Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 670–680 doi: 10.1093/ckj/sfy026 Advance Access Publication Date: 11 April 2018 CKJ Review CK J R EV IEW 1 2 2,3 Rimda Wanchoo , Carolina Bernabe Ramirez , Jacqueline Barrientos and Kenar D. Jhaveri Division of Kidney Diseases and Hypertension, Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA, Division of Hematology and Oncology, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY, USA and CLL Research and Treatment Program, Lake Success, NY, USA Correspondence and offprint requests to: Rimda Wanchoo; E-mail: Rwanchoo1@northwell.edu; Twitter handle: @renalmyeloma ABSTRACT Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia in the USA and Western Europe. Kidney disease can present in patients with CLL as a manifestation of the disease process such as acute kidney injury with inﬁltration or with a paraneoplastic glomerular disease or as a manifestation of extra renal obstruction and tumor lysis syndrome. In the current era of novel targeted therapies, kidney disease can also present as a complication of treatment. Tumor lysis syndrome associated with novel agents such as the B-cell lymphoma 2 inhibitor venetoclax and the monoclonal antibody obinutuzumab are important nephrotoxicities associated with these agents. Here we review the various forms of kidney diseases associated with CLL and its therapies. Keywords: AKI, CLL, inﬁltration, leukemia, onconephrology, paraproteinemia, venetoclax INTRODUCTION associated with severe toxicities such as myelosuppression requiring transfusion support, life-threatening infections or se- Chronic lymphocytic leukemia (CLL) is the most commonly vere organ damage. diagnosed adult leukemia in the USA and Western Europe. Reports published between 1966 and 1973 constituted the Approximately 20 000 new CLL cases are expected to be diag- basis on which Rai et al.  developed a system of staging of CLL nosed in the USA in 2017 . The disease affects primarily the that could prospectively distinguish patients according to their elderly, with the majority of patients being diagnosed at a rela- overall outlook for survival (Table 1). This method of staging tive older age (>65 years). The disease is usually monitored con- was recognized as a simple, yet accurate prognostic tool for esti- servatively until disease-related symptoms develop. Most mating survival and received wide acceptance by clinicians. In common manifestations of CLL that require initiation of ther- the current era, genetic and protein markers are also used to apy include fevers, night sweats, weight loss, organomegaly or characterize CLL. Important characteristics of CLL cells are the lymphadenopathy causing discomfort and bone marrow failure presence of the immunoglobulin variable heavy chain (IGHV) (evidenced by worsening anemia or thrombocytopenia) [2, 3]. gene repertoire and expression of stereotyped B-cell receptors Unfortunately, by the time most patients require therapy, pa- [5, 6]. Approximately half of CLL clones will demonstrate unmu- tients have acquired chronic comorbidities that limit their tated immunoglobulin heavy chain variable regions, a finding performance status and ability to tolerate therapy. Hence pa- associated with shorter overall survival and a higher risk of tients may become too frail to tolerate a regimen that may be Received: 22.12.2017. Editorial decision: 26.2.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com 670 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 The Kidney in CLL | 671 Table 1. Rai staging of CLL Median survival Risk status Stage Description (months) (modified Rai) 0 Lymphocytosis, lymphocytes in blood >15 000 lymphocytes/mm and 40% 140 Low lymphocytes in bone marrow I Stage 0 with enlarged lymph node(s) 100 Intermediate II Stages 0–I with hepatomegaly, splenomegaly or both 70 Intermediate III Stages 0–II with hemoglobin <11 g/dL or hematocrit <33% 20 High IV Stages 0–III with platelets <100 000/lL 20 High Adapted from the National Cancer Institute guidelines and Rai et al. . relapse following chemoimmunotherapy. In addition, the pres- Table 2. Summary of various causes of kidney injury in patients with CLL ence of CD38 appears to be independently associated with an adverse prognosis [5, 6]. Zeta chain–associated protein 70 Type of etiology Potential causes (ZAP70), a tyrosine kinase normally expressed by natural killer and T cells, is required for normal T-cell receptor signaling. Prerenal Poor oral intake; sepsis and hypoperfusion; ZAP70 is not normally expressed in B lymphocytes but has been heart failure; cirrhosis; medications such as diuretics, non-steroidal anti-inﬂammatory found in a subset of patients with CLL and appears to correlate agents, angiotensin receptor blockers and with survival [5, 6]. Specific cytogenetic abnormalities identified angiotensin-converting enzyme inhibitors by fluorescence in situ hybridization (FISH) analysis and abnor- Intrinsic renal Glomerular diseases malities in certain genes identified by molecular genetic testing TMA confer prognostic significance in patients with CLL. Of these, Acute tubular necrosis—sepsis, nephrotoxic del(13q) and trisomy 12 are favorable prognostic findings. agents and in some cases hyperviscosity and Historically, patients with del(17p) or del(11q) have been at high therapy agents risk of either not responding to initial treatment or relapsing Acute interstitial nephritis—infections such as soon after achieving remission [5, 6]. BK or adenovirus, urinary tract infections, medication or chemotherapy induced or ma- lignant cell inﬁltration Postrenal Obstruction from extrinsic compression of pelva- calcyceal system by tumor or lymph nodes KIDNEY DISEASES WITH CLL TLS—uric acid nephropathy and intratubular ob- struction from cancer itself or related to the Kidney disease in patients with CLL may impact survival and use of CLL-directed therapy occurs through diverse mechanisms such as leukemic infiltra- tion, extrarenal obstruction, tumor lysis syndrome (TLS), glom- erular diseases, electrolyte disorders and medication side effects. Here we review the kidney diseases associated with CLL AKI in CLL and its treatments. Strati and Shanafelt  found a 7.5% incidence of kidney AKI in patients with leukemia is common. A study looking at disease at diagnosis in a cohort of >2000 patients with CLL at >300 patients with hematologic malignancies admitted to an the Mayo Clinic. Renal insufficiency at baseline was associated intensive care unit demonstrated some form of AKI in >40% pa- with male gender, older age, more advanced disease and tients. Of those, 29% required renal replacement therapy, with CLL CD49d positivity; these patients were less likely to receive an astounding mortality rate of 72%. The etiology of AKI that purine nucleoside analogue therapy and were more likely to occurs in most hematologic malignancies, including CLL, are di- receive single alkylator-based therapy. Acute kidney injury verse . One study of patients of all hematologic malignancies (AKI) developed in 16% of patients during follow-up and noted that the most common causes of AKI were hypoperfu- was associated with older age, male gender and certain CLL sion, TLS, hemophagocytic syndrome, direct infiltration of ma- þ þ þ lignant cells and infections . Another study found the most characteristics (IGHV UM, CD49d ,CD38 ,ZAP-70 ,del17p ,or common cause of AKI in hematologic malignancies was prere- del11q ). A study from the Mayo Clinic found that the pres- nal azotemia . Based on our experience, prerenal azotemia, ence of kidney disease is independently associated with ad- acute tubular necrosis, TLS from chemotherapy agents and verse patient outcomes in CLL. Kidney disease at diagnosis of infiltrative disease are the common causes of AKI in CLL. CLL or during follow-up had a significantly decreased overall Table 2 summarizes the etiologies causing AKI in patients with survival compared with those without kidney disease . Thus CLL. the presence of kidney disease in patients with CLL affects patient treatment strategies, clinical trial candidacy and out- Renal infiltration and obstruction comes. Due to the fact that CLL usually follows an indolent course, patients with CLL rarely undergo kidney biopsy. In the The infiltration of extramedullary organs can occur in CLL, but studybyStrati et al., of all the CLL patients studied, only this complication is typically unusual. Postmortem retrospect- 1.2% of patients underwent kidney biopsy. The low rate of ive series and case reports have demonstrated an infiltration of kidney biopsy is a limiting factor in our understanding of CLL- monoclonal B cells in the kidneys of patients that developed associated kidney disease. AKI before their demise. Autopsy studies show that 60–90% of Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 672 | R. Wanchoo et al. FIGURE 1: The renal parenchyma is inﬁltrated by monomorphic lymphocytes with an immunotype characteristic of CLL/small lymphocytic lymphoma. Immunohistochemistry stains reveal strongly positive B-cell marker CD20, negative T-cell marker CD3 and aberrantly expressed T-cell marker CD5. patients may have leukemic-cell infiltration in the kidneys but, kidney involvement is detected at imaging, there is also evi- even at late stages, kidney function may remain unimpaired dence of extramedullary involvement in other sites. The most [12, 13]. This clinical phenotype has been linked to a more ag- common imaging pattern of kidney involvement in leukemia is gressive or advanced Rai stage. A retrospective study by Poitou- nephromegaly, which can affect one or both kidneys and results Verkinder et al. identified 15 patients afflicted with CLL from from diffuse or nodular parenchymal infiltration by leukemic a repository of 3950 kidney biopsies. Pathology showed that CLL cells [17, 18]. The sensitivity and specificity of this finding are monoclonal infiltrates were present in 10 of the biopsies; 9 pa- not known. For example, one series found that only 1 of 10 pa- tients had glomerulopathies, with membranoproliferative tients with biopsy-proven renal infiltration had increased kid- glomerulonephritis (MPGN) being the most commonly reported ney size . Other abnormalities include single or multiple histologic form. A large Mayo Clinic study that included patients nodules and wedge-shaped or geographic areas that enhance with both CLL and monoclonal B-cell lymphocytosis had a kid- less than the adjacent normal renal parenchyma after intraven- ney biopsy if they presented with nephrotic syndrome or renal ous contrast agent administration [17, 18]. No specific studies insufficiency. Of 4012 patients with CLL, only 49 (1.2% of all pa- have investigated how changes in imaging correlate as kidney tients) had pathological findings of CLL (infiltration and glom- function improves or worsens with CLL. erular diseases) in their kidneys . This is in striking contrast Obstructive nephropathy in the setting of CLL can be to autopsy studies done in the 1980s [12, 13]. Interestingly, the observed and is diagnosed radiographically via ultrasound, MRI pattern or extent of infiltration did not correlate with the degree or CT scan. Bilateral hydronephrosis from obstructing nodes of AKI . Another review of the literature found 17 reports of is managed with decompression and treating the underlying patients with kidney biopsies showing renal infiltration by CLL CLL . in addition to other histologic findings, with no association found between the absolute lymphocyte count and CLL renal in- Other interstitial diseases filtration . Kidney function has been noted to improve with CLL treatment in many patients with infiltrative disease on bi- Granulomatous interstitial nephritis (non-infection related) in opsy . Figure 1 shows a case of AKI with CLL infiltrative the setting of CLL has been described in case reports and small disease. case series , with partial recovery in 90% of the patients with The mechanism of AKI with CLL infiltration is not clearly CLL treatment. BK virus nephropathy in the native kidneys has established but has been hypothesized to involve tubular/ also been reported with CLL [15, 20]. microvascular compression causing intrarenal obstruction in addition to an infiltration-associated inflammatory/cytokine re- Glomerular diseases sponse [12, 16]. The radiology literature also describes the use of Several glomerular diseases have been associated with CLL, multidetector row computed tomography (CT), magnetic reson- ance imaging (MRI), positive emission tomography and ultra- with >50 cases mentioned via case reports and case series. The sound to identify CLL involvement of the kidney, but these most frequently reported findings are MPGN (36%) and mem- studies do not include histologic correlation. In general, when branous nephropathy (19%). While specific percentages are not Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 The Kidney in CLL | 673 FIGURE 2: A glomerulus with a membranoproliferative pattern of injury. There is marked mesangial expansion by matrix and cells, thickened and remodeled capillary walls and frequent inﬂammatory cells in the glomerular capillary lumens. By immunoﬂuorescence microscopy, this lesion reveals IgG-kappa restricted reactivity. Lambda light chain is completely negative. available, a large number of cases exist of CLL with amyloidosis mediated mechanism and T-cell dysfunction have been pro- as well. Other rare findings are minimal change disease (MCD), posed. The co-development of a podocytopathy along with immunotactoid glomerulopathy and focal segmental glomeru- hematologic malignancy and resolution of the glomerular dis- losclerosis [8, 14]. eases with chemotherapy strongly suggests an immune-medi- Paraprotein-mediated kidney disease has been well ated mechanism. Interestingly, MCD was described in a patient described in CLL, ranging from 2.5 to 60% of cases . In a study with monoclonal B lymphocytosis; a precursor state of CLL . from France, 6/15 patients that underwent a kidney biopsy in a Similar to monoclonal gammopathy of unclear significance that CLL cohort presented with a monoclonal dysproteinemia . can lead to kidney disease, monoclonal B lymphocytosis can Abnormal serum free light chains can be detected in 30–40% also be responsible for kidney disease . patients with CLL. Recent data suggest a significant correlation Membranous nephropathy is usually more common with between the abnormal free light chain ratio and outcome of CLL solid tumors . CLL-associated membranous nephropathy patients . The monoclonal protein secreted by the B-cell has been described and a few of them respond to chemotherapy clone can either be directly involved in the pathogenesis of the of CLL . The cases described were prior to the discovery of the lesions, as in cases of fibrillary glomerulopathy, immunotactoid M-type phospholipase A2 receptor on podocytes that has been associated with primary membranous nephropathy . nephropathy, amyloid light chain (AL) amyloidosis or type I/II cyroglobulinemia or indirectly in cases of MPGN not related to Systemic amyloidosis has been associated with CLL. A large cyroglobulinemia . Light chain cast nephropathy has also study from the Mayo Clinic reviewed all cases of CLL and amyl- been described in patients with CLL . oidosis . Over a span of 20 years, 33 patients were identified, 61% had AL amyloidosis and 39% had non-AL amyloidosis. Of By far the most common glomerular lesion noted in CLL pa- tients is MPGN (Figure 2). In most studies the majority of the pa- the 18 patients with AL amyloidosis that had typing results tients had a paraproteinemia [8, 14]. Cryoglobulin-associated available, four had a CLL clone only and the remaining 14 had MPGN was also fairly common in this subgroup . In cases of both a plasma cell and CLL clone. Six patients had both a fibrillary and immunotactoid glomerular diseases seen in CLL, plasma cell and CLL clone that shared the same light chain. For patients with AL amyloidosis associated with CLL, the patients light microscopy findings were suggestive of MPGN, with many received agents that targeted B and plasma cells. The median patients having a circulating monoclonal protein (Figure 3). Cases of MPGN presenting as C3 glomerulonephritis have also survival for AL amyloidosis patients with CLL was 38.9 months been reported, suggesting indirect damage via activation of the . Other sporadic cases of AL amyloidosis have been reported alternative complement system . with CLL and treatment is challenging, as it is not easy to de- MCD has also been reported in many cases of CLL [8, 11]. The cipher if the CLL and plasma cell dyscrasias are truly related or pathophysiology of this association is unclear. Both a B-cell- two separate entities [28–33]. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 674 | R. Wanchoo et al. Table 3. Summary of published cases of various glomerular diseases seen with CLL Kidney pathology reported Cases, n Reference MPGN 37 [8, 14] AL amyloidosis 24 [27–33] MCD 13 [8, 11, 23] Membranous nephropathy 12  AA amyloidosis 9  Proliferative GN 8 [8, 14] Thrombotic microangiopathy 6  Fibrillary GN 4 [8, 14] Immunotactoid glomerulopathy 4 [8, 14] C3 GN 3  FSGS 2 [8, 14] Most cases included direct deposition of monoclonal proteins in the form of proliferative glomerulonephritis, C3 deposits or cryoglobulinemia. AA, amyloid type A protein; GN, glomerulonephritis; FSGS, focal segmental glomerulosclerosis. survival. The term ‘CLL with renal significance’ should be con- FIGURE 3: Immunotactoid organized deposits within the mesangial matrix. The sidered for cases that present with this dilemma. deposits are composed of microtubules, sometimes in a parallel arrangement. ELECTROLYTE DISORDERS Nine patients in the above-mentioned cohort  had non-AL amyloidosis. Cases with non-AL amyloidosis that had TLS amyloid typing done comprised mostly the patients with the TLS is the most common oncologic emergency with an inci- transthyretin (seven patients) form of amyloidosis. One patient dence as high as 26% in high-grade B-cell acute lymphoblastic had insulin-type amyloid and she was a type 1 diabetic who leukemia . TLS results from rapid release of the intracellular had been on insulin for >50 years prior to diagnosis of amyloid- osis . The patients with non-AL amyloidosis with CLL contents of dying cancer cells into the bloodstream either spontaneously or in response to cancer therapy. It is bio- received no specific agents targeting plasma cell clones. The median overall survival of the non-AL amyloidosis patients was chemically characterized by hyperuricemia, hyperkalemia, 61.4 months, much better than the AL amyloidosis patients hyperphosphatemia and hypocalcemia. Cardiac arrhythmias, with CLL . seizures and superimposed AKI are common clinical presenta- The high prevalence of an abnormal serum free light chain tions (Figure 4). Table 4 summarizes the Cairo–Bishop definition ratio and increase in free light chains in general in patients with of laboratory TLS and clinical TLS. This is the classic def- CLL brings into question whether a subset of these patients inition used in diagnosing TLS. The pathophysiology of with CLL have undiagnosed AL amyloidosis . Polyclonal B TLS-mediated AKI involves intratubular obstruction and inflam- cells share the same microenvironmental interactions as tumor mation by precipitation of crystals of uric acid, calcium phos- cells and could themselves be activated by antigenic stimula- phate and/or xanthine. Preexisting kidney dysfunction favors tion of the CLL clone. This later may in turn convey activatory intratubular crystal precipitation. Consensus recommendations signals to bystander B and T lymphocytes. It is possible that the for TLS prophylaxis include volume expansion for all risk tumor-derived monoclonal free light chains can be admixed groups, use of allopurinol in medium- and high-risk groups and with variable amounts of serum free light chains produced by use of recombinant urate oxidase (rasburicase) in high-risk non-clonal bystander B cells in the lymphohematopoietic tis- groups. The utility of diuretics and urine alkalization are vari- sues . able and their efficacy is debatable [34, 35]. Thrombotic microangiopathy (TMA) has been reported in While TLS is uncommon in CLL, it is still an issue that needs patients with CLL. In the study by Strati et al., six patients to be addressed, particularly with the use of one of the novel presented with TMA (renal limited or systemic) as the renal targeted agents used in the treatment of CLL, namely the drug manifestation of CLL. Four of the six patients responded to venetoclax. The use of venetoclax, a recently approved B-cell treatment with CLL, one required a stem cell transplant- lymphoma 2 protein (bcl-2) inhibitor for use in a select group of ation and the other had simultaneous lung cancer . All six pa- patients with relapsed CLL that carry del17p (high risk of pro- tients had clinical presentation of AKI, proteinuria, hemolysis, gression), has led to drug-induced TLS in 3–6% of patients . anemia, elevated lactate dehydrogenase and presence of schis- In order to minimize the risk of TLS, a strict protocol has been tocytes on peripheral smear and low haptoglobin. Other associ- established that will be discussed in more detail in a later ated glomerular diseases with CLL are listed below in Table 3 in section. order of incidence. Glomerular diseases associated with cancer, and in this Other electrolyte disorders case CLL, can present preceding the CLL diagnosis . CLL is frequently not treated or treated late. If there is end organ The most common electrolyte disorder encountered in CLL damage and we are able to connect the kidney disease to CLL, patients is pseudohyperkalemia. Potassium tends to stay pre- perhaps treatment might be important and critical for renal dominantly in the intracellular compartment. Leakage of Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 The Kidney in CLL | 675 Tumor Lysis Syndrome Uric acid release Phosphorus release Potassium release Hyperphosphatemia Hyperuricemia Hyperkalemia Calcium phosphate crystals Uric acid crystals Arrhythmias Acute kidney injury FIGURE 4: Clinical presentation summary of tumor lysis syndrome. 8.1%, when the white blood cell count was 100 10 /L. This is Table 4. Cairo–Bishop deﬁnition of laboratory TLS and clinical TLS the first and only study to systematically look at serum potassium Electrolyte disorder Criterion values in CLL patients  demonstrating that the results are related to pseudohyperkalemia. Potassium 6 mEq/L or 25% increase from baseline Routine serum analysis leads to high measured potassium Phosphorus 4.5 mg/dL or 25% increase from baseline levels due to the release of potassium from fragile leukemic Calcium >25% decrease from baseline cells during the clotting process. But in CLL, even the plasma Uric acid 8 mg/dL or 25% increase from baseline levels of potassium are elevated. Severe leukocytosis leads to consumption of metabolic fuels that can impair sodium- Clinical criteria: laboratory criteria and one or more of the following: (i) creatinine 1.5 upper limit of normal, (ii) seizures, (iii) cardiac arrhythmia potassium ATPase activity, leading to release of potassium from or sudden death. Laboratory TLS requires that two or more of the following a high number of white cells . While in elevated platelet lev- metabolic abnormalities occur within 3 days before or up to 7 days after the initi- els, serum and plasma levels can differentiate pseudohyperka- ation of therapy: hyperuricemia, hyperkalemia, hyperphosphatemia and hypo- lemia, elevated white cell–related pseudohyperkalemia might calcemia. Clinical TLS is present when laboratory TLS is accompanied by an not be as straightforward to distinguish. While not common, increased creatinine level, seizures, cardiac dysrhythmia or death. another interesting electrolyte disorder noted in CLL patients is reverse pseudohyperkalemia [44, 45], where plasma potassium potassium from the intracellular compartment at the time of is noted to be higher than serum potassium . The mechan- collection due to hemolysis, cell fragility or heparin-induced ism is not well understood but may be due to an increase in sen- damage can lead to spurious elevation of measured potassium sitivity to heparin-mediated cell membrane damage during levels, which is known as pseudohyperkalemia. In addition, processing and centrifugation in a hematologic malignancy and myeloproliferative disorders and thrombocytosis can also lead mechanical stressors. To our knowledge, there is no specific to pseudohyperkalemia. Thrombocytosis (platelet count >1000 way to predict or correct the measured potassium value based 10 /L) can also lead to pseudohyperkalemia. Elevation of the on the white cell count. blood platelet count by 1000 10 /L can lead to an increase of The time to collection and analysis of the blood sample can 0.2 mmol/L in plasma potassium and 0.7 mmol/L in serum po- help eliminate some of these findings. Allowing serum to sit on tassium . As a result, the potassium concentration is gener- the clot for too long (>2 h) can significantly increase the potas- ally higher in serum compared with plasma from platelets sium values. Ideally, specimens for patients with significantly during clotting. Similarly, elevated potassium levels have been elevated white cell counts should be delivered in person to min- described in leukocytosis as well. An artifactually elevated serum imize hemolysis. Arterial blood gas samples in a balanced hep- potassium level or spurious hyperkalemia was first described  arin syringe for potassium measurement can decrease the with extreme leukocytosis (>600 10 /L)and severalcasereports transit time to allow for more accurate potassium measure- thereafter [39–41]. Katkish et al. reviewed >300 patients with ment. Venous blood gas measurements can be useful, but keep CLL listed in the tumor registry in the state of Minnesota between in mind that venous samples have more mechanical stressors 1997 and 2014. The researchers found that the adjusted odds of a compared with arterial blood draw techniques, making arterial patient’s potassium being elevated increased by 1.4 [95% confi- draws more accurate. We also recommend checking a simultan- dence interval (CI) 1.2–1.5; P < 0.0001] for every 10 10 /L increase eous plasma potassium level in patients with white cell counts in white blood cell count. Below a white blood cell count of 50 >100 10 /L. An electrocardiogram (EKG) can be helpful in dif- 10 cells/L, the median estimated percentage of a patient’s potas- ferentiating pseudohyperkalemia/reverse pseudohyperkalemia sium being elevated was 1.7%, but was considerably higher, at from true hyperkalemia. The absence of typical EKG changes is Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 676 | R. Wanchoo et al. Table 5. Summary of FDA adverse events by targeted agents used in CLL (2014–17) Agent AKI Hyponatremia Hypokalemia Hypophosphatemia Hypomagnesemia Hyperkalemia Proteinuria TLS Total Alemtuzumab 2500 0 0 0 3 133 Ofatumumab 2976 0 0 3 0 16 61 Ibrutinib 9 9 54 1 3 0 6 37 Idelalisib 4 1 2 0 0 3 0 8 18 Obinutuzumab 10 0 0 1 0 1 0 8 20 Venetoclax 0 4 0 0 0 0 0 2 6 Bold numbers suggest highest type of injury. usually helpful in identifying pseudohyperkalemia. High with elevated serum creatinine. In addition to reviewing the plasma lactate dehydrogenase levels may indicate hemolysis or published literature, we also reviewed the US Food and Drug rupture of fragile white blood cells seen in CLL patients. Administration (FDA) adverse event reporting system (FAERS) Consideration should be given to testing serum potassium if the quarterly legacy data file (third quarter of 2014 to second quar- plasma potassium is elevated in the context of leukocytosis, es- ter of 2017) for all recently approved targeted agents for CLL. pecially if reverse pseudohyperkalemia is suspected. In add- Well-established chemotherapy agents used in CLL such as ition, we suggest placing a warning in the electronic medical cyclophosphamide and fludarabine were excluded. The adverse record to alert clinicians to potential pseudohyperkalemia in event terms queried were hypokalemia, hypomagnesemia, patients with CLL and leukocytosis. Such recognition might hyponatremia, hypophosphatemia, hypocalcemia, hypercalce- help prevent costly and harmful emergent dialysis, intravenous mia, hyperkalemia, hypernatremia, hyperphosphatemia, pro- calcium or insulin and cancellation of procedures. teinuria, renal failure acute, AKI, TLS, hypertension and Hypercalcemia in CLL is extremely rare but 30 cases have nephritis. We reviewed the literature using MEDLINE, case ser- been reported [47–49]. In a retrospective study of 1200 patients ies and the registration studies of these agents for any reported with CLL, 7 patients had high calcium levels . Proposed nephrotoxicity. Table 5 summarizes the drugs studied and re- mechanisms causing hypercalcemia in CLL patients are para- sults found. Ofatumumab, alemtuzumab and ibrutinib were the thyroid hormone–related peptide and 1,25 vitamin D mediated top three offenders, with AKI as the most common finding re- (similar to B-cell lymphomas). Hypercalcemia should also raise ported, followed by TLS and hyponatremia. The newer agents concern for a potential CLL transformation to a large-cell used to treat CLL had fewer renal toxicities than the older lymphoma or another form of aggressive lymphoma . Other agents. Given that some of the newer agents (such as obinutu- various electrolyte disorders that present in CLL are usually zumab and venetoclax) are not yet widely used, the true rate of treatment related and are discussed below. renal toxicities may be underestimated. The mechanism of AKI is unclear in most of these agents. TLS has been rarely reported in patients treated with ibrutinib and acute interstitial nephritis TREATMENT-RELATED TOXICITIES (unpublished, personal communication) has been observed The current standard of care for a fit patient with CLL without while on ibrutinib. In addition, in the largest unpublished series comorbidities is a chemo-immunotherapeutic regimen that in- focused on hypertension in ibrutinib-treated patients, a clear cludes the purine analog fludarabine in combination with cyclo- association between ibrutinib and hypertension was noted . phosphamide and rituximab . However, this combination Nearly 40% of patients developed hypertension within regimen remains toxic for the majority of patients with CLL due 12 months of exposure. Despite aggressive management (mul- to age and comorbidities, particularly due to increased risk for tiple agents), ibrutinib-associated hypertension was persistent infectious complications . Over the last few years, treatment . The data underscore the critical need for monitoring and of CLL has slowly started to evolve from regimens with signifi- management strategies for hypertension and follow-up data on cant impact on long-term outcomes and associated concomi- renal and cardiac events. The literature reviewed in the FAERS tant toxicities to the use of novel agents that specifically target reported additional toxicities of the newer agents, such as TLS dysregulated pathways. These advances are possible given our with venetoclax, leading to early modifications of the dose esca- recent understanding of CLL biology, mainly elucidation of the lation protocol for the drug. The importance of following a strict role of the microenvironment and of the signaling mechanisms ramp-up dosing protocol cannot be emphasized enough. The that allow for survival and proliferation of the malignant CLL literature review of published case reports and series of all clone. These targeted agents include the monoclonal antibody agents used in CLL are summarized in Table 6. obinutuzumab, the Bruton’s tyrosine kinase inhibitors ibrutinib and acalabrutinib, the phosphatidylinositol 3-kinase inhibitor Venetoclax and TLS: an example idelalisib and the BCL-2 inhibitor venetoclax [54–58]. These novel agents are demonstrating unprecedented clinical activity, Venetoclax is now approved for patients with CLL that harbor the chromosome 17p deletion (high risk of progression) who especially in patients with historically low response rates, such have received at least one prior treatment and for whom there as patients with high-risk disease (unmutated IGHV). Since these drugs are relatively new, we are still learning about their are no other available therapies . The drug is currently being potential renal toxicities. reviewed by the FDA for wider approval in patients with Most medications used for the treatment of CLL are not relapsed CLL. This is based on the results presented at the an- nephrotoxic. While fludarabine has been associated with a few nual American Society of Hematology meeting of the MURANO case reports of glomerular disease , this is not a common trial, where venetoclax was used in combination with rituximab finding. Ibrutinib  and venetoclax  have been associated in relapsed/refractory patients with CLL . In the initial Phase Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 The Kidney in CLL | 677 Table 6. Adverse events with CLL therapies Commonly published renal adverse Drug Mechanism of action events Comments Alemtuzumab Anti-CD52 monoclonal antibody Antiglomerular basement membrane Used in kidney transplants without disease, AKI signiﬁcant renal effects Acalabrutinib Bruton’s tyrosine kinase inhibitor Increased creatinine Recent approval in 2017, unclear if it has any signiﬁcant kidney toxicity Bendamustine Nitrogen mustard Hypokalemia, hyponatremia and hypocalcemia Chlorambucil Alkylating agent Hyponatremia (SIADH) Cyclophosphamide Alkylating agent Hemorrhagic cystitis, urinary ﬁbrosis and retention, SIADH Dinaciclib CDK9 inhibitor TLS 3–15% (three cases thus far of TLS) Favopiridol CDK9 inhibitor TLS 25% TLS in initial trials—all of the ﬁrst ﬁve trials patients had TLS, two deaths, several cases of dialysis and hospitalizations Fludarabine Purine analog Hematuria, proteinuria and TLS Ibrutinib Bruton’s tyrosine kinase inhibitor AKI, hypertension, hypophosphatemia The TLS mentioned in the literature in and hyponatremia initial trials has not been reported postmarketing Idelalisib P13K inhibitor Hypokalemia, AKI and hyponatremia Lenalidomide Immunomodulator TLS, hypokalemia, Fanconi syndrome, Trial amended after TLS onset in 4 of AKI (biopsy proven acute interstitial the ﬁrst 18 patients (2.9%) nephritis) Obinutuzumab Anti-CD20 monoclonal antibody TLS, hypophosphatemia, hypocalce- 2–4.5% TLS; all cases resolved in initial mia, hyperkalemia and hyponatre- trials mia AKI Ofatumumab Anti-CD20 monoclonal antibody TLS, AKI 3–4% TLS; all cases resolved in initial trials Rituximab Anti-CD20 monoclonal antibody TLS In Phases II and III trials, <1% TLS Venetoclax BCL-2 inhibitor TLS Six patients with clinical TLS including two deaths during dose escalation and many clinical and laboratory TLS cases Based on references [54–79] and the FDA adverse reporting system. AKI, acute kidney injury; BTK, Bruton tyrosine kinase; CDK, cyclin-dependent kinase; P13K, phosphatidylinositol 3-kinase; SAIDH, syndrome of inappropriate antidiur- ectic hormone. 1 trial (n¼ 56) of this agent, three patients experienced clinical TLS and seven had clinical parameters of TLS despite slow in- 400 mg crements in dosing (venetoclax initiated at 50 mg and ramped 200 mg Week 5 up to a maximum target dose of 1200 mg over 3 weeks) and TLS Week 4 100 mg prophylaxis . Of the three patients, one died due to severe 50 mg Week 3 hyperkalemia and one required immediate dialysis. Clinical TLS 20 mg Week 2 occurred in two patients (resulting in one death) who initiated Week 1 venetoclax at 50 mg in the Phase Ib trial that was used as the basis for the MURANO trial . FIGURE 5: Recommended once-daily dosing schedule for venetoclax 5-week Based on this experience, a slow ramping of venetoclax was dose ramp-up used in clinical trials of patients with CLL. For patients with high tumor lysis risk (any measurable lymph nodes with largest diameter >10 cm or started with initial doses starting at 20 mg for 1 week, followed absolute lymphocyte count >25 10 /L and any measurable lymph node with by a ramp-up scheme totaling 5 weeks to a target dose of 400 mg largest diameter >5cm), then the ﬁrst doses of 20 mg and 50 mg should be inpa- along with intensive TLS prophylaxis and monitoring in real tient dosing and lab monitoring done at 0, 4, 8, 12 and 24 h. Hydration with time (Figure 5). A data review of reports of TLS with this agent 1-2 L/day of ﬂuids with rasburicase recommended. Early Nephrology consulta- revealed that a combination of tumor burden (bulky lymph tion in certain very high risk situations. nodes 5 cm and or elevated lymphocyte count 25 10 ) and reduced renal function at screening could be used to identify high-risk patients that might develop TLS . For moderate- to lysis and should prompt nephrology consultation before severe TLS ensues . With the new dosing regimen and close moni- high-risk patients, and especially with a creatinine clearance <80 cc/min, the initial 20 and 50 mg doses should be adminis- toring guidelines appropriate for the level of risk of TLS, TLS has become a less common occurrence. At our center, the nephrol- tered in the hospital with laboratory monitoring at specified timepoints (after 4, 8, 12 and 24 h), early prophylaxis with allo- ogy and intensive care unit teams are made aware of any ad- purinol or rasburicase and aggressive intravenous fluids. mission where venetoclax is planned to be administered and Phosphate measurement might be the earliest clue to tumor dose-escalated in patients with CLL. We have performed early Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/670/4967844 by Ed 'DeepDyve' Gillespie user on 17 October 2018 678 | R. Wanchoo et al. 6. Landau DA, Tausch E, Taylor-Weiner AN et al. Mutations continuous renal replacement therapy in high-risk cases to driving CLL and their evolution in progression and relapse. allow for safe dose escalation of this agent. Nephrologists need to be aware of the potential toxicity of this CLL agent. Our rec- Nature 2015; 526: 525 ommendation is that early nephrology consultation might be 7. Strati P, Shanafelt TD. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, nat- prudent in most cases of moderate to severe risk of TLS with ural history, and risk stratiﬁcation. Blood 2015; 126: 454–462 every dose escalation of venetoclax, in particular the first two 8. Strati P, Nasr SH, Leung N et al. Renal complications in dose escalations. chronic lymphocytic leukemia and monoclonal B-cell lym- In addition to the possibility of CLL affecting the kidney, it is phocytosis: the Mayo Clinic experience. 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