Patients are usually asymptomatic until kidney failure is advanced. When the GFR falls to approximately 10–15 mL/minute, nonspecific symptoms such as general malaise, weakness, insomnia, inability to concentrate, and nausea and vomiting begin to appear. Eventually other symptoms and signs that reflect generalized organ dysfunction develop as part of the uremic syndrome (Table 17–2).
Table 17–2. Clinical and Laboratory Manifestations of the Uremic Syndrome. ||Download (.pdf)
Table 17–2. Clinical and Laboratory Manifestations of the Uremic Syndrome.
Paleness and hyperpigmentation
Echymosis and hematomas
Skin necrosis (calciphylaxis)
Volume overload and systemic hypertension
Accelerated atherosclerosis and ischemic heart disease
Left ventricular hypertrophy
Peripheral and autonomic neuropathy
Nausea and vomiting
Inflammatory and ulcerative lesions
Leukocyte and immune system dysfunction (tendency to infections)
Platelet dysfunction (bleeding diathesis)
Growth retardation in children
Amyloid arthropathy secondary to
Infertility in women
Glucose intolerance due to insulin resistance
Hyponatremia (if excessive water intake)
The skin is often pale (due to anemia) and hyperpigmented [due to increased production of β-melanocyte-stimulating hormone (β-MSH) and retention of carotenes and urochromes]. Pruritus is common and can be accompanied by scratching lesions. Ecchymoses and hematomas are often seen as a result of bleeding diathesis. Uremic frost is a fine white powder visible on the skin surface that results from crystallization of urea after sweat evaporates; it is now uncommon because of earlier initiation of dialysis. Other infrequent but clinically important abnormalities include skin necrosis due to vessel calcification (calciphylaxis) and bullous lesions.
Cardiovascular manifestations are the most common cause of morbidity and mortality among patients with progressive CKD and include volume overload, edema, systemic hypertension, ischemic heart disease, left ventricular hypertrophy, heart failure, rhythm disturbances, and uremic pericarditis. Systemic hypertension is primarily due to volume overload; other contributing factors are hyperreninemia and erythropoietin therapy. Patients with chronic kidney failure (CKF) have accelerated atherosclerosis due to a high prevalence of “traditional” (ie, hypertension and hyperlipidemia) and “nontraditional” risk factors (those associated with the hemodynamic and metabolic abnormalities of CKF, such as volume overload, anemia, glucose intolerance, and hyperparathyroidism). Left ventricular hypertrophy is seen in 65–75% of patients with advanced CKF, and both arterial hypertension and anemia contribute to its development. Heart failure is usually multifactorial, with volume overload, hypertension, anemia, ischemic heart disease, and uremic cardiomyopathy as the main contributing factors. Rhythm disturbances are often precipitated by electrolyte abnormalities, metabolic acidosis, calcification of the conduction system, ischemia, and myocardial dysfunction. Uremic pericarditis occurs in 6–10% of patients with advanced uremia, just before initiation of dialysis or immediately after; it is associated with high blood urea levels (>60 mg/dL) and hemorrhagic pericardial effusion is seen in at least 50% of cases.
Cerebrovascular accidents are common in these patients due to accelerated atherosclerosis. Uremic encephalopathy occurs in patients with advanced uremia and is characterized by insomnia, sleep pattern changes, inability to concentrate, memory loss, confusion, disorientation, emotional lability, anxiety, depression, and occasionally hallucinations. Without treatment, the encephalopathy progresses to generalized seizures, coma, and death. Other manifestations may include dysarthria, tremor, and myoclonic movements, and in advanced stages, hyperreflexia, clonus, and the Babinsky sign. The electroencephalogram shows diffuse slowing of cortical activity. Dialysis improves most of the manifestations of uremic encephalopathy. Another complication is peripheral neuropathy, which typically presents insidiously as a mixed symmetric polyneuropathy of the lower extremities. It may also affect the upper extremities but only after the lower extremities have been involved. Sensory abnormalities include the restless leg syndrome and a burning sensation on the feet, which may be severe enough to prevent ambulation. Motor abnormalities occur after the sensory abnormalities and include extremity weakness, unsteady gate, decreased deep tendon reflexes, and occasionally paraparesis and even paralysis. Autonomic nerves can also be affected, which may result in orthostatic hypotension, sweating abnormalities, impotence, and an abnormal response to the Valsalva maneuver.
Anorexia, nausea, and vomiting are typical manifestations of advanced kidney failure. Anorexia usually occurs earlier, can be intermittent, and is occasionally referred to some types of food such as meat. Nausea initially presents predominantly in the morning. The combination of these symptoms together with abnormalities in protein and energy metabolism, other comorbid conditions (ie, gastroparesis in diabetic patients), and side effects of medications often leads to malnutrition. Uremic fetor is a uriniferous odor of the breath that results from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Other manifestations include a higher frequency of inflammatory and/or ulcerative lesions at all levels of the digestive tract and of gastrointestinal bleeding.
A normochromic, normocytic anemia almost invariably develops in patients with CKF. It is mainly due to deficiency in the production of erythropoietin by the diseased kidneys. Other factors may also contribute, including hyporesponsiveness of progenitor cells to erythropoietin, accelerated hemolysis secondary to uremia, vitamin deficiencies (ie, folic acid), and iron losses associated predominantly with gastrointestinal bleeding. The white blood cell count is usually normal and increases in response to infections; however, leukocyte and immune system functions are abnormal, which predisposes to more frequent and severe infections. The platelet count is also normal, but function is abnormal, which results in a prolonged bleeding time and a tendency to bleed.
The term renal osteodystrophy refers to various types of bone lesions that occur in patients with progressive CKD as a result of abnormalities in calcium and phosphorus metabolism. The lesions include secondary hyperparathyroidism, osteomalacia, adynamic bone disease, and growth retardation in children. Subcutaneous, vascular, joint, and visceral calcifications are also seen in patients with poorly controlled calcium-phosphate product. Although secondary hyperparathyroidism is the most common type of renal osteodystrophy, patients often have a predominant lesion or a combination of mixed lesions. Although close to 100% of patients have abnormalities in bone biopsy, radiologic abnormalities are found in only 40% of patients, and clinical manifestations, such as bone pain or fractures, in less than 10% of patients. Renal osteodystrophy can be prevented or attenuated with appropriate management of calcium and phosphate metabolism.
Endocrine and Metabolic Manifestations
Sexual dysfunction is common in patients with progressive CKD. Impotence, infertility, and decreased libido occur as a result of primary hypogonadism. Hyperprolactinemia also contributes to amenorrhea and galactorrhea in women. Total T4
and T3 and free T3 may be low, but free T4, reverse T3, and thyroid-stimulating hormone (TSH) are normal, suggesting a normal thyroid state. In early CKD, there is insulin resistance and glucose intolerance (azotemic pseudodiabetes), whereas in advanced CKD hypoglycemic episodes are common due to the longer half-life of insulin secondary to decreased renal catabolism and to decreased renal gluconeogenesis. Lipid abnormalities include elevated triglycerides and very low-density lipoprotein (VLDL) and decreased high-density lipoprotein (HDL); total cholesterol is normal and lipoprotein A may be elevated. Abnormalities of protein metabolism include decreased synthesis and increased catabolism.
In addition to an elevated blood urea nitrogen (BUN) and serum creatinine, which are a reflection of a decreased GFR, patients with progressive CKD develop other laboratory abnormalities, particularly if they do not comply or are not given appropriate dietary instructions as the GFR declines. Typical abnormalities include hyponatremia (due to excessive water intake), hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, and hyperuricemia. Metabolic acidosis, usually with an elevated anion gap, is also common (Table 17–2). With the exception of hypocalcemia, these fluid and electrolyte disturbances result from an imbalance between intake and output by the progressively diseased kidneys.
Renal ultrasound is particularly helpful for diagnosing some cases of CKD [ie, polycystic kidney disease (PKD), obstructive uropathy] and for distinguishing acute from chronic kidney disease. The presence of symmetrically small (<8.5 cm) kidneys supports the diagnosis of CKD, whereas the occurrence of normal-sized kidneys favors an acute rather than a chronic process. There are exceptions, however, as some causes of CKD are associated with normal-sized or even enlarged kidneys, including diabetes, PKD, and amyloidosis. Other imaging studies may help determine the cause of CKD. Duplex Doppler ultrasound of the renal arteries, renal scintigraphy, and magnetic resonance angiography are useful in patients in whom renovascular ischemic disease is suspected. Voiding cystourethrography is helpful to rule out reflux nephropathy. Computed tomography allows for assessment of kidney stone activity and for evidence of papillary necrosis.
Kidney biopsy should be reserved for patients with near-normal kidney size, in whom a clear-cut diagnosis cannot be made by less invasive means, and when a potentially treatable cause is suspected.