Clinical features and diagnosis of heme pigment-induced acute kidney injury

INTRODUCTION — Acute kidney injury (AKI) can occur in patients who have rhabdomyolysis and, less commonly, in patients with hemolysis [1,2]. In both groups, AKI is caused by the nonprotein heme pigment that is released from either myoglobin or hemoglobin and is toxic to the kidney. Hypovolemia may contribute in patients with rhabdomyolysis due to crush injury.

The clinical features and diagnosis of heme pigment-induced AKI due to nontraumatic rhabdomyolysis and to hemolysis will be reviewed here. Prevention and treatment of heme pigment-induced AKI, AKI due to crush injury, and overviews of rhabdomyolysis and hemolysis are discussed separately:

●(See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

●(See "Crush-related acute kidney injury".)

●(See "Rhabdomyolysis: Epidemiology and etiology".)

●(See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

●(See "Diagnosis of hemolytic anemia in adults".)

PATHOGENESIS — Heme pigment-containing proteins include myoglobin and hemoglobin. Myoglobin is released from muscle in patients with traumatic or nontraumatic rhabdomyolysis, whereas hemoglobin is released from hemolyzed red blood cells. Both myoglobin and hemoglobin are filtered by the glomerulus into the urinary space where they are degraded, thus releasing heme pigment.

Heme pigment may injure the kidney in three ways:

●Tubular obstruction, possibly in association with uric acid [1,3]

●Direct proximal tubular epithelial cell injury [1,4,5]

●Vasoconstriction, which results in a reduction in blood flow in the outer medulla [3]

Despite its toxic properties, heme pigment rarely causes kidney injury in the absence of predisposing conditions, which include volume depletion, metabolic acidosis, and, possibly, mild ischemia.

Volume depletion enhances both vasoconstriction and the formation of obstructing casts and has been shown in both animal models [1,3] and human studies [6-8] to be critically important for the development of heme-induced AKI. The importance of concurrent volume depletion was demonstrated in studies of military recruits undergoing intensive training and in patients with myopathies [6,7]. Whereas myoglobinuria is frequently present in such patients, the development of AKI is unusual, provided euvolemia is maintained.

An acidic urine may also favor cast formation and proximal tubular cell injury [1,3,5].

Causes of rhabdomyolysis — The causes of rhabdomyolysis are discussed in detail elsewhere (see "Rhabdomyolysis: Epidemiology and etiology"). In general, rhabdomyolysis results from the following:

●Traumatic muscle injury

●Increased voluntary or involuntary muscle activity

●Exogenous toxins including alcohol, illicit drugs, or polypharmacy

●Hereditary myopathies and inflammatory muscle diseases

●Hypokalemia, hypophosphatemia, and hyperosmolality

●Infectious etiologies (influenza, human immunodeficiency virus [HIV], Legionella, and others, including sepsis)

Risk prediction score for severe acute kidney injury or death — A risk prediction score for a composite outcome of severe AKI (defined as that requiring kidney replacement therapy [KRT]) or death was developed and validated using data from 2371 patients with creatine kinase (CK) >5000 units/L who were admitted to two separate urban hospitals [9]. Patients with end-stage kidney disease were excluded from analysis, as were those who were on KRT upon transfer, those with diagnosis of acute myocardial infarction, and those with elevated CK concentration more than three days after admission.

Predictors of the composite outcome included age, female sex, cause of rhabdomyolysis, initial serum concentrations of creatinine, CK, phosphate, calcium, and bicarbonate. The clinical conditions with the highest rate of either KRT or death were compartment syndrome, sepsis, neuroleptic malignant syndrome, abdominal or thoracic surgery, and cardiac arrest.

Using data from one hospital, the following variables were assigned scores (in parentheses) in order to define a total risk score:

●Age >50 to ≤70 years (1.5)

●Age >70 to ≤80 years (2.5)

●Age >80 years (3)

●Female sex (1)

●Initial serum creatinine 1.4 to 2.2 mg/dL (1.5)

●Initial serum creatinine >2.2 mg/dL (3)

●Initial serum calcium <7.5 mg/dL (2)

●Initial serum CK >40,000 units/L (2)

●Underlying cause other than seizures, syncope, exercise, statins, or myositis (3)

●Initial serum phosphate 4.0 to 5.4 mg/dL (1.5)

●Initial serum phosphate >5.4 mg/dL (2)

●Initial serum bicarbonate <19 mEq/L (2)

Using this model, patients with a score <5 were found to have a low risk (<3 percent) for severe AKI or death; patients with a score >10 had a high risk (>59 percent) for the clinical outcomes. If a score of 5 was used as the cutoff, the negative and positive predictive values were 97 and 30 percent, respectively. Furthermore, each one-point increase in the risk score was associated with an adjusted odds ratio of 1.49 (95% CI 1.42-1.57).

Using data from the second hospital for validation, a score <5 was associated with a risk of KRT or death of 2.3 percent, and a score >10 was associated with a risk of 61 percent. Using a score of 5 as the cutoff, the negative and positive predictive values were 98 and 27 percent, respectively.

Use of this score may allow for more accurate identification of patients who are at higher risk for adverse outcomes from rhabdomyolysis, although it needs to be validated in other studies conducted in more diverse settings before its clinical utility is known [10].

Causes of hemolysis — There are numerous causes of intravascular hemolysis, few of which are commonly encountered in clinical practice. An introduction to this topic can be found elsewhere. (See "Diagnosis of hemolytic anemia in adults".)

ABO-incompatible blood transfusions used to be the most common cause of hemolysis-associated AKI; these are now quite rare due to improved blood banking practices [11]. In the absence of transfusion-related causes, hemolysis is rarely an isolated cause of AKI. In modern practice, AKI that develops in the setting of hemolysis is usually multifactorial.

The following causes of hemoglobinuria have been associated with AKI:

●Glucose-6-phosphate dehydrogenase (G6PD) deficiency [12-14]

●Poisoning [15]

●Snake and insect bites (envenomation) [16,17]

●Drug reactions (cephalosporins) [18,19]

●Paroxysmal nocturnal hemoglobinuria (PNH) [20-22]

●Malaria (Blackwater fever) [23]

●Cardiac and vascular surgery, including placement of left ventricular assist devices (LVADs) [24-27]

●Extracorporeal membrane oxygenation (ECMO) [28,29]

Envenomation and poisonings often cause concurrent rhabdomyolysis and hemolysis, as well as immune complex-mediated glomerulonephritis, interstitial nephritis, and hemolytic uremic syndrome [15,16,30,31]. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)

Malaria-associated AKI may be attributed to hemolysis in select cases [23,32]; however, other mechanisms including the mechanical obstruction caused by infected red blood cells, cytokine-mediated injury, and immune complex deposition usually play equal, if not more important, roles in its pathogenesis [12].

Hemolysis related to cardiopulmonary bypass circuits, transfusion of stored red blood cells, and cell salvage devices may contribute to AKI that occurs following cardiac surgery [24]. Hemolysis may occur due to red cell contact with artificial surfaces or with air, which is further exacerbated by prolonged hypothermia [26]. LVADs used as bridge or destination therapies for severe heart failure are also associated with hemolysis and may contribute to the development of AKI [25,27]. Hemolysis usually signals partial or complete pump thrombosis and is an indication for pump exchange or explant or intensification of anticoagulation [33]. (See "Short-term mechanical circulatory assist devices".)

EPIDEMIOLOGY — Approximately 26,000 diagnosed cases of rhabdomyolysis occur yearly in the United States [34]. The reported percentage of cases that are complicated by AKI ranges from 15 to over 50 percent [7,35,36]. The variability in the reported incidence of AKI is likely related to differences in the severity of underlying rhabdomyolysis and varying definitions of AKI [7].

As an example, in one retrospective series of 148 patients in which rhabdomyolysis was defined as creatine kinase (CK) >1000 units/L, 29 percent developed serum creatinine elevations >2.0 mg/dL (177 micromol/L) [37]. In other reports, more severe rhabdomyolysis characterized by much higher CK levels, as may be seen following earthquakes, led to AKI requiring dialysis in 50 to 65 percent. (See "Crush-related acute kidney injury".)

There have been case reports of rhabdomyolysis and AKI occurring with extreme conditioning programs (CrossFit, Insanity, Gym Jones, and P90X). These programs include high-intensity activities with short rest periods that might predispose patients to muscle injury as well as volume depletion that can lead to AKI [38].

The incidence of AKI as a result of hemolysis is variable. In an early description of massive hemolysis that resulted from the accidental infusion of hypotonic albumin solution, AKI occurred in 5 of 10 patients [39]. However, as noted previously, massive hemolysis has become uncommon in developed countries due to better transfusion practices. In current practice, among patients with hemolysis, AKI is much more likely to be multifactorial and less likely to be attributed to hemolysis alone [11].

CLINICAL MANIFESTATIONS — Patients with heme-associated AKI initially present with the manifestations of rhabdomyolysis or hemolysis. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Hemolytic transfusion reactions" and "Non-immune (Coombs-negative) hemolytic anemias in adults".)

Marked release of hemoglobin or myoglobin typically leads to red or brown urine, unless pigment excretion is limited because of a low glomerular filtration rate (GFR) or clearance from the plasma by extrarenal mechanisms [35].

The plasma is typically normal in color in patients with rhabdomyolysis but may be reddish brown in patients who have sufficient hemolysis to cause hemoglobinuria. The red color of plasma in patients with hemolysis is due to the accumulation of hemoglobin. Hemoglobin is poorly filtered due both to its large size (mol wt 69,000 of tetramer and 34,000 of dimer) and protein binding to haptoglobin. As a result, hemoglobinuria requires a relatively high plasma hemoglobin concentration.

Myoglobin, in comparison, is a smaller molecule (mol wt 17,000) and is not protein bound. As a result, myoglobin is rapidly filtered and excreted, and plasma retains its normal color unless kidney failure limits myoglobin excretion.

In the setting of normal kidney function, the concentration of myoglobin necessary to visibly color plasma (approximately 100 mg/dL) would likely require a fatal degree of rhabdomyolysis [40].

Patients with rhabdomyolysis typically present with the triad of pigmented granular casts in the urine, a red to brown color of the urine supernatant, and a marked elevation in the plasma creatine kinase (CK) level [36,41]. Patients with hemolysis have the same urinary findings but a reduced haptoglobin and an abnormal peripheral blood smear [42]. An increased serum lactate dehydrogenase (LDH) may be seen in both disorders. (See "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

Patients with either rhabdomyolysis or hemolysis may be oliguric or anuric.

Urinalysis — The urinalysis is similar among patients with AKI due to either rhabdomyolysis or hemolysis. The standard urinary orthotolidine dipstick tests positive in the presence of heme from myoglobin or hemoglobin or due to red cells. Thus, dipstick-positive microhematuria in the absence of any visible red cell by microscopy may signal the presence of either hemoglobinuria or myoglobinuria [43]. Varying degrees of proteinuria may also be found on urinalysis [7]. Heme pigment may combine with Tamm-Horsfall protein to give rise to characteristic pigmented granular casts on urine microscopy [44]. Uric acid crystals and crystal casts may also be seen in the urine sediment examination in patients with hyperuricemia [45].

In contrast to other forms of acute tubular necrosis (ATN), the fractional excretion of sodium is often <1 percent in patients with AKI from either hemolysis or rhabdomyolysis, possibly reflecting renal vasoconstriction and concurrent volume depletion that is commonly observed (calculator 1 and calculator 2) [46]. The low fractional sodium excretion may be observed even with established tubular injury. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

Other laboratory findings

Creatine kinase — Among patients with rhabdomyolysis, CK is released from injured muscle into the circulation, resulting in a dramatic (sometimes over 1000-fold) increase in its serum concentration. Levels peak within 24 hours of a focal muscle injury and thereafter decline by 50 percent per 48 hours [47].

The degree of CK elevation does not always predict the development of AKI, although there is a weak correlation between the peak CK level and the serum creatinine [1]. In one study, 58 percent of patients with rhabdomyolysis who developed AKI had peak CK levels >16,000 units/L compared with only 11 percent in those who did not develop AKI [36]. AKI is uncommon when peak CK levels are under 5000 to 10,000 units/L [48-51]. In a study cited above, in two cohorts of 2371 patients with rhabdomyolysis, there was no evidence of a linear association between CK concentration and a composite outcome of severe AKI or death, although, in CK, >40,000 units/L was associated with increased risk in unadjusted logistic regression models. (See 'Risk prediction score for severe acute kidney injury or death' above.)

The predominant form of CK released from damaged striated muscles is the MM isoform, although a small quantity of the MB isoform may also be released. As a result, mildly elevated CK MB levels may be seen in the absence of any myocardial involvement [52,53]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Peak plasma myoglobin levels may correlate more closely than the CK with AKI, but this test is less commonly used in clinical practice [36,48]. Myoglobin has a shorter half-life (three hours) than CK and is normally cleared from the plasma by hepatic metabolism to bilirubin and, to a lesser extent, by glomerular filtration and kidney metabolism [54]. Thus, although myoglobinemia may precede the rise in CK, it will likely have resolved by the time the patient presents with AKI.

Potassium — Among patients with either rhabdomyolysis or hemolysis, hyperkalemia may develop early, even in the absence of AKI, due to the release of intracellular potassium into the extracellular fluid. The severity of hyperkalemia may appear disproportionate to the degree of kidney injury, and the serum potassium may increase rapidly despite the absence of exogenous potassium administration. The daily rate of rise in the plasma potassium concentration may exceed 1.0 mEq/L in patients with rhabdomyolysis or other hypercatabolic states [55], much greater than typically occurs with kidney failure in patients who are not hypercatabolic (maximum daily rate of rise of 0.3 mEq/L) [56].

Hyperkalemia causes severe manifestations acutely and thus should be appropriately treated. (See "Treatment and prevention of hyperkalemia in adults".)

Calcium — Abnormalities of serum calcium are common among patients with rhabdomyolysis.

●Hypocalcemia occurs in up to two-thirds of patients with significant rhabdomyolysis and is due to the increase in serum phosphate and the subsequent deposition of calcium phosphate into injured muscle, as well as decreased bone responsiveness to parathyroid hormone (PTH) [57].

●Hypercalcemia occurs during the recovery phase of rhabdomyolysis in up to 20 to 30 percent of patients [57,58]. This is due, in part, to the mobilization of calcium that has been deposited in the injured muscle [58,59]. Mild secondary hyperparathyroidism in the setting of kidney dysfunction, correction of hyperphosphatemia (resulting from the rise in GFR), and an unexplained increase in calcitriol (1,25-dihydroxyvitamin D) may contribute to this response [57-60]. To minimize this complication, the administration of calcium should be avoided during the kidney failure phase, unless the patient has symptomatic hypocalcemia or severe hyperkalemia. (See "Treatment of hypocalcemia" and "Treatment and prevention of hyperkalemia in adults".)

Phosphate — Hyperphosphatemia and a mild to moderate high anion gap acidosis may be seen due to the release of intracellular phosphate and organic acids [35]. The release of phosphate from damaged muscle cells frequently induces a confounding variable in patients with hypophosphatemia-induced rhabdomyolysis since the underlying hypophosphatemia may be masked [61]. In this setting, the demonstration of a low plasma phosphate concentration before or after the peak muscle breakdown may be the only clue to the presence of phosphate depletion.

Hypocalcemia and hyperphosphatemia are not significant features of hemolysis in the absence of AKI.

Transaminases — Intra-myocyte enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH, and aldolase may be increased in patients with rhabdomyolysis; these may be the first biochemical abnormalities to be detected. As a result, these laboratory abnormalities are often initially misinterpreted as indicating liver disease. LDH is usually elevated among patients with hemolysis, although AST, ALT and aldolase are generally normal.

Other — Hyperuricemia may be present due to the release of nucleosides from damaged myocyte nuclei, which are metabolized in the liver into purines and then converted to uric acid. Thromboplastin release from cells resulting in the development of disseminated intravascular coagulation has been reported in patients with rhabdomyolysis [62].

In addition to the laboratory abnormalities described above, hemolysis is characterized by anemia, a reduced haptoglobin level, a positive direct antiglobulin test (Coombs test), and an abnormal blood smear with increased reticulocytes and spherocytic red cells. The CK is usually normal in patients with hemolysis. (See "Diagnosis of hemolytic anemia in adults".)

DIAGNOSIS — The diagnosis of heme-induced AKI is strongly suggested by oliguria in the setting of either known rhabdomyolysis or hemolysis. As patients may be unable to provide a reliable history, the diagnosis relies heavily on the assessment of the clinical circumstances and an appreciation of the underlying potential for either rhabdomyolysis or hemolysis.

The presence of dipstick microhematuria in the absence of visible red cells by urine microscopy is compatible with both rhabdomyolysis and hemolysis. Urine sediment demonstrating dark brown granular casts suggests the diagnosis of acute tubular necrosis (ATN). As described above, in contrast to other forms of ATN, the fractional excretion of sodium is often <1 percent. (See 'Urinalysis' above.)

A markedly elevated serum creatine kinase (CK) level (ie, >20,000 to 30,000 units/L) is diagnostic of rhabdomyolysis, though a 5- to 10-fold increase in levels above the population reference range (or approximately 1000 units/L) also suggests clinically relevant rhabdomyolysis [63]. More minor elevations are relatively common and often asymptomatic. However, the interpretation of the CK level must take into account the interval from time of injury to presentation as levels quickly decline from their peak value. CK levels may also be lower in patients with liver disease or multiorgan failure, possibly due to decreased half-life of the enzyme in the circulation as a result of extracellular glutathione depletion [64].

Although an elevated myoglobin level is also diagnostic of rhabdomyolysis, this test is only mildly to moderately sensitive. Tests of myoglobinuria are unreliable and should not be used for screening [43]. In general, there is little diagnostic utility in routinely monitoring intra-myocyte enzyme levels other than CK [63].

Hemolysis is strongly suggested by reddish discoloration of plasma and by an increased serum lactate dehydrogenase (LDH). Hemolysis is confirmed by the demonstration of increased reticulocytes and spherocytic red cells on the peripheral smear, increased reticulocyte percentage, a reduced or absent level of serum haptoglobin, and a positive Coombs test. (See "Diagnosis of hemolytic anemia in adults".)

While the diagnosis of heme pigment-induced AKI relies on the presence of decreased kidney function in the appropriate clinical circumstances, various urinary and serum proteins are being investigated as possible biomarkers for the early diagnosis of AKI (see "Investigational biomarkers and the evaluation of acute kidney injury"). In the future, such biomarkers may be able to reliably discriminate between heme pigment-induced AKI and other conditions, including volume depletion and kidney ischemia.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY

●Heme pigment-induced acute kidney injury – Acute kidney injury (AKI) may occur in patients who have rhabdomyolysis and/or hemolysis. AKI is caused by the nonprotein heme pigment that is released from either myoglobin or hemoglobin and is toxic to the kidney. Predisposing conditions that contribute to heme pigment-induced injury include volume depletion, acidosis, and, possibly, mild ischemia. (See 'Introduction' above.)

●Causes of rhabdomyolysis – The major causes of rhabdomyolysis include traumatic muscle injury, increased voluntary or involuntary muscle activity, exogenous toxins including alcohol and illicit drugs, hereditary myopathies, and inflammatory muscle diseases. (See 'Causes of rhabdomyolysis' above.)

●Causes of hemolysis – The causes of intravascular hemolysis include ABO-incompatible blood transfusions, glucose-6-phosphate dehydrogenase (G6PD) deficiency, poisonings, snake and insect bites, drug reactions, paroxysmal nocturnal hemoglobinuria (PNH), malaria, and cardiac and vascular surgery, including placement of left ventricular assist devices (LVADs). (See 'Causes of hemolysis' above.)

●Clinical manifestations – The clinical manifestations of heme-induced AKI include oliguria or anuria, red or brown urine, and pigmented granular casts on urinalysis. Patients with rhabdomyolysis have increased plasma creatine kinase (CK). Patients with hemolysis have a reduced haptoglobin and an abnormal peripheral blood smear. An increased serum lactate dehydrogenase (LDH) may be seen in hemolysis and rhabdomyolysis. (See 'Clinical manifestations' above and "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

●Diagnosis – The diagnosis of heme-induced AKI is suggested by oliguria in the setting of either known rhabdomyolysis or hemolysis, dipstick microhematuria in the absence of visible red cells by urine microscopy, and the presence of dark brown granular casts. A markedly elevated serum CK level is diagnostic of rhabdomyolysis. Hemolysis is suggested by reddish discoloration of plasma and by increased levels of serum LDH and indirect (unconjugated) bilirubin and may be confirmed by examination of the peripheral smear, increased reticulocyte percentage, and a reduced or absent level of serum haptoglobin. (See 'Diagnosis' above and "Diagnosis of hemolytic anemia in adults".)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Joseph A Eustace, MB, MHS, MRCPI, who contributed to an earlier version of this topic review.

The editorial staff also acknowledge Sinead Kinsella, MD, MBS, MRCPI, now deceased, who contributed to an earlier version of this topic.