Uremic Syndrome : Uremic Syndrome Dr Sharif Zahooruddin
Adjunct Faculty, Department of Nephrology,
Malcolm X College Source:
Author: A Brent Alper Jr, MD, MPH, Associate Professor of Medicine, Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of MedicineCoauthor(s): Rajesh G Shenava, MD, Fellow, Department of Nephrology, Tulane University Medical Center; Bessie A Young, MD, MPH, Associate Professor, Division of Nephrology, Department of Medicine, University of Washington; Director of Home Hemodialysis, Northwest Kidney Center, Seattle Definition : Definition Uremia is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function. Pathophysiology : Pathophysiology Kidney is the site of hormone production and secretion, acid-base homeostasis, fluid and electrolyte regulation, and waste-product elimination. In the presence of renal failure, these functions are not performed adequately and metabolic abnormalities, such as anemia, acidemia, hyperkalemia, hyperparathyroidism, malnutrition, and hypertension, can occur.
Uremia usually develops only after the creatinine clearance falls to less than 10 mL/min, although some patients may be symptomatic at higher clearance levels, especially if renal failure acutely develops. Questions : Questions How many people in the U.S. have chronic kidney disease?
The National Kidney Foundation estimates that about 20 million adults in the U.S. have some degree of chronic kidney disease (CKD). Of these, about 300,000 have Stage 5 CKD, or kidney failure-they are on dialysis or have a glomerular filtration rate (GFR) of less than 15 mL/min. Another 400,000 have Stage 4 CKD (severe), and about 7.5 million are at Stage 3 (moderate). The rest have some kidney damage, but have normal or only mildly reduced kidney function (CKD Stages 1 and 2). Trends in the data show that the numbers of people with CKD are rising. Many people with CKD do not know they have it. Symptoms are normally subtle until late in the course of the disease. With early detection, the course of CKD can usually be slowed.
What is the difference between creatinine clearance, glomerular filtration rate (GFR) and percent kidney function?
All three of these tests measure how well your kidneys are working. Even though they are different, the terms are often used interchangeably.
Creatinine is a waste that healthy kidneys can remove. Creatinine clearance is tested by taking a 24-hour urine sample and a blood sample, and calculating how quickly your kidneys "clear" your blood of creatinine. Another way to determine creatinine clearance is by using an equation that gives an approximate value based on blood creatinine level, height, weight, and age. Creatinine clearance is reported in milliliters per minute (mL/min). For healthy men, a normal creatinine clearance is 97-137 mL/min. For healthy women, a normal creatinine clearance is 88-128 mL/min.
Glomerular filtration rate (GFR) tells how quickly your kidneys are cleaning your blood. GFR is also reported in milliliters per minute. A normal GFR is greater than 90 mL/min.
Percent kidney function is an estimate of how much function the kidneys have left. Because a GFR of 100 milliliters per minute (mL/min) is in the normal range, it is convenient to assume that 100 mL/min is about equal to 100% kidney function. So a creatinine clearance or GFR of 30 mL/min would be called "30% kidney function." Anemia : Anemia Anemia associated with renal failure can be observed when the glomerular filtration rate (GFR) is less than 50 mL/min or when the serum creatinine is greater than 2 mg/dL.
Diabetic patients may experience anemia with a GFR of less than 60 mL/min
characteristically it’s normocytic, normochromic and hypoproliferative Coagulopathy : Coagulopathy The pathogenesis of uremic bleeding tendency is related to multiple dysfunctions of the platelets. The platelet numbers may be reduced slightly, while platelet turnover is increased.
Alterations of platelet adhesion and aggregation are caused by uremic toxins, increased platelet production of NO, PGI(2), calcium and cAMP as well as renal anemia. Correction of uremic bleeding is caused by treatment of renal anemia with recombinant human erythropoietin or darbepoetin alpha, adequate dialysis, desmopressin, cryoprecipitate, tranexamic acid, or conjugated estrogens. Acidosis : Acidosis Metabolic acid-base regulation is controlled primarily by tubular cells located in the kidney, while respiratory compensation is accomplished in the lungs. Failure to secrete hydrogen ions and impaired excretion of ammonium may initially contribute to metabolic acidosis.
In uremia, metabolic acidemia may contribute to other clinical abnormalities, such as hyperventilation, anorexia, stupor, decreased cardiac response (congestive heart failure), and muscle weakness. Hyperkalemia : Hyperkalemia Hyperkalemia (potassium, >6.5 mEq/L) may be an acute or chronic manifestation of renal failure, but regardless of the etiology, a potassium level of greater than 6.5 mEq/L is a clinical emergency.
Hyperkalemia can occur in several instances, which include (1) excessive potassium intake in patients with a creatinine clearance of less than 20 mL/min, (2) hyporeninemic hypoaldosteronism or type IV renal tubular acidosis in patients with diabetes, urinary obstruction, or interstitial nephritis, (3) significant acidemia, or (4) with drug therapy. Hyperkalemia is common when drugs, such as potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene), ACE inhibitors, angiotensin-receptor blockers, beta-blockers, or nonsteroidal anti-inflammatory drugs are used in the setting of renal insufficiency or renal failure. Calcium, parathyroid, and vitamin D abnormalities : Calcium, parathyroid, and vitamin D abnormalities After exposure to the sun, vitamin D-3 is produced in the skin and transported to the liver for hydroxylation (25[OH] vitamin D-3). Hydroxylated vitamin D-3 is then transported to the kidney, where a second hydroxylation occurs, and 1,25(OH)2 vitamin D-3 is formed. As the clinically active form of vitamin D, 1,25(OH)2 vitamin D-3 is responsible for GI absorption of calcium and phosphorus and suppression of PTH. During renal failure, 1,25(OH)2 vitamin D-3 levels are reduced secondary to decreased production in renal tissue as well as hyperphosphatemia, which leads to decreased calcium absorption from the GI tract and results in low serum calcium levels. Hypocalcemia stimulates the parathyroid gland to excrete PTH, a process termed secondary hyperparathyroidism.
The direct deposit of calcium and phosphate in the skin, blood vessels, and other tissue, termed metastatic calcification, can occur when the calcium-phosphate product is greater than 70. Endocrine abnormalities : Endocrine abnormalities Other endocrine abnormalities that may occur in the setting of uremia include changes in carbohydrate metabolism, decreased thyroid hormone excretion, and abnormal sexual hormone regulation. Reduced insulin clearance and increased insulin secretion can lead to increased episodes of hypoglycemia and normalization of hyperglycemia in diabetic patients. Glycemic control may appear to be improved; however, this may be an ominous sign of renal function decline. Consider appropriate decreases in doses of antihyperglycemia medications (ie, insulin and oral antihyperglycemic medications) as renal function declines to avoid hypoglycemic reactions.
Levels of thyroid hormones, such as thyroxine, may become depressed, while reverse triiodothyronine levels may increase because of impaired conversion of triiodothyronine to thyroxine.
Reproductive hormone dysfunction is common and can cause impotence in men and infertility in women. Renal failure is associated with decreased spermatogenesis, reduced testosterone levels, increased estrogen levels, and elevated luteinizing hormone levels in men, all of which contribute to impotence and decreased libido. In women, uremia reduces the cyclic luteinizing hormone surge, which results in anovulation and amenorrhea. Infertility is common and pregnancy is rare in women with advanced uremia and renal failure, but this may be reversed with renal transplantation. Cardiovascular abnormalities : Cardiovascular abnormalities Cardiovascular abnormalities, including uremic pericarditis, pericardial effusions, calcium and phosphate deposition–associated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CRF. Left ventricular hypertrophy is a common disorder found in approximately 75% of patients who have not yet undergone dialysis. Left ventricular hypertrophy is associated with increased ventricular thickness, arterial stiffening, coronary atherosclerosis, and/or coronary artery calcification. Patients are at increased risk for cardiac arrhythmias due to underlying electrolyte and acid-base abnormalities. Renal dysfunction may contribute to associated fluid retention, which may lead to uncontrolled hypertension and congestive heart failure. Malnutrition : Malnutrition Malnutrition usually occurs as renal failure progresses and is manifested by anorexia, weight loss, loss of muscle mass, low cholesterol levels, low BUN levels in the setting of an elevated creatinine level, low serum transferrin levels, and hypoalbuminemia. However, whether uremia stimulates protein catabolism directly remains controversial.4
Comorbid diseases, such as diabetes, congestive heart failure, or other diseases, that require reduced food intake or restrictions of certain foods may contribute to anorexia.
Numerous epidemiologic studies have shown that a decreased serum albumin concentration is a very strong and independent predictor of mortality among dialysis patients. Thus, it is important that dialysis be initiated prior to the occurrence of significant malnutrition. Frequency : Frequency United States
The prevalence of uremia has not been evaluated specifically and is very difficult to ascertain, as most patients start dialysis prior to developing any uremic symptoms. For most patients, this is when the creatinine clearance is less than 10 mL/min or less than 15 mL/min in diabetic patients.The 19th Annual Data Report from the US End-Stage Renal Disease (USRDS) Program entered 106,912 patients during 2005 and had 485,012 prevalent patients; 17,429 transplants were performed, and 143,693 patients had functioning grafts at year’s end. While prevalence rates continue to increase as patients with ESRD are living longer, incidence rates have stabilized at 347 per million, and they have fallen for most people younger than 60 years, except for younger African Americans and Native Americans with diabetic ESRD.
The highest prevalence rate for treated ESRD is reported in Japan, followed by Taiwan and then the United States. Of the world's population with ESRD, 58% live in just 5 countries (ie, United States, Japan, Germany, Brazil, Italy). Clinical Findings : Clinical Findings History
Uremia can occur once the creatinine clearance is below 10-20 mL/min, and it is heralded by the clinical onset of nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, mental status changes, visual disturbances, and increased thirst.
Uremic encephalopathy can progress to seizures, stupor, coma, and, eventually, death.
Patients may report of nonspecific symptoms, which become chronic and progressive over time because of the gradual onset of the disease.
Metabolic abnormalities such as anemia, acidemia, and electrolyte abnormalities are prominent.
Cardiovascular abnormalities such as hypertension, atherosclerosis, valvular stenosis and insufficiency, congestive heart failure, and angina accelerate as renal function declines. These abnormalities may contribute to clinical symptoms of uremia if not treated appropriately.
Diabetic patients may appear to be in better glycemic control but may tend to have more hypoglycemic episodes as renal function declines. This paradoxical improvement in glycemic control is a result of increased insulin secretion and insulin half-life, both of which occur as renal function declines. Clinical Finding continued : Clinical Finding continued Physical
Typical physical findings found in persons with uremia are those associated with fluid retention, anemia, and acidemia. Severe malnutrition can contribute to muscle wasting, while electrolyte abnormalities may cause muscle cramping, cardiac arrhythmias, and mental status changes.
Skin: The classic skin finding in persons with uremia is uremic frost, which is a fine residue thought to consist of excreted urea left on the skin after evaporation of water. The skin may have a velvety appearance and feel, particularly in patients who are pigmented. Patients who are uremic also may have a sallow coloration of the skin due to urochrome, the pigment that gives urine its color. Patients may become hyperpigmented as uremia worsens (melanosis).
Head, ears, eyes, nose, and throat: Sclera may become slightly icteric. The oral pharynx may be dry. Stomatitis may be present. Calcium deposition in the sclera can cause "red eye."
Cardiovascular system: Uremic pericarditis can be associated with a pericardial rub or a pericardial effusion. Increased fluid retention may result in pulmonary edema, peripheral edema, and severe hypertension. Valvular calcification may cause aortic stenosis or accelerate underlying disease.
Lungs: Fluid retention may result in pulmonary edema and corresponding crackles in the lungs. Pleural rubs occur in the setting of uremic lungs.
Gastrointestinal system: Occult GI bleeding may occur. Nausea and vomiting are common in those with severe uremia. Uremic fetor (ammonia or urinelike odor to the breath) also may be present.
Extremities: Fluid retention, pruritus associated with calcium phosphate deposition, and nail atrophy are common in persons with uremia.
Neurologic system: Uremic encephalopathy symptoms include fatigue, muscle weakness, malaise, headache, restless legs, asterixis, polyneuritis, mental status changes, muscle cramps, seizures, stupor, and coma. Amyloid deposits may result in medial nerve neuropathy, carpal tunnel syndrome, or other nerve entrapment syndromes. Differential Diagnoses : Differential Diagnoses Acute Renal FailureHypermagnesemiaAnemiaHyperparathyroidismChronic Renal FailureHyperphosphatemiaDiabetes Mellitus, Type 1HypertensionDiabetes Mellitus, Type 2Hypertension, MalignantDiabetic NephropathyHypoalbuminemiaEncephalopathy, UremicHypocalcemiaGlomerulonephritis, AcuteIgA NephropathyGlomerulonephritis, ChronicIron Deficiency AnemiaGlomerulonephritis, Rapidly ProgressiveMetabolic AcidosisHyperchloremic AcidosisPericardial EffusionHyperkalemiaPleural Effusion Staging : Staging Staging is determined by the GFR (creatinine clearance). Currently, the National Kidney Foundation no longer recognizes the terms chronic renal insufficiency (CRI) or CRF, but rather it recognizes the 5 stages of CKD based on the estimated GFR (eGFR), as calculated by the MDRD formula.
Stage 1 - Kidney damage with normal GFR, 90 mL/min or greater
Stage 2 - Kidney damage with a mild decrease in GFR, 60-89 mL/min
Stage 3 - Kidney damage with a moderate decrease in GFR, 30-59 mL/min
Stage 4 - Kidney damage with a severe decrease in GFR, 15-29 mL/min
Stage 5 - End-stage renal disease, less than 15 mL/min or on dialysis Lab work up : Lab work up Laboratory Studies
The diagnosis of renal failure is primarily based on an abnormal GFR or creatinine clearance, usually evident due to an elevated serum creatinine level. GFR determination can be accomplished by 24-hour urine collection for creatinine clearance, although this is often cumbersome and inaccurate due to improper collection. All patients with an abnormal creatinine clearance should have their GFR estimated using one of several formulas that use easily obtained values. These include the Modification of Diet in Renal Disease (MDRD) formula or the Cockcroft-Gault formula. Both formulas have been shown to provide similar values within a wide range of patient ages and to be accurate in those with renal insufficiency, regardless of race or sex.
It is very important to determine if the renal failure is acute or chronic, as acute renal failure will likely be reversible if treated properly. Review of the patient's history as well as previous laboratory values can be very helpful in this regard.
Other laboratory tests to consider for abnormalities prevalent with clinical uremia include hemoglobin, calcium, phosphate, PTH, albumin, potassium, and serum bicarbonate values.
Urinalysis with microscopic examination should be performed on all patients to evaluate for the presence of protein, cellular casts, oval fat bodies, ketones, hemoglobin, myoglobin, and pH.
A renal ultrasound study is indicated to estimate the size of the kidneys and to evaluate for hydronephrosis or obstruction.
Hydronephrosis can occur with ureteral or bladder obstruction, retroperitoneal fibrosis, massive abdominal tumors due to cervical or prostate cancers, and other structural abnormalities.
Renal ultrasound is performed to determine the size and shape of the kidneys; large kidneys are associated with diseases, such as early diabetic nephropathy, multiple myeloma, polycystic kidney disease, or HIV associated glomerulonephritis, while small kidneys usually indicate chronic, irreversible damage from diseases, such as hypertensive nephrosclerosis, ischemic nephropathy, or any other long-standing kidney disease.
CT scan of the abdomen may be indicated to rule out retroperitoneal fibrosis, pelvic masses, lymphadenopathy, or lymphoma if bilateral hydronephrosis is found on ultrasound images and no obvious etiology is present (eg, stone, bladder mass, ureteral mass).
MRI arteriograms can be used to assess the kidneys for renal artery stenosis, acute arterial thrombosis, or aortic dissection involving the aorta and renal arteries. It is important to consider renal artery stenosis in the differential because it is one cause of renal failure that is potentially reversible by angioplasty or bypass surgery of the affected renal artery.
Consider a brain CT scan in the event of a significant change in mental status, especially if the change occurs after a fall or in association with mild trauma. Spontaneous subdural hematomas occur in patients with uremia, particularly if the BUN level is greater than 150-200 mg/dL. Labs continued : Labs continued Other Tests
Nuclear medicine radioisotope (iothalamate) clearances can also be obtained and are the criterion standard for measuring GFR. However, this test is time-consuming and more expensive than estimating GFR using either the MDRD formula or the Cockcroft-Gault formula.
To make an accurate diagnosis of ARF or CRF, a renal biopsy is necessary. However, if the renal failure has been slowly progressive and the kidneys are small, renal biopsy results are of little benefit. In the setting of rapidly progressive renal failure or ARF for which the etiology is not known, a renal biopsy is indicated to determine if potentially reversible or treatable renal disorders are present.
Histologic findings vary depending on the underlying etiology. However, in the setting of late stage CKD and uremia in which renal function has deteriorated over a prolonged period and the kidneys are relatively small, renal biopsy results may show significant glomerulosclerosis and obsolescent glomeruli (completely scarred and sclerosed) with significant interstitial fibrosis. These findings are nonspecific and do not aid in determining the underlying cause of renal failure. In the setting of uremia, performing a renal biopsy in a patient with small kidneys may be dangerous because of comorbid disease and the increased risk of bleeding. Consider this procedure if a reversible cause of renal function is in the differential. Follow up : Follow up Further Inpatient Care
Inpatient care is required when patients have a uremic emergency, such as hyperkalemia, hypervolemia, acidosis, pericardial effusion with symptoms, and uremic encephalopathy; these patients require emergent dialysis.
Initiate dialysis gently (2-h initial session) to avoid dialysis disequilibrium syndrome, but dialysis should be long enough to remove potassium if dialysis is being initiated for this reason.
Therapy should be initiated with the care and oversight of a nephrologist and may need to occur in the intensive care unit if the patient is unstable or has cardiac abnormalities secondary to acidemia or hyperkalemia.
Further Outpatient Care
Continue outpatient care under the direction of the consulting nephrologist. Outpatient care may include initiation of chronic renal replacement therapy such as peritoneal dialysis or hemodialysis. Patients with renal failure and uremia should also be considered for transplantation using a living, related donor; a living, nonrelated donor; or a cadaveric donor.
Inpatient & Outpatient Medications
Inpatient medications include medications necessary for emergent treatment of underlying disorders associated with uremia (emergent treatment of hyperkalemia, acidosis, and hypocalcemia).
Outpatient medications include EPO for anemia, iron, phosphate binders, calcitriol for PTH suppression and hypocalcemia, water-soluble vitamins (eg, folate, vitamin C), and, potentially, oral bicarbonate solution or tablets for acidosis.
Consider transferring patients to centers with dialysis capabilities if a nephrologist and/or dialysis facilities are not available to assist with management and potential interventions if necessary. Follow up continued : Follow up continued Deterrence/Prevention
Avoid nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, renal toxic aminoglycoside antibiotics, and other potential renal toxins.
N -acetyl-cystine can be administered before and after radiologic imaging that requires intravenous contrast (eg, CT scan, renal angiogram, intravenous pyelogram) to avoid nephrotoxicity. However, consider an alternative method of imaging (eg, ultrasound, MRI) in this setting to avoid ARF, particularly in patients with diabetes.
Severe complications of untreated uremia include seizure, coma, cardiac arrest, and death.
Spontaneous bleeding can occur with severe uremia and may include GI bleeding, spontaneous subdural hematomas, increased bleeding from any underlying disorder, or bleeding associated with trauma.
Cardiac arrest may occur from severe underlying electrolyte abnormalities such as hyperkalemia, metabolic acidosis, or hypocalcemia.
Severe hypoglycemic reactions may occur in diabetic patients if hyperglycemic medications are not adjusted for their decreased creatinine clearance.
Renal failure associated bone disease (renal osteodystrophy) may lead to an increased risk of osteoporosis or bone fracture with trauma.
Medication clearance is decreased in persons with renal failure and may lead to untoward adverse effects, such as a digoxin overdose, an increased sensitivity to narcotics, and a decreased excretion of normal medications.
The prognosis for patients with uremia of CRF is poor unless the uremia is treated with renal replacement therapy such as dialysis or transplantation.
The prognosis for ARF and renal failure secondary to a reversible or treatable cause, such as rapidly progressive glomerulonephritis (eg, lupus nephritis, Wegener disease, Goodpasture disease, thrombotic thrombocytopenic purpura, hemolytic uremia syndrome, multiple myeloma), depends on the timing of diagnosis and the rapidity of appropriate treatment (eg, steroids, chemotherapeutic agents, plasmapheresis).
Patients should be sent to the nephrologist early for education regarding renal disease and renal replacement therapy options and for evaluation and diagnosis of their underlying renal disease process.
Inform diabetic patients about potential changes in insulin or oral hypoglycemic medication needs.
Inform patients and their families regarding dialysis to avoid the shock of emergent dialysis and the decreased quality of life that occurs with this disease. Special Concerns : Special Concerns Pregnant patients with uremia require specialized evaluation and treatment; in this situation, seek immediate consultation with a specialist. Pregnant women should be under the care of an obstetrician who specializes in the care of high-risk pregnancies. A nephrologist should also be consulted to help with hypertension control and the potential need for dialysis during the pregnancy. Medications contraindicated in pregnancy, such as ACE inhibitors, should be immediately discontinued.
Pediatric patients also require special consideration. A pediatric nephrologist or adult nephrologist experienced in the care of pediatric nephrology patients should be involved with the care of children with proteinuria, renal insufficiency, or uremia or with children in whom dialysis is indicated.