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Acute kidney injury secondary to lymphoma.

INTRODUCTION

Onco-nephrology is a new and evolving clinical entity that highlights the importance of the interaction between cancer and kidney disease. Patients with cancer are known to have an increased risk of developing acute kidney injury (AKI) due to the malignancy or its associated treatments, which can ultimately lead to chronic kidney disease. Many antineoplastic medications used to treat cancer can cause renal disease and certain malignancies have also been linked to kidney injury, such as lymphoma.

The development of cancer-associated kidney complications is associated with poor prognosis (Darmon, Ciroldi, Tiery, Schlemmer, & Azoulay, 2006; Kitai, Matsubara, & Yanagita, 2015). Among critically ill patients with cancer, 12% to 49% experience acute renal failure and 9% to 32% require renal replacement therapy (Darmon et al., 2006). Among these patients, acute renal dysfunction commonly occurs in the context of multiple organ dysfunction and is associated with 72% to 85% mortality rates (Darmon et al., 2006). Another study reported that AKI conferred a six-month mortality of 73% in this patient population (Soares et al., 2006). Therefore, there is growing emphasis on understanding the diagnosis and management of cancer-associated kidney complications. This article will review the pathophysiology of acute kidney injury caused by lymphoma.

LYMPHOMA

Lymphoma is a hematological malignancy that develops due to the abnormal growth of lymphocytes found within the lymphatic system. Genome-wide molecular profiling has revealed subtypes of lymphoma that originate from lymphocytes differing in development stage (Lenz & Staudt, 2010). The two main subtypes of lymphoma are Hodgkin's lymphoma and non-Hodgkin's lymphoma.

Hodgkin's lymphoma is the most common cancer in adolescents and younger adults with an incidence rate of three per 100,000 person-years (Carbone, Gloghini, Castagna, Santoro, & Carlo-Stella, 2015). Hodgkin's lymphoma can be classified into classical Hodgkin's lymphoma, which accounts for 95% of all cases, and the less common nodular lymphocyte-predominant Hodgkin's lymphoma (Armitage, 2010; Carbone et al., 2015; Connors, 2005). Classical Hodgkin's lymphoma is a B-cell malignancy characterized by the presence of Hodgkin and Reed-Sternberg cells (Carbone et al., 2015). Hodgkin's lymphoma often presents as painless swelling of lymph nodes, persistent fatigue, fever and chills, and unexplained weight loss (Armitage, 2010; Connors, 2005). Cure rates approaching 80% have been achieved in patients with advanced-stage disease undergoing frst-line chemotherapy and radiation. In patients with late-relapsing and refractory Hodgkin's lymphoma, responses have been achieved with salvage high-dose chemotherapy and autologous stem cell transplantation (Armitage, 2010; Carbone et al., 2015; Connors, 2005).

Non-Hodgkin's lymphomas use the regulatory biologic features of normal cells for their own malignant purpose, and thus, their function depends largely on the diferentiation state of the cells from which they originate (Lenz & Staudt, 2010). There are over 30 types of non-Hodgkin's lymphoma, the most common form being diffuse large-B-cell lymphoma, which accounts for 30 to 50% of newly diagnosed lymphomas (Lenz & Staudt, 2010). Presentation and treatment modalities for non-Hodgkin's lymphoma are similar to those for Hodgkin's lymphoma. More than 90% of patients with early stage non-Hodgkin's lymphoma are cured with chemotherapy and radiation; however, long-term survival for those with refractory or relapsed disease is only 20% (Barth, Chu, Hanley, & Cairo, 2016).

Hodgkin's and non-Hodgkin's lymphomas can start almost anywhere in the body, usually in a group of lymph nodes in one part of the body that then spreads. Eventually, lymphomas can metastasize to almost any tissue or organ in the body through the lymphatic system or bloodstream (Armitage, 2010; Lenz & Staudt, 2010). Many case reports have been published describing cases of AKI secondary to lymphoma.

ACUTE KIDNEY INJURY

Acute kidney injury due to hematologic malignancies, such as leukemia and lymphoma, is common. In a prospective, multicentre, cohort study of 1,411 intensive care unit patients, the diagnosis of lymphoma or leukemia had the greatest risk for AKI (OR 2.23, p = 0.04) relative to other factors such as infection, cirrhosis, and cardiovascular disease (de Mendonca et al., 2000). The diagnosis of lymphoma or leukemia also had the greatest risk of death (OR 2.31, p = 0.04) in all AKI patients (de Mendonca et al., 2000). Patients presenting with AKI in the setting of lymphoma may have pre-renal, renal, or post-renal etiologies (Luciano & Brewster, 2014). Table 1 describes the potential etiologies of AKI in lymphoma patients.

PRE-RENAL ACUTE KIDNEY INJURY

Pre-renal AKI is the most common kidney injury in lymphoma (Luciano & Brewster, 2014). Volume depletion due to poor oral intake, emesis, and diarrhea contribute to pre-renal AKI (Kitai et al., 2015; Luciano & Brewster, 2014). Reduced kidney perfusion may also occur due to comorbidities, such as heart failure and cirrhosis, or medications that affect kidney afferent and efferent tone such as nonsteroidal anti-inflammatory medications (Luciano & Brewster, 2014). According to the type of volume depletion, the severity of fluid deficit, and patient signs and symptoms, oral or parenteral fluid can be given (Sarhill, Walsh, Nelson, & Davis, 2001).

RENAL ACUTE KIDNEY INJURY

Renal AKI caused by lymphoma can be subdivided into ischemic and non-ischemic acute tubular necrosis (ATN), tubulointerstitial disorders, renovascular disorders, and glomerulopathies (Luciano & Brewster, 2014). Diagnosis of renal AKI is dependent upon diagnostic imaging, urine sediment examination, and biopsy (Luciano & Brewster, 2014). Examination of urine sediment is often considered critical for diagnosis. The presence of renal tubular epithelial cells and casts indicates ATN; white cells and casts suggest infiltration or interstitial nephritis; and red blood cells and casts may indicate glomerulopathy (Luciano & Brewster, 2014).

Acute tubular necrosis is the most common renal AKI seen in lymphoma patients, with lysozyme-induced tubular necrosis and tumour lysis syndrome being common etiologies (Luciano & Brewster, 2014). Lysozyme is freely fltered by the glomerulus and reabsorbed by the proximal tubule cells, and at the high concentrations seen in lymphoma, lysozyme induces direct tubular damage (Luciano & Brewster, 2014). Treatment for lymphoma will decrease lysozyme production and improve AKI. Direct tubular damage may also occur secondary to tumour lysis syndrome due to the accumulation of uric acid crystals in renal tubules, renal vasoconstriction, and the release of pro-inflammatory cytokines in the renal interstitium (Kitai et al., 2015; Luciano & Brewster, 2014). Prevention of tumour lysis syndrome with hydration and/or direct xanthine oxidase inhibitors such as allopurinol is recommended (Kitai et al., 2015; Luciano & Brewster, 2014).

Acute kidney injury may also occur due to kidney infiltration by lymphoma, with the rate of infiltration dependent upon the stage and grade of disease (Luciano & Brewster, 2014). The kidney is the most common extranodal site for metastatic lymphoma, and involvement is typically diffuse, bilateral, and symmetrical (Obrador, Price, O'Meara, & Salant, 1997). In one autopsy study with 700 lymphoma patients, kidney infiltration was seen in 34% of patients (Obrador et al., 1997; Richmond, Sherman, Diamond, & Craver., 1962). Although kidney infiltration is fairly common, AKI from infiltration is rare and is seen in less than 1% of cases (Luciano & Brewster, 2014). Patients with kidney infiltration may present with flank pain, hematuria, hypertension, or abdominal distension (Luciano & Brewster, 2014; Obrador et al., 1997). AKI due to kidney infiltration often responds dramatically to lymphoma treatment with serum creatinine concentrations returning to normal within one to four weeks (Obrador et al., 1997).

Renovascular causes of AKI may include renal vein thrombosis and thrombotic microangiopathy (TMA). Several factors in lymphoma may contribute to kidney vasculature thrombosis, such as leukostasis, malignancy-associated nephrotic syndrome, and treatments that activate the clotting cascade (Luciano & Brewster, 2014). TMA results from intravascular platelet activation and formation of platelet-rich thrombi (Kitai et al., 2015). Most cases of lymphoma-associated TMA have been with disseminated cancer and poor prognosis.

Glomerulopathies have also been described in lymphoma, with the most common glomerular lesion associated with Hodgkin's and non-Hodgkin's lymphomas being minimal change disease (Luciano & Brewster, 2014). It is hypothesized that minimal change disease results from immune cell dysfunction with abnormal cytokine production and secretion by T-cells and the release of a glomerular permeability factor (Kitai et al., 2015; Luciano & Brewster, 2014). Glomerulopathies in Hodgkin's lymphoma occur later in the disease without correlation to progression, whereas glomerulopathies in Non-Hodgkin's lymphoma occur earlier and progress with disease (Luciano & Brewster, 2014). As with other forms of AKI in lymphoma, glomerulopathies can be treated with successful treatment of the malignancy.

POST-RENAL ACUTE KIDNEY INJURY

In patients with lymphoma, obstruction may result from direct compression of ureteral outflow by tumour or lymph nodes, retroperitoneal fibrosis, or nephrolithiasis from tumour lysis syndrome (Luciano & Brewster, 2014). Often with obstructive AKI, urine output is stable, but anuric kidney failure should raise concerns for bilateral obstruction, although this is a rare occurrence (Luciano & Brewster, 2014). In 1974, Abeloff and Lenhard reviewed 384 cases of lymphoma and found obstructive uropathy in 7.1% of patients, with less than 50% of the patients with ureteral obstruction having signs and symptoms related to the urinary tract. Signs and symptoms of obstruction may include oliguria, weakness, and flank pain, and a kidney ultrasound often demonstrates hydronephrosis (Mekori, Steiner, Bernheim, Manor, & Klajman, 1984). Decompression with nephrostomy tubes may prevent permanent injury (Luciano & Brewster, 2014).

CASE REPORTS

Various case reports have been published detailing etiologies of AKI in lymphoma patients. One retrospective study by Da'as et al. (2001) reported 66 patients with lymphoma out of 700 who experienced renal failure. The causes of renal failure are detailed in Table 2. The authors describe indirect causes of renal disease, such as obstruction or therapy-related toxicities, as being the most common causes of AKI in lymphoma patients. Da'as et al. also describe unique cases of renal failure. One case involved a 52-year-old man with mantle cell lymphoma presenting with acute renal failure, splenomegaly, and mesenteric lymphadenopathy. Urine analysis revealed telescopic sediment, and kidney biopsy showed diffuse proliferative glomerulonephritis. The patient was treated with corticosteroids, cyclophosphamide, and doxorubicin. On follow-up, the patient's kidney function returned to normal.

CONCLUSION

This article introduces the pathophysiology of AKI secondary to lymphoma. Acute kidney injury secondary to lymphoma is common and encompasses pre-renal, renal, and post-renal etiologies. Not only does AKI in cancer patients increase the risk of mortality, but patients with impaired renal function are at risk of delayed life-saving therapy or experiencing drug toxicity due to drug or metabolite accumulation. As the risk of renal disease continues to be a growing concern amongst cancer patients, nephrologists and oncologists must continue to work collaboratively to treat lymphoma while also preventing and treating kidney injury.

REFERENCES

Abelof, M.D., & Lenhard, R.E. (1974). Clinical management of ureteral obstruction secondary to malignant lymphoma. Johns Hopkins Medical Journal,134(1), 34-42.

Armitage, J.O. (2010). Early-stage Hodgkin's lymphoma. New England Journal of Medicine, 363(7), 653-62. doi:10.1056/NEJMra1003733

Barth, M.J., Chu, Y., Hanley, P.J., & Cairo, M.S. (2016). Immunotherapeutic approaches for the treatment of childhood adolescent and young adult non-Hodgkin lymphoma. British Journal of Haematology, 173(4), 597-616. doi:10.1111/bjh.14078

Carbone, A., Gloghini, A., Castagna, L., Santoro, A., & Carlo-Stella, C. (2015). Primary refractory and early-relapsed Hodgkin's lymphoma: Strategies for therapeutic targeting based on the tumour micrenvironment. Journal of Pathology, 237(1), 4-13. doi:10.1002/path.4558

Connors, J.M. (2005). State-of-the-art therapeutics: Hodgkin's lymphoma. Journal of Clinical Oncology, 23(26), 6400-6408. doi:10.1200/JCO.2005.05.016

Da'as, N., Polliack, A., Cohen, Y., Amir, G., Damon, D., Kleinman, Y., ... Ben-Yehuda, D. (2001). Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: A retrospective study in 700 patients. European Journal of Haematology, 67(3), 158-164. doi:10.1034/j.1600-0609.2001.5790493

Darmon, M., Ciroldi, M., Tiery, G., Schlemmer, B., & Azoulay, E. (2006). Clinical review: Specific aspects of acute renal failure in cancer patients. Critical Care, 10(2), 211. doi:10.1186/cc4907

de Mendonca, A., Vincent, J.L., Suter, P.M., Moreno, R., Dearden, N.M., Antonelli, M., ... Cantraine, F. (2000). Acute renal failure in the ICU: Risk factors and outcome evaluated by the SOFA score. Intensive Care Med, 26(7), 915-921.

Kitai, Y., Matsubara, T., & Yanagita, M. (2015). Onco-nephrology: Current concepts and future perspectives. Japanese Journal of Clinical Oncology, 45(7), 617-28. doi:10.1093/jjco/hyv035

Lenz, G., & Staudt, L.M. (2010). Aggressive lymphomas. New England Journal of Medicine, 362(15), 1417-29. doi:10.1056/NEJMra0807082

Luciano, R.L., & Brewster, U.C. (2014). Kidney involvement in leukemia and lymphoma. Advances in Chronic Kidney Disease, 21(1), 27-35. doi:10.1053/j.ackd.2013.07.004

Mekori, Y., Steiner, Z. P., Bernheim, J., Manor, Y., & Klajman, A. (1984). Acute anuric bilateral ureteral obstruction in malignant lymphoma. American Journal of the Medical Sciences, 287(1), 70-73.

Obrador, G.T., Price, B., O'Meara, Y., & Salant, D.J. (1997). Acute renal failure due to lymphomatous infiltration of the kidneys. Journal of the American Society of Nephrology, 8(8), 1348-1354.

Richmond, J., Sherman, R.S., Diamond, H.D., Craver, L.F. (1962). Renal lesions associated with malignant lymphomas. American Journal of the Medical Sciences, 32, 184-207.

Sarhill, N., Walsh, D., Nelson, K., & Davis, M. (2001). Evaluation and treatment of cancer-related fluid deficits: Volume depletion and dehydration. Support Care in Cancer, 9(6), 408-419. doi:10.1007/s005200100251

Soares, M., Salluh, J., Carvalho, M., Darmon, M., Rocco, J.R., & Spector, N. (2006). Prognosis of critically ill patients with cancer and acute renal dysfunction. Journal of Clinical Oncology, 24(24), 4003-10. doi:10.1200/JCO.2006.05.7869

By Patwant Dhillon and Marisa Battistella

ABOUT THE AUTHORS

Patwant Dhillon, Pharm D, Pharmacy Resident, University Health Network, Toronto, ON

Marisa Battistella, PharmD, ACPR, Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Pharmacy Clinician Scientist, Clinical Pharmacist--Nephrology, University Health Network, Toronto, ON
Table 1: Etiologies of Acute Kidney Injury in Lymphoma

Pre-renal   Intravascular volume depletion
             Nausea, emesis, diarrhea
             Hemorrhage
            Reduced kidney perfusion
             Vasoconstriction
             Sepsis
             Liver disease
             Medications (diuretics, nonsteroidal anti-inflammatory
             drugs)
Renal       Acute tubular necrosis
             Kidney ischemia
             Tumour lysis syndrome
             Medications (acetaminophen, nonsteroidal anti-inflammatory
             drugs, aminoglycosides)
            Tubulointerstitial disorders
             Secondary kidney infiltration
             Primary kidney lymphoma
            Glomerular disorders
             Amyloidosis
             IgA nephropathy
            Renovascular disorders
             Renal vein thrombosis
             Thrombotic microangiopathy
Post-Renal  Obstruction
             Exterior compression (lymphadenopathy, obstructing tumour)
             Internal obstruction (nephrolithiasis, crystalluria)

(*)Adapted from Luciano & Brewster (2014).

Table 2: Renal Failure Etiologies

Cause                              No. of patients

Direct effects (lymphoma)          19
 Infiltration of kidney             5
 Obstruction                       14
Indirect effects (paraneoplastic)   7
 Glomerulonephritis                 4
 Paraprotienemia                    1
 Cryoglobulinemia                   2
Therapy-related                    15
 Tumour lysis syndrome              4
 Cytoxan-induced cystitis           4
 Infection/nephrotoxic drugs        7
Unrelated to lymphoma              13
 Unknown                           12

(Da'as et al., 2001)
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Title Annotation:CONTINUING EDUCATION SERIES
Author:Dhillon, Patwant; Battistella, Marisa
Publication:CANNT Journal
Article Type:Report
Date:Jan 1, 2017
Words:2359
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