Background: Chronic renal failure (CRF) is characterized by progressive destruction of renal mass with irreversible sclerosis

Acute and chronic renal failure. Clinical pattern. Treatment.

The role of  a doctor-dentist   in prophylaxis.

Diseases of immune system. Allergy: anaphylactic shock, nettle rash, Quincke’s edema, medicamentous allergy. Secondary immunodeficiencies.

Background: Chronic renal failure (CRF) is characterized by progressive destruction of renal mass with irreversible sclerosis and loss of nephrons over a period of at least months to many years, depending on the underlying etiology. Glomerular filtration rate (GFR) progressively decreases with nephron loss, and the term CRF should be reserved more specifically for patients whose GFR is less than 30 cc/min. Chronic renal insufficiency (CRI) is the preferred term for patients with mild-to-moderate renal impairment, those whose GFR falls at 30-70 cc/min. End-stage renal disease (ESRD), usually associated with signs and symptoms of uremia, is the term reserved for patients whose GFR has declined to levels of less than 10 cc/min. These different stages of chronic renal impairment form a continuum in time, and the above terms should be used to render more readily appreciable the severity of renal disease.

         Pathophysiology: Approximately 1 millioephrons are present in each kidney, each contributing to the total GFR. Regardless of the etiology of renal injury, with progressive destruction of nephrons, the kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes such that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will double with a 50% reduction in GFR. A rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although still within the reference range, actually represents a loss of 50% of functioning nephron mass.

The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons noted, has been hypothesized to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop these lesions that are identical to those observed in humans with CRF.

Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following:

• Systemic hypertension

• Acute insults from nephrotoxins or decreased perfusion

• Proteinuria

• Increased renal ammoniagenesis with interstitial injury

• Hyperlipidemia

• Hyperphosphatemia with calcium phosphate deposition

• Decreased levels of nitrous oxide

Frequency:

• In the US: Although the exact incidence of CRF at its different stages is unknown, ESRD has reached epidemic levels, causing a major burden to health care resources. The incidence of new patients with ESRD in the United States in 1998 was 85,520, representing an incidence rate of 308 cases per million population; the prevalence on December 31, 1998, was 323,821 patients, representing a prevalence rate of 1160 cases per million population. An annual increase in incidence rate of approximately 7% per year since 1978 has occurred.

• Internationally: The incidence rates of ESRD have increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, with the United States taking second place.

Mortality/Morbidity: CRF is a major cause of morbidity and mortality, which are dramatic in the ESRD population. Although the diabetic population is at highest risk in the United States, in the general ESRD population (other than in the patients who have undergone transplant and who have an average of 0.6 hospital admissions per year), the hemodialysis and peritoneal dialysis populations have greater than 1.5 hospital admissions per patient per year. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%. This is approximately 20% in patients with diabetes.

Race:

• CRF affects all races, but, in the United States, a significantly higher incidence of ESRD exists in the black and Native American populations compared to Asians and whites.

• The white population has the lowest incidence of ESRD.

Sex: Both sexes are affected by CRF. In 1998, based on United States Renal Data System (USRDS) data, a higher total number of males with ESRD was found.

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

 

Ø Fatigue, increased somnolence, failure to thrive

Ø Malnutrition

Ø Erectile dysfunction, decreased libido, amenorrhea

Ø 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

 

• 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

• 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:

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

• 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)

 

Placement of renal perfusion catheter

Diet:

• Protein restriction early in CRF as a means to delay decline in GFR is controversial; however, as the patient approaches ESRD, this is recommended to delay onset of uremic symptoms. Patients with CRF who already are predisposed to becoming malnourished are at higher risk for malnutrition with overly aggressive protein restriction. Malnutrition is a well-established predictor of increased morbidity and mortality in the ESRD population and must be avoided if possible.

• Phosphate restriction starting early in CRF

• Potassium restriction

• Sodium and water restriction as needed to avoid volume overload

Phosphate-lowering agents — Hyperphosphatemia is treated with dietary phosphate binders and dietary phosphate restriction. Hypocalcemia is treated with calcium supplements and possibly calcitriol. Hyperparathyroidism is treated with calcitriol or vitamin D analogs.

Growth factors — Used to treat anemia of CRF by stimulating RBC production.

Iron salts — Nutritionally essential inorganic substances used to treat anemia.

Further Inpatient Care:

• Patients who develop potentially life-threatening complications of CRF should be hospitalized and closely monitored.

Further Outpatient Care:

• Patients with CRF should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up until initiation of chronic renal replacement therapy.

• A multidisciplinary approach to care, including involvement of the nephrologist, primary care physician, renal dietitian, nurse, and social worker, should be initiated early in the course of CRF, with close patient follow-up.

Transfer:

• Patients with CRF acutely presenting with indications for dialytic therapy should be transferred to a hospital center where acute dialysis can be performed.

• Dialysis is a treatment used when a person’s kidneys fail. Dialysis replaces the function of the kidneys by cleaning a person’s body of impurities and toxins. Dialysis treatment is typically used when a person is in the end-stage of renal failure and has less than 10% – 15% kidney function remaining.

• Dialysis treatment is crucial for people suffering from kidney failure. Without functional kidneys, they cao longer remove salts, waste, and water, and their bodies cannot maintain safe levels of sodium, potassium, and other minerals. Dialysis also helps to control blood pressure, which can rise or fall dangerously due to an imbalance of salts and minerals.

• There are two types of dialysis treatment. These are called hemodialysis and peritoneal dialysis. Each procedure works slightly differently, but operates on the same principles of replacing kidney function by removing waste products from the blood.

Hemodialysis Machine

Blood is pumped from the body to a filter where metabolic waste and excess water are removed

 

The abdominal cavity lined by the peritoneal membrane through which dialysis occurs.

 

Example of peritoneal dialysis being done manually.  It can also be automated.

 

Prognosis:

• Patients with CRF generally progress to ESRD. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventative measures, and on the individual patient.

• Patients on chronic dialysis have a high incidence of morbidity and mortality.

• Patients with ESRD who undergo renal transplantation survive longer than those on chronic dialysis.

Patient Education:

• Patients with CRF should receive education about the importance of compliance with secondary preventative measures, natural disease progression, prescribed medications (highlighting their potential benefits and side effects), diet, chronic renal replacement modalities, and permanent vascular access options for hemodialysis.

Medical/Legal Pitfalls:

• Early diagnosis and treatment of the underlying cause or/and institution of secondary preventative measures in CRF is imperative to try to delay, or possibly halt, progression. Early nephrologic referral is of extreme importance.

• Timely initiation of chronic renal replacement therapy is imperative to prevent the uremic complications of CRF that can lead to significant morbidity and death.

• In CRF, doses and intervals of drugs that are excreted or metabolized renally should be adjusted accordingly for the residual CrCl. Some drugs are contraindicated in moderate-to-severe CRF because of potentially serious effects from drug or metabolite accumulation. Routine consultation of the appropriate references should be undertaken when prescribing any new drug to a patient with CRF.

Special Concerns:

• Female patients with advanced CRF commonly develop menstrual irregularities; women with ESRD are typically amenorrheic and infertile.

Pregnancy in CRF can be associated with accelerated renal decline. In advanced CRF and ESRD, pregnancy is associated with markedly decreased fetal survival.

Acute renal failure.

Acute renal failure occurs in 5 percent of hospitalized patients. Etiologically, this common condition can be categorized as prerenal, intrinsic or postrenal. Most patients have pre-renal acute renal failure or acute tubular necrosis (a type of intrinsic acute renal failure that is usually caused by ischemia or toxins). Using a systematic approach, physicians can determine the cause of acute renal failure in most patients. This approach includes a thorough history and physical examination, blood tests, urine studies and a renal ultrasound examination. In certain situations, such as when a patient has glomerular disease, microvascular disease or obstructive disease, rapid diagnosis and treatment are necessary to prevent permanent renal damage. By maintaining euvolemia, recognizing patients who are at increased risk and minimizing exposure to nephrotoxins, physicians can decrease the incidence of acute renal failure. Once acute renal failure develops, supportive therapy is critical to maintain fluid and electrolyte balances, minimize nitrogenous waste production and sustaiutrition. Death is most often caused by infection or cardiorespiratory complications.

Acute renal failure (ARF) is a syndrome characterized by rapid decline in glomerular filtration rate (hours to days), retention of nitrogenous waste products, and perturbation of extracellular fluid volume and electrolyte and acid-base homeostasis. ARF complicates approximately 5% of hospital admissions and up to 30% of admissions to intensive care units. Oliguria (urine output < 500 mL/d) is a frequent but not invariable clinical feature (~50%). ARF is usually asymptomatic and is diagnosed when biochemical screening of hospitalized patients reveals a recent increase in plasma urea and creatinine concentrations. It may complicate a wide range of diseases, which for purposes of diagnosis and management are conveniently divided into three categories: (1) diseases that cause renal hypoperfusion without compromising the integrity of renal parenchyma (prerenal ARF, prerenal azotemia) (~55%); (2) diseases that directly involve renal parenchyma (intrinsic renal ARF, renal azotemia) (~40%); and (3) diseases associated with urinary tract obstruction (postrenal ARF, postrenal azotemia) (~5%). Most ARF is reversible, the kidney being relatively unique among major organs in its ability to recover from almost complete loss of function. Nevertheless, ARF is associated with major in-hospital morbidity and mortality, in large part due to the serious nature of the illnesses that precipitate the ARF.

Classification and Major Causes of Acute Renal Failure (ARF)

Key Symptoms and Physical Findings in Patients with Acute Renal Failure and Uremia

Symptoms

Anorexia

Fatigue

Mental status changes

Nausea and vomiting

Pruritus

Seizures (if blood urea nitrogen level is very high)

Shortness of breath (if volume overload is present)

Physical findings

Asterixis and myoclonus

Pericardial or pleural rub

Peripheral edema (if volume overload is present)

Pulmonary rales (if volume overload is present)

Elevated right atrial pressure (if volume overload is present)

Clinical findings depend on the stage at which acute renal failure is diagnosed.

 

 CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

Patients presenting with renal failure should be assessed initially to determine if the decline in GFR is acute or chronic. An acute process is easily established if a review of laboratory records reveals a recent rise in blood urea and creatinine levels, but previous measurements are not always available. Findings that suggest chronic renal failure include anemia, neuropathy, and radiologic evidence of renal osteodystrophy or small scarred kidneys. However, it should be noted that anemia may also complicate ARF, and renal size may be normal or increased in several chronic renal diseases (e.g., diabetic nephropathy, amyloidosis, polycystic kidney disease). Once a diagnosis of ARF has been established, several issues should be addressed promptly:

Ø the identification of the cause of ARF,

Ø the elimination of the triggering insult (e.g., nephrotoxin) and/or institution of disease-specific

Ø therapies,  the prevention and management of uremic complications.

 

CLINICAL ASSESSMENT

Clinical clues to prerenal ARF are symptoms of thirst and orthostatic dizziness and physical evidence of orthostatic hypotension and tachycardia, reduced jugular venous pressure, decreased skin turgor, dry mucous membranes, and reduced axillary sweating. Case records should be reviewed for documentation of a progressive fall in urine output and body weight and treatment with NSAIDs or ACE inhibitors. Careful clinical examination may reveal stigmata of chronic liver disease and portal hypertension, advanced cardiac failure, sepsis, or other causes of reduced “effective” arterial blood volume.

 

Intrinsic renal ARF due to ischemia is likely following severe renal hypoperfusion complicating hypovolemic or septic shock or following major surgery. The likelihood of ischemic ARF is increased further if ARF persists despite normalization of systemic hemodynamics. Diagnosis of nephrotoxic ARF requires careful review of the clinical data and pharmacy, nursing, and radiology records for evidence of recent exposure to nephrotoxic medications or radiocontrast agents or to endogenous toxins (e.g., myoglobin, hemoglobin, uric acid, myeloma protein, or elevated levels of serum calcium).

Although ischemic and nephrotoxic ARF account for more than 90% of cases of intrinsic renal ARF, other renal parenchymal diseases must be considered. Flank pain may be a prominent symptom following occlusion of a renal artery or vein and with other parenchymal diseases distending the renal capsule (e.g., severe glomerulonephritis or pyelonephritis). Subcutaneous nodules, livido reticularis, bright orange retinal arteriolar plaques, and digital ischemia, despite palpable pedal pulses, are clues to atheroembolization. ARF in association with oliguria, edema, hypertension, and an “active” urine sediment (nephritic syndrome) suggests acute glomerulonephritis or vasculitis. Malignant hypertension is a likely cause of ARF in patients with severe hypertension and evidence of hypertensive injury to other organs (e.g., left ventricular hypertrophy and failure, hypertensive retinopathy and papilledema, neurologic dysfunction). Fever, arthralgias, and a pruritic erythematous rash following exposure to a new drug suggest allergic interstitial nephritis, although systemic features of hypersensitivity are frequently absent.

Intrinsic Acute Renal Failure

Intrinsic acute renal failure is subdivided into four categories: tubular disease, glomerular disease, vascular disease and interstitial disease. In intrinsic acute renal failure, the renal parenchyma is injured. The damage to tubule cells leads to certain urine microscopic findings. Parenchymal injury causes impaired sodium reabsorption and results in a fractional excretion of sodium of greater than 3 percent and an isotonic urine osmolality of 250 to 300 mOsm

Appearance of red blood cells on urine microscopy. (Top) Nondysmorphic red blood cells (black arrows) and dysmorphic red blood cell (white arrow). (Center) Dysmorphic red blood cells (arrows). (Bottom) Red blood cell cast.

Hyaline and granular casts seen on urine microscopy. (left) Hyaline casts (arrows). (right) Granular casts (arrows).

TUBULAR DISEASE

Acute tubular necrosis is the most common cause of intrinsic acute renal failure in hospitalized patients. This condition is usually induced by ischemia or toxins.

In ischemic acute tubular necrosis, unlike prerenal acute renal failure, the glomerular filtration rate does not improve with the restoration of renal blood flow. Ischemic acute tubular necrosis is frequently reversible, but if the ischemia is severe enough to cause cortical necrosis, irreversible renal failure can occur.

Contrast agents and aminoglycosides are the agents most often associated with acute tubular necrosis. The condition can also be caused by pigment from myoglobinuria (rhabdomyolysis) or hemoglobinuria (hemolysis). Acute tubular necrosis has three phases.2 Renal injury evolves during the initiation phase, which lasts hours to days. In the maintenance phase, which lasts days to weeks, the glomerular filtration rate reaches its nadir and urine output is at its lowest. The recovery phase lasts days, often beginning with post-acute tubular necrosis diuresis. Hypovolemia from excess urine output is a concern during this phase. Despite recovery of urine production, patients can still have difficulty with uremia and homeostasis of electrolytes and acid because tubular function is not completely recovered. Diligent monitoring is indicated throughout all phases of acute tubular necrosis.

Patients at risk for acute tubular necrosis include those with diabetes, congestive heart failure or chronic renal insufficiency. Acute tubular necrosis may be prevented by promptly treating patients with reversible causes of ischemic or prerenal acute renal failure and by maintaining appropriate hydration in patients who are receiving nephrotoxins. Once acute tubular necrosis develops, therapy is supportive. Drugs such as mannitol, loop diuretics, dopamine and calcium channel blockers have been somewhat successful in promoting diuresis in animals, but similar results have not been obtained in humans.7

 

GLOMERULAR DISEASE

Glomerulonephritis is characterized by hypertension, proteinuria and hematuria.6 Of the many types of glomerulonephritis, most are associated with chronic renal disease. In general, the two types of glomerulonephritis that cause acute renal failure are rapidly progressive glomerulonephritis and acute proliferative glomerulonephritis. The latter type occurs in patients with bacterial endocarditis or other postinfectious conditions.

Rapidly progressive glomerulonephritis can be a primary disorder, or it can occur secondary to systemic disease (Table 5). Once this condition is suspected, treatable systemic disease must be sought through serologic markers or renal biopsy. Renal function can decline quickly in patients with rapidly progressive glomerulonephritis, and end-stage renal disease can develop in days to weeks.8

Patients with rapidly progressive glomerulonephritis are treated with glucocorticoids and cyclophosphamide (Cytoxan). Plasma exchange is believed to benefit patients with Goodpasture’s syndrome but has not been of proven benefit in patients with other types of glomerulonephritis.8

The underlying condition should be treated in patients with acute proliferative glomerulonephritis.

 

VASCULAR DISEASE

Microvascular or macrovascular disease (major renal artery occlusion or severe abdominal aortic disease) can cause acute renal failure.

The classic microvascular diseases often present with microangiopathic hemolysis and acute renal failure occurring because of glomerular capillary thrombosis or occlusion, often with accompanying thrombocytopenia. Typical examples of these diseases are thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and HELLP syndrome (hemolysis, elevated l iver enzymes and l ow platelets).

The classic pentad in thrombotic thrombocytopenic purpura includes fever, neurologic changes, renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Hemolytic uremic syndrome is similar to thrombotic thrombocytopenic purpura but does not present with neurologic changes. HELLP syndrome is a type of hemolytic uremic syndrome that occurs in pregnant women with the addition of transaminase elevations.

The microvascular diseases that cause acute renal failure are often treated with plasmapheresis and sometimes with corticosteroids.9-11 An increasing platelet count is a marker of improvement. In patients with parturition-related acute renal failure (HELLP syndrome), expedition of delivery is the initial treatment of choice.

Atheroembolic disease is another important cause of irreversible acute renal failure. Patients with atherosclerotic disease who undergo an invasive procedure (e.g., vascular surgery or interventional vascular studies) or have an acute arrhythmia are at increased risk for acute renal failure induced by atheroemboli. Acute renal failure from embolic disease may present one day to seven weeks after the inciting event.

Atheroembolism is relatively common in tertiary care and intensive care units, presenting classically with “purple toes and renal failure.” Evidence of microembolism may be present in other organs (livedo reticularis, gastrointestinal tract bleeding, pancreatitis, persisting encephalopathy and retinal embolism seen as “Hollenhorst” plaques). The diagnosis of atheroembolic disease can be confirmed on skin or renal biopsy. Treatment is nonspecific, but avoiding further vascular intervention and anticoagulation is strongly recommended.

 

INTERSTITIAL DISEASE

Acute interstitial nephritis usually presents with fever, rash and eosinophilia. Urine staining that is positive for eosinophils is suggestive of this condition. Acute interstitial nephritis is usually the result of an allergic reaction to a drug, but it may also be caused by autoimmune disease, infection or infiltrative disease.

Many drugs can cause acute interstitial nephritis, but the more common ones are NSAIDs, penicillins, cephalosporins, sulfonamides, diuretics and allopurinol (Zyloprim). Renal function should improve after the offending agent is withdrawn. Corticosteroids are sometimes helpful in speeding recovery.

Postrenal ARF presents with suprapubic and flank pain due to distention of the bladder and of the renal collecting system and capsule, respectively. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. Prostatic disease is likely if there is a history of nocturia, frequency, and hesitancy and enlargement or induration of the prostate on rectal examination. Neurogenic bladder should be suspected in patients receiving anticholinergic medications or with physical evidence of autonomic dysfunction. Definitive diagnosis of postrenal ARF hinges on judicious use of radiologic investigations and rapid improvement in renal function following relief of obstruction.

URINALYSIS

Anuria suggests complete urinary tract obstruction but may complicate severe cases of prerenal or intrinsic renal ARF. Wide fluctuations in urine output raise the possibility of intermittent obstruction, whereas patients with partial urinary tract obstruction can present with polyuria due to impairment of urine concentrating mechanisms.

In prerenal ARF, the sediment is characteristically acellular and contains transparent hyaline casts (“bland,” “benign,” “inactive” urine sediment). Hyaline casts are formed in concentrated urine from normal constitutents of urine-principally Tamm-Horsfall protein, which is secreted by epithelial cells of the loop of Henle. Postrenal ARF may also present with an inactive sediment, although hematuria and pyuria are common in patients with intraluminal obstruction or prostatic disease. Pigmented “muddy brown” granular casts and casts containing tubule epithelial cells are characteristic of ATN and suggest ischemic or nephrotoxic ARF. They are usually found in association with microscopic hematuria and mild “tubular” proteinuria (<1 g/d); the latter reflects impaired reabsorption and processing of filtered proteins by injured proximal tubules. Casts are absent, however, in 20 to 30% of patients with ischemic or nephrotoxic ARF and are not a requisite for diagnosis. In general, red blood cell casts indicate glomerular injury or, less often, acute tubulointerstitial nephritis. White cell casts and nonpigmented granular casts suggest interstitial nephritis, whereas broad granular casts are characteristic of chronic renal disease and probably reflect interstitial fibrosis and dilatation of tubules. Eosinophiluria (>5% of urine leukocytes) is a common finding (~90%) in antibiotic-induced allergic interstitial nephritis when studied using Hansel’s stain; however, lymphocytes may predominate in allergic interstitial nephritis induced by NSAIDs. Eosinophiluria is also a feature of atheroembolic ARF. Occasional uric acid crystals (pleomorphic in shape) are common in the concentrated urine of prerenal ARF but suggest acute urate nephropathy if seen in abundance. Oxalate (envelope-shaped) and hippurate (needle-shaped) crystals raise the possibility of ethylene glycol ingestion and toxicity.

Increased urine protein excretion, but <1 g/d, is common in ATN due to failure of injured proximal tubules to reabsorb filtered protein and excretion of cellular debris (“tubular proteinuria”). Proteinuria of >1 g/d suggests injury to the glomerular ultrafiltration barrier (“glomerular proteinuria”) or excretion of myeloma light chains. The latter are not detected by conventional dipsticks (which detect albumin) and must be sought by other means (e.g., sulfosalicylic acid test, immunoelectrophoresis). Heavy proteinuria is also a frequent finding (~80%) in patients who develop combined allergic interstitial nephritis and minimal change glomerulopathy when treated with NSAIDs. A similar syndrome can be triggered by ampicillin, rifampicin, or interferon a. Hemoglobinuria or myoglobinuria should be suspected if urine is strongly positive for heme by dipstick, but contains few red cells, and if the supernatant of centrifuged urine is positive for free heme. Bilirubinuria may provide a clue to the presence of hepatorenal syndrome.

 

RENAL FAILURE INDICES

Analysis of urine and blood biochemistry is particularly useful for distinguishing prerenal ARF from ischemic or nephrotoxic intrinsic renal ARF. The fractional excretion of sodium (FENa) is most useful in this regard. The FENa relates sodium clearance to creatinine clearance. Sodium is reabsorbed avidly from glomerular filtrate in patients with prerenal ARF, in an attempt to restore intravascular volume, but not in patients with ischemic or nephrotoxic intrinsic ARF, as a result of tubular epithelial cell injury. In contrast, creatinine is not reabsorbed in either setting. Consequently, patients with prerenal ARF typically have a FENa of <1.0% (frequently <0.1%), whereas the FENa in patients with ischemic or nephrotoxic ARF is usually >1.0%. The renal failure index provides comparable information, since clinical variations in serum sodium concentration are relatively small. Urine sodium concentration is a less sensitive index for distinguishing prerenal ARF from ischemic and nephrotoxic ARF as values overlap between groups. Similarly, indices of urinary concentrating ability such as urine specific gravity, urine osmolality, urine-to-plasma urea ratio, and blood urea-to-creatinine ratio are of limited value in differential diagnosis.

Many caveats apply when interpreting biochemical renal failure indices. FENa may be >1.0% in prerenal ARF if patients are receiving diuretics or have bicarbonaturia (accompanied by sodium to maintain electroneutrality), preexisting chronic renal failure complicated by salt wasting, or adrenal insufficiency. In contrast, the FENa is <1.0% in approximately 15% of patients with nonoliguric ischemic or nephrotoxic ARF. The FENa is often <1.0% in ARF due to urinary tract obstruction, glomerulonephritis, and vascular diseases.

 

LABORATORY FINDINGS

Serial measurements of serum creatinine can provide useful pointers to the cause of ARF. Prerenal ARF is typified by fluctuating levels that parallel changes in hemodynamic function. Creatinine rises rapidly (within 24 to 48 h) in patients with ARF following renal ischemia, atheroembolization, and radiocontrast exposure. Peak creatinine levels are observed after 3 to 5 days with contrast nephropathy and return to baseline after 5 to 7 days. In contrast, creatinine levels typically peak later (7 to 10 days) in ischemic ARF and atheroembolic disease. The initial rise in serum creatinine is characteristically delayed until the second week of therapy with many tubule epithelial cell toxins (e.g., aminoglycosides, cisplatin) and probably reflects the need for accumulation of these agents within cells before GFR falls.

Hyperkalemia, hyperphosphatemia, hypocalcemia, and elevations in serum uric acid and creatine kinase (MM isoenzyme) levels at presentation suggest a diagnosis of rhabdomyolysis. Hyperuricemia [>890 umol/L (>15 mg/dL)] in association with hyperkalemia, hyperphosphatemia, and increased circulating levels of intracellular enzymes such as lactate dehydrogenase may indicate acute urate nephropathy and tumor lysis syndrome following cancer chemotherapy. A wide serum anion and osmolal gap (measured serum osmolality minus the serum osmolality calculated from serum sodium, glucose, and urea concentrations) indicate the presence of an unusual anion or osmole in the circulation and are clues to diagnosis of ethylene glycol or methanol ingestion. Severe anemia in the absence of hemorrhage raises the possibility of hemolysis, multiple myeloma, or thrombotic microangiopathy. Systemic eosinophilia suggests allergic interstitial nephritis but is also a feature of atheroembolic disease and polyangiitis nodosa.

RADIOLOGIC FINDINGS

Imaging of the urinary tract by ultrasonography is useful to exclude postrenal ARF. Computed tomography and magnetic resonance imaging are alternative imaging modalities. Whereas pelvicalyceal dilatation is usual with urinary tract obstruction (98% sensitivity), dilatation may be absent immediately following obstruction or in patients with ureteric encasement (e.g., retroperitoneal fibrosis, neoplasia). Retrograde or anterograde pyelography are more definitive investigations in complex cases and provide precise localization of the site of obstruction. A plain film of the abdomen, with tomography if necessary, is a valuable initial screening technique in patients with suspected nephrolithiasis. Doppler ultrasonography and magnetic resonance flow imaging appear promising for assessment of patency of renal arteries and veins in patients with suspected vascular obstruction; however, contrast angiography is usually required for definitive diagnosis.

RENAL BIOPSY

Biopsy is reserved for patients in whom prerenal and postrenal ARF have been excluded and the cause of intrinsic renal ARF is unclear. Renal biopsy is particularly useful when clinical assessment and laboratory investigations suggest diagnoses other than ischemic or nephrotoxic injury that may respond to disease-specific therapy. Examples include glomerulonephritis, vasculitis, hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and allergic interstitial nephritis.

COMPLICATIONS

ARF impairs renal excretion of sodium, potassium, and water and perturbs divalent cation homeostasis and urinary acidification mechanisms. As a result, ARF is frequently complicated by intravascular volume overload, hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and metabolic acidosis. In addition, patients are unable to excrete nitrogenous waste products and are prone to develop the uremic syndrome. The speed of development and the severity of these complications reflect the degree of renal impairment and catabolic state of the patient.

Expansion of extracellular fluid volume is an inevitable consequence of diminished salt and water excretion in oliguric or anuric individuals. Whereas milder forms are characterized by weight gain, bibasilar lung rales, raised jugular venous pressure, and dependent edema, continued volume expansion may precipitate life-threatening pulmonary edema. Hypervolemia may be particularly problematic in patients receiving multiple intravenous medications and enteral or parenteral nutrition. Excessive administration of free water either through ingestion and nasogastric administration or as hypotonic saline or isotonic dextrose solutions (dextrose being metabolized) can induce hypoosmolality and hyponatremia, which, if severe, lead to cerebral edema and neurologic abnormalities, including seizures.

Hyperkalemia is a frequent complication of ARF. Serum potassium typically rises by 0.5 mmol/L per day in oliguric and anuric patients due to impaired excretion of ingested or infused potassium and potassium released from injured tissue. Coexistent metabolic acidosis may exacerbate hyperkalemia by promoting potassium efflux from cells. Hyperkalemia may be particularly severe, even at the time of diagnosis, in patients with rhabdomyolysis, hemolysis, and tumor lysis syndrome. Mild hyperkalemia (<6.0 mmol/L) is usually asymptomatic. Higher levels are typically associated with electrocardiographic abnormalities and/or increased cardiac excitability.

Metabolism of dietary protein yields between 50 and 100 mmol/d of fixed nonvolatile acids that are normally excreted by the kidneys. Consequently, ARF is typically complicated by metabolic acidosis, often with an increased serum anion gap. Acidosis can be particularly severe when endogenous production of hydrogen ions is increased by other mechanisms (e.g., diabetic or fasting ketoacidosis; lactic acidosis complicating generalized tissue hypoperfusion, liver disease, or sepsis; metabolism of ethylene glycol or methanol).

Mild hyperphosphatemia is an almost invariable complication of ARF. Severe hyperphosphatemia may develop in highly catabolic patients or following rhabdomyolysis, hemolysis, or tumor lysis. Metastatic deposition of calcium phosphate can lead to hypocalcemia, particularly when the product of serum calcium (mg/dL) and phosphate (mg/dL) concentrations exceeds 70. Other factors that contribute to hypocalcemia include tissue resistance to the actions of parathyroid hormone and reduced levels of 1,25-dihydroxyvitamin D. Hypocalcemia is often asymptomatic but can cause perioral paresthesias, muscle cramps, seizures, hallucinations and confusion, and prolongation of the QT interval and nonspecific T-wave changes on electrocardiography.

Anemia develops rapidly in ARF and is usually mild and multifactorial in origin. Contributing factors include impaired erythropoiesis, hemolysis, bleeding, hemodilution, and reduced red cell survival time. Prolongation of the bleeding time and leukocytosis are also common. Common contributors to the bleeding diathesis include mild thrombocytopenia, platelet dysfunction, and/or clotting factor abnormalities (e.g., factor VIII dysfunction), whereas leukocytosis usually reflects sepsis, a stress response, or other concurrent illness. Infection is a common and serious complication of ARF, occurring in 50 to 90% of cases and accounting for up to 75% of deaths. It is unclear whether patients with ARF have a clinically significant defect in host immune responses or whether the high incidence of infection reflects repeated breaches of mucocutaneous barriers (e.g., intravenous cannulae, mechanical ventilation, bladder catheterization). Cardiopulmonary complications of ARF include arrhythmias, myocardial infarction, pericarditis and pericardial effusion, pulmonary edema, and pulmonary embolism. Mild gastrointestinal bleeding is common (10 to 30%) and is usually due to stress ulceration of gastric or small intestinal mucosa.

Protracted periods of severe ARF are invariably associated with the development of the uremic syndrome. A vigorous diuresis can occur during the recovery phase of ARF (see above) and lead to intravascular volume depletion and delayed recovery of GFR by causing secondary prerenal ARF. Hypernatremia can also complicate recovery if water losses via hypotonic urine are not replaced or if losses are inappropriately replaced by relatively hypertonic saline solutions. Hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia are less common metabolic complications during this period.

General Treatment of Acute Renal Failure

 

Initial treatment should focus on correcting fluid and electrolyte balances and uremia while the cause of acute renal failure is being sought. A volume-depleted patient is resuscitated with saline. More often, however, volume overload is present, especially if patients are oliguric or anuric.

Furosemide (Lasix) administered intravenously every six hours is the initial treatment for volume overload. Depending on whether the patient takes furosemide regularly, the initial dose can be between 20 and 100 mg. If an inadequate response occurs in one hour, the dose is doubled. This process is repeated until adequate urine output is achieved. A continuous furosemide drip may be required. The last resort is ultrafiltration via dialysis.

The main electrolyte disturbances in the acute setting are hyperkalemia and acidosis. The aggressiveness of treatment depends on the degree of hyperkalemia and the changes seen on the electrocardiogram. Intravenously administered calcium (10 mL of a 10 percent solution of calcium gluconate) is cardioprotective and temporarily reverses the neuromuscular effects of hyperkalemia.

Potassium can be temporarily shifted into the intracellular compartment using intravenously administered insulin (10 units) and glucose (25 g), inhaled beta agonists or intravenously administered sodium bicarbonate (three ampules in 1 L of 5 percent dextrose).15 Potassium excretion is achieved with sodium polystyrene sulfonate (Kayexalate) and/or diuretics. Sodium polystyrene sulfonate is given orally (25 to 50 g mixed with 100 mL of 20 percent sorbitol) or as an enema (50 g in 50 mL of 70 percent sorbitol and 150 mL of tap water).15 If these measures do not control the potassium level, dialysis should be initiated.

Acidosis is treated with intravenously or orally administered sodium bicarbonate if the serum bicarbonate level is less than 15 mEq per L (15 mmol per L) or the pH is less than 7.2. The amount of supplemental bicarbonate needed is determined on the basis of the bicarbonate deficit equation: bicarbonate deficit (mEq per L) = 0.5 × weight (kg) × (24 – actual serum bicarbonate level).

Sodium bicarbonate ampules are available in two concentrations: 44.6 and 50 mEq per 50 mL. Patients can also be treated orally with sodium bicarbonate tablets (a 300-mg tablet contains 3.6 mEq of sodium bicarbonate), Shohl’s solution in 30-mL doses (1 mEq of sodium bicarbonate per mL) or powdered sodium bicarbonate (Arm and Hammer baking soda provides approximately 50 mEq of sodium bicarbonate per rounded teaspoon). Serum bicarbonate levels and pH should be followed closely. Intractable acidosis requires dialysis.

Because acute renal failure is a catabolic state, patients can become nutritionally deficient. Total caloric intake should be 30 to 45 kcal (126 to 189 kJ) per kg per day, most of which should come from a combination of carbohydrates and lipids. In patients who are not receiving dialysis, protein intake should be restricted to 0.6 g per kg per day. Patients who are receiving dialysis should have a protein intake of 1 to 1.5 g per kg per day.16

Finally, all medications should be reviewed, and their dosages should be adjusted based on the glomerular filtration rate and the serum levels of medications.

 

 

Between 20 and 60 percent of patients require short-term dialysis, particularly when the BUN exceeds 100 mg per dL (35.7 mmol per L of urea) and the serum creatinine level exceeds the range of 5 to 10 mg per dL (442 to 884 μmol per L). Indications for dialysis include acidosis or electrolyte disturbances that do not respond to pharmacologic therapy, fluid overload that does not respond to diuretics, and uremia. In patients with progressive acute renal failure, urgent consultation with a nephrologist is indicated.

 

Diseases of immune system. Allergy: anaphylactic shock, nettle rash,

Quincke’s edema, medicamentous allergy. Secondary immunodeficiencies.

Anaphylaxis is a serious hypersensitivity allergic reaction to the ingestion or injection of a substance (a protein or drug) resulting from prior contact with a substance, that is rapid in onset and may cause death. It typically causes a number of symptoms including an itchy rash, throat swelling, and low blood pressure. Common causes include insect bites/stings, foods, and medications.

 

Angioedema of the face such that the boy cannot open his eyes.

This reaction was caused by an allergen exposure.

On a pathophysiologic level, anaphylaxis is caused by the release of mediators from certain types of white blood cells triggered either by immunologic or non-immunologic mechanisms. It is diagnosed based on the presenting symptoms and signs. The primary treatment is injection of epinephrine, with other measures being complementary.

Worldwide 0.05–2% of people are estimated to have anaphylaxis at some point in their life and rates appear to be increasing. The term comes from the Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.

 

Signs and symptoms

Anaphylaxis typically presents with many different symptoms over minutes or hours with an average onset of 5 to 30 minutes if exposure is intravenous and 2 hours for foods. The most common areas affected include: skin (80–90%), respiratory (70%), gastrointestinal (30–45%), heart and vasculature (10–45%), and central nervous system (10–15%) with usually two or more being involved.

Anaphylaxis may begin with severe itching of the eyes or face and, within minutes, progress to more serious symptoms. These symptoms include swallowing and breathing difficulties, abdominal pain, cramps, vomiting, diarrhea, hives, and angioedema (swelling similar to hives, but the swelling is beneath the skin instead of on the surface).

Anaphylactic shock: A widespread and very serious allergic reaction. Symptoms include dizziness, loss of consciousness, labored breathing, swelling of the tongue and breathing tubes, blueness of the skin, low blood pressure, heart failure, and death. Immediate emergency treatment is required for this type of shock, including administration of antivenom in the case of bee or wasp stings. A sudden, life-threatening allergic reaction, characterized by dilation of blood vessels with a sharp drop in blood pressure and bronchial spasm with shortness of breath. Anaphylactic shock is caused by exposure to a foreign substance, such as a drug or bee venom, to which the individual has been previously exposed. The substances act as antigens, provoking a preliminary immune response during the first exposure that results in a full-blown, immediate response during secondary exposure, called an immediate hypersensitivity reaction. Emergency treatment, including epinephrine injections, must be administered to prevent death. Also called  anaphylaxis.

Skin

Symptoms typically include generalized hives, itchiness, flushing or swelling of the lips. Those with swelling or angioedema may describe a burning sensation of the skin rather than itchiness. Swelling of the tongue or throat occurs in up to about 20% of cases. Other features may include a runny nose and swelling of the conjunctiva. The skin may also be blue tinged because of lack of oxygen.

 

Respiratory

Respiratory symptoms and signs that may be present, including shortness of breath, wheezes or stridor. The wheezing is typically caused by spasms of the bronchial muscles while stridor is related to upper airway obstruction secondary to swelling. Hoarseness, pain with swallowing, or a cough may also occur.

Cardiac

Coronary artery spasm may occur with subsequent myocardial infarction, dysrhythmia, or cardiac arrest. hose with underlying coronary disease are at greater risk of cardiac effects from anaphylaxis. The coronary spasm is related to the presence of histamine-releasing cells in the heart. While a fast heart rate caused by low blood pressure is more common, a Bezold–Jarisch reflex has been described in 10% of cases, where a slow heart rate is associated with low blood pressure. A drop in blood pressure or shock (either distributive or cardiogenic) may cause the feeling of lightheadedness or loss of consciousness. Rarely very low blood pressure may be the only sign of anaphylaxis.

Other

Gastrointestinal symptoms may include crampy abdominal pain, diarrhea, and vomiting. There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine crampsation of blood vessels around the brain may cause headaches. A feeling of anxiety or of “impending doom” has also been described.

Causes

Anaphylaxis can occur in response to almost any foreign substance. Common triggers include venom from insect bites or stings, foods, and medication. Foods are the most common trigger in children and young adults while medications and insect bites and stings are more common in older adults. Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives such as monosodium glutamate and food colors, and topical medications. Physical factors such as exercise (known as exercise-induced anaphylaxis) or temperature (either hot or cold) may also act as triggers through their direct effects on mast cells. Exercise induced events are frequently associated with the ingestion of certain foods. During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes. The cause remains unknown in 32-50% of cases, referred to as “idiopathic anaphylaxis”.

Food

Many foods can trigger anaphylaxis; this may occur upon the first known ingestion. Common triggering foods vary around the world. In Western cultures, ingestion of or exposure to peanuts, wheat, tree nuts, shellfish, fish, milk, and eggs are the most prevalent causes. Sesame is common in the Middle East, while rice and chickpea are frequently encountered as sources of anaphylaxis in Asia. Severe cases are usually caused by ingesting the allergen, but some people experience a severe reaction upon contact. Children can outgrow their allergies. By age 16, 80% of children with anaphylaxis to milk or eggs and 20% who experience isolated anaphylaxis to peanuts can tolerate these foods.

Medication

Any medication may potentially trigger anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs. Other antibiotics are implicated less frequently and the reactions to NSAIDs are agent specific meaning that if one is allergic to one NSAID they can typically tolerate a different one. Other relatively common causes include chemotherapy, vaccines, protamine and herbal preparations. Some medications (vancomycin, morphine, x-ray contrast among others) cause anaphylaxis by directly triggering mast cell degranulation.

The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties. Anaphylaxis to penicillins or cephalosporins only occurs after they bind to proteins inside the body with some agents binding more easily than other. Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of treatment, with death occurring in less than one in every 50,000 courses of treatment. Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons. If someone has a reaction to penicillins their risk of a reaction to cephalosporins is greater but still less than one in 1000. The old radiocontrast agents caused reactions in 1% of cases while the newer lower osmolar agents cause reactions in 0.04% of cases.

Venom

Venom from stinging or biting insects such as Hymenoptera (bees and wasps) or Triatominae (kissing bugs) may induce anaphylaxis in susceptible people. Previous systemic reactions, which are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis; however, half of fatalities have had no previous systemic reaction.

Risk factors

People with atopic diseases such as asthma, eczema, or allergic rhinitis are at high risk of anaphylaxis from food, latex, and radiocontrast but not from injectable medications or stings. One study in children found that 60% had a history of previous atopic diseases, and of those who die from anaphylaxis more than 90% have asthma. Those with mastocytosis or of a higher socioeconomic status are at increased risk. The longer the time since the last exposure to the agent in question the lower the risk.

Pathophysiology

Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems. It is due to the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immunologic reaction but sometimes non-immunologic mechanism.

Immunologic

In the immunologic mechanism, immunoglobulin E (IgE) binds to the antigen (the foreign material that provokes the allergic reaction). Antigen-bound IgE then activates FcεRI receptors on mast cells and basophils. This leads to the release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression. There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.

Non-immunologic

Non-immunologic mechanisms involved substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast medium, opioids, temperature (hot or cold), and vibration.

Diagnosis

Anaphylaxis is diagnosed based on clinical criteria. When any one of the following three occurs within minutes/hours of exposure to an allergen there is a high likelihood of anaphylaxis:

Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure

Two or more of the following symptoms:-

a.     Involvement of the skin or mucosa

b.     Respiratory difficulties

c.      Low blood pressure

d.     Gastrointestinal symptoms

Low blood pressure after exposure to a known allergen.

During an attack, blood tests for tryptase or histamine (released from mast cells) might be useful in diagnosing anaphylaxis due to insect stings or medications. However these tests are of limited utility if the cause is food or if the person has a normal blood pressure, and they are not specific for the diagnosis.

Classification

There are three main classifications of anaphylaxis. Anaphylactic shock is associated with systemic vasodilation that causes low blood pressure which is by definition 30% lower than the person’s baseline or below standard values. Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours with no further exposure to the allergen. Reports of incidence vary, with some studies claiming as many as 20% of cases. The recurrence typically occurs within 8 hours. It is managed in the same manner as anaphylaxis. Pseudoanaphylaxis or anaphylactoid reactions are a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation. Non-immune anaphylaxis is the current term use by the World Allergy Organization with some recommending that the old terminology no longer be used.

 

Allergy testing

Skin allergy testing being carried out on the right arm

 

Allergy testing may help in determining the trigger. Skin allergy testing (such as patch testing) is available for certain foods and venoms. Blood testing for specific IgE can be useful to confirm milk, egg, peanut, tree nut and fish allergies. Skin testing is available to confirm penicillin allergies but is not available for other medications. Non-immune forms of anaphylaxis can only be determined by history or exposure to the allergen in question, and not by skin or blood testing.

Differential diagnosis

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncopy, and panic attacks. Asthma however typically does not entail itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives. Other conditions that may present similarly include: scrombroidosis and anisakiasis.

Post-mortem findings

In a person who died from anaphylaxis, autopsy may show an “empty heart” attributed to reduced venous return from vasodilation and redistribution of intravascular volume from the central to the peripheral compartment. Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion. Laboratory findings could detect increased levels of serum tryptase, increase in total and specific IgE serum levels.

Prevention

Avoidance of the trigger of anaphylaxis is recommended. In cases where this may not be possible, desensitization may be an option. Immunotherapy with Hymenoptera venoms is effective at desensitizing 80–90% of adults and 98% of children against allergies to bees, wasps, hornets, yellowjackets, and fire ants. Oral immunotherapy may be effective at desensitizing some people to certain food including milk, eggs, nuts and peanuts; however adverse effects are common. Desensitization is also possible for many medications, however it is advised that most people simply avoid the agent in question. In those who react to latex it may be important to avoid cross-reactive foods such as avocados, bananas, and potatoes among others.

Management

Anaphylaxis is a medical emergency that may require resuscitation measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring. Administration of epinephrine is the treatment of choice with antihistamines and steroids often used as adjuncts. A period of in hospital observation for between 2 and 24 hours is recommended for people once they have returned to normal due to concerns of biphasic anaphylaxis.

Epinephrine

An old version of an EpiPen auto-injector

 

Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use. It is recommended that an epinephrine solution be given intramuscularly into the mid anterolateral thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response. A second dose is needed in 16-35% of episodes with more than two doses rarely required. The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption. Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.

People on β-blockers may be resistant to the effects of epinephrine. In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.

If necessary, it can also be given intravenously using a dilute epinephrine solution. Intravenous epinephrine however has been associated both with dysrhythmia and myocardial infarction. Epinephrine autoinjector used for self-administration typically in two doses, one for adults or children who weigh more than 25 kg and one for children who weigh 10 to 25 kg.

Adjuncts

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence. A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations and they are not believed to have an effect on airway edema or spasm. Corticosteroids are unlikely to make a difference in the current episode of anaphylaxis, but may be used in the hope of decreasing the risk of biphasic anaphylaxis. Their prophylactic effectiveness in these situations is uncertain. Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine. Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.

Preparedness

People prone to anaphylaxis are advised to have an “allergy action plan”, and parents are advised to inform schools of their children’s allergies and what to do in case of an anaphylactic emergency. The action plan usually includes use of epinephrine auto-injectors, the recommendation to wear a medical alert bracelet, and counseling on avoidance of triggers. Immunotherapy is available for certain triggers to prevent future episodes of anaphylaxis. A multi-year course of subcutaneous desensitization has beenfound effective against stinging insects, while oral desensitization is effective for many foods.[

Prognosis

In those in whom the cause is known and prompt treatment is available, the prognosis is good. Even if the cause is unknown, if appropriate preventative medication is available, the prognosis is generally good. If death occurs, it is usually due to either respiratory (typically asphyxia) or cardiovascular causes (shock), with 0.7–20% of cases causing death. There have been cases of death occurring within minutes. Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.

Epidemiology

The incidence of anaphylaxis is 4–5 per 100,000 persons per year, with a lifetime risk of 0.5–2%. Rates appear to be increasing: incidence in the 1980s was approximately 20 per 100,000 per year, while in the 1990s it was 50 per 100,000 per year. The increase appears to be primarily for food-induced anaphylaxis. The risk is greatest in young people and females.

Currently, anaphylaxis leads to 500–1,000 deaths per year (2.4 per million) in the United States, 20 deaths per year in the United Kingdom (0.33 per million), and 15 deaths per year in Australia (0.64 per million). Mortality rates have decreased between the 1970s and 2000s. In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males. Death from anaphylaxis is most commonly triggered by medications.

History

The term “aphylaxis” was coined by Charles Richet in 1902 and later changed to “anaphylaxis” due to its nicer quality of speech. He was subsequently awarded the Nobel Prize in Medicine and Physiology for his work on anaphylaxis in 1913. The phenomenon itself however has been described since ancient times. The term comes from the Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.

Research

There are ongoing efforts to develop sublingual epinephrine to treat anaphylaxis. Subcutaneous injection of the anti-IgE antibody omalizumab is being studied as a method of preventing recurrence, but it is not yet recommended.

Secondary immunodeficiencies.

Immunodeficiency (or immune deficiency) is a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance.

Immunodeficiencies can be primary or secondary, according to their etiology. Secondary immunodeficiencies result from the adverse consequences of exposure to a variety of factors including infectious agents, drugs, metabolic diseases, and environmental conditions. These conditions may affect the immune function in a manner that varies in presentation and severity, and the restoration of complete immunity is achieved with the improvement of the primary disease or the removal of the offending agent. Secondary immunodeficiencies are far more common than primary immunodeficiencies, which are caused by genetic defects.

Secondary immunodeficiencies affecting the immune system.

 

Most cases of immunodeficiency are acquired (“secondary”) but some people are born with defects in their immune system, or primary immunodeficiency. Transplant patients take medications to suppress their immune system as an anti-rejection measure, as do some patients suffering from an over-active immune system. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone.

By affected component

Humoral immune deficiency, with signs or symptoms depending on the cause, but generally include signs of hypogammaglobulinemia (decrease of one or more types of antibodies) with presentations including repeated mild respiratory infections, and/or agammaglobulinemia (lack of all or most antibody production) which results in frequent severe infections and is often fatal.

T cell deficiency, often causes secondary disorders such as acquired immune deficiency syndrome.

Granulocyte deficiency, including decreased numbers of granulocytes (called granulocytopenia or, if absent, agranulocytosis) such as of neutrophil granulocytes (termed neutropenia). Granulocyte deficiencies also include decreased function of individual granulocytes, such as in chronic granulomatous disease.

Asplenia, where there is no function of the spleen

Complement deficiency is where the function of the complement system is deficient

In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary).

Primary or secondary

Distinction between primary versus secondary immunodeficiencies are based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it.

Primary immunodeficiency (PID)

A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as congenital immunodeficiencies. Many of these disorders are hereditary and are autosomal recessive or X-linked. There are over 80 recognised primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as lymphocytes or granulocytes.

The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) stem cell transplantation.

 

Secondary immunodeficiencies ( Immunosuppression)

Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging and particular medications (e.g. chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids). For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection.

Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly.