Prerenal acute kidney injury

Prerenal AKI is the most common kidney injury in leukemia. Poor oral fluid intake (78%), anorexia (64%), early satiety (50%), emesis (23%), and diarrhea (16%) lead to volume depletion and this can lead to a prerenal AKI. Volume depletion can be exacerbated by insensible losses and decreased effective circulating volume from comorbid conditions, such as cirrhosis or heart failure, or through the use of medications that affect kidney afferent and efferent tone, including renin-angiotensin blockade or nonsteroidal antiinflammatory medications (NSAIDs), or diuretics used for hypertension or to control peripheral edema. Prerenal AKI is often suspected based on the clinical course and history, and supported with physical examination findings that demonstrate signs of volume depletion, including hypotension and orthostatic blood pressure changes, tachycardia, flat neck veins, or poor skin turgor. Laboratory data that can be suggestive of a prerenal AKI include hyponatremia or hypernatremia (depending on the degree of free water loss relative to sodium and water loss) and an elevation in blood urea nitrogen (BUN) and serum creatinine, with the BUN to creatinine ratio generally greater than 20. The urinalysis may show an elevated specific gravity with possible ketonuria; if appetite has been exceedingly poor, urine electrolytes usually reveal a very low urine sodium (< 20 mEq/L) and low fractional excretion of sodium (< 1%), and the urine sediment is usually bland, with occasional hyaline casts or cellular elements. Treatment is supportive, with crystalloid expansion and removal of exacerbating factors that have led to the volume depletion.

Postrenal acute kidney injury

In patients with leukemia, obstruction is relatively uncommon, but case reports have demonstrated tumor directly impeding ureteral outflow, extramedullary hematopoiesis causing retroperitoneal fibrosis, or more commonly nephrolithiasis from tumor lysis syndrome. In patients with obstructive AKI, hematuria and pyuria may also be present, and kidney ultrasound should demonstrate hydronephrosis, unless collecting system dilatation is prevented by fibrosis or if the patient has severe volume depletion ( Fig. 37.1 ). Treatment is supportive with immediate decompression of the obstruction with nephrostomy tubes to prevent ongoing and permanent injury.

Ultrasound image from a patient with acute myeloid leukemia, with acute kidney injury from obstruction. White arrow is pointing to severe hydronephrosis. White asterisk is within a benign kidney cyst.

Intrarenal acute kidney injury

Intrarenal causes of kidney injury in leukemia can be grouped into ischemic and nonischemic ATN, tubulointerstitial disorders, renovascular disorders, and glomerulopathies. Hemodynamically mediated injury, caused by severe volume depletion, heart failure, or sepsis, and drug-induced injury are common with leukemia. However, it is critical to separate these processes from AKI directly caused by leukemia, as therapy is targeted towards the malignancy as opposed to general supportive measures, and prognosis depends on successful treatment of the underlying disease. Subsequent sections will focus on intrarenal AKI specific to hematologic malignancy.

Diagnosis of intrarenal AKI often relies on ancillary tests. Diagnostic imaging, which is involved in staging of leukemia, may be the first insight into kidney involvement. Computed tomography scan may show glomerulomegaly with diffuse bilateral enlargement, pointing to kidney infiltration ( Fig. 37.2 A ). Examination of the urine sediment is critical as its diagnostic potential is significant at a low cost. Renal tubular epithelial cells (RTEC) casts point towards ATN. White cells and white cell casts suggest an underlying malignant infiltration, acute interstitial nephritis, or severe pyelonephritis ( Fig. 37.2 B ). Dysmorphic red cells and red cell casts indicate a glomerular involvement. Kidney biopsy remains the gold standard in diagnosis and can help delineate all forms of intrarenal injury. Light microscopy with hematoxylin and eosin staining can demonstrate glomerular, tubulointerstitial, or vascular disorders. Special clonal cellular immunohistochemistry can elucidate the nature of the cells on the specimen. Immunofluorescence and electron microscopy can provide additional information on glomerular involvement. However, biopsy may be difficult in a patient with leukemia because of thrombocytopenia, which increases the risk of bleeding.

A patient with chronic myeloid leukemia. A. Computed tomography showing bilateral enlargement of kidneys. B. Urine sediment under light microscopy at 160 ×, showing a white blood cell cast.

Acute tubular necrosis

ATN is the most common cause of intrinsic AKI in leukemia. In a single center study, out of all patients with hematologic malignancy with AKI, 83% had ATN, with 96% of those patients experiencing sepsis and 88% receiving nephrotoxic medications. ATN can be detected through evaluation of the urinary sediment with the presence of granular casts or RTEC ( Fig. 37.3 A ). If the diagnosis is ambiguous, biopsy can be performed and would demonstrate acute tubular injury, as manifested as renal tubular cells with nuclear dropout, loss of brush border, and cytoplasmic vacuolization ( Fig. 37.3 B ). Disease specific etiologies of ATN are discussed later.

Acute tubular necrosis in a patient with acute kidney injury from severe volume depletion and hypotension in the setting of chronic lymphocytic leukemia. A. 16× light microscopy showing many dense granular casts. B. 40× specimen from a kidney biopsy (stained with hematoxylin and eosin), showing dilated renal tubules, renal tubular cell cytoplasmic vacuolization, and nuclear dropout.

Lysozyme-induced tubular necrosis is a rare but documented cause of kidney injury in patients with leukemia. Lysozyme is a cationic enzyme stored in macrophages and monocytes that may be released to lyse bacterial cell walls. In certain leukemias, clonal expansion increases lysozyme production, which is freely filtered by the glomerulus and then reabsorbed by the proximal tubule cells. At high concentrations, as seen in leukemia, lysozyme induces direct tubular damage causing kaliuresis and proteinuria. High concentrations of urinary lysozyme, exacerbated by proximal tubule injury, which prevents reabsorption, can present as nephrotic range proteinuria, leading to a pseudonephrotic syndrome. When suspected, the protein can be measured with serum and urine protein electrophoresis revealing increased γ globulin levels, and confirmed with immunofixation to exclude monoclonal paraproteins. Treatment of the underlying malignancy will decrease lysozyme and improve kidney function.

Tumor lysis syndrome results from the release of intracellular potassium, phosphate, and nucleic acids from rapidly growing cancer cells. This can be spontaneous or the direct effect of chemotherapy. Purine nucleic acids are converted to xanthine and then to uric acid by xanthine oxidase. At high levels, uric acid crystals can precipitate in renal tubules, leading to direct tubular injury. This can be seen through evaluation of the urinary sediment demonstrating uric acid crystals in isolation or incorporated in casts ( Fig. 37.4 A and B ). In addition, uric acid is a vasoconstrictor that may exacerbate renal tubular damage, recruit proinflammatory cytokines to the renal interstitium, and delay recovery. Direct tubular injury can be seen by the presence of RTEC or granular casts in the urine sediment ( Fig. 37.4 C and D ). Prevention of tumor lysis syndrome with adequate hydration or direct xanthine oxidase inhibitors, such as allopurinol or febuxostat, is ideal. If uric acid levels increase despite these efforts, rasburicase, a recombinant urate oxidase that converts uric acid to allantoin, can be used.

Urine sediment from a patient with tumor lysis syndrome and hyperuricemia. A. 160× light microscopy showing urate crystal cast. B. 160× light microscopy with polarization showing birefringence of urate crystal cast. C. 40× light microscopy showing urate crystals and granular casts urate crystals. D. 40× light microscopy with polarization demonstrating birefringence of urate crystals.

Acute kidney injury from kidney infiltration

The kidney is the most common extrareticular and extrahematopoietic organ infiltrated by leukemia, with infiltration seen in 60% to 90% of patients with hematologic malignancy. Kidney dysfunction varies from asymptomatic increases in serum creatinine to severe AKI requiring dialytic support. The rate of infiltration parallels stage and grade of disease. In a series of 1200 autopsy cases, the prevalence of renal infiltration was 63% in chronic lymphocytic leukemia (CLL), 54% in acute lymphoblastic leukemia (ALL), 34% in chronic myeloid leukemia (CML), and 33% in acute myeloid leukemia (AML); however, the association with elevated serum creatinine and AKI was not reported. Although infiltration is possible, kidney failure primarily caused by leukemic infiltration is rare. AKI from infiltration is seen in only 1% of cases of all patients with acute leukemias and even less commonly in chronic leukemia.

Symptoms and signs that may be associated with infiltration include flank pain, hematuria, abdominal distension, or hypertension. Infiltration has to be bilateral in nature, as circulating cells have access to both kidneys, and enlargement is usually uniform throughout the superior, inferior, and mid-pole regions of the kidney. Renal biopsy is often useful in patients with leukemia who present with AKI in the setting of enlarged kidneys. Biopsy will reveal the extent of infiltration and underlying fibrosis both of which tend to influence prognosis ( Fig. 37.5 A ). Kidney injury resulting from infiltration is thought to be secondary to acute tubular compression and disruption of the renal microvasculature, from increased interstitial pressure leading to ATN. Biopsy may also help differentiate subtypes of leukemia and alter disease treatment ( Fig. 37.5 B ). Specific stains can be used to identify cellular markers of differentiation leading to targeted chemotherapy. Regression and improvement in kidney function should be prompt once therapy is initiated, even occurring within 2 to 3 days of therapy.

Kidney biopsy from a patient with chronic lymphocytic leukemia and acute kidney injury. A. 160× light microscopy image of kidney biopsy specimen (stained with hematoxylin and eosin) showing extensive interstitial inflammation and renal tubule compression. B. 160× light microscopy image of kidney biopsy specimen (stained with anti-CD3 T-cell marker) showing a significant infiltrate of CD3 positive T-cells.

Acute kidney injury from renovascular disorders

Renovascular-mediated kidney injury includes disorders that lead to the thrombosis of large vessels that perfuse (arteries) or drain (veins) the kidneys or endothelial damage and injury to the microvasculature of the kidney. In these diseases, several factors contribute to thrombosis of the renal vasculature, including leukostasis, malignancy-associated nephrotic syndrome leading to loss of procoagulant molecules, and comorbid conditions or treatments that can lead to activation of the clotting cascade. Both renal artery and renal vein thrombosis have been described in leukemia. Thrombotic microangiopathies have also been reported in both acute and chronic leukemias, resulting in AKI.

Although quite rare, AKI from leukostasis has been reported. In an autopsy study consisting of patients with AML, 6% of patients had intravascular leukocyte thrombi and fibrin strands in the renal vasculature. Leukocytosis causing AKI is more commonly seen in myeloid leukemias when white blood cell (WBC) counts exceed 100 × 1000 cells/μL. This is thought to be secondary to the morphology and poor distensibility of rigid myeloblasts in hyperviscous plasma. Despite the predominance of leukostasis-associated AKI in myeloid leukemia, cases of similar AKI in lymphocytic leukemia have also been reported. Treatment of the underlying malignancy and subsequent improvement in leukocyte count usually resolves the injury. Failure of the kidney injury to improve may be suggestive of either prolonged injury leading to interstitial fibrosis and tubular atrophy or a concomitant injury that has not been treated.