g/dL), pre-albumin (<18 mg/dL), and transferrin (<180 ug/dL). Metabolic and nutritional studies indicate that protein requirements for patients with CRD are similar to those for normal adults, approximately 0.6 g/kg per day. However, there is a particular requirement in patients with CRD that the composition of dietary protein be higher in essential amino acids, and that this be combined with an overall energy supply sufficient to mitigate a catabolic state. Energy requirements in the range of 35 kcal/kg per day are recommended.

Fortunately, even patients with advanced CRD are able to activate the same adaptive responses to dietary protein restriction as healthy individuals, i.e., a postprandial suppression of whole-body protein degradation and a marked inhibition of amino acid oxidation. After at least 1 year of therapy with a low-protein diet (range 12 to 24 months) these same adaptive responses persist, indicating that the compensatory responses to dietary protein restriction are sustained during long-term therapy. Further evidence that low-protein diets are safe in CRD patients is provided by the finding that nutritional indices remain normal during long-term therapy.

4.1.2. Correction of the electrolytes abnormalities.

The metabolic acidosis can usually be corrected by treating the patient with 20 to 30 mmol of sodium bicarbonate or sodium citrate daily.

Secondary hyperparathyroidism and osteitis fibrosa are best prevented and treated by reducing serum PO43- concentration through the use of a PO43- restricted diet as well as oral PO43--binding agents. Calcium carbonate and calcium acetate are the preferred PO43- binding agents, but in some rare circumstances a combination of short-term aluminum hydroxide and calcium carbonate is necessary. Daily oral calcitriol, or intermittent oral or intravenous pulses, appear to exert a direct suppressive effect on PTH secretion, in addition to the indirect effect mediated through raising Ca2+ levels. Intravenous pulses are especially convenient for patients on hemodialysis. In the dialysis population, dialysate Ca2+, calcium carbonate, calcium acetate, aluminum hydroxide, and calcitriol must be properly balanced to maintain the serum PO43- concentration at approximately 1.4 mmol/L (4.5 mg/dL) and the serum Ca2+ at approximately 2.5 mmol/L (10 mg/dL) in an attempt to suppress parathyroid hyperplasia, thus avoiding or reversing osteitis fibrosa cystica, osteomalacia, and myopathy. It is particularly important to maintain the Ca2+-PO43- product in the normal range to avoid metastatic calcification.

Adynamic bone disease is often a consequence of overzealous treatment of secondary hyperparathyroidism. Therefore, suppression of PTH levels to less than 120 pg/mL in uremic patients may not be desirable. The incidence of aluminum-induced osteomalacia has been greatly reduced with the recognition of aluminum as the principal culprit. Therapy for this disorder is continued avoidance of aluminum, with possible use of a chelating agent such as desferoxamine along with high-flux dialysis. Management of metabolic acidosis should aim to maintain a nearly normal level of plasma HCO3-, with the administration of calcium acetate or calcium carbonate in the first instance, and with the addition of NaHCO3 if necessary. Excessive administration of alkali should be avoided to minimize risk of urinary precipitation of calcium phosphate.

At present, there is no good therapy for dialysis-related amyloidosis. Local physical therapy, glucocorticoid injections, and NSAIDs constitute current options.

Other Solutes Treatment of hyperuricemia is not necessary unless recurrent gout becomes a problem. When recurrent symptomatic gout occurs, a reduced dose of allopurinol (100 to 200 mg/d) is usually sufficient to inhibit uric acid synthesis. Hypophosphatemia is rare and, when it occurs, is usually a consequence of overzealous oral administration of phosphate-binding gels. Because serum magnesium levels tend to rise in CRD, magnesium-containing antacids and cathartics should be avoided.

4.2. Hemodialysis.

Figure. A type of vehicle is a “artificial kidney” and principle of work of dialysis column

Figure. A leadthrough of procedure of hemodialysis | is in a dialysis hall

4.2.1. Indication to hemodialisis.

The choice between hemodialysis and peritoneal dialysis involves the interplay of various factors that include the patient's age, the presence of comorbid conditions, the ability to perform the procedure, and the patient's own conceptions about the therapy. Peritoneal dialysis is favored in younger patients because of their better manual dexterity and greater visual acuity, and because younger patients prefer the independence and flexibility of home-based peritoneal dialysis treatment. In contrast, larger patients (>80 kg), patients with no residual renal function, and patients who have truncal obesity with or without prior abdominal surgery are more suited to hemodialysis. Larger patients with no residual renal function are more appropriate for hemodialysis because these patients have a large volume of distribution of urea and require significantly higher amounts of peritoneal dialysis, which may be difficult to achieve because of the limited willingness of patients to perform more than four exchanges each day. In some patients, the inability to obtain vascular access predicates a switch from hemodialysis to peritoneal dialysis.

HEMODIALYSIS

This consists of diffusion that occurs bi-directionally across a semipermeable membrane. Movement of metabolic waste products takes place down a concentration gradient from the circulation into the dialysate, and in the reverse direction. The rate of diffusive transport increases in response to several factors, including the magnitude of the concentration gradient, the membrane surface area, and the mass transfer coefficient of the membrane. The latter is a function of the porosity and thickness of the membrane, the size of the solute molecule, and the conditions of flow on the two sides of the membrane. According to the laws of diffusion, the larger the molecule, the slower its rate of transfer across the membrane. A small molecule such as urea (60 Da) undergoes substantial clearance, whereas a larger molecule such as creatinine (113 Da), is cleared much less efficiently. In addition to diffusive clearance, movement of toxic materials such as urea from the circulation into the dialysate may occur as a result ofultrafiltration. Convective clearance occurs because of solvent drag with solutes getting swept along with water across the semipermeable dialysis membrane.

A chart of connecting of hand of patient is to the dialyser

GOALS OF DIALYSIS

The hemodialysis procedure is targeted at removing both small and large molecular weight solutes. The procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 300 to 500 mL/min, while dialysate flows in an opposite counter-current direction at 500 to 800 mL/min. The clearance of urea ranges from 200 to 350 mL/min, while the clearance of b2 microglobulin is more modest and ranges from 20 to 25 mL/min. The efficiency of dialysis is determined by blood and dialysate flow through the dialyzer, as well as dialyzer characteristics (i.e., its efficiency in removing solute). The dose of dialysis, which is defined as the magnitude of urea clearance during a single dialysis treatment, is further governed by patient size, residual renal function, dietary protein intake, the degree of anabolism or catabolism, and the presence of comorbid conditions. Since the landmark studies of Sargent and Gatch relating the measurement of the dose of dialysis using urea concentration with patient outcome, the delivered dose of dialysis has been correlated with morbidity and mortality. This has led to the development of two major models for assessing the adequacy of the dialysis dose. Fundamentally, these two widely used measures of the adequacy of dialysis are calculated from the decrease in the blood urea nitrogen concentration during the dialysis treatment-that is, the urea reduction ratio (URR), and KT/V, an index based on the urea clearance rate, K, and the size of the urea pool, represented as the urea distribution volume, V. K, which is the sum of clearance by the dialyzer plus renal clearance, is multiplied by the time spent on dialysis, T. Increasingly, KT/V has become the preferred marker for dialysis adequacy. Currently, a URR of 65% and a KT/V of 1.2 per treatment are minimal standards for adequacy; lower levels of dialysis treatment are associated with increased morbidity and mortality.

For the majority of patients with chronic renal failure, between 9 and 12 h of dialysis is required each week, usually divided into three equal sessions. However, the dialysis dose must be individualized. The measurement of dialysis adequacy using KT/V or the URR serve only as a guide; body size, residual renal function, dietary intake, complicating illness, degree of anabolism or catabolism, and the presence of large interdialytic fluid gains are important factors in consideration of the dialysis prescription.

4.2.2. Complications which can occur during hemodialysis.

Hypotension is the most common acute complication of hemodialysis. Numerous factors appear to increase the risk of hypotension, including excessive ultrafiltration with inadequate compensatory vascular filling, impaired vasoactive or autonomic responses, osmolar shifts, food ingestion, impaired cardiac reserve, the use of antihypertensive drugs, and vasodilation due to the use of warm dialysate. Because of the vasodilatory and cardiodepressive effects of acetate, the use of acetate as the buffer in dialysate was once a common cause of hypotension. Since the introduction of bicarbonate-containing dialysate, dialysis-associated hypotension has become common. The management of hypotension during dialysis consists of discontinuing ultrafiltration, the administration of 100 to 250 cc of isotonic saline, and, in patients with hypoalbuminemia, administration of salt-poor albumin. Hypotension during dialysis can frequently be prevented by careful evaluation of the dry weight, holding of antihypertensive medications on the day prior to and on the day of dialysis, and avoiding heavy meals during dialysis. Additional maneuvers include the performance of sequential ultrafiltration followed by dialysis and cooling of the dialysate during dialysis treatment.

Muscle cramps during dialysis are also a common complication of the procedure. However, since the introduction of volumetric controls on dialysis machines and sodium modelling, the incidence of cramps has fallen. The etiology of dialysis-associated cramps remains obscure. Changes in muscle perfusion because of excessively aggressive volume removal, particularly below the estimated dry weight and the use of low sodium containing dialysate, have been proposed as precipitants of dialysis-associated cramps. Strategies that may be used to prevent cramps include reducing volume removal during dialysis, the use of higher concentrations of sodium in the dialysate, and the use of quinine sulfate (260 mg 2 h before treatment).

Anaphylactoid reactions to the dialyzer, particularly on its first use, have been reported most frequently with the bioincompatible cellulosic-containing membranes. With the gradual phasing out of cuprophane membranes in the United States, the first use syndrome has become relatively uncommon. The first use syndrome consists of either an intermediate hypersensitivity reaction due to an IgE mediated reaction to ethylene oxide used in the sterilization of new dialyzers, or a symptom complex of nonspecific chest and back pain, which appears to result from complement activation and cytokine release.

The major cause of death in patients with ESRD receiving chronic dialysis is cardiovascular disease. The rate of death from cardiac disease is higher in patients on hemodialysis as compared to patients on peritoneal dialysis and renal transplantation. The underlying cause of cardiovascular disease is unclear but may be related to the inadequate treatment of hypertension; the presence of hyperlipidemia, homocystinemia and anemia; the calcification of coronary arteries in patients with an elevated calcium-phosphorus product; and perhaps alterations in cardiovascular dynamics during the dialysis treatment. Intensive investigation of the mechanisms and potential interventions that could impact on reducing the mortality from cardiovascular causes is currently underway.

4.3. Peritoneal dialysis.

This consists of infusing 1 to 3 L of a dextrose-containing solution into the peritoneal cavity and allowing the fluid to dwell for 2 to 4 h. As with hemodialysis, toxic materials are removed through a combination of convective clearance generated through ultrafiltration, and diffusive clearance down a concentration gradient. The clearance of solute and water during a peritoneal dialysis exchange depends on the balance between the movement of solute and water into the peritoneal cavity versus absorption from the peritoneal cavity. The rate of diffusion diminishes with time and eventually stops when equilibriation between plasma and dialysate is reached. Absorption of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the lymphatic circulation. The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs such as beta blockers and calcium channel blockers, and by physical factors such as position and exercise.

Figure . A chart of placing of catheter of Tenkkhoffa is on a front abdominal wall

FORMS OF PERITONEAL DIALYSIS

Peritoneal dialysis may be carried out as continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), or nocturnal intermittent peritoneal dialysis (NIPD). In CAPD, dialysis solution is manually infused into the peritoneal cavity during the day and exchanged 3 to 4 times daily. A nighttime dwell is frequently instilled at bedtime and remains in the peritoneal cavity through the night. The drainage of spent dialysate (effluence) is performed manually with the assistance of gravity to move fluid out of the abdomen. In CCPD, exchanges are performed in an automated fashion, usually at night; the patient is connected to the automated cycler, which then performs 4 to 5 exchange cycles while the patient sleeps. Peritoneal dialysis cyclers automatically cycle dialysate in and out of the abdominal cavity. In the morning the patient, with the last exchange remaining in the abdomen, is disconnected from the cycler and goes about his regular daily activities. In NIPD, the patient is given approximately 10 h of cycling each night, with the abdomen left dry during the day.

Peritoneal dialysis solutions are available in various volumes ranging from 0.5 to 3.0 L. Lactate is the preferred buffer in peritoneal dialysis solutions. Acetate in peritoneal dialysis solutions appears to accelerate peritoneal sclerosis, whereas use of bicarbonte results in precipitation of calcium and caramelization of glucose. The most common additives to peritoneal dialysis solutions are heparin and antibiotics during an episode of acute peritonitis. Insulin may also be added in patients with diabetes mellitus.

4.4. Transplantation of the human kidney.

Transplantation of the human kidney is frequently the most effective treatment of advanced chronic renal failure. Worldwide, tens of thousands of such procedures have been performed. When azathioprine and prednisone were initially used as immunosuppressive drugs in the 1960s, the results with properly matched familial donors were superior to those with organs from cadaveric donors, namely, 75 to 90% compared with 50 to 60% graft survival rates at 1 year. During the 1970s and 1980s, the success rate at the 1-year mark for cadaveric transplants rose progressively. By the time cyclosporine was introduced in the early 1980s, cadaveric donor grafts had a 70% 1-year survival and reached the 80 to 85% level in the mid 1990s. After the first year, graft survival curves show an exponential decline in numbers of functioning grafts from which a half-life (t1/2) in years is calculated. Mortality rates after transplantation are highest in the first year and are age-related: 2% for ages 6 to 45 years, 7% for ages 46 to 60 years, and 10% for ages over 60 years, and lower thereafter. These rates compare favorably to those in the chronic dialysis population, even after risk adjustments for age, diabetes, and cardiovascular status. Occasionally, acute irreversible rejection may occur after many months of good function, especially if the patient neglects to take the immunosuppressive drugs. Most grafts, however, succumb at varying rates to a chronic vascular and interstitial obliterative process termed chronic rejection, although its pathogenesis is incompletely understood. Overall, transplantation returns the majority of patients to an improved life-style and an improved life expectancy, as compared to patients on dialysis; however, careful prospective cohort studies have yet to be reported.

Rice. Chart of placing of the transplanted kidney

4.4.1. Immunosuppressive treatment.

Diagnosis of the rejection and side-effects of the immunosuppressive therapy

Immunosuppressive therapy, as presently available, generally suppresses all immune responses, including those to bacteria, fungi, and even malignant tumors. In the 1950s when clinical renal transplantation began, sublethal total-body irradiation was employed. We have now reached the point where sophisticated pharmacologic immunosuppression is available, but it still has the hazard of promoting infection and malignancy. In general, all clinically useful drugs are more selective to primary than to memory immune responses. Agents to suppress the immune response are discussed in the following paragraphs, and those currently in clinical use are listed in Table 1.

Table 1. Maintenance Immunosuppressive Drugs
Agent	Pharmacology	Mechanisms	Side Effects
Glucocorticoids	Increased bioavailability with hypoalbuminemia and liver disease; prednisone/prednisolone generally used	Binds cytosolic receptors and heat shock proteins. Blocks transcription of IL-1,-2,-3,-6, TNF-, and IFN-	Hypertension, glucose intolerance, dyslipidemia, osteoporosis
Cyclosporine (CsA)	Lipid-soluble polypeptide, variable absorption, microemulsion more predictable	Trimolecular complex with cyclophilin and calcineurin ® block in cytokine (e.g., IL-2) production; however, stimulates TGF- production	Nephrotoxicity, hypertension, dyslipidemia, glucose intolerance, hirsutism/hyperplasia of gums
Tacrolimus (FK506)	Macrolide, well absorbed	Trimolecular complex with FKBP-12 and calcineurin ® block in cytokine (e.g., IL-2) production; may stimulate TGF- production	Similar to CsA, but hirsutism/hyperplasia of gums unusual, and diabetes more likely
Azathioprine	Mercaptopurine analogue	Hepatic metabolites inhibit purine synthesis	Marrow suppression (WBC  RBC  platelets)
Mycophenolate Mofetil (MMF)	Metabolized to mycophenolic acid	Inhibits purine synthesis via inosine monophosphate dehydrogenase	Diarrhea/cramps; dose-related liver and marrow suppression is uncommon
Sirolimus	Macrolide, poor oral bioavailability	Complexes with FKBP-12 and then blocks p70 S6 kinase in the IL-2 receptor pathway for proliferation	Hyperlipidemia, thrombocytopenia
NOTE: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; FKBP-12, FK506 binding protein 12; WBC, white blood cells; RBC, red blood cells.

Drugs. Azathioprine, an analogue of mercaptopurine, was for two decades the keystone to immunosuppressive therapy in humans. This agent can inhibit synthesis of DNA, RNA, or both. Because cell division and proliferation are a necessary part of the immune response to antigenic stimulation, suppression by this agent may be mediated by the inhibition of mitosis of immunologically competent lymphoid cells, interfering with synthesis of DNA. Alternatively, immunosuppression may be brought about by blocking the synthesis of RNA (possibly messenger RNA), inhibiting processing of antigens prior to lymphocyte stimulation. Therapy with azathioprine in doses of 1.5 to 2.0 mg/kg per day is generally added to cyclosporine as a means of decreasing the requirements for the latter. Because azathioprine is rapidly metabolized by the liver, its dosage need not be varied directly in relation to renal function, even though renal failure results in retention of the metabolites of azathioprine. Reduction in dosage is required because of leukopenia and occasionally thrombocytopenia. Excessive amounts of azathioprine may also cause jaundice, anemia, and alopecia. If it is essential to administer allopurinol concurrently, the azathioprine dose must be reduced, since inhibition of xanthine oxidase delays degradation. This combination is best avoided.

Mycophenolate mofetil is now used in place of azathioprine in many centers. It has a similar mode of action and a mild degree of gastrointestinal toxicity but produces minimal bone marrow suppression. Its advantage is its increased potency in preventing or reversing rejection.

Glucocorticoids are important adjuncts to immunosuppressive therapy. Of all the agents employed, prednisone has effects that are easiest to assess, and in large doses it is usually effective for the reversal of rejection. In general, 200 to 300 mg prednisone is given immediately prior to or at the time of transplantation, and the dosage is reduced to 30 mg within a week. The side effects of the glucocorticoids, particularly impairment of wound healing and predisposition to infection, make it desirable to taper the dose as rapidly as possible in the immediate postoperative period. Customarily, methylprednisolone, 0.5 to 1.0 g intravenously, is administered immediately upon diagnosis of beginning rejection and continued once daily for 3 days. When the drug is effective, the results are usually apparent within 96 h. Such "pulse" doses are not effective in chronic rejection. Most patients whose renal function is stable after 6 months or a year do not require large doses of prednisone; maintenance doses of 10 to 15 mg/d are the rule. Many patients tolerate an alternate-day course of steroids without an increased risk of rejection.

A major effect of steroids is on the monocyte-macrophage system, preventing the release of IL-6 and IL-1. Lymphopenia after large doses of glucocorticoids is primarily due to sequestration of recirculating blood lymphocytes to lymphoid tissue.

Cyclosporine is a fungal peptide with potent immunosuppressive activity. It acts on the calcineurin pathway to block transcription of mRNA for IL-2 and other proinflammatory cytokines, thereby inhibiting T cell proliferation. Although it works alone, cyclosporine is more effective in conjunction with glucocorticoids. Since cyclosporine blocks production of IL-2 by T cells, its combination with steroids is expected to produce a double block in the macrophage ® IL-6/IL-1 ® T cell ® IL-2 sequence. As noted, clinical results with tens of thousands of renal transplants have been impressive. Of its toxic effects (nephrotoxicity, hepatoxicity, hirsutism, tremor, gingival hyperplasia, diabetes), only nephrotoxicity presents a serious management problem.

Tacrolimus (FK-506) is a fungal macrolide that has the same mode of action, and a similar side effect profile, as cyclosporine. It does not produce hirsutism or gingival hyperplasia, however. De novo induction of diabetes mellitus is more common with tacrolimus. The drug was first used in liver transplantation, and may substitute for cyclosporine entirely, or be tried as an alternative in renal patients whose rejections are poorly controlled by cyclosporine.

Sirolimus (previously called rapamycin) is another fungal macrolide but has a different mode of action: namely, it inhibits T cell growth factor pathways, preventing the response to IL-2 and other cytokines. It shows some promise in clinical trials in combination with cyclosporine.

Antibodies to Lymphocytes When serum from animals made immune to host lymphocytes is injected into the recipient, a marked suppression of cellular immunity to the tissue graft results. The action on cell-mediated immunity is greater than on humoral immunity. A globulin fraction of serum [antilymphocyte globulin (ALG)] is the agent generally employed. For use in humans, peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas have been injected into horses, rabbits, or goats to produce antilymphocyte serum, from which the globulin fraction is then separated. Monoclonal antibodies against defined lymphocyte subsets offer a more precise and standardized form of therapy. OKT3 is directed to the CD3 molecules that form a portion of the T cell antigen-receptor complex; hence CD3 is expressed on all mature T cells. CD4 or CD8 molecules also form part of the fully activated cluster of molecules, and monoclonal antibodies to these offer the potential for more selective targeting of T cell subsets. Another approach to more selective therapy is to target the 55-kDa alpha chain of the IL-2 receptor, expressed only on T cells that have been recently activated. The problem with such mouse antibodies is the potential for developing human antimouse antibodies (HAMA), an event that limits the effective period of use. Genetically engineered monoclonal antibodies can solve this problem. Two such antibodies to the IL-2 receptor, in which either a chimeric protein has been made between mouse Fab with human Fc (basiliximab) or "humanized" by splicing the cmbining sites of the mouse into a molecule that is 90% human IgG (daclizumab), have been approved for use, after clinical evidence of reduction of rejection episodes. Their precise clinical role is under study.

4.1.2. Correction of the electrolytes abnormalities.

The metabolic acidosis can usually be corrected by treating the patient with 20 to 30 mmol of sodium bicarbonate or sodium citrate daily.

Secondary hyperparathyroidism and osteitis fibrosa are best prevented and treated by reducing serum PO43- concentration through the use of a PO43- restricted diet as well as oral PO43--binding agents. Calcium carbonate and calcium acetate are the preferred PO43- binding agents, but in some rare circumstances a combination of short-term aluminum hydroxide and calcium carbonate is necessary. Daily oral calcitriol, or intermittent oral or intravenous pulses, appear to exert a direct suppressive effect on PTH secretion, in addition to the indirect effect mediated through raising Ca2+ levels. Intravenous pulses are especially convenient for patients on hemodialysis. In the dialysis population, dialysate Ca2+, calcium carbonate, calcium acetate, aluminum hydroxide, and calcitriol must be properly balanced to maintain the serum PO43- concentration at approximately 1.4 mmol/L (4.5 mg/dL) and the serum Ca2+ at approximately 2.5 mmol/L (10 mg/dL) in an attempt to suppress parathyroid hyperplasia, thus avoiding or reversing osteitis fibrosa cystica, osteomalacia, and myopathy. It is particularly important to maintain the Ca2+-PO43- product in the normal range to avoid metastatic calcification.

Adynamic bone disease is often a consequence of overzealous treatment of secondary hyperparathyroidism. Therefore, suppression of PTH levels to less than 120 pg/mL in uremic patients may not be desirable. The incidence of aluminum-induced osteomalacia has been greatly reduced with the recognition of aluminum as the principal culprit. Therapy for this disorder is continued avoidance of aluminum, with possible use of a chelating agent such as desferoxamine along with high-flux dialysis. Management of metabolic acidosis should aim to maintain a nearly normal level of plasma HCO3-, with the administration of calcium acetate or calcium carbonate in the first instance, and with the addition of NaHCO3 if necessary. Excessive administration of alkali should be avoided to minimize risk of urinary precipitation of calcium phosphate.

At present, there is no good therapy for dialysis-related amyloidosis. Local physical therapy, glucocorticoid injections, and NSAIDs constitute current options.

Other Solutes Treatment of hyperuricemia is not necessary unless recurrent gout becomes a problem. When recurrent symptomatic gout occurs, a reduced dose of allopurinol (100 to 200 mg/d) is usually sufficient to inhibit uric acid synthesis. Hypophosphatemia is rare and, when it occurs, is usually a consequence of overzealous oral administration of phosphate-binding gels. Because serum magnesium levels tend to rise in CRD, magnesium-containing antacids and cathartics should be avoided.

4.2. Hemodialysis.

4.2.1. Indication to hemodialisis.

The choice between hemodialysis and peritoneal dialysis involves the interplay of various factors that include the patient's age, the presence of comorbid conditions, the ability to perform the procedure, and the patient's own conceptions about the therapy. Peritoneal dialysis is favored in younger patients because of their better manual dexterity and greater visual acuity, and because younger patients prefer the independence and flexibility of home-based peritoneal dialysis treatment. In contrast, larger patients (>80 kg), patients with no residual renal function, and patients who have truncal obesity with or without prior abdominal surgery are more suited to hemodialysis. Larger patients with no residual renal function are more appropriate for hemodialysis because these patients have a large volume of distribution of urea and require significantly higher amounts of peritoneal dialysis, which may be difficult to achieve because of the limited willingness of patients to perform more than four exchanges each day. In some patients, the inability to obtain vascular access predicates a switch from hemodialysis to peritoneal dialysis.

HEMODIALYSIS

This consists of diffusion that occurs bi-directionally across a semipermeable membrane. Movement of metabolic waste products takes place down a concentration gradient from the circulation into the dialysate, and in the reverse direction. The rate of diffusive transport increases in response to several factors, including the magnitude of the concentration gradient, the membrane surface area, and the mass transfer coefficient of the membrane. The latter is a function of the porosity and thickness of the membrane, the size of the solute molecule, and the conditions of flow on the two sides of the membrane. According to the laws of diffusion, the larger the molecule, the slower its rate of transfer across the membrane. A small molecule such as urea (60 Da) undergoes substantial clearance, whereas a larger molecule such as creatinine (113 Da), is cleared much less efficiently. In addition to diffusive clearance, movement of toxic materials such as urea from the circulation into the dialysate may occur as a result ofultrafiltration. Convective clearance occurs because of solvent drag with solutes getting swept along with water across the semipermeable dialysis membrane.

GOALS OF DIALYSIS

The hemodialysis procedure is targeted at removing both small and large molecular weight solutes. The procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 300 to 500 mL/min, while dialysate flows in an opposite counter-current direction at 500 to 800 mL/min. The clearance of urea ranges from 200 to 350 mL/min, while the clearance of b2 microglobulin is more modest and ranges from 20 to 25 mL/min. The efficiency of dialysis is determined by blood and dialysate flow through the dialyzer, as well as dialyzer characteristics (i.e., its efficiency in removing solute). The dose of dialysis, which is defined as the magnitude of urea clearance during a single dialysis treatment, is further governed by patient size, residual renal function, dietary protein intake, the degree of anabolism or catabolism, and the presence of comorbid conditions. Since the landmark studies of Sargent and Gatch relating the measurement of the dose of dialysis using urea concentration with patient outcome, the delivered dose of dialysis has been correlated with morbidity and mortality. This has led to the development of two major models for assessing the adequacy of the dialysis dose. Fundamentally, these two widely used measures of the adequacy of dialysis are calculated from the decrease in the blood urea nitrogen concentration during the dialysis treatment-that is, the urea reduction ratio (URR), and KT/V, an index based on the urea clearance rate, K, and the size of the urea pool, represented as the urea distribution volume, V. K, which is the sum of clearance by the dialyzer plus renal clearance, is multiplied by the time spent on dialysis, T. Increasingly, KT/V has become the preferred marker for dialysis adequacy. Currently, a URR of 65% and a KT/V of 1.2 per treatment are minimal standards for adequacy; lower levels of dialysis treatment are associated with increased morbidity and mortality.

For the majority of patients with chronic renal failure, between 9 and 12 h of dialysis is required each week, usually divided into three equal sessions. However, the dialysis dose must be individualized. The measurement of dialysis adequacy using KT/V or the URR serve only as a guide; body size, residual renal function, dietary intake, complicating illness, degree of anabolism or catabolism, and the presence of large interdialytic fluid gains are important factors in consideration of the dialysis prescription.

4.2.2. Complications which can occur during hemodialysis.

Hypotension is the most common acute complication of hemodialysis. Numerous factors appear to increase the risk of hypotension, including excessive ultrafiltration with inadequate compensatory vascular filling, impaired vasoactive or autonomic responses, osmolar shifts, food ingestion, impaired cardiac reserve, the use of antihypertensive drugs, and vasodilation due to the use of warm dialysate. Because of the vasodilatory and cardiodepressive effects of acetate, the use of acetate as the buffer in dialysate was once a common cause of hypotension. Since the introduction of bicarbonate-containing dialysate, dialysis-associated hypotension has become common. The management of hypotension during dialysis consists of discontinuing ultrafiltration, the administration of 100 to 250 cc of isotonic saline, and, in patients with hypoalbuminemia, administration of salt-poor albumin. Hypotension during dialysis can frequently be prevented by careful evaluation of the dry weight, holding of antihypertensive medications on the day prior to and on the day of dialysis, and avoiding heavy meals during dialysis. Additional maneuvers include the performance of sequential ultrafiltration followed by dialysis and cooling of the dialysate during dialysis treatment.

Muscle cramps during dialysis are also a common complication of the procedure. However, since the introduction of volumetric controls on dialysis machines and sodium modelling, the incidence of cramps has fallen. The etiology of dialysis-associated cramps remains obscure. Changes in muscle perfusion because of excessively aggressive volume removal, particularly below the estimated dry weight and the use of low sodium containing dialysate, have been proposed as precipitants of dialysis-associated cramps. Strategies that may be used to prevent cramps include reducing volume removal during dialysis, the use of higher concentrations of sodium in the dialysate, and the use of quinine sulfate (260 mg 2 h before treatment).

Anaphylactoid reactions to the dialyzer, particularly on its first use, have been reported most frequently with the bioincompatible cellulosic-containing membranes. With the gradual phasing out of cuprophane membranes in the United States, the first use syndrome has become relatively uncommon. The first use syndrome consists of either an intermediate hypersensitivity reaction due to an IgE mediated reaction to ethylene oxide used in the sterilization of new dialyzers, or a symptom complex of nonspecific chest and back pain, which appears to result from complement activation and cytokine release.

The major cause of death in patients with ESRD receiving chronic dialysis is cardiovascular disease. The rate of death from cardiac disease is higher in patients on hemodialysis as compared to patients on peritoneal dialysis and renal transplantation. The underlying cause of cardiovascular disease is unclear but may be related to the inadequate treatment of hypertension; the presence of hyperlipidemia, homocystinemia and anemia; the calcification of coronary arteries in patients with an elevated calcium-phosphorus product; and perhaps alterations in cardiovascular dynamics during the dialysis treatment. Intensive investigation of the mechanisms and potential interventions that could impact on reducing the mortality from cardiovascular causes is currently underway.

4.3. Peritoneal dialysis.

This consists of infusing 1 to 3 L of a dextrose-containing solution into the peritoneal cavity and allowing the fluid to dwell for 2 to 4 h. As with hemodialysis, toxic materials are removed through a combination of convective clearance generated through ultrafiltration, and diffusive clearance down a concentration gradient. The clearance of solute and water during a peritoneal dialysis exchange depends on the balance between the movement of solute and water into the peritoneal cavity versus absorption from the peritoneal cavity. The rate of diffusion diminishes with time and eventually stops when equilibriation between plasma and dialysate is reached. Absorption of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the lymphatic circulation. The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs such as beta blockers and calcium channel blockers, and by physical factors such as position and exercise.

FORMS OF PERITONEAL DIALYSIS

Peritoneal dialysis may be carried out as continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), or nocturnal intermittent peritoneal dialysis (NIPD). In CAPD, dialysis solution is manually infused into the peritoneal cavity during the day and exchanged 3 to 4 times daily. A nighttime dwell is frequently instilled at bedtime and remains in the peritoneal cavity through the night. The drainage of spent dialysate (effluence) is performed manually with the assistance of gravity to move fluid out of the abdomen. In CCPD, exchanges are performed in an automated fashion, usually at night; the patient is connected to the automated cycler, which then performs 4 to 5 exchange cycles while the patient sleeps. Peritoneal dialysis cyclers automatically cycle dialysate in and out of the abdominal cavity. In the morning the patient, with the last exchange remaining in the abdomen, is disconnected from the cycler and goes about his regular daily activities. In NIPD, the patient is given approximately 10 h of cycling each night, with the abdomen left dry during the day.

Peritoneal dialysis solutions are available in various volumes ranging from 0.5 to 3.0 L. Lactate is the preferred buffer in peritoneal dialysis solutions. Acetate in peritoneal dialysis solutions appears to accelerate peritoneal sclerosis, whereas use of bicarbonte results in precipitation of calcium and caramelization of glucose. The most common additives to peritoneal dialysis solutions are heparin and antibiotics during an episode of acute peritonitis. Insulin may also be added in patients with diabetes mellitus.

4.4. Transplantation of the human kidney.

Transplantation of the human kidney is frequently the most effective treatment of advanced chronic renal failure. Worldwide, tens of thousands of such procedures have been performed. When azathioprine and prednisone were initially used as immunosuppressive drugs in the 1960s, the results with properly matched familial donors were superior to those with organs from cadaveric donors, namely, 75 to 90% compared with 50 to 60% graft survival rates at 1 year. During the 1970s and 1980s, the success rate at the 1-year mark for cadaveric transplants rose progressively. By the time cyclosporine was introduced in the early 1980s, cadaveric donor grafts had a 70% 1-year survival and reached the 80 to 85% level in the mid 1990s. After the first year, graft survival curves show an exponential decline in numbers of functioning grafts from which a half-life (t1/2) in years is calculated. Mortality rates after transplantation are highest in the first year and are age-related: 2% for ages 6 to 45 years, 7% for ages 46 to 60 years, and 10% for ages over 60 years, and lower thereafter. These rates compare favorably to those in the chronic dialysis population, even after risk adjustments for age, diabetes, and cardiovascular status. Occasionally, acute irreversible rejection may occur after many months of good function, especially if the patient neglects to take the immunosuppressive drugs. Most grafts, however, succumb at varying rates to a chronic vascular and interstitial obliterative process termed chronic rejection, although its pathogenesis is incompletely understood. Overall, transplantation returns the majority of patients to an improved life-style and an improved life expectancy, as compared to patients on dialysis; however, careful prospective cohort studies have yet to be reported.

4.4.1. Immunosuppressive treatment.

Diagnosis of the rejection and side-effects of the immunosuppressive therapy

Immunosuppressive therapy, as presently available, generally suppresses all immune responses, including those to bacteria, fungi, and even malignant tumors. In the 1950s when clinical renal transplantation began, sublethal total-body irradiation was employed. We have now reached the point where sophisticated pharmacologic immunosuppression is available, but it still has the hazard of promoting infection and malignancy. In general, all clinically useful drugs are more selective to primary than to memory immune responses. Agents to suppress the immune response are discussed in the following paragraphs, and those currently in clinical use are listed in Table 1.

Table 1. Maintenance Immunosuppressive Drugs
Agent	Pharmacology	Mechanisms	Side Effects
Glucocorticoids	Increased bioavailability with hypoalbuminemia and liver disease; prednisone/prednisolone generally used	Binds cytosolic receptors and heat shock proteins. Blocks transcription of IL-1,-2,-3,-6, TNF-, and IFN-	Hypertension, glucose intolerance, dyslipidemia, osteoporosis
Cyclosporine (CsA)	Lipid-soluble polypeptide, variable absorption, microemulsion more predictable	Trimolecular complex with cyclophilin and calcineurin ® block in cytokine (e.g., IL-2) production; however, stimulates TGF- production	Nephrotoxicity, hypertension, dyslipidemia, glucose intolerance, hirsutism/hyperplasia of gums
Tacrolimus (FK506)	Macrolide, well absorbed	Trimolecular complex with FKBP-12 and calcineurin ® block in cytokine (e.g., IL-2) production; may stimulate TGF- production	Similar to CsA, but hirsutism/hyperplasia of gums unusual, and diabetes more likely
Azathioprine	Mercaptopurine analogue	Hepatic metabolites inhibit purine synthesis	Marrow suppression (WBC  RBC  platelets)
Mycophenolate Mofetil (MMF)	Metabolized to mycophenolic acid	Inhibits purine synthesis via inosine monophosphate dehydrogenase	Diarrhea/cramps; dose-related liver and marrow suppression is uncommon
Sirolimus	Macrolide, poor oral bioavailability	Complexes with FKBP-12 and then blocks p70 S6 kinase in the IL-2 receptor pathway for proliferation	Hyperlipidemia, thrombocytopenia
NOTE: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; FKBP-12, FK506 binding protein 12; WBC, white blood cells; RBC, red blood cells.

Drugs. Azathioprine, an analogue of mercaptopurine, was for two decades the keystone to immunosuppressive therapy in humans. This agent can inhibit synthesis of DNA, RNA, or both. Because cell division and proliferation are a necessary part of the immune response to antigenic stimulation, suppression by this agent may be mediated by the inhibition of mitosis of immunologically competent lymphoid cells, interfering with synthesis of DNA. Alternatively, immunosuppression may be brought about by blocking the synthesis of RNA (possibly messenger RNA), inhibiting processing of antigens prior to lymphocyte stimulation. Therapy with azathioprine in doses of 1.5 to 2.0 mg/kg per day is generally added to cyclosporine as a means of decreasing the requirements for the latter. Because azathioprine is rapidly metabolized by the liver, its dosage need not be varied directly in relation to renal function, even though renal failure results in retention of the metabolites of azathioprine. Reduction in dosage is required because of leukopenia and occasionally thrombocytopenia. Excessive amounts of azathioprine may also cause jaundice, anemia, and alopecia. If it is essential to administer allopurinol concurrently, the azathioprine dose must be reduced, since inhibition of xanthine oxidase delays degradation. This combination is best avoided.

Mycophenolate mofetil is now used in place of azathioprine in many centers. It has a similar mode of action and a mild degree of gastrointestinal toxicity but produces minimal bone marrow suppression. Its advantage is its increased potency in preventing or reversing rejection.

Glucocorticoids are important adjuncts to immunosuppressive therapy. Of all the agents employed, prednisone has effects that are easiest to assess, and in large doses it is usually effective for the reversal of rejection. In general, 200 to 300 mg prednisone is given immediately prior to or at the time of transplantation, and the dosage is reduced to 30 mg within a week. The side effects of the glucocorticoids, particularly impairment of wound healing and predisposition to infection, make it desirable to taper the dose as rapidly as possible in the immediate postoperative period. Customarily, methylprednisolone, 0.5 to 1.0 g intravenously, is administered immediately upon diagnosis of beginning rejection and continued once daily for 3 days. When the drug is effective, the results are usually apparent within 96 h. Such "pulse" doses are not effective in chronic rejection. Most patients whose renal function is stable after 6 months or a year do not require large doses of prednisone; maintenance doses of 10 to 15 mg/d are the rule. Many patients tolerate an alternate-day course of steroids without an increased risk of rejection.

A major effect of steroids is on the monocyte-macrophage system, preventing the release of IL-6 and IL-1. Lymphopenia after large doses of glucocorticoids is primarily due to sequestration of recirculating blood lymphocytes to lymphoid tissue.

Cyclosporine is a fungal peptide with potent immunosuppressive activity. It acts on the calcineurin pathway to block transcription of mRNA for IL-2 and other proinflammatory cytokines, thereby inhibiting T cell proliferation. Although it works alone, cyclosporine is more effective in conjunction with glucocorticoids. Since cyclosporine blocks production of IL-2 by T cells, its combination with steroids is expected to produce a double block in the macrophage ® IL-6/IL-1 ® T cell ® IL-2 sequence. As noted, clinical results with tens of thousands of renal transplants have been impressive. Of its toxic effects (nephrotoxicity, hepatoxicity, hirsutism, tremor, gingival hyperplasia, diabetes), only nephrotoxicity presents a serious management problem.

Tacrolimus (FK-506) is a fungal macrolide that has the same mode of action, and a similar side effect profile, as cyclosporine. It does not produce hirsutism or gingival hyperplasia, however. De novo induction of diabetes mellitus is more common with tacrolimus. The drug was first used in liver transplantation, and may substitute for cyclosporine entirely, or be tried as an alternative in renal patients whose rejections are poorly controlled by cyclosporine.

Sirolimus (previously called rapamycin) is another fungal macrolide but has a different mode of action: namely, it inhibits T cell growth factor pathways, preventing the response to IL-2 and other cytokines. It shows some promise in clinical trials in combination with cyclosporine.

Antibodies to Lymphocytes When serum from animals made immune to host lymphocytes is injected into the recipient, a marked suppression of cellular immunity to the tissue graft results. The action on cell-mediated immunity is greater than on humoral immunity. A globulin fraction of serum [antilymphocyte globulin (ALG)] is the agent generally employed. For use in humans, peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas have been injected into horses, rabbits, or goats to produce antilymphocyte serum, from which the globulin fraction is then separated. Monoclonal antibodies against defined lymphocyte subsets offer a more precise and standardized form of therapy. OKT3 is directed to the CD3 molecules that form a portion of the T cell antigen-receptor complex; hence CD3 is expressed on all mature T cells. CD4 or CD8 molecules also form part of the fully activated cluster of molecules, and monoclonal antibodies to these offer the potential for more selective targeting of T cell subsets. Another approach to more selective therapy is to target the 55-kDa alpha chain of the IL-2 receptor, expressed only on T cells that have been recently activated. The problem with such mouse antibodies is the potential for developing human antimouse antibodies (HAMA), an event that limits the effective period of use. Genetically engineered monoclonal antibodies can solve this problem. Two such antibodies to the IL-2 receptor, in which either a chimeric protein has been made between mouse Fab with human Fc (basiliximab) or "humanized" by splicing the cmbining sites of the mouse into a molecule that is 90% human IgG (daclizumab), have been approved for use, after clinical evidence of reduction of rejection episodes. Their precise clinical role is under study.

ACUTE RENAL FAILURE (ARF)(ACUTE KIDNEY INJURY)

Acute renal failure (ARF) is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia). It often results from severe trauma, illness, or surgery but is sometimes caused by a rapidly progressive, intrinsic renal disease. Symptoms include anorexia, nausea, and vomiting. Seizures and coma may occur if the condition is untreated. Fluid, electrolyte, and acid-base disorders develop quickly. Diagnosis is based on laboratory tests of renal function, including serum creatinine. Urinary indices, urinary sediment examination, and often imaging and other tests are needed to determine the cause. Treatment is directed at the cause but also includes fluid and electrolyte management and sometimes dialysis.

In all cases of ARF, creatinine and urea build up in the blood over several days, and fluid and electrolyte disorders develop. The most serious of these disorders are hyperkalemia and fluid overload (possibly causing pulmonary edema). Phosphate retention leads to hyperphosphatemia. Hypocalcemia is thought to occur because the impaired kidney no longer produces calcitriol and because hyperphosphatemia causes Ca phosphate precipitation in the tissues. Acidosis develops because hydrogen ions cannot be excreted. With significant uremia, coagulation may be impaired, and pericarditis may develop. Urine output varies with the type and cause of ARF.

Etiology

Causes of ARF can be classified as prerenal, renal, or postrenal.

Prerenal azotemia is due to inadequate renal perfusion. The main causes are ECF volume depletion and cardiovascular disease. Prerenal conditions cause about 50 to 80% of ARF but do not cause permanent renal damage (and hence are potentially reversible) unless hypoperfusion is severe enough to cause tubular ischemia. Hypoperfusion of an otherwise functioning kidney leads to enhanced reabsorption of Na and water, resulting in oliguria with high urine osmolality and low urine Na.

Renal causes of ARF involve intrinsic renal disease or damage. Renal causes are responsible for about 10 to 40% of cases. Overall, the most common causes are prolonged renal ischemia and nephrotoxins (including IV use of iodinated radiopaque contrast agents). Disorders may involve the glomeruli, tubules, or interstitium. Glomerular disease reduces GFR and increases glomerular capillary permeability to proteins; it may be inflammatory (glomerulonephritis) or the result of vascular damage from ischemia or vasculitis. Tubules also may be damaged by ischemia and may become obstructed by cellular debris, protein or crystal deposition, and cellular or interstitial edema. Tubular damage impairs reabsorption of Na, so urinary Na tends to be elevated, which is helpful diagnostically. Interstitial inflammation (nephritis) usually involves an immunologic or allergic phenomenon. These mechanisms of tubular damage are complex and interdependent, rendering the previously popular term acute tubular necrosis an inadequate description.

Postrenal azotemia (obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system and is responsible for about 5 to 10% of cases. Obstruction can also occur within the tubules when crystalline or proteinaceous material precipitates. This form of renal failure is often grouped with postrenal failure because the mechanism is obstructive. Obstructed ultrafiltrate flow in tubules or more distally increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 h, the renal blood flow is reduced, and by 24 h, it has fallen to < 50% of normal because of increased resistance of renal vasculature. Renovascular resistance may take up to a week to return to normal after relief of a 24-h obstruction. To produce significant azotemia, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney. Bladder outlet obstruction is probably the most common cause of sudden, and often total, cessation of urinary output in men.

Urine output: Prerenal causes typically manifest with oliguria, not anuria. Anuria usually occurs only in obstructive uropathy or, less commonly, in bilateral renal artery occlusion, acute cortical necrosis, or rapidly progressive glomerulonephritis.

A relatively preserved urine output of 1 to 2.4 L/day is initially present in most renal causes. In acute tubular injury, output may have 3 phases.

· The prodromal phase,with usually normal urine output, varies in duration depending on causative factors (eg, the amount of toxin ingested, the duration and severity of hypotension).

· The oliguric phase, with output typically between 50 and 400 mL/day, lasts an average of 10 to 14 days but varies from 1 day to 8 wk. However, many patients are never oliguric. Nonoliguric patients have lower mortality and morbidity and less need for dialysis.

· In the postoliguric phase, urine output gradually returns to normal, but serum creatinine and urea levels may not fall for several more days. Tubular dysfunction may persist and is manifested by Na wasting, polyuria (possibly massive) unresponsive to vasopressin, or hyperchloremic metabolic acidosis.

Symptoms and Signs

Initially, weight gain and peripheral edema may be the only findings. Often, predominant symptoms are those of the underlying illness or those caused by the surgical complication that precipitated renal deterioration. Later, as nitrogenous products accumulate, symptoms of uremia may develop, including anorexia, nausea and vomiting, weakness, myoclonic jerks, seizures, confusion, and coma; asterixis and hyperreflexia may be present on examination. Chest pain (typically worse with inspiration or when recumbent), a pericardial friction rub, and findings of pericardial tamponade may occur if uremic pericarditis is present. Fluid accumulation in the lungs may cause dyspnea and crackles on auscultation.

Other findings depend on the cause. Urine may be cola-colored in glomerulonephritis or myoglobinuria. A palpable bladder may be present with outlet obstruction.

Diagnosis

· Serum creatinine

· Urinary sediment

· Urinary diagnostic indices

· Postvoid residual bladder volume if postrenal cause suspected

ARF is suspected when urine output falls or serum BUN and creatinine rise. Evaluation should determine the presence and type of ARF and seek a cause. Blood tests generally include CBC, BUN, creatinine, and electrolytes (including Ca and phosphate). Urine tests include Na and creatinine concentration and microscopic analysis of sediment. Early detection and treatment increase the chances of reversing renal failure. A progressive daily rise in serum creatinine is diagnostic of ARF. Serum creatinine can increase by as much as 2 mg/dL/day (180 μmol/L/day), depending on the amount of creatinine produced (which varies with lean body mass) and total body water. A rise of > 2 mg/dL/day suggests overproduction due to rhabdomyolysis. Urea nitrogen may increase by 10 to 20 mg/dL/day (3.6 to 7.1 mmol urea/L/day), but BUN may be misleading because it is frequently elevated in response to increased protein catabolism resulting from surgery, trauma, corticosteroids, burns, transfusion reactions, parenteral nutrition or GI or internal bleeding. When creatinine is rising, 24-h urine collection for creatinine clearance and the various formulas used to calculate creatinine clearance from serum creatinine are inaccurate and should not be used in estimating GFR, because the rise in serum creatinine concentration is a delayed function of GFR decline.

Other laboratory findings are progressive acidosis, hyperkalemia, hyponatremia, and anemia. Acidosis is ordinarily moderate, with a plasma HCO₃ content of 15 to 20 mmol/L. Serum K concentration increases slowly, but when catabolism is markedly accelerated, it may rise by 1 to 2 mmol/L/day. Hyponatremia usually is moderate (serum Na, 125 to 135 mmol/L) and correlates with a surplus of water. Normochromic-normocytic anemia with an Hct of 25 to 30% is typical.

Hypocalcemia is common and may be profound in patients with myoglobinuric ARF, apparently because of the combined effects of Ca deposition in necrotic muscle, reduced calcitriol production, and resistance of bone to parathyroid hormone (PTH). During recovery from ARF, hypercalcemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and Ca deposits are mobilized from damaged tissue.

Determination of cause: Immediately reversible prerenal or postrenal causes must be excluded first. ECF volume depletion and obstruction are considered in all patients. The drug history must be accurately reviewed and all potentially renal toxic drugs stopped. Urinary diagnostic indices are helpful in distinguishing prerenal azotemia from acute tubular injury, which are the most common causes of ARF in hospitalized patients.

Prerenal causes are often apparent clinically. If so, correction of an underlying hemodynamic abnormality (eg, with volume infusion) should be attempted. Abatement of ARF confirms a prerenal cause.

Postrenal causes should be sought in most cases of acute renal failure. Immediately after the patient voids, a urethral catheter is placed or bedside ultrasonography is used to determine the residual urine in the bladder. A postvoid residual urine volume > 200 mL suggests bladder outlet obstruction, although detrusor muscle weakness and neurogenic bladder may also cause residual volume of this amount. The catheter may be kept in for the first day to monitor hourly output but is removed once oliguria is confirmed (if bladder outlet obstruction is not present) to decrease risk of infection. Renal ultrasonography is then done to diagnose more proximal obstruction. However, sensitivity for obstruction is only 80 to 85% when ultrasonography is used because the collecting system is not always dilated, especially when the condition is acute, an intrarenal pelvis is present, the ureter is encased (eg, in retroperitoneal fibrosis or neoplasm), or the patient has concomitant hypovolemia. If obstruction is strongly suspected, CT can establish the site of obstruction and guide therapy.

The urinary sediment may provide etiologic clues. A normal urine sediment occurs in prerenal azotemia and sometimes in obstructive uropathy. With renal tubular injury, the sediment characteristically contains tubular cells, tubular cell casts, and many brown-pigmented granular casts. Urinary eosinophils suggest allergic tubulointerstitial nephritis. RBC casts indicate glomerulonephritis or vasculitis.

Renal causes are sometimes suggested by clinical findings. Patients with glomerulonephritis often have edema, marked proteinuria (nephrotic syndrome), or signs of arteritis in the skin and retina, often without a history of intrinsic renal disease. Hemoptysis suggests Wegener's granulomatosis or Goodpasture's syndrome. Certain rashes (eg, erythema nodosum, cutaneous vasculitis, discoid lupus) suggest polyarteritis, cryoglobulinemia, SLE, or Henoch-Schönlein purpura. Tubulointerstitial nephritis and drug allergy are suggested by a history of drug ingestion and a maculopapular or purpuric rash.

To further differentiate renal causes, antistreptolysin-O and complement titers, antinuclear antibodies, and antineutrophil cytoplasmic antibodies are determined. Renal biopsy may be done if the diagnosis remains elusive

Imaging: In addition to renal ultrasonography, other imaging tests are occasionally of use. In evaluating for ureteral obstruction, noncontrast CT is preferred over antegrade and retrograde urography. In addition to its ability to delineate soft-tissue structures and Ca-containing calculi, CT can detect nonradiopaque calculi.

Contrast agents should be avoided if possible. However, renal arteriography or venography may sometimes be indicated if vascular causes are suggested clinically. Magnetic resonance angiography was increasingly being used for diagnosing renal artery stenosis as well as thrombosis of both arteries and veins because MRI used gadolinium, which was thought to be safer than the iodinated contrast agents used in angiography and contrast-enhanced CT. However, recent evidence suggests that gadolinium may be involved in the pathogenesis of nephrogenic systemic fibrosis, a serious complication that occurs only in patients with renal failure. Thus, many experts recommend avoiding gadolinium in patients with renal failure.

Kidney size, as determined with imaging tests, is helpful to know, because a normal or enlarged kidney favors reversibility, whereas a small kidney suggests chronic renal insufficiency.

Prognosis

Although many causes are reversible if diagnosed and treated early, the overall survival rate remains about 50% because many patients with ARF have significant underlying disorders (eg, sepsis, respiratory failure). Death is usually the result of these disorders rather than the renal failure itself. Most survivors have adequate kidney function. About 10% require dialysis or transplantation—half right away and the others as renal function slowly deteriorates.

Treatment

· Immediate treatment of pulmonary edema and hyperkalemia

· Dialysis as needed to control hyperkalemia, pulmonary edema, metabolic acidosis, and uremic symptoms

· Adjustment of drug regimen

· Usually restriction of water, Na, and K intake, but provision of adequate protein

· Possibly phosphate binders and Na polystyrene sulfonate

Emergency treatment: Life-threatening complications are addressed, preferably in a critical care unit. Pulmonary edema is treated with O₂, IV vasodilators (eg,nitroglycerin), and diuretics (often ineffective in ARF). Hyperkalemia is treated as needed with IV infusion of 10 mL of 10% Ca gluconate, 50 g of dextrose, and 5 to 10 units of insulin.These drugs do not reduce total body K, so further (but slower acting) treatment with 30 g of oral or rectal Na polystyrene sulfonate is begun. Although correction of an anion gap metabolic acidosis with NaHCO₃ is controversial, correction of the nonanion gap portion of severe metabolic acidosis (pH < 7.20) is less controversial. The nonanion gap portion may be treated with IV NaHCO₃ in the form of a slow infusion (≤ 150 mEq NaHCO₃ in 1 L of 5% D/W at a rate of 50 to 100 mL/h). The nonanion gap portion of metabolic acidosis is determined by calculating the increase in anion gap above normal and then subtracting this number from the decrease in HCO₃ from 24 mmol/L. HCO₃ is given to raise the serum HCO₃ by this difference. Because variations in body buffer systems and the rate of acid production are hard to predict, calculating the amount of HCO₃ needed to achieve a full correction is usually not recommended. Instead, HCO₃ is given via continuous infusion and the anion gap is monitored serially.

Hemodialysis or hemofiltration is initiated when

· Severe electrolyte abnormalities cannot otherwise be controlled (eg, K > 6 mmol/L)

· Pulmonary edema persists despite drug treatment

· Metabolic acidosis is unresponsive to drug treatment

· Uremic symptoms occur (eg, vomiting thought to be due to uremia, asterixis, encephalopathy, pericarditis, seizures)

BUN and creatinine levels are probably not the best guides for initiating dialysis in ARF. In asymptomatic patients who are not seriously ill, particularly those in whom return of renal function is considered likely, dialysis can be deferred until symptoms occur, thus avoiding placement of a central venous catheter with its attendant complications.

General measures: Nephrotoxic drugs are stopped, and all drugs excreted by the kidneys (eg,digoxin, some antibiotics) are adjusted; serum levels are useful.

Daily water intake is restricted to a volume equal to the previous day's urine output plus measured extrarenal losses (eg, vomitus) plus 500 to 1000 mL/day for insensible loss. Water intake can be further restricted for hyponatremia or increased for hypernatremia. Although weight gain indicates excess fluid, water intake is not decreased if serum Na remains normal; instead, dietary Na is restricted. Na and K intake is minimized except in patients with prior deficiencies or GI losses. An adequate diet should be provided, including daily protein intake of about 0.8 to 1 g/kg. If oral or enteral nutrition is impossible, parenteral nutrition is used, but in ARF, risks of fluid overload, hyperosmolality, and infection are increased by IV nutrition. Ca salts (carbonate, acetate) or synthetic non–Ca-containing phosphate binders before meals help maintain serum phosphate at < 5 mg/dL (< 1.78 mmol/L). To help maintain serum K at < 6 mmol/L in the absence of dialysis, a cation-exchange resin, Na polystyrene sulfonate, is given 15 to 60 g po or rectally 1 to 4 times/day as a suspension in water or in a syrup (eg, 70% sorbitol). An indwelling bladder catheter is rarely needed and should be used only when necessary because of an increased risk of UTI and urosepsis. In many patients, a brisk and even dramatic diuresis after relief of obstruction is a physiologic response to the expansion of ECF during obstruction and does not compromise volume status. However, polyuria accompanied by the excretion of large amounts of Na, K, Mg, and other solutes may cause hypokalemia, hyponatremia, hypernatremia, hypomagnesemia, or marked contraction of ECF volume with peripheral vascular collapse. In this postoliguric phase, close attention to fluid and electrolyte balance is mandatory. Overzealous administration of salt and water after relief of obstruction can prolong diuresis. When postoliguric diuresis occurs, replacement of urine output with 0.45% saline at about 75% of urine output prevents volume depletion and the tendency for excessive free water loss while allowing the body to eliminate excessive volume if this is the cause of the polyuria.

Prevention

ARF can often be prevented by maintaining normal fluid balance, blood volume, and BP in patients with trauma, burns, or major hemorrhage and in those undergoing major surgery. Infusion of isotonic saline and blood may be helpful. Use of contrast agents should be minimized, particularly in at-risk groups (eg, the elderly and those with preexisting renal insufficiency, volume depletion, diabetes, or heart failure). If contrast agents are necessary, risk can be lowered by minimizing volume of the IV contrast agent, using nonionic and low osmolal or iso-osmolal contrast agents, avoiding NSAIDs, and pretreating with normal saline at 1 mL/kg/h IV for 12 h before the test. Isotonic NaHCO₃ has been used successfully instead of normal saline in some patients. However, further study is needed to confirm this finding. N-acetylcysteine 600 mg po bid the day before and the day of IV contrast administration has been used to prevent contrast nephropathy, but reports of its efficacy are conflicting.Before cytolytic therapy is initiated in patients with certain neoplastic diseases (eg, lymphoma, leukemia), treatment with allopurinol should be considered along with increasing urine flow by increasing oral or IV fluids to reduce urate crystalluria. Making the urine more alkaline (by giving oral or IV NaHCO₃ or acetazolamide) has been recommended by some but is controversial because it may also induce urinary Ca phosphate precipitation and crystalluria, which may cause ARF. The renal vasculature is very sensitive to endothelin, a potent vasoconstrictor that reduces renal blood flow and GFR. Endothelin is implicated in progressive renal damage, and endothelin receptor antagonists have successfully slowed or even halted experimental renal disease. Antiendothelin antibodies and endothelin-receptor antagonists are being studied to protect the kidney against ischemic ARF.

BIBLIOGRAPHY

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