Renal Failure Associated with Cancer and Its Treatment: An Update
Benjamin D. Humphreys*,
Robert J. Soiffer and
Colm C. Magee*
* Renal Division, Department of Medicine, Brigham and Women’s Hospital, and Dana Farber Cancer Institute, Boston, Massachusetts
Address correspondence to: Dr. Colm Magee, Renal Division, MRB-4, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-7199; Fax: 617-732-6392; E-mail: cmagee{at}partners.org
Kidney disease frequently complicates malignancy and its treatment.The spectrum of disease in this setting includes acute renalfailure (ARF), chronic renal failure, and tubular disorders.Fortunately, these complications are often preventable or reversiblewith prompt diagnosis and treatment. This review focuses onrecent progress in the management of ARF and chronic renal failureassociated with cancer and its treatment. Particular emphasisis placed on the following conditions: Uric acid nephropathy,gemcitabine-associated thrombotic microangiopathy, bisphosphonate-inducedcollapsing glomerulopathy, and hematopoietic cell transplant(HCT)-associated renal failure. The classic entities such aslymphomatous infiltration of the kidney and paraneoplastic glomerulopathiesalso are reviewed with a focus on recent developments.
Renal failure in the cancer patient is often multifactorial,but it is still clinically useful to consider causes as prerenal,intrinsic, and postrenal (1,2) (Table 1). Not surprising, prerenalfailure is common. The spectrum of intrinsic renal disease inthis patient population is broad. Multiple myeloma-related renalfailure is a particularly important cause of renal failure andESRD. Roughly 20% of patients with myeloma have renal failure,and these patients have more advanced disease at diagnosis andshortened survival (3). Although it causes only 1% of all cancers,myeloma-related ESRD accounted for 58% of all malignancy-relatedcases between 1997 and 2001 (4). Common forms of renal failurein myeloma include (in decreasing order of frequency) cast nephropathy,amyloidosis, and light-chain nephropathy. Myeloma patients areadditionally at risk for ARF associated with hypercalcemia andperhaps with radiocontrast (5).
Table 1. Causes of renal failure in cancer patientsa
Postrenal causes of ARF in cancer patients are more common thanin the general population and should always be considered. Obstructionmay occur at any level of the urogenital tract (Table 1), andcommon obstructing tumors include those of the prostate, bladder,uterus, and uterine cervix (2). Obstructive uropathy remainsa possibility even in the absence of hydronephrosis becauseencasement of the collecting system by retroperitoneal tumoror retroperitoneal fibrosis may prevent pelvi-ureteric dilation.Retroperitoneal fibrosis is uncommon and primarily idiopathic,but it can be associated with previous pelvic irradiation ormalignancies such as lymphoma and a variety of solid tumors(6,7).
Although many solid and hematologic cancers may involve therenal parenchyma, clinical sequelae are usually not prominent.Lymphomas and leukemias are the most common such cancers, with6 to 60% incidence in patients with diffuse lymphoma at autopsy(8–10). Lymphomatous invasion of the kidneys may occasionallypresent with ARF, proteinuria, or hematuria, but the diagnosisis usually incidental. In one large autopsy series, only 0.5%of those with renal involvement had developed ARF (10). In only10 of the 55 cases of renal lymphoma reported to date was thediagnosis suspected before biopsy (11). Renal imaging revealedbilateral enlargement in a majority of these cases. Prompt recognitionof this syndrome is warranted because ARF associated with lymphomatousinfiltration may respond well to therapy aimed at the underlyingcancer (12). Resolution of ARF with anticancer therapy is thestrongest evidence that lymphomatous infiltration of the kidneywas the underlying cause (8).
Metastatic extrarenal solid tumors only rarely cause ARF. Pulmonarycarcinoma—followed by gastric and breast carcinomas—isthe most common solid tumor to metastasize to kidney (13). Fewcases of ARF resulting from solid tumor infiltration have beenreported, usually with widespread parenchymal replacement (14).
Tumor lysis syndrome describes the metabolic complications ofeither rapid tumor cell turnover or chemotherapy-induced tumorcell lysis. The syndrome is characterized by hyperuricemia,hyperphosphatemia, hypocalcemia, hyperkalemia, and ARF (15,16).Two forms of ARF are thought to occur but may coexist: ARF associatedwith large increases in plasma uric acid and with large increasesin plasma phosphate. The pathophysiology of uric acid nephropathyincludes intratubular precipitation of uric acid causing mechanicalobstruction, direct toxicity to epithelial and endothelial cells,and potentially activation of the innate immune system (17–19).The pathophysiology of hyperphosphatemia-associated ARF is thoughtto involve intrarenal calcium phosphate precipitation and directtubular toxicity of phosphate (20,21).
Tumor lysis syndrome may arise with a variety of tumors butis most commonly associated with poorly differentiated lymphomassuch as Burkitt’s or with leukemias, particularly acutelymphoblastic leukemia (22). Occasionally, patients will developthe syndrome spontaneously, but the majority of cases are associatedwith chemotherapy (23). Before the widespread adoption of prophylaxis,most cases of ARF in tumor lysis syndrome were due to uric acidnephropathy (24). Standard prophylaxis consists of oral or intravenousallopurinol to block uric acid formation coupled with intravenoushydration with or without urinary alkalinization. Urinary alkalinizationhas historically been recommended, but its use is controversial(25). The above regimen has dramatically reduced the incidenceof uric acid nephropathy but not eliminated it. In a study of41 patients who had acute leukemia and all received allopurinolprophylaxis before chemotherapy, 22 patients developed mild,two patients moderate, and one patient severe tumor lysis syndrome,although none required renal replacement therapy (26). Allopurinolhas other limitations, including hypersensitivity reactions,drug interactions, dose adjustment in renal failure, and responsetime of several days.
A rare complication of allopurinol therapy is xanthine nephropathyresulting from intratubular crystallization of xanthine. Inhibitionof xanthine oxidase by allopurinol causes accumulation of xanthine(Figure 1) and hyperxanthinuria (27). Xanthine is threefoldless soluble than uric acid in urine and has a higher pKa (7.4for xanthine, 5.6 for uric acid), so intratubular precipitationis possible despite alkaline urine (27–29).
Figure 1. Mechanisms of renal toxicity in tumor lysis syndrome. Chemoradiotherapy induces tumor cell lysis with release of intracellular constituents, including potassium, phosphate, and nucleic acids. Purine degradation creates xanthine, which is metabolized to uric acid and normally excreted by the kidney. In tumor lysis syndrome, very high levels of uric acid may accumulate, leading to intratubular crystallization and renal failure. Allopurinol blocks the metabolism of xanthine to uric acid, thereby preventing uric acid nephropathy, although rarely xanthine crystallization may occur instead as a result of poor solubility of xanthine in urine. Plasma expansion and alkaline urine inhibit crystal nephropathy. Intravenous administration of rasburicase results in rapid metabolism of uric acid to the more soluble allantoin, which is readily excreted by the kidney.
Treatment of established tumor lysis syndrome consists of vigoroushydration and management of electrolyte abnormalities. Severetumor lysis syndrome associated with ARF may respond well toaggressive intermittent hemodialysis or continuous renal replacementaimed at clearance of uric acid and phosphate; the ARF is generallyreversible.
A new approach toward the prophylaxis and treatment of uricacid nephropathy is the enzyme uricase, which catalyzes theoxidation of uric acid to the more water-soluble allantoin (Figure 1)(30). The Food and Drug Administration has recently approvedrasburicase, a polyethylene glycol-modified recombinant uricasepreparation, for the prevention of tumor lysis syndrome in pediatricpatients. A nonrecombinant formulation of urate oxidase hasbeen used in Europe since 1975 but has been associated witha 5% rate of allergic reactions (31). Rasburicase is effectiveand well tolerated with fewer allergic reactions. Goldman etal. (32) demonstrated reduced area under the curve over 96 hfor uric acid in patients who were at risk for tumor lysis with128 + 70 mg/dl in the Rasburicase group versus 329 + 129 mg/dlin the allopurinol group (P < 0.001). One patient in theallopurinol group required hemodialysis, but none in the rasburicasegroup did. In another study of 49 hyperuricemic adult patients,Rasburicase treatment for a median of 3 d resulted in a decreasein plasma uric acid levels from a median of 11.9 to 0.7 mg/dl(33). Coiffier et al. (34) followed 100 adult patients who hadaggressive non-Hodgkin’s lymphoma and were given a prophylacticregimen of 0.2 mg/kg intravenous Rasburicase beginning the daybefore chemotherapy plus intravenous hydration. All patientsachieved control of plasma uric acid within 4 h of injection,and none developed hyperuricemia throughout the observationperiod. No patient had an increase in plasma creatinine or requiredhemodialysis.
Case reports have also suggested that Rasburicase therapy maybe beneficial even after uric acid nephropathy and ARF havedeveloped (35,36). Urate oxidase can dissolve precipitated uricacid crystals, so if it is filtered at the glomerulus, thenit could reverse intratubular obstruction (35). Further studiesare needed to clarify the role for Rasburicase in this setting.Rasburicase does not directly control plasma phosphorous levelsin tumor lysis syndrome, and ARF in the setting of hyperphosphatemiaand hypocalcemia has been reported (37).
Although the overall frequency of glomerular disease in malignancyis low, paraneoplastic glomerular disease is well described(38–40). Published reports cite membranous nephropathyas the most common malignancy-associated glomerulopathy, occurringwith many carcinomas and occasionally with leukemia and lymphoma,but this association has been questioned (41) and registry datado not consistently support it (42–44). Burstein et al.(45) reported the presence of an underlying cancer in nine (8.4%)of 107 patients with biopsy-proven membranous nephropathy, andin earlier reports, the incidence was similar, ranging from5.8 to 10.6% (46,47). Because of this strong association, somesuggest limited tumor screening in older patients who receivea diagnosis of idiopathic membranous nephropathy (44,45). Themechanism by which malignancy induces disease remains unprovedbut may involve deposition of tumor antigen in the subepithelialspace with in situ immune complex formation and subsequent complementactivation (48,49). Treatment of the underlying malignancy maylead to resolution of the nephrotic syndrome, lending indirectsupport to this theory (48,50).
An association between minimal-change disease and Hodgkin’sdisease is well established but uncommon, with an incidenceof 0.4% among 1700 patients (40,41). There are also reportsof membranoproliferative and rapidly progressive glomerulonephritisin the setting of malignancy (39). With regard to the associationof antineutrophil cytoplasmic antibody (ANCA) vasculitis andmalignancy, Pankhurst et al. (51) recently performed a retrospectivecase-control study comparing 200 consecutive patients with ANCA-associatedvasculitis with age- and gender-matched control subjects. Theauthors found an increased risk for malignancy in those withvasculitis (relative risk 6.02), and one third of the patientsreceived a diagnosis of malignancy concurrent with their renaldiagnosis. They concluded that malignancy should be consideredin the differential diagnosis of patients who present with ANCAvasculitis. A link between cyclophosphamide chemotherapy (particularlywhen given daily, orally) and bladder cancer is known, but thisstudy confirms previous small series that suggested a directlink between ANCA vasculitis and cancer independent of therapyused to treat the vasculitis (52,53).
The term thrombotic microangiopathy (TMA) describes a set ofpathologic changes seen in a variety of clinical syndromes,including thrombotic thrombocytopenic purpura, hemolytic uremicsyndrome, scleroderma, preeclampsia, antiphospholipid antibodysyndrome, and radiation nephropathy (54,55). These pathologiccharacteristics include intrarenal or systemic microvascularthrombi with endothelial swelling and microvascular obstruction(54). For the purpose of this review, we use the term TMA syndromesto encompass the various clinical syndromes with these pathologicabnormalities. There is no consensus on diagnostic criteriarequired to diagnose a TMA syndrome, but laboratory featuresinclude microangiopathic hemolytic anemia and thrombocytopenia.Renal failure, neurologic abnormalities, and gastrointestinalsymptoms are common (54,56,57).
TMA syndromes are known to be a complication both of the tumorstate itself and of certain treatment regimens (58). TMA hasmost commonly been associated with carcinomas. An early prospectivestudy determined that 5.7% of patients with metastatic carcinomahave microangiopathic hemolytic anemia (59). Gastric carcinomaaccounts for more than half of cases, followed by breast andlung carcinomas (60). Renal failure is an uncommon feature ofcancer-associated TMA syndromes in the absence of chemotherapy.
Antineoplastic drugs have been strongly associated with TMAsyndromes. Mitomycin C is the prototypical agent, with a 2 to10% risk that increases significantly after a cumulative doseof 40 mg/m2 (61–63). Bleomycin, cisplatin, and 5-fluorouracilhave less frequently been associated. Gemcitabine is now a widelyused nucleoside analog approved for treatment of pancreaticcarcinoma and bladder and advanced non-small-cell lung cancers.In 2003, for example, worldwide sales of gemcitabine exceeded$1 billion (64). It has been implicated in the development ofTMA (65,66) and we have recently reported the presentation andoutcome of gemcitabine-associated TMA (67). The cumulative incidencewas 0.31%, significantly higher than the previously reportedestimate of 0.015% (65). Median time to diagnosis after initiationof gemcitabine was 8 mo with a cumulative dose ranging from9 to 56 g/m2. In our series, new or exacerbated hypertensionwas a prominent feature in seven of nine patients with gemcitabine-associatedTMA, and, most important, it preceded the TMA diagnosis in allcases. Hypertension has been associated with TMA syndromes,and, in some series, the severity of hypertension correlateswith poorer outcome (61,68). The mechanism by which TMA induceshypertension is likely glomerular ischemia induced by microvascularcapillary obstruction (69). Weekly visits to the infusion unitby patients who receive gemcitabine represent a chance to detectnew or exacerbated hypertension as it develops. This could leadto earlier identification of gemcitabine-associated TMA andARF (67).
The bisphosphonates are antiresorptive agents that are widelyprescribed to treat osteolytic metastases and hypercalcemiaof malignancy. Pamidronate is proved to reduce skeletal complicationsin patients with either multiple myeloma or advanced breastcancer (70,71). Expanding indications for use in cancer patientswarrant careful review of the renal toxicities associated withthis medication class. Bisphosphonates are excreted unchangedby the kidneys, and elevation in plasma creatinine after infusionhas been noted in animals and humans since this class of drugswas originally described (72). Second-generation bisphosphonatesare more potent, and lower doses are used, which may partiallyexplain their probable lower nephrotoxicity.
Markowitz and colleagues (73,74) first reported seven patientswho developed nephrotic syndrome while undergoing treatmentwith pamidronate. Histology revealed collapsing glomerulopathy(75). These patients were all HIV negative, and five of sevenreceived pamidronate dosing at levels two to four times higherthan recommended. Notably, the three patients in whom pamidronatewas discontinued after diagnosis of nephrotic syndrome had subsequentimprovements in plasma creatinine, whereas the four who continuedto receive the drug progressed to ESRD that required renal replacementtherapy. One patient was rechallenged with pamidronate afterdeveloping pamidronate-induced collapsing glomerulopathy. Althoughher proteinuria had improved off the drug, it worsened afterrechallenge, providing further evidence for causality betweenpamidronate and collapsing glomerulopathy (76).
Histopathologic characteristics of this entity include focalglomerulosclerosis with marked wrinkling and retraction of theglomerular basement membranes. Podocytes exhibit diffuse lossof their highly differentiated cytoarchitecture, including footprocess effacement over 84% (range 60 to 100%) of the glomerularcapillary area (73). Proximal tubule damage is also seen, andseveral cases of bisphosphonate-induced acute tubular necrosishave been reported (77–79). Collapsing glomerulopathyhas not been reported in association with bisphosphonates otherthan pamidronate, however.
These studies highlight important renal toxicities for thisuseful drug class. Although long-term prospective studies examiningnephrotoxicity are lacking, current information suggests thatnephrotoxicity among patients who receive bisphosphonates, particularlypamidronate, can probably be reduced by simple measures. Theseinclude careful monitoring for development of proteinuria, avoidinghigher doses than the recommended 90 mg/mo intravenously, reduceddosing in renal insufficiency, and halting therapy should proteinuriaor renal failure develop.
A complete list of chemotherapeutic agents with known nephrotoxicityis lengthy and beyond the scope of this review. Important examplesinclude methotrexate, which at high doses may cause obstructionsecondary to intratubular precipitation, and cisplatin, whichcauses proximal tubule damage. A variety of chemotherapy drugssuch as cisplatin and ifosfamide also cause renal electrolyteand water-handling disorders. The reader is directed to a recentreview of chemotherapy-related renal disease for a comprehensivediscussion (80).
Overview
The general purpose of HCT is to allow administration of otherwiselethal (and hopefully curative) doses of chemoradiotherapy followedby engraftment of stem or progenitor cells for marrow recovery.Roughly 50,000 adult HCT are performed annually worldwide (Figure 2)(81). There are more HCT performed than renal transplantsin the United States: 17,700 HCT compared with 14,779 renaltransplants in 2002 (United Network for Organ Sharing). Themean age of HCT recipients is steadily increasing (81).
Figure 2. Annual numbers of blood and marrow transplants worldwide, 1970 to 2002. The recent plateau in autotransplants reflects a decrease in the number performed for breast cancer. The plateau in the number of allotransplants reflects a decrease in the number performed for chronic myelogenous leukemia. Adapted from reference 81 with permission.
Stem and progenitor cells may be harvested from bone marrow,peripheral blood, or umbilical cord blood. Conventional myeloablative(allogeneic and autologous) HCT use intensive conditioning regimensthat consist of high-dose chemotherapy and radiotherapy to ablatedisease and bone marrow, followed by reconstitution of the hematopoieticsystem via infusion and engraftment of stem cells. In autologousHCT, the patient’s own stem cells support recovery fromchemoradiotherapy, whereas in allogeneic HCT, the stem cellsare nonself. The toxicities of myeloablative conditioning excludeolder and sicker patients. Thus, nonmyeloablative conditioningregimens have recently been developed to allow allogeneic HCTin such patients. These so-called "mini-allo" transplants involveless toxic conditioning because eradication of disease is mediatedby allogeneic immunologic mechanisms—the "graft versustumor" effect.
The incidence and causes of ARF have been most thoroughly examinedafter myeloablative allogeneic HCT. Zager et al. (82) originallyreported that 53% of patients developed ARF (defined as 50%reduction in GFR) after allogeneic HCT, with half of these patientsrequiring dialysis. More recent studies have confirmed theseresults, with a 21 to 33% incidence of ARF requiring dialysisand an associated mortality of >80% (83,84). Table 2 summarizesthe published rates of ARF and mortality.
The incidence of ARF after autologous HCT is lower than afterallogeneic HCT. Merouani et al. (85) examined 232 patients whohad breast cancer and underwent autologous HCT and found a 21%rate of moderate to severe ARF associated with a mortality rateof 18.4%. Because graft versus host disease does not occur inautologous HCT, immunosuppressive agents (which can be nephrotoxic)are not required—the absence of both graft versus hostdisease and drugs such as calcineurin inhibitors probably explainsin part the lower rate of ARF in autologous HCT.
Fewer studies have assessed renal outcomes after nonmyeloablativeallogeneic HCT. A recent study by Parikh et al. (86) reportedthe incidence and causes of ARF in this setting. These authorsfound lower rates of ARF compared with myeloablative HCT. Thecumulative incidence of ARF (defined as doubling of serum creatinine[Scr] at 4 mo) was still high at 40.4%, but only 4.4% of allpatients required dialysis (86). Other differences in renaloutcomes in myeloablative compared with nonmyeloablative HCTwere noted. Most cases of ARF were related to calcineurin inhibitorsand resolved with lowering of doses. In contrast to myeloablativeHCT, veno-occlusive disease (VOD) was not a major cause of ARF.Finally, the timing of ARF in nonmyeloablative HCT was distributedover the first 3 mo after HCT, whereas in myeloablative HCT,ARF occurs primarily in the first 3 wk. Most of these differencescan be attributed to the milder conditioning regimen used innonmyeloablative HCT.
The cause of HCT-associated ARF can be categorized accordingto the time period after transplantation (Table 3) (87,88).In the first days after the transplant, patients are at riskfor tumor lysis syndrome and marrow infusion toxicity. Tumorlysis prophylaxis has made this a rare complication of chemoradiotherapeuticconditioning. Marrow infusion toxicity may occur in autologousHCT and is probably mediated by DMSO, a cryopreservative usedin the storage of autologous stem cells. DMSO induces hemolysisof contaminating red blood cells during stem cell storage andmay also induce in vivo hemolysis and ultimately pigment nephropathy(89,90). Advances in cryopreservation have made this complicationrare also (91).
Within the first few weeks of myeloablative HCT, recipientsare at high risk for many forms of ARF (88). These include aprerenal state induced by vomiting and diarrhea, usually asa result of conditioning regimens or acute graft versus hostdisease, or calcineurin inhibitors. Exposure to a variety ofnephrotoxic agents, including amphotericin B, aminoglycosides,intravenous contrast, and calcineurin inhibitors, may predisposeto the development of acute tubular necrosis. Thrombocytopeniaand neutropenia predispose to hemorrhagic or septic shock, respectively,and may also lead to acute tubular necrosis. Obstructive uropathyis rarer but can develop in the setting of severe hemorrhagiccystitis (itself the result of cyclophosphamide, adenovirus,or BK/polyoma virus infection) or of fungal infection in thecollecting system.
VOD
Despite the wide variety of possible renal complications inthe early posttransplantation period, the most common causeof severe ARF after myeloablative HCT is hepatorenal syndrome.More than 90% of hepatorenal syndrome cases are due to VOD,with rare cases from acute hepatic graft versus host diseaseor viral or drug-related hepatitis (82). The incidence of VODvaries according to the diagnostic criteria used but rangesbetween 5 and 70% in different reports (92). VOD is considereda conditioning-related toxicity and is associated most commonlywith regimens that include cyclophosphamide, busulfan, and/ortotal body irradiation (93). Other risk factors for the developmentof VOD include older age, female gender, advanced malignancy,previous abdominal radiation, amphotericin B exposure, and vancomycinor acyclovir therapy (the last three presumably markers of infection)(94).
Clinical features of VOD include weight gain, painful hepatomegaly,and jaundice. Diagnosis is complicated by the variety of conditionsthat mimic VOD, such as acute hepatic graft versus host disease,sepsis or drug-induced cholestasis, calcineurin inhibitor toxicity,gall bladder disease, and use of total parenteral nutrition(94). Timing of symptom onset aids in diagnosis: VOD generallyappears during the first 30 d after HCT. In the early stagesof the syndrome, sodium retention predominates with consequentweight gain, edema, and ascites. Jaundice and right upper quadrantpain follow. ARF then often arises and may be precipitated byrenal insults such as sepsis or nephrotoxins. Roughly 50% ofthose with VOD develop ARF, but some degree of renal insufficiencyexists in every patient (83,95). Severity of disease varies.In mild cases, hepatic injury is self-limited with completeresolution of symptoms and signs. In moderate disease, diuresisor analgesia for right upper quadrant pain may be required,but the syndrome eventually resolves completely. Severe VODconsists of progressive hepatic failure accompanied by renalfailure and carries a mortality approaching 100% by day 100after HCT (96).
The clinical features of VOD-associated renal failure are verysimilar to those seen in hepatorenal syndrome. Many patientsare oliguric with low urine sodium concentration. Severe sodiumand water overload are common. Patients generally have low BPand hyponatremia. Although VOD is characterized histologicallyby hepatic microangiopathy, no such lesion in the kidney isidentified at autopsy (97), in keeping with the notion thatthe renal injury in hepatorenal syndrome is hemodynamic ratherthan structural.
A central role for endothelial damage has been hypothesizedto initiate VOD, and so the coagulation cascade may be a pointof intervention in this disease. Previous trials investigatingantithrombotic and thrombolytic agents have been disappointing,but promising results from recent controlled trials have beenreported with defibrotide, a single-stranded polydeoxyribonucleotide(98,99). This agent binds vascular endothelium and has fibrinolytic,antithrombotic, and anti-ischemic properties. Prospective trialsare under way to confirm its efficacy in the prophylaxis andtreatment of VOD.
Management of ARF after HCT
Evaluation of the patient should be as for any patient withhospital-acquired ARF but with particular focus on the contribution—ifany—of hepatorenal syndrome to the clinical picture. Wherepossible, further exposure to nephrotoxic drugs should be minimized:If calcineurin inhibitor trough concentrations are high, thenreduction in dose should be considered; alternatives to amphotericinare now available (100). No randomized controlled trials havecompared intermittent hemodialysis with continuous therapiesin the setting of severe ARF after HCT. Whatever the modalityused, it should be noted that the prognosis in those who developsevere liver and renal failure is very poor. Continuous therapiesdo offer at least two potential advantages: (1) in the settingof hepatorenal syndrome, there is some evidence that they areassociated with less increase in intracranial pressure (101);(2) the daily obligate fluid intake in these patients is frequentlymassive and is most easily controlled by a continuous method.Vascular access can be problematic because of thrombocytopeniaand neutropenia predisposing to bleeding and infection, respectively.
Chronic kidney disease (CKD) is an important long-term complicationof HCT, particularly allogeneic HCT (developing in 15 to 20%of survivors of the latter) (88). Given the number of allogeneictransplants performed yearly (Figure 1), the overall burdenof CKD in survivors of allogeneic HCT represents a significantfuture public health problem (102).
The majority of cases of CKD after HCT are thought to be relatedto a low-grade renal thrombotic microangiopathy (102). Characteristicclinical features are slowly rising plasma creatinine, hypertension,and disproportionate anemia. Some cases have a more fulminantpresentation, however. Urine dipstick shows variable proteinuriaand hematuria. Careful review of previous laboratory tests willoften show evidence of a (low-grade) thrombotic microangiopathy:Intermittent or persistent elevation in plasma lactate dehydrogenase,low serum haptoglobin, low platelets, and low hemoglobin andsometimes schistocytosis. Renal imaging is usually unremarkable.In our opinion, kidney biopsy is very rarely required—unlessthe presentation is very atypical—as the laboratory featuresare often suggestive (although not diagnostic), biopsy findingsare unlikely to significantly alter management, and biopsy carriesincreased risks in these patients with thrombocytopenia andother morbidities. Typical histology includes mesangiolysis,basement membrane duplication, glomerular endothelial cell swelling,and tubular injury with interstitial fibrosis (103). Certainly,other forms of glomerular disease, such as membranous nephropathy,have been described after HCT, but these are relatively rare.
Thrombotic microangiopathy after HCT is probably multifactorialin cause. Current thinking regarding causes is summarized inFigure 3. The conditioning regimen—particularly the irradiation—isthought to be the primary cause of renal endothelial damage,with post-HCT factors such as graft versus host disease, infections,and medications (e.g., the calcineurin inhibitors) playing alater modulatory role (104). Tubular damage and interstitialfibrosis are seen in animal models of radiation nephropathy,and whether these changes are secondary to the glomerular damageor the direct result of irradiation remains unresolved (105).Note that the time course for development of renal failure (oftenmany months after HCT) is typical of radiation-induced kidneydamage: Kidney cells have much slower turnover than mucosalcells and thus manifest radiation damage much later (106).
Figure 3. Simplified schema of putative thrombotic microangiopathy (TMA) pathogenesis after hematopoietic cell transplant (HCT). Renal irradiation, as part of pre-HCT conditioning, damages renal microvasculature. Factors that affect progression are not well defined but may include concurrent chemotherapy, genetic factors, use of calcineurin inhibitors, presence of graft versus host disease or procoagulant state, and infection. Damage to the endothelial cell causes loss of thromboresistance with fibrin deposition, swelling, and microvascular obstruction causing microangiopathic hemolysis. Resultant glomerular ischemia may cause hypertension and over time lead to fibrosis and renal failure.
Risk factors for development of TMA syndromes after HCT arenot well defined and certainly require further study. Dose ofradiotherapy and use of concurrent cytotoxic chemotherapy arethought to be important (107); conversely, renal shielding duringtotal body irradiation is somewhat protective (108,109). Calcineurininhibitors do not worsen radiation nephropathy in an animalmodel, but their role in humans is unclear (110). Our grouphas reported that sirolimus-when added to calcineurin inhibitortherapy-may be associated with a higher incidence of TMA, but,fortunately, this is often reversible (111). A recent studythat examined angiotensin-converting enzyme genotype in HCT-associatedrenal failure suggested that genotype influences renal injury,but the result was of borderline significance (109). The managementof TMA after HCT is discussed below.
Calcineurin Inhibitor Toxicity
It is important to note that moderate to severe graft versushost disease carries a mortality of 10 to 50% (112). When usedwith glucocorticoids, cyclosporine or tacrolimus reduces theincidence of both acute and chronic graft versus host diseaseafter allogeneic HCT. Furthermore, these drugs do not suppressthe bone marrow. Long-term use of these calcineurin inhibitorsafter HCT very likely contributes to CKD, as has been well describedin nonrenal solid organ transplantation and autoimmune disease(113). Fortunately, calcineurin inhibitors are discontinuedin the majority of HCT recipients after 4 to 12 mo (114). Thus,the contribution of this drug class to CKD is probably modestin many HCT patients. It is likely that in some, cases calcineurininhibitors exacerbate the TMA, which can arise after HCT (calcineurininhibitor-induced TMA has been well described after kidney transplantation,for example [115,116], but this is difficult to assess).
Management of HCT-Related CKD
Careful review of the patient’s pre- and post-HCT historyis essential. Attention should be paid to the following: Typeof HCT and type of conditioning regimen (in particular, whethertotal body irradiation was used and at what dose) and degreeof exposure to nephrotoxins (e.g., prolonged treatment withamphotericin). The examination frequently shows hypertension,hypervolemia, and skin graft versus host disease. Blood testsshould be reviewed carefully and repeated to assess for TMA—itshould be noted that laboratory features are often intermittentand not florid. As discussed above, we believe that kidney biopsyis rarely indicated. Renal ultrasound is often used to excludepostrenal causes, but other imaging studies are rarely required.
General treatment—including control of hypertension—shouldbe as recommended for any CKD patient (117). Anemia and hyperkalemiamay be more common than in patients with other forms of CKDand require more aggressive treatment (88). Angiotensin-convertingenzyme or angiotensin receptor blockade retards progressionin animal models of radiation nephropathy and is recommendedfor this and for the usual CKD indications (106). Although hyperkalemiamay be problematic, our preference is to try to continue thisstrategy, using a low-potassium diet, diuretics, and low-dosesodium polystyrene, if tolerated (118). In the absence of data,it seems worthwhile to minimize calcineurin inhibitor dosage—ifpossible—as is sometimes done in solid organ transplantation(113). Although plasma exchange is sometimes used in floridforms of TMA after HCT, there is no evidence to date of benefit(119).
A subset of patients will progress to ESRD, and, overall, thesepatients may have worse survival on hemodialysis than patientswith ESRD from other causes (120). Suitability for renal transplantationmust be judged on a case-by-case basis. It is interesting thatthose who receive a renal allograft from the same donor as theiroriginal HCT will need minimal or no immunosuppression as aresult of immunologic tolerance of the allograft (121).
Renal failure remains an important complication of cancer andits treatment. The spectrum of cancer-associated renal diseasehas changed in the past 20 years, in large part as a resultof the use of newer chemoradiotherapy regimens. Nevertheless,a simple and systematic approach to assess and treat potentialprerenal, intrarenal, and postrenal causes is indicated in allpatients. Early diagnosis and treatment of renal failure isvital—both to improve renal outcomes and to ensure thatpatients are best prepared for further oncologic treatment.Close cooperation with oncology colleagues is essential to improveoutcomes in these complex patients.
Acknowledgments
B.D.H. is supported by National Institutes of Health Grant F32DK069037-01.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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50% reduction in GFR) after allogeneic HCT, with half of these patients requiring dialysis. More recent studies have confirmed these results, with a 21 to 33% incidence of ARF requiring dialysis and an associated mortality of >80% (83,84). Table 2 summarizes the published rates of ARF and mortality. 
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Introduction
Renal Failure in the...
