Uremia

Etiology

Uremia can arise from various conditions, ranging from primary renal disorders such as immunoglobulin A (IgA) nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and polycystic kidney disease to systemic disorders that cause renal damage. Systemic disorders include conditions such as diabetes mellitus, systemic lupus erythematosus, multiple myeloma, amyloidosis, antiglomerular basement membrane disease, thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome.

Diabetes is the leading cause of ESRD in the United States, accounting for 40% of new dialysis patients. Additional causes, listed in order of decreasing incidence, include hypertension, glomerulonephritis, interstitial disease, cystitis, and neoplasms. Globally, diabetes remains the primary cause of kidney failure; nonetheless, glomerulonephritis emerges as the predominant underlying cause in developing nations.

Uremia may also result from acute kidney injury if the injury involves a sudden increase in urea or creatinine levels.[10][11][12] Notably, uremia likely stems from the retention of various toxic biochemicals that may act synergistically. Numerous studies have associated different toxins with uremic symptoms, and in vitro experimental models have shown associated adverse effects.[6][13][14] These toxins may vary in their solubility in water or binding to proteins, and they may have different molecular weights.[15] In addition, evidence indicates that certain anti-inflammatory and vasodilator compounds, such as glutathione and arginine, are reduced in renal failure, which could also contribute to some aspects of uremic pathology.[6][13]

Epidemiology

Determining the exact prevalence of uremia in the United States poses challenges because patients with ESRD often start dialysis before exhibiting uremic symptoms. Uremic symptoms typically manifest when creatinine clearance drops below 10 or 15 mL/min in diabetic patients. According to the United States Renal Data System (USRDS) 2009 data, the reported incidence and prevalence of advanced chronic kidney disease (CKD) in the United States were 354 and 1665 per million people per year, respectively. In 2009, 116,395 patients initiated renal replacement therapy, yielding an unadjusted incidence rate of 371 per million.[16] This number continues to rise as the life expectancy of those with ESRD is increasing.

Improved survival rates among patients with diabetes or cardiovascular disease, coupled with improved access to renal therapy, have led to a notable increase in the incidence of ESRD among individuals aged 75 or older. Conversely, there is a declining trend in the number of individuals aged 60 or younger with ESRD, except for Black or Native American patients with diabetic ESRD. Japan has the highest prevalence of ESRD patients in the world, followed by Taiwan.[17] Remarkably, only 5 countries account for 58% of the world's ESRD patients—the United States, Japan, Brazil, Germany, and Italy.[18]

The majority of patients with ESRD  are White (59.8%), with the remaining patients being Black (33.2%), Asian (3.6%), or Native American (1.6%). However, the incidence of ESRD among Black individuals is 3.7 times higher than among the White population. Similarly, the incidence among Native Americans is 1.8 times greater than among the White population. Additionally, minority populations tend to initiate dialysis care later in the course of renal disease, usually after a significant decline in the glomerular filtration rate (GFR). However, it remains uncertain whether racial or ethnic backgrounds influence the predisposition to developing uremic symptoms.

Men are 1.2 times more likely to develop ESRD than women, although women are 1.7 times more likely to delay the initiation of dialysis than men. Furthermore, women are more susceptible to developing uremic symptoms at lower creatinine levels, attributed to their reduced muscle mass and lower baseline serum creatinine levels.[19][20][21]

Pathophysiology

Impaired kidney function can lead to dysregulation in several vital processes, including acid-base balance, fluid and electrolyte regulation, hormone production and secretion, and waste elimination. Collectively, these dysfunctions contribute to metabolic disturbances and give rise to conditions such as anemia, coagulopathy, metabolic acidosis, hyperkalemia, hyperparathyroidism, and cardiac dysfunction.

Anemia associated with kidney disease is typically characterized as normocytic, normochromic, and hypoproliferative. The condition arises due to reduced erythropoietin production by the failing kidneys and is associated with a GFR of less than 50 mL/min (or GFR <60 mL/min with diabetes) or when serum creatinine exceeds 2 mg/dL.[22] Additional factors associated with CKD alone may further contribute to the development of anemia. These factors 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. During inflammatory states, hepcidin levels increase, inhibiting iron absorption from the small intestine and iron release from macrophages.[23]

The accumulation of uremic toxins in the blood can also contribute to the development of coagulopathy. This occurs due to reduced platelet adhesion to the vascular endothelial wall, increased platelet turnover, and a slight decrease in the absolute number of platelets.[24] Bleeding diathesis, which refers to an increased susceptibility to bleeding and hemorrhage, is a common observation in patients with ESRD.

Another major metabolic complication associated with uremia and ESRD is acidosis, as renal tubular cells are the primary regulators of acid-base balance in the body. With progressive kidney failure, metabolic changes include reduced secretion of hydrogen ions, impaired excretion of ammonium, and eventual accumulation of phosphate and other organic acids such as lactic acid, sulfuric acid, and hippuric acid. Consequently, heightened metabolic acidosis can lead to symptoms such as hyperventilation, lethargy, anorexia, muscle weakness, and congestive heart failure due to decreased cardiac contractility.

Hyperkalemia can occur in acute and chronic renal failure settings, and it becomes a medical emergency when serum potassium levels exceed 6.5 mEq/L. Excessive potassium intake or the use of certain medications, such as potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, β-blockers, and non-steroidal anti-inflammatory drugs (NSAIDs), can exacerbate this level.[25] Acidosis resulting from renal failure may also contribute to the development of hyperkalemia.

Renal failure can lead to hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels. Hypocalcemia results from decreased production of active vitamin D (1,25 dihydroxyvitamin D), which normally facilitates gastrointestinal absorption of calcium and phosphorus and suppresses parathyroid hormone excretion. Hyperphosphatemia occurs due to impaired phosphate excretion in renal failure. Both hypocalcemia and hyperphosphatemia stimulate parathyroid gland hypertrophy, leading to increased parathyroid hormone production and secretion. These changes in calcium metabolism can contribute to renal osteodystrophy (known as CKD-metabolic bone disease) and may cause calcium deposition throughout the body (metastatic calcification).[26]

Declining renal function can result in decreased insulin clearance, necessitating a decrease in the dosage of antihyperglycemic medications to prevent hypoglycemia. Uremia can also cause impotence in men or infertility in women, manifested as dysfunctional reproductive hormone regulation, such as anovulation or amenorrhea.

The buildup of uremic toxins may also contribute to uremic pericarditis and pericardial effusions, leading to abnormalities in cardiac function. When coupled with metastatic calcification due to declining renal function, these factors may exacerbate underlying valvular dysfunction or suppression of myocardial contractility.[27][28]

History and Physical

Symptomatic uremia typically occurs when creatinine clearance drops below 10 to 20 mL/min unless kidney failure develops acutely. In such cases, some patients may experience symptoms even at higher clearance rates. Patients with uremia may present with various symptoms, including nausea, vomiting, fatigue, anorexia, weight loss, dysgeusia (bad taste in the mouth), chest pain, palpitations, dyspnea, muscle cramps, restless legs, pruritus, easy bleeding, or mental status changes. Neurological symptoms such as confusion, forgetfulness, and memory loss in uremia may have a gradual onset, often unnoticed by patients themselves. Therefore, physicians must maintain a high index of suspicion for uremic symptoms, and obtaining a corroborating history from family members or caregivers becomes crucial. The metabolic disturbances linked to uremia contribute to its clinical presentation, including fatigue due to anemia. Diagnosing uremia in young children can be challenging due to the nonspecific nature of clinical manifestations.

Hypertension, atherosclerosis, valvular stenosis and insufficiency, chronic heart failure, and angina can all develop due to the accumulation of uremic toxins and metastatic calcification associated with uremia and ESRD. If treatment is not initiated promptly, these abnormalities may contribute to the clinical manifestations of uremia. Occult gastrointestinal bleeding, resulting from platelet abnormalities, may present with nausea or vomiting.[29]

Uremia can have a profound impact on the central nervous system, leading to uremic encephalopathy characterized by symptoms such as fatigue, malaise, somnolence, confusion, memory problems, seizures, stupor, and coma. Additionally, nervous system manifestations may include muscle weakness, restless legs, headache, asterixis, polyneuritis, hyperreflexia, myoclonus, and muscle cramps.[30] Amyloid deposits could result in medial carpal tunnel syndrome, neuropathy, or other nerve entrapment syndromes. Dermatologic findings, including skin color changes, xerosis, pruritus, bullous dermatosis, and metastatic calcinosis, as well as hair, nail, and oral mucosa changes, are also prevalent.

Typical physical examination findings in patients with uremia include signs 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. Other commonly observed examination findings in patients with uremia include: 

• Uremic frost (whitish urea crystals deposited on the skin) [31]
• Uremic fetor (urine-like odor of the breath)
• Gingival hyperplasia, petechiae, enamel hypoplasia, or gingival bleeding [32]
• Pericardial rub
• Pulmonary edema (rales, decreased breath sounds at lung bases)
• Peripheral edema
• Severe hypertension
• Facial swelling
• Asterixis
• Papilledema

Evaluation

Diagnosing renal failure relies on abnormalities in GFR or creatinine clearance.[33] Differentiating between acute and chronic renal failure is crucial due to the potential reversibility of acute kidney injury. Laboratory studies evaluating hemoglobin, calcium, phosphate, parathyroid hormone, albumin, potassium, and bicarbonate levels, along with urinalysis (including microscopic examination), aid in identifying potential etiologies underlying uremic symptoms.

A 24-hour urine collection can offer insights into GFR and creatinine clearance, although this method can be burdensome and may yield inaccuracies if not collected precisely. Another option is a nuclear medicine radioisotope (iothalamate) clearance assay that directly measures GFR. However, this test is time-consuming and expensive compared to the Cockcroft-Gault or Modification of Diet in Renal Disease formulas, which are commonly used alternatives.

According to the National Kidney Foundation, patients with CKD are staged based on their estimated GFR, which is calculated using the Modification of Diet in Renal Disease formula.

• Stage 1: Normal GFR (90 mL/min or greater)
• Stage 2: Mildly reduced GFR (60-90 mL/min)
• Stage 3a: Moderately reduced GFR (45-59 mL/min)
• Stage 3b: Moderate-to-severely reduced GFR (30-44 mL/min)
• Stage 4: Severely reduced GFR (15-29 mL/min)
• Stage 5: ESRD (GFR <15 mL/min or patient is on dialysis)

A renal ultrasound helps determine the size and shape of the kidneys and evaluates hydronephrosis and ureteral/bladder obstruction. These issues may stem from various causes such as kidney stones, neurologic abnormalities, trauma, pregnancy, prostate enlargement, retroperitoneal fibrosis, or abdominal tumors (linked to cervical or prostate cancers), among other structural abnormalities. Conditions such as early diabetic nephropathy, multiple myeloma, polycystic kidney disease, and HIV-associated glomerulonephritis may present with enlarged kidneys on ultrasound.[34]

Smaller, echogenic kidneys indicate more chronic, irreversible changes resulting from long-standing kidney disease, ischemic nephropathy, or hypertensive nephrosclerosis. Patients with uremia secondary to urinary obstruction should undergo Foley catheterization to relieve the obstruction. Afterward, the cause of obstruction should be evaluated, and a permanent management plan should be implemented.

Measuring urine protein excretion is valuable in diagnosing glomerulopathies, which can lead to ESRD. Recent evidence suggests that alterations in dipstick proteinuria levels independently predict the risk of ESRD. Monitoring changes in proteinuria over 2 years can provide insights for predicting the risk of ESRD.[35]

A brain computed tomography (CT) scan may be warranted for patients showing significant changes in mental status. Uremic patients with elevated blood urea nitrogen levels (greater than 150-200 mg/dL) are at an increased risk of developing spontaneous subdural hematomas. Due to the heightened risk of bleeding and hemorrhage in uremia, especially following falls or trauma, a CT scan of the brain and abdomen may also be warranted. Furthermore, an abdominal CT scan can help better understand the underlying cause of hydronephrosis if observed on ultrasound.

Magnetic resonance imaging (MRI) can be useful in evaluating renal artery stenosis, thrombosis, or aortic and renal artery dissection, which are potentially reversible causes of renal failure. Additionally, a renal biopsy can aid in determining the reversibility or treatability of renal injury and may be necessary for accurately diagnosing acute kidney injury or CKD. However, in cases of small kidneys, a biopsy should be avoided due to associated comorbidities, increased risk of bleeding, and a lower likelihood of identifying a reversible process.[36]

Treatment / Management

Dialysis is recommended for any patient experiencing symptomatic uremia, such as nausea, vomiting, refractory hyperkalemia, or metabolic acidosis, that cannot be managed through medical interventions. The presence of uremic symptoms warrants the initiation of dialysis irrespective of the patient's GFR.[37][38][39] In cases of uremic emergencies, such as hyperkalemia, metabolic acidosis, symptomatic pericardial effusion, or uremic encephalopathy, immediate dialysis is necessary. Care should be taken to initiate dialysis gently to prevent dialysis disequilibrium syndrome, which may manifest as neurologic symptoms due to cerebral edema occurring during or shortly after the procedure.(B3)

Renal transplantation is the most effective renal replacement therapy, offering improved survival and enhanced quality of life compared to dialysis.[40] While long-term hemodialysis and peritoneal dialysis can serve as temporary measures for patients awaiting transplants or those ineligible for transplantation, early consideration of transplant is crucial. Transplant should be considered early (before the need for dialysis) as the waiting list for transplantation is often longer than 2 to 3 years. The Organ Procurement and Transplantation Network (OPTN) suggests referral for a preemptive kidney transplant (before dialysis is needed) when GFR is between 20 and 30, depending on the rate of kidney function decline.(B2)

In addition, preparation for renal replacement therapy, such as hemodialysis or peritoneal dialysis access, should be initiated months before renal replacement is needed to avoid potential complications from emergently starting dialysis. Most studies show no improvement with initiating dialysis at higher versus lower GFRs, and the decision for dialysis initiation is a clinical decision based on patient signs and symptoms rather than absolute numbers. Uremia is the most common indication for dialysis initiation; therefore, clinicians must be able to recognize the associated characteristics.[41]

Iron replacement should be initiated in patients with anemia of CKD and underlying iron deficiency. This can be administered during dialysis sessions or via oral or intravenous (IV) therapy if dialysis has not yet commenced. Erythropoiesis-stimulating agents, such as erythropoietin or darbepoetin, may also be considered when hemoglobin levels drop below 10 g/dL. See StatPearls' companion resource, "Anemia of Chronic Renal Disease," for more information.[42] 

Hyperparathyroidism, along with associated or isolated hypocalcemia and hyperphosphatemia, can be managed using several treatment options, including oral calcium carbonate or calcium acetate, oral vitamin D therapy, and oral phosphate binders, such as calcium carbonate, calcium acetate, sevelamer, or lanthanum carbonate. Calcitriol (activated vitamin D) is often necessary for individuals with CKD and ESRD.[43] See StatPearls' companion resource, "Chronic Kidney Disease-Metabolic Bone Disorder," for more information.[44]

A dietitian should be consulted if dietary alterations are being considered. Patients with CKD should adhere to a diet low in potassium and phosphate, while sodium intake should be restricted to 2 to 3 g. Although some evidence is conflicting regarding protein intake in kidney failure patients, current recommendations for a low-protein diet before dialysis initiation suggest consuming 0.8 to 1 g of protein per kilogram of body weight daily, with an additional gram of protein for every gram lost in urine for patients with nephrotic syndrome.[45] (B2)

Significant evidence shows that a low-protein diet helps delay the progression of CKD—a strategy widely adopted in certain regions. Although concerns about malnutrition are valid, close nutritional monitoring alongside supplementation as necessary can sufficiently meet all metabolic requirements on a low-protein diet.[46][47] In addition, significant evidence indicates that adopting a plant-based diet can decelerate the progression of CKD and delay dialysis initiation. Animal protein intake contributes to uremia by elevating nitrogenous waste levels, leading to increased intraglomerular pressure and greater glomerular hyperfiltration.[48][49]

Patients with a creatinine clearance of less than 20 mL/min should exercise caution regarding potassium intake and the use of specific medications, such as potassium-sparing diuretics, ACE inhibitors, angiotensin-receptor blockers, β-blockers, and NSAIDs. In addition, due to the accumulation of uremic toxins and the potential for increased bleeding and hemorrhage risk, prescribing oral anticoagulants or antiplatelet medications to ESRD patients requires careful consideration and monitoring. Nephrotoxic medications such as NSAIDs and aminoglycoside antibiotics should be avoided in all CKD patients. The administration of N-acetylcysteine before IV contrast for radiologic imaging may help reduce the risk of nephrotoxicity. However, considering alternative imaging modalities such as MRI is advisable in these patients to prevent the risk of acute kidney injury altogether.[50]

Differential Diagnosis

Uremia is usually a straightforward diagnosis in the setting of elevated renal function labs. However, similar signs and symptoms can manifest in other conditions as well. For instance, hepatic encephalopathy resulting from hyperammonemia can present with asterixis and changes in mental status. Liver failure may lead to hypoalbuminemia, resembling the presentation of nephrotic syndrome. Congestive heart failure can manifest as pulmonary edema and signs of volume overload. Pericarditis, whether infectious or from other causes, can produce a pericardial rub similar to that seen in uremic pericarditis.

Furthermore, intoxication from various substances can also induce changes in mental status, and patients with renal failure may experience reduced clearance of certain substances. Electrolyte imbalances, such as hypermagnesemia and hypercalcemia, are additional factors that can lead to alterations in mental status. Differential diagnosis typically relies on basic laboratory studies and a comprehensive assessment of the clinical presentation to distinguish between these various conditions.

Prognosis

The prognosis for acute kidney injury and kidney failure resulting from reversible causes, such as lupus nephritis, anti-glomerular basement membrane disease, granulomatosis with polyangiitis, thrombotic thrombocytopenic purpura, multiple myeloma, and hemolytic-uremic syndrome, is significantly improved with early diagnosis and prompt initiation of treatment.[51]

Without treatment, the prognosis for uremic patients is poor. However, with dialysis or transplantation, the prognosis significantly improves. Close monitoring is essential as many patients develop complications during treatment. While mortality rates have decreased over the past three decades, individuals with renal failure still face a higher risk of death compared to the general population, especially during the initial months after starting dialysis. 

Complications

Patients with uremia can develop various complications, including hyperpigmented skin, severe itching, pericarditis, pericardial effusion, pulmonary edema, valvular calcification, uremic encephalopathy, electrolyte abnormalities, cardiovascular disease, and uremic pancreatitis.