The Kidney in CancersColm Magee | Lynn Redahan

31

Kidney disease frequently complicates cancer and its treat-ment. The spectrum of disease in this setting includes acute kidney injury (AKI), chronic kidney disease (CKD), and dis-orders of electrolyte and water balance. Fortunately, these complications are often preventable or reversible with early diagnosis and treatment. Although the causes and manage-ment of AKI and CKD in cancer patients overlap signifi-cantly with causes in non-cancer patients, certain conditions are either unique to or more common in cancer patients.

This chapter provides a general overview of kidney dis-eases in individuals with cancer, focusing on conditions such as tumor lysis syndrome, hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP), bisphosphonate nephrotoxicity, and kidney disease follow-ing hematopoietic cell transplantation. Myeloma associated kidney disease is discussed in Chapter 26.

ACUTE KIDNEY INJURY IN THE CANCER PATIENT

Acute kidney injury in the cancer patient is often multifacto-rial, but, as in other clinical settings, it is clinically useful to consider pre renal, intrarenal, and postrenal causes (Box 31.1).

PRERENAL ACUTE KIDNEY INJURY

Anorexia, vomiting, and diarrhea (from the cancer itself or, more commonly, from chemotherapy) may predispose to prerenal injury. Additionally, pain is common in can-cer patients, and nonsteroidal antiinflammatory drugs (NSAIDs) may be used as treatment. The diagnosis and management of prerenal AKI is similar to that of the general patient, with several conditions more common. Several less common causes include hypercalcemia, interleukin-2 (IL-2) therapy, and hepatorenal syndrome.

HYPERCALCEMIAHypercalcemia is a relatively common complication of malignancy and is most often associated with lung cancer, breast cancer, and multiple myeloma. The various types of hypercalcemia associated with malignancy are summarized in Table 31.1. Humoral hypercalcemia, mediated mainly by parathyroid hormone–related peptide (PTHrp), is the most common form. The effects of PTHrp are similar to those of parathyroid hormone, increasing both bone break-down and renal tubular calcium reabsorption. AKI associ-ated with hypercalcemia is predominantly due to renal vasoconstriction and hypovolemia. Nephrogenic diabetes insipidus can also occur. Treatment involves administration of large volumes of normal saline (+/− loop diuretics) and

277

bisphosphonates. Measurement of PTHrp or 1,25 vitamin D3 is rarely required, because treatment is urgent and test results would not alter management. Early control of hyper-calcemia usually restores kidney function.

INTERLEUKIN-2IL-2 therapy is used for selected patients with metastatic renal cell carcinoma or metastatic malignant melanoma. Its use has been limited by severe toxicity, including capillary leak syn-drome, which leads to decreased effective circulating volume and a fall in glomerular filtration rate. Vomiting and diarrhea may exacerbate this prerenal syndrome. The typical presen-tation is oliguria in the first 24 hours of treatment followed by a rising creatinine. Prevention of AKI involves withholding antihypertensive and nephrotoxic medications, administer-ing intravenous fluids, and closely monitoring vital signs and urine output. Treatment of established AKI involves stopping IL-2 therapy and administering intravenous fluids, with close monitoring for development of pulmonary edema.

HEPATORENAL SYNDROMEHepatorenal syndrome can occur following certain forms of hematopoietic cell transplantation, discussed later in this chapter. Much less commonly, it is seen with massive infiltra-tion of the liver by neoplastic cells. Acute severe hepatitis and hepatorenal syndrome also have been reported with tyrosine kinase inhibitors such as erlotinib.

INTRARENAL AKI

GLOMERULAR DISEASESDeposition of monoclonal paraproteins in the glomeruli can cause nephrotic syndrome, kidney failure, and, rarely, nephritic syndrome; these conditions are discussed in Chap-ter 26. Paraneoplastic glomerular disease is a rare but well-described complication of malignancy (Fig. 31.1), in which glomerular disease likely is caused by factors secreted by tumor cells rather than by direct infiltration of the kidney or by deposition of a paraprotein. The diagnosis should be considered if glomerular disease and cancer present at sim-ilar times or if the glomerular lesion remits with successful treatment of the malignancy. Membranous nephropathy is the classic example, although the strength of the association (more with solid organ than hematologic cancers) is disputed. The policy in our center is to perform age- and gender-appropriate standard cancer screening in patients with unexplained membranous nephropathy. A careful history and examination may suggest further testing. An association between minimal change disease and Hodgkin’s disease is well established albeit uncommon, with an incidence of about 0.4%. Minimal change disease has also been reported with

278 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

leukemia, non-Hodgkin’s lymphoma, thymoma, and a vari-ety of solid organ tumors. Nephrotic syndrome in such cases often improves with treatment of the underlying malignancy.

Paraneoplastic membranoproliferative glomerulonephri-tis (MPGN) has been reported in cases of lymphoprolifera-tive disorders and carcinomas. Pankhurst and colleagues

Prerenal

Hypovolemia (poor fluid intake, vomiting, diarrhea, capillary leak syndrome with IL-2)NSAIDsHypercalcemiaHepatorenal syndrome (after HCT, massive infiltration by cancer cells)

Intrarenal

Glomerular

Membranous nephropathyANCA vasculitisAmyloidosisLight chain deposition diseaseCollapsing glomerulopathy (pamidronate)

Tubulointerstitial

ATN due to sepsis, hypovolemia, IV contrastATN due to drugs (cisplatin, ifosfamide, zoledronate)Acute cast nephropathy (myeloma)*Tumor lysis syndrome (uric acid and calcium-phosphate deposition)*Methotrexate*

Vascular

HUS/TTP (gemcitabine, mitomycin C, and other drugs; condi-tioning regimen for allogeneic HCT)

Postrenal

Obstruction of both urinary tracts by urological and nonuro-logical cancersRetroperitoneal fibrosis

Other

Bilateral nephrectomy (renal cancer)Massive infiltration of kidneys by lymphoma

*Associated with both tubular injury and tubular obstruction.

Box 31.1 Common Causes of Kidney Injury in Cancer Patients

performed a case-control study comparing 200 patients with antineutrophil cytoplasmic antibody (ANCA)–associated vas-culitis and 129 with Henoch-Schönlein purpura (HSP)to age- and sex-matched controls. Because the rate of malignancy was significantly increased in those with ANCA-associated vas-culitis or with HSP (relative risk 6.0 and 5.2, respectively), the authors concluded that malignancy should be considered in the differential diagnosis of patients who present with ANCA vasculitis. Of note, cyclophosphamide therapy (particularly when given in small, daily, oral doses) for ANCA vasculitis can cause bladder cancer, often years after administration. Although paraneoplastic glomerulonephritides are rare, they are important to bear in mind when evaluating a patient with malignancy and features suggestive of a glomerular lesion. Treatment should be directed at the underlying malignancy.

TUMOR INFILTRATIONAlthough many solid organ and hematologic cancers can involve the kidney parenchyma, clinical sequelae are usually not prominent. Lymphomas and leukemias are the most com-mon such cancers, and kidney involvement has been found in up to 50% of autopsy cases of non-Hodgkin lymphoma far exceeding the numbers with clinically evident kidney disease. Accordingly, although lymphomatous involvement of the kidneys may present with AKI, the diagnosis is usu-ally incidental. Typical findings include enlarged kidneys with bland urinalysis. Although kidney biopsy may yield the diagnosis of lymphoma, in cases of known lymphoma with AKI and enlarged kidneys, a presumptive diagnosis of kidney involvement is reasonable and improvement in kidney func-tion and reduction in kidney size with successful chemother-apy can provide further post hoc support for this diagnosis.

Despite advances in nephron-sparing surgery and abla-tive therapies, full nephrectomy is sometimes still required for primary kidney cancers, including renal cell carcinomas. Patients with preexisting CKD will have significant worsen-ing of their CKD after radical nephrectomy and should be counseled beforehand about this inevitable complication. Occasionally, patients will have bilateral kidney involvement, requiring simultaneous (or staged) bilateral nephrectomy and precipitating "acute" end-stage renal disease (ESRD). Fortunately, patients without extrarenal metastases may still be candidates for kidney transplantation.

TUMOR LYSIS SYNDROMETumor lysis syndrome (TLS) describes the metabolic compli-cations of either spontaneous rapid tumor cell turnover or,

Table 31.1 Causes of Hypercalcemia in Individuals With Cancer

Type Proportion Bone Metastases Mediator(s) Typical Cancers

Humoral hypercalcemia of malignancy

80% Minimal PTHrp Squamous cell (of lung, head/neck, cervix), ovarian cell, renal cell

Local bone breakdown 20% Common and extensive Cytokines, chemokines Multiple myeloma, breast cancer, lymphoma

Excess 1,25 vitamin D3 <1% Variable 1,25 vitamin D3 LymphomasExcess (ectopic) PTH <1% Variable PTH Variable

Modified from Stewart AF: Hypercalcemia associated with cancer, N Engl J Med 352:373, 2005.PTH, Parathyroid hormone; PTHr, parathyroid hormone–related peptide.

more commonly, chemotherapy-induced tumor cell lysis. It occurs most often with the treatment of leukemias and lym-phomas but can occur with any rapidly proliferating malig-nancy that is highly sensitive to treatment. The syndrome is characterized by hyperuricemia, hyperphosphatemia, hypo-calcemia, hyperkalemia, and AKI, often with progressive oli-guria. Severe forms of TLS are potentially life threatening. The two major mechanisms causing AKI in TLS are the depo-sition of urate crystals in the renal tubules and the precipita-tion of calcium-phosphate in the interstitium (Figure 31.2). Urate crystals are both directly toxic to the tubular epithelial cells and also cause intratubular obstruction. Calcium-phos-phate precipitation may be exacerbated by alkalinization of the urine.

TLS usually occurs 24 to 72 hours after initiation of che-motherapy, and the cornerstone of management is preven-tion. Patients at high risk for developing TLS (high tumor burden, rapid cell turnover, hypovolemia, or preexisting kidney disease) should be identified before starting chemo-therapy. Preventive measures are shown in Table 31.2. Of note, because alkalinization of the urine exacerbates intra-renal calcium-phosphate precipitation, bicarbonate admin-istration is not recommended. AKI associated with TLS is a medical emergency and management involves immedi-ate treatment of electrolyte abnormalities, administration of rasburicase, and diuresis. Severe cases require immedi-ate, high-dose hemodialysis or hemofiltration. The kidney prognosis is good if the patient survives the immediate complications.

279 CHAPTER 31 — THE KIDNEY IN CANCERS

MULTIPLE MYELOMA AND RELATED PLASMA CELL DYSCRASIASMultiple myeloma and related plasma cell dyscrasias are the most common oncologic causes of severe acute and chronic kidney injury, including cast nephropathy, amyloi-dosis, and light-chain deposition disease. Myeloma patients are also at increased risk for hypercalcemia-induced AKI and, in some reports, contrast nephropathy and bisphos-phonate nephrotoxicity. Multiple myeloma is discussed in detail in Chapter 26.

BISPHOSPHONATE-INDUCED KIDNEY DISEASEIntravenous bisphosphonates are antiresorptive agents widely used to treat osteolytic metastases and hypercalcemia of malignancy. Their use is particularly common in breast cancer and myeloma. Both nephrotic syndrome and kidney dysfunction have been reported with use of intravenous bisphosphonates in cancer patients, pamidronate being associated with the former and zoledronate with the latter. Risk factors for kidney complications include myeloma, pre-existing kidney disease, and higher bisphosphonate dose. Markowitz and colleagues first reported seven patients who developed nephrotic syndrome and kidney dysfunction while receiving pamidronate; histology showed collapsing glomerulopathy with varying degrees of tubular injury. Five of these patients had received very high-dose pamidronate. Notably, the three patients in whom pamidronate was dis-continued had subsequent kidney function improvement, whereas the four who continued to receive pamidronate

Figure 31.1 Paraneoplastic glomer-ulonephritis associated with solid tumors. Data are presented as number of reported cases of specific types of paraneoplastic glomerulonephritides associated with each type of cancer. IgAN, IgA nephropathy; MCD, minimal change disease; MN, membranous nephropathy; MPGN, membranopro-liferative glomerulonephritis; RPGN, rapidly progressive glomerulonephritis. (From Lien YH, Lai LW: Pathogenesis, diagnosis and management of para-neoplastic glomerulonephritis, Nat Rev Nephrol 7:85-95, 2011.)

30

25

20

15

10

5

0MN MCD MPGN RPGN IgAN

Lung CA

Gastric CA

Renal CA

Prostate CA

Breast CA

Colon CA

Num

ber

of r

epor

ted

case

s

280 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

Potassium

Massive tumor cell lysis

Phosphate

Xanthine

Allantoin

AKI

Arrhythmias

Urinary excretion

Uric acid

Allopurinol -

Purines Calcium-phosphate precipitation

Rasburicase +

Figure 31.2 The two major mechanisms causing acute kidney injury (AKI) in tumor lysis syndrome are the deposition of urate crystals in the lumina of renal tubules and the precipitation of calcium-phosphate in the interstitium. Hyperkalemia may lead to the development of arrhythmias.

developed kidney failure. Severe tubular injury, which is not always reversible, has been reported with zoledronate. Common-sense strategies to reduce the risk for bisphospho-nate nephrotoxicity are shown in Box 31.2. In patients in whom bisphosphonate nephrotoxicity is a major concern, denosumab, a monoclonal antibody targeting receptor acti-vator of nuclear factor-κB ligand (RANKL), may prove to be an alternative.

METHOTREXATEHigh-dose intravenous methotrexate is used to treat leuke-mia, lymphoma, and less commonly, solid organ cancers.

Table 31.2 Prevention of Tumor Lysis Syndrome in a High-Risk Patient

Therapy Comment

Large volume of intravenous saline

Aim to keep urine output >150 mL/hr

Allopurinol High doses neededSafe and moderately

efficaciousInexpensive

Rasburicase Can be used to treat estab-lished cases

Methotrexate is mainly excreted by the kidneys, and high-dose protocols can cause AKI, both by direct toxic effects on renal tubular cells and by precipitation of the drug and its metabolites within the tubular lumen. Intraluminal crystalli-zation is exacerbated by lower urine pH. Other factors associ-ated with development of nephrotoxicity include preexisting kidney disease, concomitant use of other nephrotoxic drugs, hypovolemia, and higher plasma concentrations of the drug at 72 hours postinfusion. An abrupt rise in creatinine dur-ing or immediately after the infusion is the typical present-ing feature. Once methotrexate nephrotoxicity develops, reduced elimination of the drug results in persistent high

Avoid supratherapeutic dosesIf agents are excreted by the kidneys, adjust dose for lower GFRAdminister high volumes of normal saline or other solution to

maintain high urine output before, during, and after infusion of drug

Monitor patient for rising creatinine and proteinuria; consider switching or postponing therapy if these occur

Avoid other nephrotoxins such as NSAIDs and iodinated contrast

Box 31.2 Strategies to Minimize the Risk for Bisphosphonate or Chemotherapy Nephrotoxicity

plasma levels and an increased risk for severe myelosuppres-sion and hepatitis; thus early recognition and treatment of this complication are vital. The estimated incidence of meth-otrexate nephrotoxicity is 1.8%. Prevention involves dose adjustment for kidney function, maintenance of both a high urine output and a urine pH higher than 7.0 (by administra-tion of high volumes of sodium bicarbonate fluids before, during, and after methotrexate infusion), and avoidance of other nephrotoxins. Folinic acid (leucovorin) rescue is routinely prescribed. Treatment of established nephrotoxic-ity involves continued alkalinization of the urine, adminis-tration of additional folinic acid, and, in anticipated severe cases, glucarpidase (which rapidly converts methotrexate to nontoxic metabolites). Although hemodialysis is only mod-erately efficient in removing methotrexate and a rebound in plasma levels may occur upon cessation of dialysis, high-dose hemodialysis may prove useful as a temporizing measure, pending availability of glucarpidase.

CISPLATINCisplatin is commonly used for the treatment of solid organ malignancies, but dose-related nephrotoxicity is a major limiting factor in its use. Tubular injury, which can be per-manent, may result in acute and subacute kidney injury, a Fanconi-like syndrome and severe hypomagnesemia. HUS can also occur when the drug is combined with bleomycin or gemcitabine. Strategies to minimize cisplatin nephrotox-icity are summarized in Box 31.2. In some cases, carboplatin can be used as a less nephrotoxic alternative.

IFOSFAMIDEHigh cumulative doses of ifosfamide can cause severe tubu-lar damage, manifesting clinically as acute or chronic kidney dysfunction, a Fanconi-like syndrome, or diabetes insipidus. The incidence of AKI in adults treated with various doses of ifosfamide is 4% to 17%. Ifosfamide-associated kidney dys-function can progress weeks or even months after the drug is stopped, and the Fanconi-like syndrome can be severe and permanent.

OTHER DRUGSThe nitrosoureas (lomustine, carmustine, streptozocin) occasionally cause severe and progressive renal tubular damage. Tyrosine kinase inhibitors such as sunitinib and imatinib have been associated with various forms of kidney injury, including reduced glomerular filtration rate (GFR), proteinuria, and thrombotic microangiopathy.

VASCULAR DISEASESThe most common vascular cause of AKI in patients with can-cer is HUS/TTP, which may occur as a complication of cancer itself or, more commonly, as a complication of its treatment (Table 31.3). Carcinomas, particularly gastric, breast, lung, and pancreatic, are the most frequently implicated cancers, whereas mitomycin C, gemcitabine, bleomycin, and cisplatin are the most frequently implicated drugs. HUS/TTP occurs in 0.3% of patients treated with gemcitabine, with median time to diagnosis of 8 months after initiation of gemcitabine. Hypertension is a prominent feature in most cases, with either new or worsened hypertension preceding the diagno-sis of HUS/TTP. Patients treated with chemotherapy regi-mens that are associated with HUS/TTP should be watched

281 CHAPTER 31 — THE KIDNEY IN CANCERS

closely for subtle signs of an evolving syndrome, including increasing blood pressure, creatinine and lactate dehydroge-nase (LDH), schistocytosis, and falling haptoglobin. Anemia and thrombocytopenia may also occur, but these are difficult to interpret in the setting of chemotherapy. Full-blown HUS/TTP can arise many months after initiation (or completion) of chemotherapy; a similar phenomenon occurs after HCT (see below). Treatment involves cessation of the offend-ing agent, control of hypertension, and other supportive measures. There are few data to support the use of plasma exchange, but some centers use it in severe, resistant cases. Hypertension, proteinuria, and HUS/TTP can also compli-cate therapy with vascular endothelial growth factor (VEGF) inhibitors, even when these agents are given by the intraocu-lar route alone!

POSTRENAL ACUTE KIDNEY INJURY

Intratubular obstruction due to uric acid (in TLS), metho-trexate, or myeloma casts has been discussed earlier. Bilat-eral urinary tract obstruction, which can occur at any level of the urinary tract, is relatively common in cancer patients and should be considered in the differential diagnosis of AKI. Common obstructing tumors include prostate, blad-der, uterus, and cervix cancers (Figure 31.3). Not sur-prisingly, prognosis is poor, because bilateral obstruction implies high tumor bulk. Nevertheless, nephrostomies and internal ureteric stents can be a good short- and medium-term treatment option. Obstructive uropathy can occur in the absence of hydronephrosis because encasement of the collecting system by retroperitoneal tumor or fibrous tissue may prevent pelviureteric dilation. Retroperitoneal fibrosis can be associated with previous pelvic irradiation or malig-nancies such as lymphomas and sarcomas.

ELECTROLYTE DISORDERS

Malignancy can be associated with a variety of electrolyte dis-orders, including hypercalcemia, hypokalemia, hypomagne-semia, hyponatremia, and hypernatremia. Hypercalcemia

Table 31.3 Settings in Which HUS/TTP May Arise in Individuals With Cancer

Setting Comment

Spontaneously (before chemotherapy)

Rare

During/after chemotherapy Gemcitabine, bleomycin + cisplatin, mitomycin C most commonly implicated drugs

During/after VEGF therapy Uncommon

After HCT Mainly associated with allo-geneic HCT; onset may be delayed

HCT, Hematopoietic cell transplantation; HUS/TTP, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; VEGF, vascular endothelial growth factor.

282 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

has been discussed earlier. Hypokalemia can result from gastrointestinal or kidney losses, with the latter most often due to tubular injury from ifosfamide or cisplatin. Tubular injury from these drugs can also cause long-term magne-sium wasting and hypomagnesemia.

A

B

Figure 31.3 A shows hydronephrosis of the right kidney on ultra-sonography. This patient was diagnosed with obstructive uropathy secondary to a tumor of the uterine cervix and required insertion of bilateral nephrostomies (indicated by arrows on B).

Malignancy is a common cause of the syndrome of inap-propriate antidiuretic hormone secretion (SIADH; see Chapter 7). Intravenous cyclophosphamide, vincristine, and vinblastine can also cause SIADH, whereas hypovole-mic hyponatremia may occur with chemotherapy-related gastrointestinal fluid losses. Hypernatremia is less com-mon, although both primary brain tumors and brain metastases can cause central diabetes insipidus, whereas hypercalcemia can cause nephrogenic diabetes insipidus (Chapter 8).

KIDNEY DISEASE IN HEMATOPOIETIC CELL TRANSPLANTATION

The general purpose of hematopoietic cell transplantation (HCT) is to allow administration of otherwise lethal (and ideally curative) doses of chemoradiotherapy, followed by engraftment of stem or progenitor cells for marrow recovery. Most commonly, HCT is used to treat hemato-logic cancers, but other indications include genetic disor-ders (e.g., immunodeficiencies) and severe autoimmune diseases. Conventional myeloablative HCT uses an inten-sive conditioning regimen (high-dose chemotherapy and radiotherapy) to ablate cancer cells and bone marrow; the hematopoietic system is then reconstituted by infusion and engraftment of stem cells. In allogeneic myeloablative HCT, nonself stem cells are used, whereas in autologous myeloablative HCT, the patient’s own cells are used. Non-myeloablative conditioning regimens have been developed to allow allogeneic HCT in older and sicker patients who would not tolerate standard regimens. In both forms of allogeneic HCT, acute and chronic graft-versus-host disease (GVHD) can be problematic, and calcineurin inhibitors often are used to prevent and treat this complication. The main organs affected by GVHD are the liver, gastrointesti-nal tract, and skin. Both AKI and CKD are common com-plications of HCT and are associated with higher early and late mortality. Types and kidney complications of HCT are summarized in Table 31.4.

Table 31.4 Overview of HCT Types and Their Kidney Complications

Allogeneic Myeloablative Autologous MyeloablativeAllogeneic Nonmyeloablative

Cancers treated Many leukemias, lymphomas, myelodysplastic syndromes

Lymphomas, multiple myeloma As for allogeneic myeloablative

Intensity of conditioning regimen

High High Low

GVHD after HCT Yes (CNIs used as prophylaxis) No Yes (CNIs used as prophylaxis)

AKI after HCT Common; sometimes severe Rare Common; rarely severe

Causes of AKI (usually first 3 months)

VOD, shock syndromes, nephrotoxic drugs, CNIs

Shock syndromes, nephrotoxic drugs, occasionally VOD

CNIs

CKD after HCT Common Common (but not severe) Mild forms probably common

Causes of CKD Irreversible AKI, renal TMA, CNIs; membranous nephropathy

Irreversible AKI; recurrence of original disease (myeloma)

Irreversible AKI, CNIs, mem-branous nephropathy

AKI, Acute kidney injury; CKD, chronic kidney disease; CNI, calcineurin inhibitors; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; TMA, thrombotic microangiopathy; VOD, venoocclusive disease.

AKI AFTER HCT

CAUSES AND PRESENTATIONAKI is common after HCT (see Table 31.4), most often occurring after myeloablative allogeneic HCT, reflecting the propensity of this regimen to cause profound immu-nosuppression (with associated risk for severe sepsis) and liver damage (with associated risk for hepatorenal syndrome). Furthermore, calcineurin inhibitors are rou-tinely prescribed for the first 100 days after myeloablative allogeneic HCT, potentially exacerbating the effects of volume depletion and hypoperfusion on the kidney. Mye-loablative autologous HCT has an intermediate incidence of AKI, whereas severe AKI is least common after nonmy-eloablative HCT, because of the shorter period of pan-cytopenia and low incidence of hepatorenal syndrome. Regardless of the form of HCT, if dialysis is required for severe AKI, the overall prognosis is very poor (early mortality >70%).

It is useful to consider the causes of AKI according to the time period after HCT. Immediate AKI from TLS or stem cell infusion toxicity is rare; however, during the first few weeks of myeloablative HCT, when the conditioning regi-men has caused pancytopenia, mucositis, and liver damage, recipients are at high risk for many forms of AKI. These include prerenal syndromes due to calcineurin inhibitors (CNIs), hypovolemia (caused by vomiting, diarrhea, or bleeding), acute liver disease, and ATN due to septic shock and nephrotoxic drugs (amphotericin, aminoglycosides). Obstructive uropathy is unusual but can be due to severe hemorrhagic cystitis (high-dose cyclophosphamide or viral infection) or fungal infection.

Venoocclusive disease (VOD) of the liver, also known as sinusoidal obstruction syndrome, is one of the more common causes of severe AKI after myeloablative HCT, especially allogeneic HCT. The cause is thought to be radiotherapy- and chemotherapy-induced damage to the endothelium of hepatic venules with subsequent venular thrombosis and sinusoidal and portal hypertension. Risk factors for development of VOD include older age, female sex, preexisting liver disease, use of cyclophosphamide or busulfan in the conditioning regimen, and exposure to methotrexate, progesterone, or antimicrobial drugs. VOD manifests as a form of hepatorenal syndrome, usu-ally within the first 30 days of HCT. The severity of disease varies greatly. Diagnosis is based on typical clinical and laboratory features, including fluid overload, right upper quadrant pain and tenderness, and abnormal LFTs. Occa-sionally, liver biopsy is performed to exclude other forms of liver disease. Mild to moderate cases often resolve with supportive therapy alone, but severe VOD complicated by liver, kidney, and frequently respiratory failure carries a mortality approaching 100%.

DIAGNOSIS AND MANAGEMENTThe evaluation of AKI following HCT should be similar to that of any patient with hospital-acquired AKI but with particular attention to the possibility of VOD. The patient’s cancer diagnosis, conditioning regimen, and type of HCT should be carefully reviewed. Where possible, further expo-sure to nephrotoxic drugs should be minimized. Reduction in CNI dosage should be considered, particularly if trough

283 CHAPTER 31 — THE KIDNEY IN CANCERS

concentrations are high. Mild to moderate forms of VOD require supportive therapy, including fluid restriction and cautious diuresis, whereas severe forms of VOD involve multiorgan support, including kidney replacement therapy, often with continuous therapies. Defibrotide, a polynucleo-tide with antithrombotic and antiischemic properties, may be a promising agent to treat VOD that arises after HCT.

CKD AFTER HCT

CKD is an important long-term complication of HCT, par-ticularly allogeneic HCT. Reported rates vary widely, with one recent review reporting an incidence of 17% in those surviving at least 100 days after HCT. Causes of CKD are summarized in Table 31.4.

RENAL THROMBOTIC MICROANGIOPATHYSubacute or chronic renal thrombotic microangiopathy (TMA) is an important cause of CKD (particularly severe CKD) after HCT. It typically presents 3 to 12 months after HCT. Characteristic clinical features are slowly rising cre-atinine, hypertension, and disproportionate anemia. Urine dipstick shows variable proteinuria and hematuria. Some cases have a more fulminant presentation (e.g., nephritic syndrome). Careful review of laboratory data will often show evidence of a low-grade TMA: intermittent or persis-tent elevation in LDH, low serum haptoglobin, low plate-lets, low hemoglobin, and sometimes schistocytosis. Kidney imaging is usually unremarkable, and kidney biopsy is rarely required unless the presentation is atypical, because biopsy findings are unlikely to significantly alter manage-ment and biopsy carries increased risks in patients with thrombocytopenia and other comorbidities. Histopathol-ogy typically shows microthrombi in arterioles and glo-merular capillaries, mesangiolysis, glomerular basement membrane duplication, and tubular injury with interstitial fibrosis (Figure 31.4). The main cause of TMA after HCT likely is direct damage to the renal endothelium and tubu-lointerstitium by the chemoradiotherapy conditioning regimen (particularly the radiotherapy component, Figure 31.5). Kidney tissue has slower turnover than mucosal cells and thus manifests such damage much later. Other factors, such as infection, GVHD, CNIs, and activation of the renin angiotensin system, may play a role. Treatment is mainly supportive, whereas prevention involves shielding the kid-neys from radiation and avoidance of nephrotoxic agents at the time of conditioning.

CALCINEURIN INHIBITOR AND SIROLIMUS NEPHROTOXICITYCalcineurin inhibitors are routinely prescribed after allo-geneic HCT to prevent and treat GVHD; however, because CNIs are often stopped 3 to 6 months after HCT (unless there is ongoing GVHD), their contribution to CKD is gen-erally thought to be limited. We have noted a high incidence of TMA when sirolimus is added to CNI therapy, but fortu-nately this is often reversible.

GLOMERULAR DISEASENephrotic syndrome has been described after both alloge-neic and autologous HCT. In allogeneic HCT, it appears to be strongly associated with the presence of GVHD and

284 SECTION 4 — THE KIDNEY IN SYSTEMIC DISEASE

Figure 31.4 Renal biopsy shows typical features of renal TMA with microthrombi in the arterioles (A) and glomerular capillaries, mesan-giolysis, and duplication of the glo-merular basement membrane (B).

BA

responds to additional immunosuppression. De novo mem-branous nephropathy is the most common biopsy finding, although minimal change disease has also been reported. The original hematologic disease (such as myeloma) may also recur with kidney involvement.

Chemotherapy Renal shielding–+

+

++

+

+

CNIs, sirolimus

Hypertension AKI/CKD

Procoagulant state Pro-inflammatorycytokines

Damage and inflammationof renal endothelium

Glomerular ischemia Microangiopathichemolytic anemia

TMA syndrome

Radiation

“Initial injury”

GVHD

Infection

- Platelet and fibrin deposition- Microvascular obstruction

Figure 31.5 Putative pathogenesis of thrombotic microangiopa-thy after after hematopoietic cell transplantation. AKI, Acute kidney injury; CKD, chronic kidney disease; CNI, calcineurin inhibitors; GVHD, graft-versus-host disease; TMA, thrombotic microangiopathy.

DIAGNOSIS AND MANAGEMENTCareful review of the patient's pre- and post-HCT history is essential. Attention should be paid to the type of HCT and conditioning regimen (in particular, whether total body irradiation was used and at what dose) and degree of exposure to nephrotoxins. Examination frequently shows hypertension and hypervolemia and sometimes skin GVHD. Laboratory results should be reviewed carefully and tests repeated to assess for TMA because the laboratory features of TMA are often intermittent and not florid. Urine dipstick findings of hematuria and moderate proteinuria are sug-gestive of renal TMA but are not specific to this condition. As with AKI after HCT, kidney ultrasound is often used to exclude postrenal causes, but other imaging studies are usu-ally unnecessary. As discussed earlier, kidney biopsy is rarely indicated. Treatment is similar to that recommended for any patient with CKD, and blood pressure control is warranted. In particular, blockade of the renin-angiotensin system slows progression in animal models of radiation nephropathy and is recommended both for this reason and for its beneficial effects in hypertensive proteinuric CKD. CNI doses should probably be minimized if safe to do so. Plasma exchange does not appear to be beneficial in this setting.

A subset of patients will progress to ESRD, and these patients have worse survival when treated with dialysis than non-HCT controls. Suitability for kidney transplantation should be judged on a case-by-case basis. Occasionally, the allogeneic stem cell donor can donate a kidney; a great benefit of this approach is that a state of tolerance to the allograft should exist, and hence minimal or no immuno-suppression is required. If this option is not available and the patient receives a conventional kidney transplant, low-dose immunosuppression should be prescribed because HCT recipients may not have normal immunity and thus remain at higher risk for infection.

CONCLUSION

Acute kidney injury and CKD are important complications of cancer and its treatment. As new chemotherapy regimens

are constantly introduced or modified, the spectrum of cancer-associated kidney disease changes. Nevertheless, a simple and systematic approach to assess and treat poten-tial prerenal, intrarenal, and postrenal causes is indicated in all patients. Prompt diagnosis and treatment of kidney disease is vital—both to improve kidney outcomes and to ensure that patients are in optimal condition for fur-ther cancer therapy. Close cooperation with oncology col-leagues is essential to improve outcomes in these complex patients.

KEY BIBLIOGRAPHYAndo M, Mori J, Ohashi K, et al: A comparative assessment of the RIFLE,

AKIN and conventional criteria for acute kidney injury after hemato-poietic SCT, Bone Marrow Transplant 45(9):1427-1434, 2010 Sep.

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Full bibliography can be found on www.expertconsult.com.