Uremia

Continuing Education Activity

Uremia is a clinical condition associated with worsening renal function. It is characterized by fluid, electrolyte, hormonal, and metabolic abnormalities. Uremia most commonly occurs in the setting of chronic and end-stage renal disease but may also occur due to acute kidney injury. This activity reviews the evaluation and management of uremia and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Identify the leading causes of uremia.
• Describe the pathophysiology of uremia.
• Summarize the evaluation of a patient with suspected uremia.
• Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of uremic patients.

Introduction

Uremia, a clinical condition associated with worsening renal function, is characterized by fluid, electrolyte, hormone imbalances, and metabolic abnormalities. The literal meaning of uremia is "urine in the blood," which develops most commonly in chronic and end-stage renal disease (ESRD). Still, it may also occur due to acute kidney injury if loss of kidney function happens rapidly. Urea itself is both directly and indirectly toxic to a range of tissues.[1] For instance, neurological complications also occur with uremia, and polyneuropathy is a common manifestation of uremia, especially when treatment with renal replacement therapy is started too late.[2]

Patients with uremia generally present with nausea, vomiting, fatigue, anorexia, muscle cramps, pruritus, and altered mentation.[3][4] There could also be other signs and symptoms, such as increased thirst and visual changes. Uremia can lead to various cutaneous abnormalities, such as changes in skin color, xerosis, pruritus, hair, nail, and oral changes, bullous dermatosis, and metastatic calcinosis. These manifestations affect a patient's quality of life considerably. Early recognition of skin changes and prompt management initiation can dramatically alter the course of illness and decrease morbidity.[5]

Putative uremic toxins include parathyroid hormone, macroglobulin, advanced glycosylation end products, and beta2 microglobulin, though no specific uremic toxin has been identified as responsible for all clinical manifestations of uremia.[6][7][8]

Etiology

Uremia can result from some conditions ranging from primary renal disorders, for example, IgA nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, polycystic kidney disease) to systemic disorders that can lead to renal damage. Systematic disorders can include diabetes mellitus, systemic lupus erythematosus, multiple myeloma, amyloidosis, Goodpasture disease, thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome.

The leading cause of ESRD in the United States is diabetes accounting for 40% of new dialysis patients. Additional causes, listed in order of decreasing incidence, include hypertension, glomerulonephritis, interstitial disease, cystitis, and neoplasms. Diabetes is the leading cause of kidney failure worldwide; however, glomerulonephritis is the more predominant underlying cause in developing countries.

Uremia may also result from acute kidney injury if the injury involves a sudden increase in urea or creatinine.[9][10][11]

Epidemiology

It is difficult to determine the exact prevalence of uremia in the United States because patients with ESRD typically begin dialysis before developing uremic symptoms. Uremic symptoms typically arise once creatinine clearance is less than 10mL/min or 15mL/min in the case of diabetic patients. According to the United States Renal Data System (USRDS) 2009 data, the incidence and prevalence of advanced chronic kidney disease in the United States were reported to be 354 and 1665 per million people per year. In 2009, 116,395 patients started renal replacement therapy, accounting for an unadjusted incidence of 371 per million.[12] This number continues to rise as the life expectancy of those with ESRD is increasing. Improved survival in patients with diabetes or cardiovascular disease, in addition to increased access to renal therapy, has resulted in the highest increase in the incidence of ESRD in patients aged 75 years or above. On the other hand, the number of individuals under 60 with ESRD is declining, except for African American or Native American patients with diabetic ESRD.

Japan has the highest prevalence of end-stage renal disease patients in the world, followed by Taiwan.[13] Of the world's patients with ESRD, 58% are in just five countries, the United States, Japan, Brazil, Germany, and Italy.[14]

The majority of patients with ESRD are Whites (59.8%), and the remainder is African American (33.2%), Asian (3.6%), or Native American (1.6%). However, the incidence of ESRD among Black individuals is 3.7 times higher than the white population. Similarly, the incidence among Native Americans is 1.8 times greater than it is among whites.

Additionally, minority populations tend to initiate dialysis care later in the course of renal disease; usually once there is a significant decline in the glomerular filtration rate (GFR). It is unknown, however, whether racial or ethnic background affects predisposition to developing uremic symptoms.

Men are 1.2 times more likely than women to develop ESRD, though women are 1.7 times more likely to delay the initiation of dialysis. Women are also more prone to developing uremic symptoms at lower creatinine levels due to the decreased amount of muscle mass and baseline serum creatinine levels.[15][16][17]

Pathophysiology

When the kidneys are not functioning correctly, dysfunction can occur in acid-base homeostasis, fluid and electrolyte regulation, hormone production and secretion, and waste elimination. Altogether, these abnormalities can result in metabolic disturbances and conditions such as anemia, hypothyroidism, hypertension, acidemia, hyperkalemia, and malnutrition.

Anemia associated with kidney disease is typically normocytic, normochromic, and hypoproliferative. It occurs as a result of decreased erythropoietin production by the failing kidneys. This is associated with a glomerular filtration rate (GFR) of less than 50 mL/min (unless the patient has diabetes, then they may have anemia at GFR less than 60mL/min) or when serum creatinine is greater than 2 mg/mL. In a study of 832 patients with diabetes, it was observed that 334 patients had anemia, which was higher than that reported in ambulatory patients. Additionally, 39% of the anemic patients had kidney failure.[18] Additional factors associated with chronic kidney disease alone may further contribute to the development of anemia. These include iron or vitamin deficiencies, hyperparathyroidism, hypothyroidism, or a decreased lifespan of red blood cells. Studies have revealed that hepcidin, an acute-phase protein, is involved with iron metabolism and plays a crucial role in erythropoiesis. In states of inflammation, hepcidin is up-regulated and prevents iron absorption from the small intestine and iron release from macrophages.[19]

The buildup of uremic toxins in the blood may additionally contribute to the development of coagulopathy as a result of reduced platelet adhesion to the vascular endothelial wall, increased platelet turnover, and a slightly reduced absolute number of platelets.[20] A common finding in patients with ESRD is bleeding diathesis, increased susceptibility to bleeding, and hemorrhage.

Another major metabolic complication associated with uremia and ESRD is acidosis because renal tubular cells are the body's primary regulators of acid-base homeostasis. As kidney failure progresses, there is decreased secretion of hydrogen ions, impaired excretion of ammonium, and, eventually, a buildup of phosphate and other organic acids (e.g., lactic acid, sulfuric acid, and hippuric acid). In turn, increased anion-gap metabolic acidosis may lead to hyperventilation, lethargy, anorexia, muscle weakness, and congestive heart failure (due to a decreased cardiac response).

Hyperkalemia may also occur in acute or chronic renal failure settings. This condition becomes a medical emergency when serum potassium reaches a level greater than 6.5 mEq/L. This level may be exacerbated with excessive potassium intake or use of certain medications (e.g., potassium-sparing diuretics, angiotensin-converting enzymes (ACE) inhibitors, angiotensin-receptor blockers, beta-blockers, NSAIDs, etc.).[21] Acidosis resulting from renal failure may additionally contribute to the development of hyperkalemia.

Hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels may also occur due to renal failure. Hypocalcemia occurs due to decreased production of active vitamin D (1,25 dihydroxyvitamin D), responsible for gastrointestinal (GI) absorption of calcium and phosphorus and suppression of parathyroid hormone excretion. Hyperphosphatemia occurs because of impaired phosphate excretion in the setting of renal failure. Both hypocalcemia and hyperphosphatemia stimulate hypertrophy of the parathyroid gland and increase the production and secretion of parathyroid hormone. Altogether, these changes in calcium metabolism can result in osteodystrophy (renal bone disease) and may lead to calcium deposition throughout the body (i.e., metastatic calcification).[22]

Declining renal function can result in decreased insulin clearance, necessitating a decrease in the dosage of antihyperglycemic medications to avoid hypoglycemia. Uremia may also lead to impotence in men or infertility (e.g., anovulation, amenorrhea) in women due to dysfunctional reproductive hormone regulation.

The buildup of uremic toxins may also contribute to uremic pericarditis and pericardial effusions, leading to abnormalities in cardiac function. Together with metastatic calcification resulting from declining renal function, these may contribute to worsening underlying valvular dysfunction or suppression of myocardial contractility.[23][24]

History and Physical

Symptomatic uremia tends to occur once creatinine clearance decreases below 10-20 mL/min unless kidney failure develops acutely, in which case, some patients may become symptomatic at higher clearance rates. Patients with uremia typically complain of nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus, or changes in mental status. The clinical presentation of uremia can be explained by the metabolic disturbances associated with the condition. Fatigue resulting from anemia is considered one of the significant components of uremic syndrome. Patients with a history of diabetes may report improved glycemic control but are at a greater risk of developing hypoglycemic episodes as kidney function worsens. Diagnosis of uremia in young children may be difficult because of the nonspecificity of clinical manifestations.

Hypertension, atherosclerosis, valvular stenosis and insufficiency, chronic heart failure, and angina may all develop due to a buildup of uremic toxins and metastatic calcification associated with uremia and ESRD. These abnormalities may play a role in the clinical manifestations of uremia if treatment is not started timely. Occult GI bleeding resulting from platelet abnormalities may present with nausea or vomiting. Uremic fetor, ammonia, or urine-like odor of the breath may also occur in uremic patients.[25]

Uremia can affect the central nervous system causing uremic encephalopathy, which presents with fatigue, muscle weakness, malaise, restless legs, headache, asterixis, polyneuritis, muscle cramps, mental status changes, seizures, stupor, and coma.[26] Amyloid deposits could result in medial carpal tunnel syndrome, nerve neuropathy, or other nerve entrapment syndromes.

Typical physical findings on examination in patients with uremia are those associated with anemia, fluid retention, and acidemia. In addition, severe malnutrition may result in muscle wasting, while electrolyte abnormalities could lead to muscle cramping, mental status changes, and cardiac arrhythmias. The following are some commonly seen examination findings in patients with uremia:

• Uremic frost[27]
• Mild icterus
• Gingival hyperplasia, petechiae, enamel hypoplasia, or gingival bleeding[28]
• Pericardial rub
• Pulmonary edema
• Peripheral edema
• Severe hypertension

Evaluation

A diagnosis of renal failure is based on abnormalities in GFR or creatinine clearance.[29] It is essential to determine whether a patient presenting with uremic symptoms is experiencing acute or chronic renal failure, as acute kidney injury is reversible. Laboratory studies to evaluate for abnormalities in hemoglobin, calcium, phosphate, parathyroid hormone, albumin, potassium, and bicarbonate, in addition to urinalysis (with microscopic examination), will help point toward any potential abnormalities.

A 24-hour urine collection may provide insight into GFR and creatinine clearance, though this method is both burdensome and often inaccurate. Alternatively, a nuclear medicine radioisotope (iothalamate) clearance assay may be used to measure GFR. However, this test is also time-consuming and expensive relative to the Cockcroft-Gault formula [creatinine clearance = Sex times ((140 - Age) / (serum creatinine)) times (weight / 72)] or the Modification of Diet in Renal Disease formula [(GFR (mL/min/1.73 m) = 175 x (S) times (Age) times (0.742 if female) or times (1.212 if African American)] that are often used instead.

As per the National Kidney Foundation, patients presenting with chronic kidney disease are staged based on the estimated GFR (creatinine clearance) as calculated by the Modification of Diet in Renal Disease formula.

• Stage 1 – normal GFR (90 mL/min or greater)
• Stage 2 – mildly reduced GFR (60 mL/min to 90 mL/min)
• Stage 3 – moderately reduced GFR (30 mL/min to 59 mL/min)
• Stage 4 – severely reduced GFR (15 mL/min to -29 mL/min)
• Stage 5 – ESRD (GFR < 15 mL/min or patient is on dialysis)

A renal ultrasound may be helpful to determine the size and shape of the kidneys and to evaluate for hydronephrosis or ureteral and/or bladder obstruction. This may result from kidney stones, neurologic abnormalities, trauma, pregnancy, prostate enlargement, retroperitoneal fibrosis, abdominal tumors (secondary to cervical or prostate cancers), or additional structural abnormalities. Early diabetic nephropathy, multiple myeloma, polycystic kidney diseases, and glomerulonephritis associated with human immunodeficiency virus (HIV) are all associated with enlarged kidneys on ultrasound.[30] Smaller kidneys indicate more chronic, irreversible changes resulting from long-standing kidney disease, ischemic nephropathy, or hypertensive nephrosclerosis.

Measuring the excretion of proteins in a patient's urine could also help clinch the diagnosis, as glomerulopathies are not an uncommon cause of ESRD. There is increasing evidence to support that the changes in dipstick proteinuria are an independent predictor of ESRD. Changes in proteinuria over two years may be relevant for the risk prediction of ESRD.[31]

A brain computed tomography (CT) scan may be warranted if a patient presents with significant alterations in mental status. Uremic patients with a blood urea nitrogen (BUN) level greater than 150 mg/dL to 200 mg/dL are also at an increased risk of developing spontaneous subdural hematomas. Given the increased risk of bleeding and hemorrhage in uremia (especially in the setting of a fall or trauma), a CT scan of the brain and abdomen may also be considered. In addition, an abdominal CT scan might help further elucidate the underlying cause of hydronephrosis if it was found on ultrasound without any obvious etiology.

Finally, magnetic resonance imaging (MRI) may be considered to assess for renal artery stenosis, thrombosis, or aortic and renal artery dissection - all potentially reversible causes of renal failure.

A renal biopsy may help determine the reversibility or treatability of the renal injury. It may ultimately be required to diagnose acute kidney injury or chronic kidney disease accurately. However, a biopsy should not be performed in the case of small kidneys because of the associated comorbidities and increased risk of bleeding.[32]

Treatment / Management

Dialysis is indicated for a patient with symptomatic uremia (e.g., nausea, vomiting, refractory hyperkalemia, metabolic acidosis, etc.) that is not treatable by medical means. It should be initiated as soon as possible, regardless of the patient’s GFR.[33][34][35]

Patients presenting with a uremic emergency (e.g., hyperkalemia, acidosis, symptomatic pericardial effusion, or uremic encephalopathy) require emergent dialysis, which should be initiated gently to avoid dialysis disequilibrium syndrome. These are neurologic symptoms secondary to cerebral edema occurring during or shortly after the initiation of dialysis.

The best renal replacement therapy is renal transplantation, although practitioners may consider long-term hemodialysis and peritoneal dialysis. Renal transplantation is associated with improvements in both survival and quality of life.[36] It should be considered early (before the need for dialysis) as the waiting list for transplantation is often longer than two to three years.

Iron replacement should be initiated in patients with anemia of chronic kidney disease and underlying iron deficiency (as long as serum ferritin is greater than 100 mcg/mL). This can be done with dialysis treatments or oral therapy if dialysis has not yet been initiated. Erythropoiesis-stimulating agents, such as erythropoietin or darbepoetin, may additionally be used in low doses (due to the increased risk of cardiovascular mortality) once hemoglobin levels reach below 10 g/dL.[37]

Hyperparathyroidism and associated or isolated hypocalcemia and hyperphosphatemia can be treated with oral calcium carbonate or calcium acetate, oral vitamin D therapy, and oral phosphate binders (e.g., calcium carbonate, calcium acetate, sevelamer or lanthanum carbonate).[38]

Patients with uremia secondary to urinary obstruction should undergo Foley catheterization to relieve the obstruction. Afterward, the cause of obstruction should be looked into, and a permanent management plan should be sorted.

A dietitian should be consulted if dietary alterations are being considered. Patients with chronic kidney disease should reduce potassium, phosphate, and sodium intake to 2 g to 3 g, 2 g, and 2 g per day, respectively. Though there is some conflicting evidence regarding protein intake in patients with kidney failure, the current low-protein diet recommendations before initiation of dialysis are 0.8 g to 1 g of protein/kg of weight per day with an added gram of protein for each gram of protein lost in the urine in patients with nephrotic syndrome.[39]

A low-protein diet is not recommended in patients with advanced uremia or malnutrition, as this type of diet can result in worsening malnutrition and has been associated with an increased risk of mortality with the initiation of dialysis.

Patients with a creatinine clearance of less than 20 mL/min should avoid excessive potassium intake and use certain medications with caution (e.g., potassium-sparing diuretics, angiotensin-converting enzymes (ACE) inhibitors, angiotensin-receptor blockers, beta-blockers, NSAIDs, etc.).

Due to the buildup of uremic toxins and potentially increased risk of bleeding and hemorrhage, extra care must be taken when prescribing oral anticoagulants or antiplatelet medications to ESRD patients.

Finally, nephrotoxic medications, such as NSAIDs and aminoglycoside antibiotics, should be avoided in all patients with renal disease. N-acetylcysteine may be administered before administering intravenous contrast for radiologic imaging to avoid nephrotoxicity. However, alternative modes of imaging like MRI should be considered in these patients to avoid the risk of acute kidney injury altogether.[40]

Differential Diagnosis

Undertake an evaluation for the underlying cause of kidney disease if the etiology is unclear. Slowly declining renal function and uremia may be seen in a patient with bilateral renal artery stenosis using ACE inhibitors or ARBs. Other conditions in the list of differential diagnoses of uremia include:

• Diabetic nephropathy
• Acute glomerulonephritis
• Chronic kidney disease
• Hypertensive renal disease
• Renal artery stenosis
• Obstruction due to an enlarged prostate
• Hyperchloremic acidosis
• Hyperkalemia
• Hypermagnesemia
• Hyperphosphatemia
• Hyperparathyroidism
• Hypertension
• Diabetic nephropathy

Prognosis

Without treatment, the prognosis for uremic patients is poor. With dialysis or transplantation, the prognosis is improved, but close monitoring is essential as many patients develop complications. The mortality rates have dropped over the past three decades, but renal failure patients still have a higher risk of death compared to the general population. The most common cause of death is cardiovascular disease which is progressive.

The prognosis for AKI and kidney failure due to a reversible cause, such as lupus nephritis, anti-glomerular basement membrane disease, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, multiple myeloma, and hemolytic-uremic syndrome, is better if an early diagnosis is made and prompt treatment is started.[41]

The risk of developing cardiovascular disease is five to ten times greater in patients with CKD and ESRD as opposed to age-matched controls.[42] In ESRD patients, cardiovascular disease is the commonest cause of death, followed by cerebrovascular disease and sepsis.

Complications

Patients with uremia can develop various complications due to the building up of toxins in the body, such as:

• Hyperpigmented skin
• Severe itching
• Pericarditis and pericardial effusion
• Pulmonary edema
• Valvular calcification
• Uremic encephalopathy
• Electrolyte abnormalities
• Cardiovascular disease
• Uremic pancreatitis

Deterrence and Patient Education

Avoid nephrotoxic medications such as renal-toxic aminoglycoside antibiotics, NSAIDs, and other potential renal toxins. Administration of N -acetyl-cysteine before and after a radiologic investigation that requires intravenous contrast can help avoid nephrotoxicity. However, providers should consider an alternative radiological investigation, such as ultrasonography or MRI, in such settings to prevent AKI, especially in patients with diabetes.

Patients should be educated that low-protein and plant-based diets are more likely to slow the progression of CKD. At the same time, using prebiotics, synbiotics, probiotics, and laxatives could have beneficial effects on toxin generation.[43] However, a dietician is better suited to make dietary changes, such as cutting down protein intake, and should always be consulted.

Pearls and Other Issues

Uremic encephalopathy occurs in patients with acute or chronic renal failure once the estimated GFR (eGFR) declines and stays below 15 mL/min. It is essential to recognize the signs and symptoms early, as untreated uremic encephalopathy can progress to coma, while dialysis quickly reverses symptoms. Early symptoms of uremic encephalopathy include nausea, anorexia, restlessness, drowsiness, and slowing of concentration and cognitive functions. As uremic encephalopathy progresses, patients typically become more disoriented and confused and may exhibit bizarre behavior and emotional instability. Eventually, severe uremic encephalopathy will result in a stupor and coma. Physical examination may reveal altered mental status, signs of cranial nerve involvement (e.g., nystagmus), or papilledema. Patients may additionally display hyperreflexia, clonus or asterixis, and eventually, coma.

A patient with uremic encephalopathy should improve clinically following the initiation of dialysis. However, electroencephalographic (EEG) findings may not instantly enhance, such as slowing or losing alpha frequency waves, confusing signals, and slow background activity with intermittent bursts of theta and delta waves. Improvement may take several months, and one may never return entirely to normal. Treating uremic encephalopathy involves addressing many of the same parameters when treating any patient with ESRD, for example, correcting associated anemia, regulating calcium or phosphate imbalances, and monitoring the adequacy of dialysis.

Enhancing Healthcare Team Outcomes

Once uremia has been diagnosed, patient education is vital. An interprofessional team approach is necessary to avoid the high morbidity and mortality of uremia. The healthcare provider, nephrologist, transplant surgeon, and pharmacist should work in an interprofessional team to educate the patient on dialysis, renal transplant, and the potential complications of these therapies. The pharmacist should ensure that the patient is on no nephrotoxic medications and is on erythropoiesis-stimulating treatment, calcitriol, iron, and phosphate binders. The diabetic nurse should educate the patient about the importance of blood glucose control. The dietitian should inform the patient about a low-protein diet. The clinician should ensure that the patient's cardiovascular risk factors are minimized by eating a healthy diet, discontinuing smoking, controlling diabetes, and maintaining a healthy body weight.

Finally, the nurse should always ensure that any patient with uremia undergoing an imaging study that requires contrast is adequately hydrated. If possible, another imaging modality that does not use contrast should be selected. Renal function should be closely monitored, and the patient should be urged to control the blood pressure. Medication compliance is vital. The social worker should be involved to ensure that the patient has adequate financial support to continue with the treatments. Only with such a team approach can the morbidity of uremia be lowered.[44][45][46] [Level 5]

Outcomes

The prognosis for patients with uremia is generally poor unless they are treated with renal replacement therapy such as transplantation or dialysis. When the cause of uremia is a reversible cause, the prognosis is better than in patients with an irreversible cause. Uremic patients require frequent admission to hospitals and have high morbidity and mortality without treatment. While dialysis has improved the management of uremic patients, vascular access is still a major problem in the long run. In addition, there are not enough kidney donors. Patients with uremia are also at high risk for adverse cardiac events and stroke compared to the general population. Finally, the cost of care for a dialysis patient is prohibitively expensive, costing the healthcare system billions of dollars each year.[47][48](Level V)

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Disclosure: Michael Zemaitis declares no relevant financial relationships with ineligible companies.

Disclosure: Lisa Foris declares no relevant financial relationships with ineligible companies.

Disclosure: Shravan Katta declares no relevant financial relationships with ineligible companies.

Disclosure: Khalid Bashir declares no relevant financial relationships with ineligible companies.