Uremia

Normally, the 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. ^[7]

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 develops acutely. The syndrome may be heralded by the clinical onset of the following symptoms:

• Nausea
• Vomiting
• Fatigue
• Anorexia ^[8]
• Weight loss
• Muscle cramps
• Pruritus
• Change in mental status

Anemia

Anemia-induced fatigue is thought to be one of the major contributors to the uremic syndrome. Erythropoietin (EPO), a hormone necessary for red blood cell production in bone marrow, is produced by peritubular cells in the kidney in response to hypoxia. 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 level is greater than 2 mg/dL. Patients with diabetes may experience anemia with a GFR of less than 60 mL/min.

In a study of 832 hospitalized patients with diabetes, Almoznino-Sarafian et al determined that 334 of the patients had anemia, a rate (40%) higher than that reported in ambulatory patient populations. The investigators found that the anemic patients tended to be older (mean age 71.4 years) than were the nonanemic patients with diabetes (mean age 64.4 years) and that a greater percentage were female (52.4% vs 44.4% of the nonanemic patients). In addition, 39% of the anemic patients had renal dysfunction. ^[9]

Anemia associated with chronic kidney disease is characteristically normocytic, normochromic, and hypoproliferative.

Anemia in chronic renal failure

In the setting of CKD, anemia may be due to other clinical factors or diseases, such as iron deficiency, vitamin deficiencies (eg, folate, vitamin B-12), hyperparathyroidism, hypothyroidism, and decreased red blood cell survival. Iron deficiency, which may occur as a result of occult GI bleeding or frequent blood draws, should be excluded in all patients.

Elevated PTH levels are thought to be associated with marrow calcification, which may suppress red blood cell production and lead to a hypoproliferative anemia. Parathyroid-induced marrow calcification tends to regress after parathyroidectomy.

Studies have shown that hepcidin, an acute phase protein involved with iron metabolism, plays a key role in erythropoiesis. ^[10] Hepcidin, up-regulated in states of inflammation, prevents iron absorption in the small intestine, as well as iron release from macrophages. ^[11]

Coagulopathy

Bleeding diatheses are characteristic findings in patients with end-stage renal disease (ESRD). 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.

The reduced adhesion of platelets to the vascular subendothelial wall is due to reduction of GPIb and altered conformational changes of GPIIb/IIIa receptors. 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 accomplished through treatment of renal anemia with recombinant human erythropoietin or darbepoetin alpha, adequate dialysis, desmopressin, cryoprecipitate, tranexamic acid, or conjugated estrogens.

Patients with ESRD are at significantly increased risk for bleeding if placed on oral anticoagulants or antiplatelet agents. Thus, these classes of medicines need to be prescribed with extreme caution.

Acidosis

Acidosis is another major metabolic abnormality associated with uremia. 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.

As kidney disease continues to progress, accumulation of phosphate and other organic acids, such as sulfuric acid, hippuric acid, and lactic acid, creates an increased anion-gap 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.

In patients with CKD who are not yet on dialysis, treatment of the acidosis with oral bicarbonate supplementation has been demonstrated to help slow the progression of the renal disease.

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. As renal function declines, the nephron is unable to excrete a normal potassium load, which can lead to hyperkalemia if dietary intake remains constant. In addition, other metabolic abnormalities, such as acidemia or type IV renal tubular acidosis, may contribute to decreased potassium excretion and lead to hyperkalemia. (Most cases of hyperkalemia are multifactorial in etiology.)

Hyperkalemia can occur in several instances, including the following:

• Excessive potassium intake in patients with a creatinine clearance of less than 20 mL/min

• Hyporeninemic hypoaldosteronism or type IV renal tubular acidosis in patients with diabetes, urinary obstruction, or interstitial nephritis

• Significant acidemia

• Drug therapy - Hyperkalemia is common when drugs, such as potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, beta blockers, or nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the setting of renal insufficiency or renal failure

Hyperparathyroidism

In the setting of renal failure, there are a number of abnormalities of the calcium-vitamin D metabolic pathway, such as hypocalcemia, hyperphosphatemia, and increased PTH levels, that ultimately lead to renal bone disease (osteodystrophy).

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.

Hyperphosphatemia occurs as excretion of phosphate decreases with progressive renal failure. Hyperphosphatemia stimulates parathyroid gland hypertrophy and stimulates increased production and secretion of PTH.

Elevated PTH levels have been associated with uremic neuropathy and other metabolic disturbances, which include altered pancreatic response, erythropoiesis, and cardiac and liver function abnormalities. 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. ^[12]

Treatment

The vitamin D deficiency can be treated orally or intravenously with 1,25(OH)2 vitamin D-3 (calcitriol). There are several new vitamin D analogues that have become available for use and are more specific for vitamin D receptors in the parathyroid gland. Use of one of these analogues, paricalcitol, has been found to be associated with improved survival compared with use of calcitriol. ^[13] In addition, these new vitamin D analogs cause less elevation in serum calcium and phosphorus levels. ^[14]

Cinacalcet, a new medication that stimulates the calcium sensing receptor in the parathyroid gland and causes negative feedback on PTH production and release, can also be used to treat secondary hyperparathyroidism. Several studies have shown the following benefits of cinacalcet usage: (1) greater associated likelihood of achieving an intact PTH level of less than 300 pg/mL and (2) greater likelihood of maintaining calcium and phosphorus levels within the target range. ^[15] Cinacalcet usage has also been shown to lower the risk of fracture and of cardiovascular hospitalization. ^[16] It is as yet unknown if cinacalcet improves patient mortality rates.

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 antihyperglycemic 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, including uremic pericarditis, ^[17] pericardial effusions, calcium and phosphate deposition–associated worsening of underlying valvular disorders, and uremic suppression of myocardial contractility, are common in patients with CKD. ^{[18, 19]}

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.

The function of high-density lipoprotein (HDL) cholesterol is impaired in patients with uremia. This impairment, which involves increased electronegativity and compositional changes, is associated with increased risk of coronary artery disease. ^[20]

Renal dysfunction may contribute to associated fluid retention, which may lead to uncontrolled hypertension and congestive heart failure.

Malnutrition

Malnutrition usually occurs as renal failure progresses; it is manifested by the following symptoms:

• Anorexia
• Weight loss
• Loss of muscle mass
• Low cholesterol levels
• Low blood urea nitrogen (BUN) levels in the setting of an elevated creatinine level
• Low serum transferrin levels
• Hypoalbuminemia

However, the question of whether uremia stimulates protein catabolism directly remains controversial. ^[21]

Comorbid diseases, such as diabetes and congestive heart failure, 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.

The etiologies of CKD range from primary renal disorders to systemic disorders causing renal injury. Primary glomerular and tubular disorders that may result in CKD include the following:

• Membranoproliferative glomerulonephritis
• Focal segmental glomerulosclerosis
• IgA nephropathy
• Polycystic kidney disease

Systemic disorders associated with CKD include the following

• Diabetes mellitus
• Lupus
• Amyloidosis
• Anti–glomerular basement membrane disease (Goodpasture disease)
• Multiple myeloma
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome

AKI may be caused by multiple etiologies, but it is associated with uremia when a rapid rise in urea or creatinine occurs.

Diabetes is the primary cause of ESRD in the United States and accounts for 40% of new dialysis patients. Other causes include the following:

• Hypertension (25.2% of cases)
• Glomerulonephritis (11.3%)
• Interstitial disease (3.8%)
• Cystitis (2.8%)
• Neoplasms (1.7%)

Although diabetes is the primary cause of renal disease in most other countries, other glomerulonephropathies, particularly IgA nephropathy, may be the primary cause of ESRD, depending on the country.

In a whole-genome microarray case-control study of 75 patients with ESRD and 20 healthy controls, more than 9,000 genes were differentially expressed in uremic patients compared with controls (fold change: -5.3 to +6.8), and more than 65% were lower in patients with uremia. These changes appeared to be regulated through key networks involving cMYC, SP1, P53, AP1, NFkB, HNF4 alpha, HIF1A, c-Jun, STAT1, STAT3 and CREB1.

In patients with uremia, protein transport, mRNA processing and transport, chaperone functions, the unfolded protein response, and genes involved in tumor genesis were prominently lower, while neuroactive receptor interaction, insulin-like growth factor activity, the complement system, lipoprotein metabolism, and lipid transport were higher. Down-regulation of pathways involving cytoskeletal remodeling, the clathrin-coated endosomal pathway, T-cell receptor signaling, and CD28 pathways were observed, along with up-regulation of the ubiquitin pathway. ^[22]

Occurrence in the 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, these symptoms arise is when creatinine clearance is less than 10 mL/min; in patients with diabetes, such symptoms appear with clearance rates of less than 15 mL/min.

Data from the US End-Stage Renal Disease (USRDS) Program showed that during 2007, the incidence rate for ESRD maintained relatively stable at 354 cases per million, with a total dialysis prevalent population of greater than 368,000 (>90% on hemodialysis).

While prevalence rates continue to increase because patients with ESRD are living longer, they have fallen for most people younger than 60 years, except for younger African Americans and Native Americans with diabetic ESRD. It has been estimated that by 2020, more than 750,000 Americans will have ESRD.

International occurrence

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).

Race-related demographics

ESRD disproportionately affects minority populations. Whites represent the majority of the ESRD population (59.8%), while African Americans (33.2%), Asians (3.6%), and Native Americans (1.6%) make up the rest. However, the incidence rate of ESRD among African Americans and Native Americans is 3.7-fold and 1.8-fold higher, respectively, than it is for whites.

Minority populations are more likely to have delayed onset of dialysis care and are more likely to start dialysis when their GFRs are significantly decreased.

Whether, among patients with equivalent GFRs, having a certain racial or ethnic background predisposes individuals to develop symptoms of uremia more so than other patients remains unknown.

Sex-related demographics

ESRD is slightly more prevalent in men than in women (male-to-female ratio, 1.2:1). However, women are 1.7-fold more likely to have delayed initiation of dialysis than are men. In addition, due to lower muscle mass and baseline serum creatinine levels, women are more likely to develop uremic symptoms at a lower creatinine level.

Age-related demographics

ESRD is much more prevalent in older adults, but the prevalence of uremia among different age groups is unknown.

Individuals aged 75 years and older have experienced the greatest increase in incidence (98% over the last decade), attributable in part to improved survival of individuals with cardiovascular disease and diabetes mellitus and expanded access to renal replacement therapy for older patients.

Information from the United States Renal Data System indicates that older adults are 31% less likely to have delayed initiation of dialysis than are patients who were younger than 40 years at the initiation of dialysis.

The prognosis for patients with uremia of ESRD is poor unless the uremia is treated with renal replacement therapy, such as dialysis or transplantation.

The prognosis for AKI and renal failure secondary to a reversible or treatable cause, such as rapidly progressive glomerulonephritis (eg, lupus nephritis, granulomatosis with polyangiitis, anti–glomerular basement membrane disease, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, ^[23] multiple myeloma), depends on the timing of diagnosis and the rapidity of appropriate treatment (eg, steroids, chemotherapeutic agents, plasmapheresis).

Morbidity and mortality

CKD is associated with a very high morbidity and hospitalization rate, likely due to existing comorbid conditions, such as hypertension, coronary artery disease, and peripheral vascular disease. The rate of hospitalization and hospital days is 3 times greater than for the general public and not much different from dialysis patients.

Although still unacceptably high, the mortality rate for ESRD patients has been improving, especially since 1999. Indeed, the 5-year survival for patients who initiated dialysis sometime between 1998 and 2002 (34%) was found to be 10% higher than for those who initiated dialysis sometime between 1993 and 1997 (31%).

The risk for developing cardiovascular disease is 5- to 10-fold higher in patients with CKD and ESRD than in age-matched controls. ^[24] In patients with ESRD, cardiovascular disease is the primary cause of death, followed by sepsis and cerebrovascular disease. The dialysis population in the United States has a 10- to 20-fold higher risk of death due to cardiovascular complications than does the general population after adjusting for age, race, and sex. The relative risk with respect to the general population is much higher in younger patients.

Patients who have delayed initiation of dialysis have a 1.5-fold higher risk of a low serum albumin level and a 1.8-fold higher risk of starting dialysis with a hematocrit value lower than 28% than do patients who do not have a low creatinine clearance.

However, patients with delayed onset of dialysis are not more likely to have prevalent cardiac disease, peripheral vascular disease, hypertension, or poor functional status than are those without a delayed onset of dialysis. Thus, the timing of the initiation of dialysis remains controversial.