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Kidney Involvement in Leukemia and Lymphoma

  • Randy L. Luciano
    Affiliations
    Yale University School of Medicine, New Haven, CT; and Section of Nephrology, Yale University School of Medicine, New Haven, CT
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  • Ursula C. Brewster
    Correspondence
    Address correspondence to Ursula C. Brewster, MD, Section of Nephrology, Yale University School of Medicine, 330 Cedar Street, Boardman Building 121, New Haven, CT 06520.
    Affiliations
    Yale University School of Medicine, New Haven, CT; and Section of Nephrology, Yale University School of Medicine, New Haven, CT
    Search for articles by this author
      Leukemia and lymphoma are hematologic malignancies that can affect any age group. Disease can be aggressive or indolent, often with multiorgan system involvement. Kidney involvement in leukemia and lymphoma can be quite extensive. Acute kidney injury (AKI) is quite prevalent in these patients, with prerenal and acute tubular necrosis being the most common etiologies. However other prerenal, intrinsic, and obstructive etiologies are possible. AKI can be a direct effect of the malignancy, a complication of the malignancy, or the consequence or side effect of chemotherapy. Nephrotic syndrome and glomerulonephritis, often presenting without overt kidney failure, have also been seen in all forms of leukemia and lymphoma. Lastly, the direct effects of the malignancy and complications from the tumor often result in numerous electrolyte disturbances and acid-base disorders, with life-threatening consequences if left untreated.

      Key Words

      Introduction

      • Acute kidney injury (AKI) is quite common in patients with hematologic malignancies, contributing to increased morbidity and mortality.
      • Diagnosing AKI in patients with hematologic malignancy is similar to other forms of AKI, but certain disease-specific entities (such as lysozyme-induce kidney injury, tumor lysis syndrome, direct kidney infiltration, and hematologic-mediated obstruction) are not uncommon occurrences.
      • Acute and chronic leukemias and Hodgkin's and non-Hodgkin's lymphomas are associated with nephrotic syndrome and glomerulonephritis.
      • Disorders of potassium, magnesium, phosphate, sodium, and calcium as well as type B lactic acidosis are prevalent in patients with hematologic malignancies.
      Leukemia and lymphoma are hematologic malignancies derived from bone marrow or lymphoid cells, respectively. Although uncommon, more patients are living longer lives with disease or in remission. Leukemia and lymphoma can involve other organs, including the kidney. Kidney manifestations encompass a broad spectrum of disease: prerenal acute kidney injury (AKI), acute tubular necrosis (ATN), renovascular disease, parenchymal infiltration, obstruction, glomerulopathies, and electrolyte and acid-base abnormalities. Kidney injury may result from the underlying malignancy itself or as a secondary complication of therapy. It may delay treatment, which in turn can affect prognosis and mortality. The overlap of these cancers and the kidney will be discussed.

       AKI in Lymphoma and Leukemia

      AKI in patients with lymphoma and leukemia is common. A study looking at 349 patients with hematologic malignancy admitted to the intensive care unit demonstrated some form of AKI in 149 patients (43%). Of those patients with AKI, 29% required renal replacement therapy with a mortality rate of 72%.
      • Lanore J.J.
      • Brunet F.
      • Pochard F.
      • et al.
      Hemodialysis for acute renal failure in patients with hematologic malignancies.
      In a study of 1411 intensive care unit patients, the diagnosis of lymphoma or leukemia had the greatest risk for AKI (odds ratio 2.23) relative to other factors, including infection, cirrhosis, and cardiovascular disease. It also had the greatest risk of death (odds ratio 2.31) in all AKI patients.
      • de Mendonca A.
      • Vincent J.L.
      • Suter P.M.
      • et al.
      Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score.
      The approach to a patient presenting with AKI in the setting of lymphoma or leukemia must assess prerenal, intrarenal, and postrenal etiologies (Table 1).
      Table 1Etiology of Acute Kidney Injury in Leukemia and Lymphoma
      Prerenal
      • Intravascular volume depletion
        • Nausea, emesis, diarrhea (from chemotherapy or treatment)
        • Hemorrhage
        • Increased insensible losses (fever, tachypnea)
      • Reduced kidney perfusion
        • Vasoconstriction (hypercalcemia, hyperuricemia)
        • Sepsis
        • Liver disease
        • Medications (renin-angiotensin-aldosterone system blockers, nonsteroidal anti-inflammatory drugs, diuretics)
      Intrarenal
      • Acute tubular necrosis
        • Kidney ischemia
        • Lysozymuria
        • Tumor lysis syndrome
        • Medications (antibiotics, chemotherapy)
      • Tubulointerstitial disorders
        • Secondary kidney infiltration
        • Primary kidney lymphoma
        • Allergic interstitial nephritis
      • Glomerular disorders
      • Renovascular disorders
        • Renal vein thrombosis
        • Thrombotic microangiopathy
        • Leukostasis
      Postrenal
      • Obstruction
        • Exterior compression (lymphadenopathy, obstructing tumor)
        • Retroperitoneal fibrosis
        • Internal obstruction (nephrolithiasis, crystalluria)

      Prerenal AKI

      Prerenal AKI is the most common kidney injury in lymphoma or leukemia. Volume depletion from poor oral fluid intake (78%), anorexia (64%), early satiety (50%), emesis (23%), and diarrhea (16%) contribute to prerenal AKI.
      • Sarhill N.
      • Walsh D.
      • Nelson K.
      • Davis M.
      Evaluation and treatment of cancer-related fluid deficits: volume depletion and dehydration.
      Insensible losses and decreased effective circulating volume can be exacerbated by comorbid conditions such as cirrhosis or heart failure. Medications that affect kidney afferent and efferent tone, including renin-angiotensin blockade, nonsteroidal anti-inflammatory medications, and diuretics used for hypertension, may also contribute. Prerenal AKI is often suspected based on clinical course and history and supported with physical exam and laboratory data. The urine sediment is usually bland, with occasional hyaline casts or cellular elements. Treatment is supportive, with crystalloid expansion and removal of exacerbating factors.

      Postrenal AKI

      In patients with lymphoma or leukemia, obstruction may result from direct compression or encasement of ureteral outflow by tumor or lymph nodes, retroperitoneal fibrosis, or nephrolithiasis from tumor lysis syndrome.
      • Chong B.H.
      • Trew P.
      • Meng L.
      • Pitney W.R.
      Anuric renal failure due to encasement of the ureters by lymphoma–ureteric obstruction without dilatation.
      • Mekori Y.A.
      • Steiner Z.P.
      • Bernheim J.
      • Manor Y.
      • Klajman A.
      Acute anuric bilateral ureteral obstruction in malignant lymphoma.
      Anuric kidney failure should raise the concern for bilateral obstruction, but often with obstructive AKI, urine output is stable. Hematuria and pyuria may be present, and kidney ultrasound should demonstrate hydronephrosis unless collecting system dilatation is prevented by fibrosis. Immediate decompression with nephrostomy tubes may prevent permanent injury.

      Intrarenal AKI

      Intrarenal causes of kidney injury in hematologic malignancy can be grouped into ischemic and nonischemic ATN, tubulointerstitial disorders, renovascular disorders, and glomerulopathies. Hemodynamically mediated injury (for example, severe volume depletion, heart failure, or sepsis) and drug-induced injury are common with hematologic malignancy. However, it is critical to separate these processes from kidney injury directly caused by hematological malignancy because therapy and hopes of improvement of kidney function depend on treatment of the underlying disease. In subsequent sections, we 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 hematologic malignancy, may be the first insight into kidney involvement. Computed tomography scan may show renomegaly with diffuse bilateral enlargement pointing to kidney infiltration (Fig 1). Examination of the urine sediment is critical, is often underutilized, and may replace costly laboratory tests. Renal tubular epithelial cells and casts point toward ATN. White cells and white cell casts suggest an underlying malignant infiltration, interstitial nephritis, or severe pyelonephritis. Dysmorphic red cells and red cell casts indicate a glomerulopathy. Biopsy remains the gold standard in diagnosis and can help delineate the aforementioned causes of intrarenal injury. Light microscopy with hematoxylin and eosin staining can elucidate glomerular, tubulointerstitial, or vascular disorders. Immunofluorescence and electron microscopy can provide additional information on glomerular involvement. However, biopsy may be difficult in a patient with hematologic malignancy because of thrombocytopenia and uremia, which increase bleeding risk.
      Figure thumbnail gr1
      Figure 1Computed tomography scan of abdomen and pelvis without radiocontrast showing bilateral kidney enlargement.

      Acute Tubular Necrosis

      ATN is the most common cause of intrinsic AKI in lymphoma and leukemia. In a single-center study, of all patients with hematologic malignancy with AKI, 83% had ATN, with 96% of those patients experiencing sepsis and 88% receiving nephrotoxic medications.
      • Harris K.P.
      • Hattersley J.M.
      • Feehally J.
      • Walls J.
      Acute renal failure associated with haematological malignancies: a review of 10 years experience.
      The disease-specific etiologies of ATN are discussed below.
      Lysozyme-induced tubular necrosis occurs in patients with hematologic malignancies.
      • Patel T.V.
      • Rennke H.G.
      • Sloan J.M.
      • DeAngelo D.J.
      • Charytan D.M.
      A forgotten cause of kidney injury in chronic myelomonocytic 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. Lysozyme 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. The high concentrations of urinary lysozyme, exacerbated by proximal tubule injury, which prevents reabsorption, can present as nephritic-range proteinuria leading to a pseudonephrotic syndrome.
      • Patel T.V.
      • Rennke H.G.
      • Sloan J.M.
      • DeAngelo D.J.
      • Charytan D.M.
      A forgotten cause of kidney injury in chronic myelomonocytic leukemia.
      When suspected, the protein can be measured with serum and urine protein electrophoresis revealing increased γ globulin levels; this can be confirmed with immunofixation to exclude monoclonal paraproteins.
      • Levinson S.S.
      • Elin R.J.
      • Yam L.
      Light chain proteinuria and lysozymuria in a patient with acute monocytic leukemia.
      Treatment of the underlying malignancy will decrease lysozyme and improve AKI.
      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.
      • Wilson F.P.
      • Berns J.S.
      Onco-nephrology: tumor lysis syndrome.
      At high levels uric acid crystals can precipitate in renal tubules, leading to direct tubular injury. In addition, uric acid is a vasoconstrictor that may exacerbate renal tubular damage, recruit proinflammatory cytokines to the renal interstitium, and delay recovery.
      • Cirillo P.
      • Gersch M.S.
      • Mu W.
      • et al.
      Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells.
      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.
      • Wilson F.P.
      • Berns J.S.
      Onco-nephrology: tumor lysis syndrome.

      AKI From Kidney Infiltration

      The kidney is the most common extrareticular and extrahematopoietic organ infiltrated by leukemia and lymphoma, with infiltration seen in 60% to 90% of patients with hematologic malignancy.
      • Richmond J.
      • Sherman R.S.
      • Diamond H.D.
      • Craver L.F.
      Renal lesions associated with malignant lymphomas.
      Kidney dysfunction varies from asymptomatic to severe and requiring renal replacement therapy. The rate of infiltration parallels the stage and grade of disease. In a series of 1200 autopsy cases, the prevalence of kidney 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).
      • Barcos M.
      • Lane W.
      • Gomez G.A.
      • et al.
      An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).
      In a separate autopsy study in 700 patients with lymphoma, kidney infiltration was present in 34% of patients with Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL).
      • Richmond J.
      • Sherman R.S.
      • Diamond H.D.
      • Craver L.F.
      Renal lesions associated with malignant lymphomas.
      Kidney failure primarily due to lymphomatous or 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 and lymphomas.
      • Lundberg W.B.
      • Cadman E.D.
      • Finch S.C.
      • Capizzi R.L.
      Renal failure secondary to leukemic infiltration of the kidneys.
      Symptoms and signs that may be associated with infiltration include flank pain, hematuria, abdominal distension, or hypertension.
      • Obrador G.T.
      • Price B.
      • O'Meara Y.
      • Salant D.J.
      Acute renal failure due to lymphomatous infiltration of the kidneys.
      Infiltration has to be bilateral in nature, and enlargement is usually uniform. Kidney biopsy is often useful in these patients for 2 reasons. First, the extent and location of infiltration tends to influence prognosis. Interstitial infiltration tends to be associated with AKI, as opposed to glomerular infiltration, which presents as a glomerulopathy (Fig 2A).
      • Tornroth T.
      • Heiro M.
      • Marcussen N.
      • Franssila K.
      Lymphomas diagnosed by percutaneous kidney biopsy.
      Second, biopsy may help differentiate subtypes of lymphoma or leukemia and alter disease treatment. Specific stains can be used to identify cellular markers of differentiation (Fig 2B). Targeting these cells with chemotherapy is important because improvement of kidney function depends on treatment of the underlying disease. Regression and improvement in kidney function should be prompt (ie, occurring sometime within 2-3 days of therapy).
      • Obrador G.T.
      • Price B.
      • O'Meara Y.
      • Salant D.J.
      Acute renal failure due to lymphomatous infiltration of the kidneys.
      Kidney failure resulting from infiltration is thought to be secondary to acute tubular compression and disruption of the kidney microvasculature from increased interstitial pressure leading to ATN.
      Figure thumbnail gr2
      Figure 2(A) Kidney biopsy stained with hematoxylin and eosin at 60× magnification. (B) Tissue stained with B-cell-specific marker anti-CD38 at 200× magnification.
      Primary renal lymphoma, characterized by primary localization of the lymphoma to the kidney, is extremely rare, with an incidence of 0.7% of all extranodal lymphomas.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
      Because the kidney itself is devoid of any significant lymphoid tissue, the small amount of lymphoid tissue in the renal capsule and renal sinus lymph nodes is the proposed source of the malignancy. However, chronic inflammation in the kidney is likely necessary to stimulate lymphoid transformation, similar to the transformation of chronic inflammatory processes in other organs (for example, the association of Hashimoto's thyroiditis with thyroid lymphoma). Primary renal lymphoma usually presents with AKI and hypertension. Histology demonstrates interstitial infiltration with minimal fibrosis, and prognosis is poor.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.

      AKI From Renovascular Disorders

      In these diseases, several factors contribute to thrombosis of the kidney 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. Renal artery and renal vein thrombosis have been described.
      • Levin M.D.
      • Betjes M.G.
      • V d Kwast T.H.
      • Wenberg B.L.
      • Leebeek F.W.
      Acute renal cortex necrosis caused by arterial thrombosis during treatment for acute promyelocytic leukemia.
      Antiphospholipid syndrome, acquired through antiphospholipid antibody production in malignant states, has been seen with lymphomas. This can increase the risk of venous and arterial thrombus formation, with resultant kidney infarcts.
      • Gómez-Puerta J.A.
      • Cervera R.
      • Espinosa G.
      • et al.
      Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients.
      Thrombotic microangiopathies have also been reported in acute and chronic leukemias and lymphomas, resulting in AKI.
      • Clarke R.T.
      • Mitchell C.
      Haemolytic uraemic syndrome in a patient with acute lymphoblastic leukaemia.
      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 kidney vasculature.
      • McKee L.C.
      • Collins R.D.
      Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia.
      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 been reported.
      • Dietrich P.Y.
      • Pedraza E.
      • Casiraghi O.
      • Bayle C.
      • Hayat M.
      • Pico J.L.
      Cardiac arrest due to leucostasis in a case of prolymphocytic leukaemia.
      Treatment of the underlying malignancy usually resolves the injury.

       Glomerular Disease With Hematologic Malignancies

      Glomerulopathies have been described in all hematologic malignancies. The following section outlines specific glomerular lesions based on the underlying malignancy (Table 2). When urinalysis suggests glomerular pathology, a biopsy should be performed. As with other forms of kidney injury in hematologic malignancy, glomerulopathies require successful treatment of the underlying disease.
      Table 2Summary of Glomerulopathies Seen in Leukemia and Lymphoma
      MalignancyGlomerular LesionsImportant Points
      ALLMCD

      FSGS
      • Proteinuria can be due to lysozymuria induced tubular damage
      • More often glomerular damage precedes malignancy
      • Predominantly seen in children
      AMLMCD

      FSGS

      MPGN

      Mesangioproliferative GN
      • Proteinuria can be due to lysozymuria-induced tubular damage
      • Possible association with oncornavirus antigens
      CLLMCD

      FSGS

      Membranous nephropathy

      MPGN IgG kappa and lambda

      Amyloidosis (AA)

      Crescentic GN

      Immunotactoid GN

      Mesangioproliferative GN
      • Associated with autoimmune disease
      • Infiltration in 90% of patients (asymptomatic and symptomatic)
      CMLMCD

      Membranous nephropathy

      MPGN
      • Very rare with primary disease
      • Associated with interferon- α therapy and posthematopoietic stem cell transplantation
      MDS/MPNMDS: Membranous nephropathy

      Mesangioproliferative GN

      Amyloidosis (AL)

      PV: FSGS

      Mesangioproliferative GN

      IgA nephropathy

      ET: FSGS

      Mesangioproliferative GN

      MF: FSGS

      Mesangioproliferative GN

      Amyloidosis

      CMML: Amyloidosis (AL)
      • MPN glomerulopathy has been described in patients with PV, ET, and MF. Includes a collection of histological findings: mesangial sclerosis and hypercellularity, segmental sclerosis, chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration
      HLMCD

      FSGS

      Amyloidosis (AA)

      Crescentic GN
      • Occur late in disease
      • No correlation with disease progression or severity
      • Associated with elevated VEGF-25,TGF-βexpression in models
      NHLMCD

      FSGS

      Membranous nephropathy

      MPGN

      Mesangioproliferative GN

      Crescentic GN

      Amyloidosis (AL)

      IgA nephropathy

      Immunotactoid GN

      Fibrillary GN
      • Occur early in disease
      • Severity mirrors disease progression
      • Associated with hepatitis C and Epstein-Barr viral infections
      Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic monomyelocytic leukemia; ET, essential thrombocytosis; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HL, Hodgkin's lymphoma; Ig, immunoglobulin; MCD, minimal change disease; MDS, myelodysplastic syndrome; MF, primary myelofibrosis; MPGN, membranoproliferative glomerulonephritis; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin's lymphoma; PV, polycythemia vera; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

      Acute Lymphoblastic Leukemia

      Proteinuria in ALL is usually pseudonephrotic syndrome, associated with lysozymuria.
      • Patel T.V.
      • Rennke H.G.
      • Sloan J.M.
      • DeAngelo D.J.
      • Charytan D.M.
      A forgotten cause of kidney injury in chronic myelomonocytic leukemia.
      However, in children, nephrotic syndrome may portend a future diagnosis of ALL. In 8 pediatric cases, focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) preceded the diagnosis of ALL by less than 1 year.
      • Bhatia M.
      • Kher K.
      • Minniti C.P.
      Acute lymphoblastic leukemia in a child with nephrotic syndrome.
      • Muller W.
      • Brandis M.
      Acute leukemia after cytotoxic treatment for nonmalignant disease in childhood. A case report and review of the literature.
      • Sathiapalan R.K.
      • Velez M.C.
      • McWhorter M.E.
      • et al.
      Focal segmental glomerulosclerosis in children with acute lymphocytic leukemia: case reports and review of literature.
      At presentation, these patients demonstrated abnormal leukocyte profiles and were treated with glucocorticoids. It is unclear whether nephrotic syndrome is an early manifestation of ALL or whether immunosuppressive treatment causes proliferation of an abnormal WBC clone. MCD has been diagnosed during induction chemotherapy for known ALL, suggesting that an immune cell dysregulation is common between the 2 disease entities. However, given the paucity of cases, mechanisms are purely speculative. Because ALL is mostly a disease of childhood, glomerular lesions have not been reported in adults.

      Acute Myeloid Leukemia

      Proteinuria in AML can also be related to lysozymuria. Biopsies from patients with nephritic-range proteinuria, in the absence of lysozymuria, have identified FSGS, MCD, mesangioproliferative glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN).
      • Dosa S.
      • Phillips T.M.
      • Antonovych T.T.
      • Segal A.
      • Guha A.
      • Thompson A.M.
      Acute myelomonocytic leukemia associated with nephrotic syndrome. A case report with immunological studies.
      • Omura K.
      • Kawamura T.
      • Utsunomiya Y.
      • Abe A.
      • Joh K.
      • Sakai O.
      Development of nephrotic syndrome in a patient with acute myeloblastic leukemia after treatment with macrophage-colony-stimulating factor.
      In 2 of these cases, nephritic-range proteinuria was present at the time of disease diagnosis, with a positive correlation between the degree of proteinuria and leukemic burden. In other cases, nephrotic syndrome came months after diagnosis or in association with chemotherapy. The etiology of glomerulonephritis (GN) and nephrotic syndrome in AML is currently unclear and likely multifactorial. Studies of subclinical immune complexes in kidneys of patients with AML have identified antigens related to oncornaviruses, suggesting a possible viral-related etiology to the immune-mediated glomerular lesions.
      • Sutherland J.C.
      • Mardiney Jr., M.R.
      Immune complex disease in the kidneys of lymphoma-leukemia patients: the presence of an oncornavirus-related antigen.

      Chronic Lymphocytic Leukemia

      CLL infiltrates the kidney interstitium of approximately 90% of patients at the time of autopsy; however, clinical kidney disease is uncommon.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
      Although many glomerular lesions have been reported, MPGN is the most common, followed by membranous.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
      Other reported glomerulopathies are presented in detail in Table 2. The pathophysiology of GN is thought to be multifactorial. CLL is characterized by aberrant proliferation of a monoclonal B-cell clone, and it is the deposition of the monoclonal immune complexes in the glomerulus that is thought to be pathologic.
      • Seney Jr., F.D.
      • Federgreen W.R.
      • Stein H.
      • Kashgarian M.
      A review of nephrotic syndrome associated with chronic lymphocytic leukemia.
      CLL is also associated with various autoimmune disorders, and this association may predispose patients to cryoglobulin production and subsequent immune complex deposition.
      • Gale R.P.
      • Foon K.A.
      Biology of chronic lymphocytic leukemia.
      Lastly, CLL patients are prone to infection, from either immunosuppression due to clonal expansion or functional asplenism, both of which may contribute to infection-related GN.

      Chronic Myeloid Leukemia

      Glomerular disease associated with CML is rare. Reports of nephrotic syndrome have mostly been the result of interferon-α therapy or hematopoietic stem cell transplants.
      • Budak-Alpdogan T.
      • Lawrence R.A.
      • Bayik M.
      • Akoglu E.
      Nephrotic syndrome associated with alpha interferon therapy in chronic myeloid leukemia.
      However, cases of MPGN, membranous nephropathy, and MCD associated with CML have been reported.
      • Agarwal R.G.
      • Gupta K.D.
      • Bharadwaj T.P.
      Nephrotic syndrome in the possible terminal blast-cell crisis in myeloid leukaemia (a case report).
      • Talwar R.
      • Dash S.C.
      • Kucheria K.
      A case of chronic myeloid leukemia complicated with minimal change nephrotic syndrome.
      Glomerular injury in CML has occurred in blast crisis and the chronic phase of malignancy, making an association with disease state difficult. Speculation on the cause of glomerular lesions in CML includes infection-related processes in the setting of splenomegaly-induced immunosuppression, autoimmune dysregulation, or deposition of disease-mediated immune complexes. However, given the very low incidence, the etiology remains poorly understood.

      Myeloproliferative Neoplasms/Myelodysplastic Syndromes

      Myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS) are a group of diseases with malignant potential of varying degrees. MPN, which consists of CML (see above), essential thrombocytosis, polycythemia vera, and myelofibrosis, may progress to the more aggressive MDS or AML. MDS itself has a 20% to 30% prognosis of progression to refractory AML. Within this group of disorders is chronic myelomonocytic leukemia, a disease with features of MPN and MDS. Kidney involvement in these specific disorders is presented in Table 2.
      • Plomley R.F.
      • Sullivan J.R.
      • Whitworth J.A.
      • Kincaid-Smith P.S.
      • Fairley K.F.
      • Brown R.W.
      Polycythemia vera and glomerulonephritis.
      • Saitoh T.
      • Murakami H.
      • Uchiumi H.
      • et al.
      Myelodysplastic syndromes with nephrotic syndrome.
      • Ferhanoglu B.
      • Erzin Y.
      • Baslar Z.
      • Tuzuner H.A.
      Secondary amyloidosis in the course of idiopathic myelofibrosis.
      • Au W.Y.
      • Chan K.W.
      • Lui S.L.
      • Lam C.C.
      • Kwong Y.L.
      Focal segmental glomerulosclerosis and mesangial sclerosis associated with myeloproliferative disorders.
      • Kasuno K.
      • Ono T.
      • Kamata T.
      • et al.
      IgA nephropathy associated with polycythaemia vera: accelerated course.
      • Chan K.W.
      • Ho C.P.
      Amyloidosis complicating idiopathic myelofibrosis.
      • Morschhauser F.
      • Wattel E.
      • Pagniez D.
      • et al.
      Glomerular injury in chronic myelomonocytic leukemia.
      A case series of patients with MPN has yielded the findings of mesangial sclerosis and hypercellularity, segmental sclerosis, chronic thrombotic microangiopathies, and intracapillary hematopoietic cell infiltration, termed MPN glomerulopathy.
      • Said S.M.
      • Leung N.
      • Sethi S.
      • et al.
      Myeloproliferative neoplasms cause glomerulopathy.
      In these cases, kidney disease does not appear to correlate with malignant potential of the underlying disorder.

      Hodgkin's Lymphoma

      The most common glomerular lesion associated with HL is MCD, although FSGS has also been reported.
      • Mallouk A.
      • Pham P.T.
      • Pham P.C.
      Concurrent FSGS and Hodgkin's lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies.
      Amyloidosis (AA amyloid) has been described in HL; however, the prevalence has decreased with improved treatment.
      • Mallouk A.
      • Pham P.T.
      • Pham P.C.
      Concurrent FSGS and Hodgkin's lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies.
      Anti-glomerular basement membrane disease, which occurs with a frequency several-fold higher than in patients without malignancy, and pauci-immune crescentic GN have been reported.
      • Cil T.
      • Altintas A.
      • Isikdogan A.
      • Batun S.
      Prevalence of antineutrophil cytoplasmic antibody positivity in patients with Hodgkin's and non-Hodgkin lymphoma: a single center experience.
      The development of a glomerulopathy in HL is likely secondary to abnormal cytokine production and secretion by affected T-cells. This leads to alterations in glomerular permeability and thereby proteinuria. In particular, Reed Sternberg cells express vascular endothelial growth factor-25 and transforming growth factor (TGF)-β126, cytokines linked to the pathogenesis of FSGS.
      • Doussis-Anagnostopoulou I.A.
      • Talks K.L.
      • Turley H.
      • et al.
      Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin-Reed-Sternberg cells in Hodgkin's disease.
      The association of MCD or FSGS with HL may ultimately depend on the specific cytokines and growth factors secreted and the proto-oncogenes expressed by the affected T-cells.

      Non-Hodgkin's Lymphoma

      Glomerular lesions in patients with NHL vary widely and depend on the stage of lymphoma. In contrast to HL, in which glomerular involvement occurs later in the disease without correlation to progression or aggressiveness, glomerulopathies in NHL occur earlier and progress with disease. Proliferative lesions are more common in NHL, compared with HL, and may account for up to 30% of glomerular diseases.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
      MPGN, with or without immune complex deposition, has been reported.
      • Audard V.
      • Larousserie F.
      • Grimbert P.
      • et al.
      Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature.
      In a series of 37 patients with NHL, crescentic GN was seen in 5 cases, immunoglobulin A nephropathy in 4 cases, and fibrillary GN in 1 case.
      • Da'as N.
      • Polliack A.
      • Cohen Y.
      • et al.
      Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
      Amyloidosis, as with HL, is less common with current chemotherapeutic options, but unlike HL it tends to be the AL amyloid subtype.
      • Audard V.
      • Larousserie F.
      • Grimbert P.
      • et al.
      Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature.
      Other lesions are reported in Table 2. NHL is thought to cause GN through dysfunctional cytokine production leading to immune complex deposition and cellular proliferation. A subset of patients with NHL may develop kidney lesions in association with concurrent hepatitis C virus infection with or without cryoglobulinemia. Other viral infections such as Epstein-Barr virus have been implicated in immune complex deposition, causing glomerulopathies in NHL.

       Electrolyte and Acid-Base Disorders

      Various electrolyte and acid-base abnormalities have been described in lymphomas and leukemias (Table 3). These disorders are due to the malignancy itself, direct infiltration of organs, cell lysis, or chemotherapeutic agents leading to AKI. Hypokalemia is the most prevalent abnormality (43-64%), followed by hypomagnesemia (25-32%) and hypophosphatemia (16-30%).
      • Filippatos T.D.
      • Milionis H.J.
      • Elisaf M.S.
      Alterations in electrolyte equilibrium in patients with acute leukemia.
      Here we focus on these disorders in addition to disorders of sodium and calcium and type B lactic acidosis.
      Table 3Electrolyte and Acid-Base Disorders in Leukemia and Lymphoma
      Electrolyte DisorderEtiology
      Hypokalemia
      • Gastrointestinal loss (diarrhea, emesis)
      • Kaliuresis
        • Tubular dysfunction (medications, lysozymuria)
        • Hypomagnesemia
      • Renin-angiotensin-aldosterone system activation
        • Volume depletion
        • Paraneoplastic renin release
      • Intracellular shift
        • Entry into actively proliferating cells
      HyperkalemiaCellular lysis (tumor lysis syndrome)

      Reduced GFR (acute kidney injury)

      Pseudohyperkalemia (cell lysis associated with collection)
      Hypomagnesemia
      • Gastrointestinal losses
      • Magnesuria
        • Tubular dysfunction (lysozyme, medications)
      • Intracellular shifts
      HypophosphatemiaGastrointestinal loss

      Phosphaturia (tubular dysfunction)

      Intracellular shift
      HyperphosphatemiaCellular lysis (tumor lysis syndrome)

      Reduced GFR (acute kidney injury)
      HyponatremiaHypovolemic hyponatremia

      SIADH
      HypernatremiaCentral diabetes insipidus
      HypocalcemiaCalcium-phosphate precipitation in tumor lysis syndrome

      Low vitamin D

      Chronic respiratory alkalosis

      Hypoalbuminemia

      Hypomagnesemia
      HypercalcemiaPTHrP expression

      Upregulation of RANK-L by cytokines
      Metabolic acidosisType B lactic acidosis
      Abbreviations: GFR, glomerular filtration rate; PTHrP, parathyroid-hormone-related protein; RANK-L, receptor activator of nuclear factor kappa-B ligand; SIADH, syndrome of inappropriate antidiuretic hormone.

      Potassium Disorders

      In a case series of 22 patients with acute leukemia, total body potassium per kilogram of body weight was significantly lower in leukemic patients when compared with healthy controls.
      • Lantz B.
      • Carlmark B.
      • Reizenstein P.
      Electrolytes and whole body potassium in acute leukemia.
      Patients with malignancy may have a reduction in caloric intake, but this is rarely the cause of hypokalemia unless potassium intake is decreased to 20 mEq/day or less.
      • Gallen I.W.
      • Rosa R.M.
      • Esparaz D.Y.
      • et al.
      On the mechanism of the effects of potassium restriction on blood pressure and renal sodium retention.
      Emesis and the loss of H+ ions and associated metabolic alkalosis may lead to increased kidney potassium losses. This process leads to metabolic alkalosis, resulting in increased serum bicarbonate levels, which eventually overwhelm the tubular reabsorptive capacity of bicarbonate. As a result, there is increased distal delivery of sodium bicarbonate leading to enhanced potassium excretion by the already active principal cell. Medications not uncommon to patients with leukemia and lymphoma, such as penicillins, aminoglycosides, and amphotericin, may also lead to increased kidney potassium wasting because of direct effects on tubules or potassium channels or by disruption of the net charge in the tubule lumen. A hypothesized cause of hypokalemia in hematologic malignancy is the increased uptake of potassium into metabolically active cells via active Na+/K+ ATPase. A less common cause of hypokalemia that has been reported in AML is through paraneoplastic activation of the renin-angiotensin-aldosterone system by the production of renin.
      • Wulf G.G.
      • Jahns-Streubel G.
      • Strutz F.
      • et al.
      Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells.
      Hyperkalemia in lymphoma and leukemia is less common. It is most often due to potassium release from cell lysis, either from natural destruction of a rapidly growing cell or as a chemotherapy consequence.
      • Wilson F.P.
      • Berns J.S.
      Onco-nephrology: tumor lysis syndrome.
      These patients tend to have very elevated WBC counts; therefore, pseudohyperkalemia from postphlebotomy cell destruction needs to be considered.
      • Bronson W.R.
      • DeVita V.T.
      • Carbone P.P.
      • Cotlove E.
      Pseudohyperkalemia due to release of potassium from white blood cells during clotting.
      It is important to recognize this phenomenon to avoid unnecessary treatment of normal potassium levels that can lead to potentially dangerous hypokalemia.

      Magnesium Disorders

      Magnesium balance is influenced by gastrointestinal, hematologic, and kidney mechanisms. Diarrhea or poor oral intake may contribute. As with potassium, magnesium shifts into the intracellular environment occur in patients with leukocytosis and high metabolic activity.
      • Filippatos T.D.
      • Milionis H.J.
      • Elisaf M.S.
      Alterations in electrolyte equilibrium in patients with acute leukemia.
      Hypermagnesuria occurs in approximately 15% in acute leukemic patients; this correlates with one half of all hypomagnesemic patients, suggesting a primary renal mechanism.
      • Milionis H.J.
      • Bourantas C.L.
      • Siamopoulos K.C.
      • Elisaf M.S.
      Acid-base and electrolyte abnormalities in patients with acute leukemia.
      Lysozymuria through direct tubular toxicity has been shown to lead to magnesuria.
      • Patel T.V.
      • Rennke H.G.
      • Sloan J.M.
      • DeAngelo D.J.
      • Charytan D.M.
      A forgotten cause of kidney injury in chronic myelomonocytic leukemia.
      Many pharmacologic agents (such as aminoglycosides, amphotericin, and pentamidine) used in infectious complications in immunosuppressed patients have been implicated in decreased magnesium absorption through paracellular or active transport.

      Phosphate Disorders

      As with potassium and magnesium, hypophosphatemia may be multifactorial in patients with a hematologic malignancy. Acute diarrhea leads to significant phosphate loss, as can acute antacid ingestion. Dietary phosphate complexes with calcium or other metals in the antacid preparations to impede absorption. Hypophosphatemia can occur from acute shifts of phosphate into metabolically active cells, as seen in leukemia.
      • Zamkoff K.W.
      • Kirshner J.J.
      Marked hypophosphatemia associated with acute myelomonocytic leukemia. Indirect evidence of phosphorus uptake by leukemic cells.
      Direct tubular damage can lead to tubular dysfunction and Fanconi's syndrome, resulting in increased urinary phosphate loss.
      Hyperphosphatemia is most commonly seen in the setting of AKI, leading to decreased kidney phosphate excretion, and in tumor lysis syndrome. Patients with acute hematological malignancies may be predisposed to hyperphosphatemia because lymphoblasts have been shown to have a 4-fold higher concentration of phosphate as opposed to a normal lymphocyte.

      Sodium Disorders

      Hyponatremia has been estimated to occur in approximately 10% of patients with acute hematologic malignancies.
      • Filippatos T.D.
      • Milionis H.J.
      • Elisaf M.S.
      Alterations in electrolyte equilibrium in patients with acute leukemia.
      The most common cause of hyponatremia in these patients is hypovolemic hyponatremia due to volume depletion in the setting of poor oral intake, emesis, and diarrhea. Euvolemic hyponatremia in the form of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion is uncommon. However, SIADH may be present in the setting of an underlying lung infection or disease infiltration or central nervous system involvement. Hypernatremia is extremely rare in hematologic malignancy, but it can be associated with poor access to free water, or rarely it has been associated with central nervous system leukemic or lymphomatous infiltration, producing a central diabetes insipidus state.
      • Miller V.I.
      • Campbell Jr., W.G.
      Diabetes insipidus as a complication of leukemia. A case report with a literature reviews.
      • Zheng W.L.
      • Zhang G.S.
      • Tan C.L.
      • Shen J.K.
      • Yang J.J.
      • Zhong H.Y.
      Diabetes insipidus as main presentation of non-Hodgkin's lymphoma with hypophyseal involvement: two case reports.
      It is interesting to note that the presence of certain cytogenetic abnormalities with AML has been linked to the development of diabetes insipidus.
      • Dy P.
      • Chua P.
      • Kelly J.
      • Liebman S.
      Central diabetes insipidus in the setting of acute myelogenous leukemia.

      Calcium Disorders

      Hypercalcemia is the most common disturbance of calcium homeostasis in hematologic malignancies. In leukemia, hypercalcemia can occur in the acute and chronic phases. In CML, it usually presents with blast crisis or an accelerated phase of leukemia. Inflammatory mediators such as TGF-α, TGF-β, prostaglandin E2, and interleukin-6 are elevated in CML blast crisis and acute leukemia, and these mediators may cause upregulation of receptor activator of nuclear factor kappa-B ligand (RANK-L) expression and 1,25-dihydroxy-vitamin D3 (calcitrol).
      • Noguchi M.
      • Oshimi K.
      Extensive bone marrow necrosis and symptomatic hypercalcemia in B cell blastic transformation of chronic myeloid leukemia: report of a case and review of the literature.
      RANK-L leads to increased osteoclast activity, thereby contributing to increased serum calcium levels, whereas activated vitamin D leads to increased bone turnover and increased intestinal reabsorption of calcium. Elevations of serum parathyroid hormone related protein (PTHrP) have been described in a few cases of CML.
      • Miyoshi N.
      • Tanaka H.
      • Ito T.
      • et al.
      Use of imatinib mesylate for favorable control of hypercalcemia mediated by parathyroid hormone-related protein in a patient with chronic myelogenous leukemia at blast phase.
      PTHrP leads to increased levels of calcium by increasing bone resorption and increased distal tubule calcium reabsorption.
      Hypercalcemia occurs in approximately 13% of patients with NHL and in 5.4% of patients with HL.
      • Burt M.E.
      • Brennan M.F.
      Incidence of hypercalcemia and malignant neoplasm.
      In NHL, hypercalcemia correlates with more advanced disease and the median survival is significantly shorter at 10 months compared with 21 months. Calcitriol has been implicated as a key mediator of hypercalcemia in almost all cases of HL and in 30% to 40% of cases of NHL.
      • Seymour J.F.
      • Gagel R.F.
      Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas.
      Local osteolysis with increased expression of osteoclast-activating factors, including macrophage inflammatory proteins 1a and 1b and RANK-L, in diffuse large B-cell lymphoma cells causes hypercalcemia.
      • Matsuhashi Y.
      • Tasaka T.
      • Uehara E.
      • et al.
      Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis.
      PTHrP has also been reported as a proposed factor for hypercalcemia in some cases with B-cell NHL, especially in cases with Richter's transformation.
      • Beaudreuil J.
      • Lortholary O.
      • Martin A.
      • et al.
      Hypercalcemia may indicate Richter's syndrome: report of four cases and review.
      Hypocalcemia is rare in hematologic malignancy. It can result from various factors, including hypoalbuminemia, malnutrition, malabsorption, vitamin D deficiency, co-existing hypomagnesaemia, or chronic respiratory alkalosis. Tumor lysis with its high serum phosphorous concentrations can lead to calcium-phosphate deposition, thereby lowering serum calcium levels.

      Acid-Base Disorders

      Acid-base disorders are quite common in hematologic malignancies, with 1 study showing metabolic alkalosis in 30% of patients and metabolic acidosis in 10% of patients with acute leukemia.
      • Mir M.A.
      • Delamore I.W.
      Metabolic disorders in acute myeloid leukaemia.
      However, the complexity of patients with acute hematologic malignancies makes the interpretation of acid-base disorders somewhat challenging; rarely is there 1 explanation for the underlying disorder and often there is a mixed acid-base disorder. Specific to hematologic malignancies, a type B lactic acidosis may also occur with the generation of lactate in the absence of tissue hypoperfusion or severe hypoxemia.
      • Ruiz J.P.
      • Singh A.K.
      • Hart P.
      Type B lactic acidosis secondary to malignancy: case report, review of published cases, insights into pathogenesis, and prospects for therapy.
      There also may be deficient conversion of lactate to pyruvate and glucose by dysfunctional kidneys and livers in the state of active tumor growth, which largely uses anaerobic metabolism. Also, a relative thiamine deficiency may reduce pyruvate dehydrogenase activity leading to lactate production from pyruvate.

      Conclusion

      With the increased incidence of hematologic malignancy and new therapies that are prolonging survival in patients with leukemia and lymphoma, kidney injury and complications will undoubtedly become more prevalent. Because the differential is broad for AKI in these patients, the nephrologist must be thorough to correctly diagnose the cause of injury. Therapy for AKI, glomerulopathies, or electrolyte disorders is largely supportive, with treatment of the underling malignancy the mainstay.

      References

        • Lanore J.J.
        • Brunet F.
        • Pochard F.
        • et al.
        Hemodialysis for acute renal failure in patients with hematologic malignancies.
        Crit Care Med. 1991; 19: 346-351
        • de Mendonca A.
        • Vincent J.L.
        • Suter P.M.
        • et al.
        Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score.
        Intensive Care Med. 2000; 26: 915-921
        • Sarhill N.
        • Walsh D.
        • Nelson K.
        • Davis M.
        Evaluation and treatment of cancer-related fluid deficits: volume depletion and dehydration.
        Support Care Cancer. 2001; 9: 408-419
        • Chong B.H.
        • Trew P.
        • Meng L.
        • Pitney W.R.
        Anuric renal failure due to encasement of the ureters by lymphoma–ureteric obstruction without dilatation.
        Aust N Z J Med. 1981; 11: 542-544
        • Mekori Y.A.
        • Steiner Z.P.
        • Bernheim J.
        • Manor Y.
        • Klajman A.
        Acute anuric bilateral ureteral obstruction in malignant lymphoma.
        Am J Med Sci. 1984; 287: 70-73
        • Harris K.P.
        • Hattersley J.M.
        • Feehally J.
        • Walls J.
        Acute renal failure associated with haematological malignancies: a review of 10 years experience.
        Eur J Haematol. 1991; 47: 119-122
        • Patel T.V.
        • Rennke H.G.
        • Sloan J.M.
        • DeAngelo D.J.
        • Charytan D.M.
        A forgotten cause of kidney injury in chronic myelomonocytic leukemia.
        Am J Kidney Dis. 2009; 54: 159-164
        • Levinson S.S.
        • Elin R.J.
        • Yam L.
        Light chain proteinuria and lysozymuria in a patient with acute monocytic leukemia.
        Clin Chem. 2002; 48: 1131-1132
        • Wilson F.P.
        • Berns J.S.
        Onco-nephrology: tumor lysis syndrome.
        Clin J Am Soc Nephrol. 2012; 7: 1730-1739
        • Cirillo P.
        • Gersch M.S.
        • Mu W.
        • et al.
        Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells.
        J Am Soc Nephrol. 2009; 20: 545-553
        • Richmond J.
        • Sherman R.S.
        • Diamond H.D.
        • Craver L.F.
        Renal lesions associated with malignant lymphomas.
        Am J Med. 1962; 32: 184-207
        • Barcos M.
        • Lane W.
        • Gomez G.A.
        • et al.
        An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).
        Cancer. 1987; 60: 827-837
        • Lundberg W.B.
        • Cadman E.D.
        • Finch S.C.
        • Capizzi R.L.
        Renal failure secondary to leukemic infiltration of the kidneys.
        Am J Med. 1977; 62: 636-642
        • Obrador G.T.
        • Price B.
        • O'Meara Y.
        • Salant D.J.
        Acute renal failure due to lymphomatous infiltration of the kidneys.
        J Am Soc Nephrol. 1997; 8: 1348-1354
        • Tornroth T.
        • Heiro M.
        • Marcussen N.
        • Franssila K.
        Lymphomas diagnosed by percutaneous kidney biopsy.
        Am J Kidney Dis. 2003; 42: 960-971
        • Da'as N.
        • Polliack A.
        • Cohen Y.
        • et al.
        Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients.
        Eur J Haematol. 2001; 67: 158-164
        • Levin M.D.
        • Betjes M.G.
        • V d Kwast T.H.
        • Wenberg B.L.
        • Leebeek F.W.
        Acute renal cortex necrosis caused by arterial thrombosis during treatment for acute promyelocytic leukemia.
        Haematologica. 2003; 88: ECR21
        • Gómez-Puerta J.A.
        • Cervera R.
        • Espinosa G.
        • et al.
        Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients.
        Semin Arthritis Rheum. 2006; 35: 322-332
        • Clarke R.T.
        • Mitchell C.
        Haemolytic uraemic syndrome in a patient with acute lymphoblastic leukaemia.
        Pediatr Blood Cancer. 2010; 55: 1402-1405
        • McKee L.C.
        • Collins R.D.
        Intravascular leukocyte thrombi and aggregates as a cause of morbidity and mortality in leukemia.
        Medicine (Baltimore). 1974; 53: 463-478
        • Dietrich P.Y.
        • Pedraza E.
        • Casiraghi O.
        • Bayle C.
        • Hayat M.
        • Pico J.L.
        Cardiac arrest due to leucostasis in a case of prolymphocytic leukaemia.
        Br J Haematol. 1991; 78: 122-123
        • Bhatia M.
        • Kher K.
        • Minniti C.P.
        Acute lymphoblastic leukemia in a child with nephrotic syndrome.
        Pediatr Nephrol. 2004; 19: 1290-1293
        • Muller W.
        • Brandis M.
        Acute leukemia after cytotoxic treatment for nonmalignant disease in childhood. A case report and review of the literature.
        Eur J Pediatr. 1981; 136: 105-108
        • Sathiapalan R.K.
        • Velez M.C.
        • McWhorter M.E.
        • et al.
        Focal segmental glomerulosclerosis in children with acute lymphocytic leukemia: case reports and review of literature.
        J Pediatr Hematol Oncol. 1998; 20: 482-485
        • Dosa S.
        • Phillips T.M.
        • Antonovych T.T.
        • Segal A.
        • Guha A.
        • Thompson A.M.
        Acute myelomonocytic leukemia associated with nephrotic syndrome. A case report with immunological studies.
        Nephron. 1983; 34: 125-129
        • Omura K.
        • Kawamura T.
        • Utsunomiya Y.
        • Abe A.
        • Joh K.
        • Sakai O.
        Development of nephrotic syndrome in a patient with acute myeloblastic leukemia after treatment with macrophage-colony-stimulating factor.
        Am J Kidney Dis. 1996; 27: 883-887
        • Sutherland J.C.
        • Mardiney Jr., M.R.
        Immune complex disease in the kidneys of lymphoma-leukemia patients: the presence of an oncornavirus-related antigen.
        J Natl Cancer Inst. 1973; 50: 633-644
        • Seney Jr., F.D.
        • Federgreen W.R.
        • Stein H.
        • Kashgarian M.
        A review of nephrotic syndrome associated with chronic lymphocytic leukemia.
        Arch Intern Med. 1986; 146: 137-141
        • Gale R.P.
        • Foon K.A.
        Biology of chronic lymphocytic leukemia.
        Semin Hematol. 1987; 24: 209-229
        • Budak-Alpdogan T.
        • Lawrence R.A.
        • Bayik M.
        • Akoglu E.
        Nephrotic syndrome associated with alpha interferon therapy in chronic myeloid leukemia.
        Clin Nephrol. 1997; 48: 59-60
        • Agarwal R.G.
        • Gupta K.D.
        • Bharadwaj T.P.
        Nephrotic syndrome in the possible terminal blast-cell crisis in myeloid leukaemia (a case report).
        J Assoc Physicians India. 1972; 20: 799-801
        • Talwar R.
        • Dash S.C.
        • Kucheria K.
        A case of chronic myeloid leukemia complicated with minimal change nephrotic syndrome.
        Acta Haematol. 2003; 109: 101-103
        • Plomley R.F.
        • Sullivan J.R.
        • Whitworth J.A.
        • Kincaid-Smith P.S.
        • Fairley K.F.
        • Brown R.W.
        Polycythemia vera and glomerulonephritis.
        Aust N Z J Med. 1983; 13: 125-129
        • Saitoh T.
        • Murakami H.
        • Uchiumi H.
        • et al.
        Myelodysplastic syndromes with nephrotic syndrome.
        Am J Hematol. 1999; 60: 200-204
        • Ferhanoglu B.
        • Erzin Y.
        • Baslar Z.
        • Tuzuner H.A.
        Secondary amyloidosis in the course of idiopathic myelofibrosis.
        Leuk Res. 1997; 21: 897-898
        • Au W.Y.
        • Chan K.W.
        • Lui S.L.
        • Lam C.C.
        • Kwong Y.L.
        Focal segmental glomerulosclerosis and mesangial sclerosis associated with myeloproliferative disorders.
        Am J Kidney Dis. 1999; 34: 889-893
        • Kasuno K.
        • Ono T.
        • Kamata T.
        • et al.
        IgA nephropathy associated with polycythaemia vera: accelerated course.
        Nephrol Dial Transplant. 1997; 12: 212-215
        • Chan K.W.
        • Ho C.P.
        Amyloidosis complicating idiopathic myelofibrosis.
        Am J Kidney Dis. 1999; 34: E27
        • Morschhauser F.
        • Wattel E.
        • Pagniez D.
        • et al.
        Glomerular injury in chronic myelomonocytic leukemia.
        Leuk Lymphoma. 1995; 18: 479-483
        • Said S.M.
        • Leung N.
        • Sethi S.
        • et al.
        Myeloproliferative neoplasms cause glomerulopathy.
        Kidney Int. 2011; 80: 753-759
        • Mallouk A.
        • Pham P.T.
        • Pham P.C.
        Concurrent FSGS and Hodgkin's lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies.
        Clin Exp Nephrol. 2006; 10: 284-289
        • Cil T.
        • Altintas A.
        • Isikdogan A.
        • Batun S.
        Prevalence of antineutrophil cytoplasmic antibody positivity in patients with Hodgkin's and non-Hodgkin lymphoma: a single center experience.
        Int J Hematol. 2009; 90: 52-57
        • Doussis-Anagnostopoulou I.A.
        • Talks K.L.
        • Turley H.
        • et al.
        Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin-Reed-Sternberg cells in Hodgkin's disease.
        J Pathol. 2002; 197: 677-683
        • Audard V.
        • Larousserie F.
        • Grimbert P.
        • et al.
        Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature.
        Kidney Int. 2006; 69: 2251-2260
        • Filippatos T.D.
        • Milionis H.J.
        • Elisaf M.S.
        Alterations in electrolyte equilibrium in patients with acute leukemia.
        Eur J Haematol. 2005; 75: 449-460
        • Lantz B.
        • Carlmark B.
        • Reizenstein P.
        Electrolytes and whole body potassium in acute leukemia.
        Acta Med Scand. 1979; 206: 45-50
        • Gallen I.W.
        • Rosa R.M.
        • Esparaz D.Y.
        • et al.
        On the mechanism of the effects of potassium restriction on blood pressure and renal sodium retention.
        Am J Kidney Dis. 1998; 31: 19-27
        • Wulf G.G.
        • Jahns-Streubel G.
        • Strutz F.
        • et al.
        Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells.
        Ann Hematol. 1996; 73: 139-141
        • Bronson W.R.
        • DeVita V.T.
        • Carbone P.P.
        • Cotlove E.
        Pseudohyperkalemia due to release of potassium from white blood cells during clotting.
        N Engl J Med. 1966; 274: 369-375
        • Milionis H.J.
        • Bourantas C.L.
        • Siamopoulos K.C.
        • Elisaf M.S.
        Acid-base and electrolyte abnormalities in patients with acute leukemia.
        Am J Hematol. 1999; 62: 201-207
        • Zamkoff K.W.
        • Kirshner J.J.
        Marked hypophosphatemia associated with acute myelomonocytic leukemia. Indirect evidence of phosphorus uptake by leukemic cells.
        Arch Intern Med. 1980; 140: 1523-1524
        • Miller V.I.
        • Campbell Jr., W.G.
        Diabetes insipidus as a complication of leukemia. A case report with a literature reviews.
        Cancer. 1971; 28: 666-673
        • Zheng W.L.
        • Zhang G.S.
        • Tan C.L.
        • Shen J.K.
        • Yang J.J.
        • Zhong H.Y.
        Diabetes insipidus as main presentation of non-Hodgkin's lymphoma with hypophyseal involvement: two case reports.
        Leuk Res. 2010; 34: e32-e34
        • Dy P.
        • Chua P.
        • Kelly J.
        • Liebman S.
        Central diabetes insipidus in the setting of acute myelogenous leukemia.
        Am J Kidney Dis. 2012; 60: 998-1001
        • Noguchi M.
        • Oshimi K.
        Extensive bone marrow necrosis and symptomatic hypercalcemia in B cell blastic transformation of chronic myeloid leukemia: report of a case and review of the literature.
        Acta Haematol. 2007; 118: 111-116
        • Miyoshi N.
        • Tanaka H.
        • Ito T.
        • et al.
        Use of imatinib mesylate for favorable control of hypercalcemia mediated by parathyroid hormone-related protein in a patient with chronic myelogenous leukemia at blast phase.
        Int J Hematol. 2005; 82: 333-337
        • Burt M.E.
        • Brennan M.F.
        Incidence of hypercalcemia and malignant neoplasm.
        Arch Surg. 1980; 115: 704-707
        • Seymour J.F.
        • Gagel R.F.
        Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas.
        Blood. 1993; 82: 1383-1394
        • Matsuhashi Y.
        • Tasaka T.
        • Uehara E.
        • et al.
        Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis.
        Leuk Lymphoma. 2004; 45: 397-400
        • Beaudreuil J.
        • Lortholary O.
        • Martin A.
        • et al.
        Hypercalcemia may indicate Richter's syndrome: report of four cases and review.
        Cancer. 1997; 79: 1211-1215
        • Mir M.A.
        • Delamore I.W.
        Metabolic disorders in acute myeloid leukaemia.
        Br J Haematol. 1978; 40: 79-92
        • Ruiz J.P.
        • Singh A.K.
        • Hart P.
        Type B lactic acidosis secondary to malignancy: case report, review of published cases, insights into pathogenesis, and prospects for therapy.
        ScientificWorldJournal. 2011; 11: 1316-1324