Acute Kidney Injury following Hematopoietic Cell Transplantation and Severe Burns

Justin M. Belcher

Chirag R. Parikh

Acute kidney injury (AKI) occurs, with varying prevalence, across virtually all hospital settings. The most common etiologies of hospital-based AKI—acute tubular necrosis (ATN), contrast induced nephropathy, and prerenal azotemia—are familiar to every practicing nephrologist. However, AKI can also be uniquely associated with specific conditions. Two such situations are following hematopoietic cell transplantation (HCT) and in the setting of severe burns. Care for HCT and burn patients is highly specialized, typically restricted to tertiary care centers, and involves a limited number of patients. Thus, many nephrologists may have limited experience evaluating and managing AKI in these settings. However, although not commonly encountered, HCT and burns are associated with a remarkable incidence of AKI that portends subsequent worse outcomes. Therefore, this chapter explores the epidemiology, pathogenesis, and outcomes of AKI in these unique settings.

BACKGROUND

HCT is an increasingly common treatment that offers the possibility of cure for a variety of once fatal malignant and nonmalignant disorders. Initially conceived in the late 1950s as a treatment for hematologic malignancies, the spectrum of illnesses treated with HCT has burgeoned to include solid tumors,¹ red blood cell dyscrasias,² inborn errors of metabolism,³ and autoimmune disorders.⁴ The coming years hold the potential of an even greater role for HCT including the tantalizing possibility of inducing tolerance in solid organ transplantation and treating chronic ailments such as Parkinson disease and diabetes mellitus.⁵ Current common indications for transplantation are listed in Table 38.1. Overall, approximately 50,000 to 60,000 HCTs are performed annually worldwide with roughly 40% of these occurring in the United States (www.cibmtr.org). The 5-year survival rate has improved steadily and now stands at over 50%. Additional improvements have been achieved over the past two decades in engraftment time, graft-versus-host disease (GVHD), relapse or malignant progression, and nonrelapse mortality.¹² Much of this improvement is attributable to more accurate human lymphocytic antigen (HLA) matching, more effective and tolerable infection prophylaxis, and a reduction in the intensity of chemoradiation conditioning regimens. Despite these striking advances, the procedure remains fraught with potential complications, one of the most severe of which is AKI.

The development of AKI can be detrimental, beyond its own sequelae, because it interferes with the usual adequate dosing of immunosuppressants and thus predisposes for GVHD, rejection, and interruption of treatment. AKI can also contribute to other organ dysfunction, such as lung and liver, due to volume overload, coagulation abnormalities, and cytokine mediated pulmonary dysfunction. There are at present three types of transplantation: myeloablative autologous (autologous), myeloablative allogeneic (allogeneic), and nonmyeloablative allogeneic, or reduced intensity conditioning (RIC). In the United States, 57% of transplants are autologous with the remainder being conventional and reduced intensity allogeneic.⁶,⁷ The incidence, risk factors for development, etiology, severity, and outcomes of AKI differ markedly among the three transplant modalities.

Sources of Cells

In the early days of HCT bone marrow was the source of cells for most transplants, reflected in the older term “bone marrow transplant.” However, the potential sources of cells for HCT have expanded over time. The use of recombinant human granulocyte colony stimulating factor, which can increase the entry of stem cells into the peripheral blood by up to 1,000-fold, has allowed cytapheresis harvested peripheral cells to become the current dominant source for HCT. Autologous transplants involve the harvesting of one’s own bone marrow or peripheral blood cells or, most recently, the use of banked umbilical cord cells. Allogeneic transplants utilize family members or HLA-matched unrelated donors and can again derive
cells from bone marrow, peripheral blood, or umbilical cord blood. By 2007, 80% of allogeneic and nearly 100% of autologous transplants involved the use of peripheral blood cells.⁶,⁷ AKI has been found to be more common in recipients of marrow transplant as opposed to peripheral stem cells in some studies¹¹ but not in others.¹³ Conversely, chronic GVHD (cGVHD) may be more prevalent in recipients of peripheral stem cell transplantation due to the greater dose of delivered T cells.¹³,¹⁵,¹⁶,¹⁷ No association has been established between the number of infused stem cells per body weight and AKI.¹⁸

TABLE 38.1 Common Indications for Hematopoietic Cell Transplantation

Autologous	Allogeneic
Multiple myeloma	Acute myelogenous leukemia
Non-Hodgkin lymphoma^a	Acute lymphocytic leukemia
Hodgkin lymphoma	Myelodysplastic syndrome/myelodysplastic disorder
Other cancers^c	Non-Hodgkin lymphoma^a
Neuroblastoma	Nonmalignant disease^b
Breast cancer		-AL amyloidosis -Paroxysmal nocturnal hemoglobinuria -Thalassanemia -Sickle cell disease -Systemic lupus erythematous
	Chronic myelogenous leukemia Aplastic anemia Multiple myeloma
^aNon-Hodgkin lymphomas include lymphoblastic, Burkitt, diffuse large B cell, follicular, mantle cell, T cell. ^bNonmalignant disease includes Fanconi anemia, Blackfan-Diamond anemia, rheumatoid arthritis, Crohn disease, multiple sclerosis, systemic sclerosis, juvenile rheumatoid arthritis, Evan syndrome, chronic inflammatory demyelinating polyneuropathy, Niemann-Pick disease, Kostmann syndrome, osteopetrosis, Hurler syndrome, adrenoleukodystrophy (ALD)/metachromic dystrophy (MLD), Di-George syndrome, chronic granulomatous disease, common variable disease, severe combined immunodeficiency, Wiskott-Aldrich syndrome, POEMS syndrome, familial erythrophagocytic lymphohistiocytosis. ^cOther cancers include chronic lymphocytic leukemia, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma, Wilms tumor, osteogenic sarcoma, hepatic blastoma, juvenile chronic myeloid leukemia, desmoplastic small round cell tumor, germ cell, ovarian, renal cell, small-cell lung, soft cell sarcoma.
Data is from references 6 to 11.

Myeloablative versus Nonmyeloablative

Conventional myeloablative allogeneic HCT involves high-dose chemotherapy and radiation to eradicate the underlying disease and immunosuppression to prevent rejection of the transplant graft. The allograft then serves to reconstitute the marrow and correct the treatment associated pancytopenia. Survival is contingent on recovery from the cytoablative therapy, successful engraftment, prevention and treatment of infections and GVHD, and eradication of the underlying disease. The potent myeloablative procedure is associated with significant rates of acute conditioning associated complications due to its high-dose chemotherapy and total-body irradiation (TBI), restricting its use to younger, healthier HCT recipients. However, many of the hematologic and malignant conditions wherein HCT holds the greatest potential for cure present primarily in patients older than the standard myeloablative cutoff of 55 to 60 years old or with baseline organ dysfunction or previous high-dose chemotherapy sufficient to render them ineligible for the procedure.

For years these patients were necessarily excluded from treatment. In 1997, a nonmyeloablative procedure was proposed wherein a reduced intensity conditioning regimen would allow its use in older patients and those with significant burdens of comorbidities.¹⁹ Unlike in myeloablative transplant, the low dose chemoradiation in RIC is not intended to kill all residual cancer cells but to provide sufficient immunosuppression so as to allow engraftment of the transplanted stem cells, facilitating their subsequent eradication of the cancer via a donor mediated immune response known as the graft-versus-tumor effect.¹⁹,²⁰,²¹,²²,²³ RIC has demonstrated low toxicity and similar efficacy compared to conventional myeloablation in several malignancies without an increased rate of disease recurrence.¹⁹,²⁰ RIC constituted approximately 20% of allogeneic transplants in 2006 and it is increasingly employed in low-grade lymphoma, chronic leukemia, acute leukemia in remission, renal cell carcinoma, and multiple myeloma.²⁴ Utilization of RIC is likely to continue to increase given the aging population, expanded indications, and technologic advances for transplants across histocompatibility barriers. Distinguishing features of the three types of hematopoietic cell transplants are charted in Table 38.2.

Conditioning Treatments and Prophylaxis

Although all modalities of HCT expose recipients to potentially nephrotoxic medications in the course of conditioning and infection prophylaxis, the specific risks vary by type of transplant. Myeloablative allogeneic regimens typically are cyclophosphamide based along with either TBI or busulfan whereas autologous recipients receive a combination of cyclophosphamide or busulfan along with other agents. For RIC, a very low dose of TBI or fludarabine is substituted for cyclophosphamide or cyclophosphamide dosing is individualized. Allogeneic recipients receive prophylaxis against acute graft-versus-host disease (aGVHD) with
immunosuppressive drugs, typically cyclosporine or tacrolimus plus methotrexate, although mycophenolate mofetil and sirolimus can also be used.³⁰ Prophylactic drugs may be withdrawn earlier in RIC to facilitate graft-versus-tumor effect. Prophylaxis for infection includes acyclovir for patients seropositive for herpes simplex virus (HSV), trimethoprim/sulfamethoxazole to prevent Pneumocystis jiroveci infection, oral fluconazole for fungal prevention, and preemptive ganciclovir or foscarnet for cytomegalovirus (CMV) infection in viremic recipients.³¹,³² Amphotericin, voriconazole, or micafungin are used for patients at risk for aspergillus infection.³³ Comparing outcomes in allogeneic recipients in the periods between 1993 and 1997 and 2003 and 2007, there has been a significant decrease in bacterial, fungal, and CMV infections.¹² In addition to improvements in the use of prophylactic antimicrobials, the increased use of peripheral blood donor cells has resulted in significantly faster neutrophil engraftment and earlier reconstitution of immunity.

TABLE 38.2 Distinguishing Features of the Three Modalities of Hematopoietic Cell Transplant

^	^	Myeloablative Autologous	Myeloablative Allogeneic	Nonmyeloablative Allogeneic
Number in U.S. (annual)		21,000	4,300	2,700
Age % recipients age >60		Mostly younger 34%	Younger <10%	Older 40%
Conditioning regimen
^	Radiation Cytotoxic therapy	+/− High dose	12 Gy High dose	2 Gy Low dose
Donor cells		PB (98%) Other (2%)	PB (68%) BM (24%) CB (8%)	PB (96%) Other (4%)
GVT effect		None	Mild/moderate	Main effect
SOS (incidence)		4%-7%	2%-54%	Rare
TM (incidence)		0%-27%	0%-76%	Extremely rare
Pancytopenia		Shorter (˜2 weeks)	Longer (˜3 weeks)	Shorter (˜2 weeks)
Acute GVHD (II-V)
^	Timing Incidence Prophylaxis	N/A N/A N/A	Early (weeks) 7%-91% MTX/CsA ± Pred	Later 13%-77% CsA or Tac ± Pred
Chronic extensive GVHD (incidence)		N/A	13%-71%	11%-73%
Overall mortality
^	100 days 1 year	˜5%-20% ˜25%-30%	˜20%-25% ˜40%-45%	˜5%-15% ˜35%-40%
HCT, hematopoietic cell transplantation; U.S., United States; Gy, Gray; PB, peripheral blood; BM, bone marrow; CB, cord blood; GVT, graft-versus-tumor; SOS, sinusoidal obstruction syndrome; TM, thrombotic microangiopathy; GVHD, graft-versus-host disease; N/A; not applicable; MTX, methotrexate; CsA, cyclosporine; Tac, tacrolimus; Pred, prednisone. Adapted and modified from reference 10. Data from references 6, 7, 10, and 25 to 29.

Epidemiology of Acute Kidney Imjury

Estimates of the incidence of AKI post-HCT vary widely, ranging from 14% to 100%.¹⁴,³⁴ The likelihood of kidney injury is impacted by transplant type (allogeneic or autologous), donor type (related or unrelated), degree of HLA matching (full match or mismatched), conditioning regimen (myeloablative or nonmyeloablative), and specific
conditioning regimens, immunosuppressants, prophylactic medications, and length of follow-up. In addition, the lack of a standardized definition for AKI has been vexing to those seeking to understand the epidemiology of the disease. Two recently proposed sets of diagnostic criteria, RIFLE (risk, injury, failure, loss of kidney function, end-stage kidney disease)³⁵ and AKIN (Acute Kidney Injury Network),³⁶ have facilitated diagnostic standardization and allowed for significant advances in understanding the epidemiology and outcomes of AKI at large.³⁷ The definitions employed by three common classification systems for AKI following HCT are shown in Table 38.3. Although many studies of post-HCT AKI have used a variation of the classification system utilized by Parikh et al.,³⁸ the sensitivity of the RIFLE and AKIN criteria has recently been evaluated for diagnosis and prediction of long-term, all-cause mortality associated with post-HCT AKI.³⁹ AKIN identified the smallest number of patients as having AKI across all three modalities due to a reduced sensitivity for identifying the lowest category of AKI. For severe AKI, denoted as RIFLE ≥ injury, AKIN ≥ stage 2, or Parikh ≥ grade 2, all three systems performed identically. As seen in multiple other settings,⁴⁰,⁴¹ RIFLE and AKIN stages, along with those of the Parikh classification, were associated in a stepwise manner with mortality. The HCT-Comorbidity (HCT-CI) index is composed of cardiac, pulmonary, hepatic, gastrointestinal, and renal function tests that are sensitive for the detection of subclinical organ impairment and has been shown to predict nonrelapse mortality.⁴²,⁴³ Both intermediate, hazard ratio (HR) 2.42, and high risk, HR 4.69, HCT-CI scores were independently associated with the development of RIFLE “I” and “F” in a combined cohort of myeloablative and RIC allogeneic recipients.⁴³

TABLE 38.3 Commonly Utilized Definitions of Acute Kidney Injury in Hematopoietic Cell Transplant Studies

RIFLE
^	Risk	Increase in Scr ≥ 1.5 × baseline or decrease in GFR ≥25%
^	Injury	Increase in Scr ≥ 2 × baseline or decrease in GFR ≥50%
^	Failure	Increase in Scr ≥ 3 × baseline or decrease in GFR ≥75% or an absolute Scr ≥4.0 mg/dL with an acute rise of at least 0.5 mg/dL
^	Loss	Persistent AKI >4 weeks
^	ESRD	ESRD >3 months
AKIN
^	Stage 1	Increase in Scr ≥0.3 mg/dL or increase to 150%-199% (1.5-1.9 fold) from baseline
^	Stage 2	Increase in Scr 200-299% (>2.0-2.9 fold) from baseline
^	Stage 3	Increase in Scr ≥300% (≥3-fold) from baseline or Scr ≥4.0 mg/dL with an acute rise of at least 0.5 mg/dL
Parikh-Schrier
^	Grade 0	Decrease in GFR <25% of baseline
^	Grade 1	Increase in Scr <2-fold from baseline with a decrease in GFR >25% but <50% of baseline
^	Grade 2	Increase in Scr ≥2-fold from baseline but not requiring dialysis
^	Grade 3	Increase in Scr ≥2-fold from baseline and need for dialysis
AKI, acute kidney injury; RIFLE, risk, injury, failure, loss, end-stage renal disease; Scr, serum creatinine; GFR, glomerular filtration rate; mg/dL; milligrams/deciliter; ESRD, end-stage renal disease; AKIN, Acute Kidney Injury Network.

INCIDENCE AND TIMING OF ACUTE KIDNEY INJURY

Myeloablative Allogeneic

Following the initial seminal study by Zager et al.,⁴⁴ AKI has been recognized as a common and devastating complication of myeloablative allogeneic HCT. In that initial cohort of 272 patients, 53% developed AKI at a median of 14 days. Numerous retrospective and prospective studies have since evaluated the incidence of AKI following myeloablative allogeneic HCT (Tables 38.4 and 38.5). Utilizing multiple definitions, AKI has been noted in 21% to 100% of patients with a weighted mean of 60%. Severe AKI occurs in a weighted mean of 40% of recipients. Although AKI following myeloablative allogeneic HCT has historically been thought to occur primarily in the first 2 to 3 weeks posttransplant, reflective of conditioning toxicity,⁴⁴,⁵² the median onset across all studies ranges from 15 to 60 days with a weighted mean of 30 days. The requirement for dialysis has ranged from 0% to 36%,⁸,¹⁸,²⁸,⁴⁴,⁴⁹,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵,⁶⁰,⁶²,⁶⁴,⁶⁷,⁶⁸ with some the lowest incidences¹⁸,⁶⁴ occurring more recently, perhaps reflecting refinements in conditioning and prophylactic regimens.
Befitting the discrepant patient populations, conditioning regimens, and prophylactic medications seen in these studies, myriad risk factors have been found for AKI. Conflicting results have been reported for multiple factors. Additionally, many studies have not utilized adjusted analysis, calling the true influence of postulated risk factors with potential colinearity into question. Those that have been found significant after adjustment in multiple studies include sinusoidal obstruction syndrome (SOS),²⁸,⁴⁸,⁵⁰,⁵¹,⁵²,⁵³,⁶³,⁶⁷,⁶⁸ cyclosporine use/toxicity,⁴⁵,⁵³,⁶⁴ hyperbilirubinemia/jaundice,⁴⁶,⁴⁸ amphotericin,²⁸,⁵⁰ aGVHD,⁴⁸,⁵¹ and chronic kidney disease (CKD).⁴⁶,⁵⁵ A full listing of risk factors for AKI in myeloablative allogeneic as well as autologous and RIC HCT are provided in Table 38.6.

TABLE 38.4 Comparison of Acute Kidney Injury in Single Modality Hematopoietic Cell Transplant Studies

Type of Conditioning	Year	Design	No. of Patients	Incidence of AKI/Severe AKI	Dialysis	Risk Factors	Median Onset (days)	AKI Definition	Mortality (AKI vs. no AKI)/Time Frame
Myeloablative Allogeneic
Myeloablative allo⁴⁵	2010	Retro	75	37%/14%	NA	Calcineurin inhibitor	46	AKIN	NA
Myeloablative allo¹⁸	2010	Pro	39	51%/23%	0%	NA	NA	Doubling of Scr or 50% decrease in CrCl	10% vs. 5% (3 month)^a
Myeloablative allo⁴⁶	2009	Retro	86	31%	NA	CKD, sepsis/septic shock, hyperbilirubinemia	60	Doubling	44% vs. 9% (6 month)
Myeloablative allo⁴⁷	2009	Pro	34 (peds)	26%	NA	NA	NA	Doubling of pre-txp or > normal age-sex levels	NA
Myeloablative allo²⁸ (cyclo 150-200 ng/mL)	2009	Pro	57 (peds)	42%/21%	2%	Amphotericin B and SOS	31	AKIN	21% vs. 6% (3 month)^a
Myeloablative allo⁴⁸	2008	Retro	120	61%/27%	NA	SOS, aGVHD, hyperbilirubinemia	33	NA	NA
Myeloablative allo³³ (cyclo <250 ng/mL)	2008	Retro	54	28%	0%	NA	11-20 days Scr peak	Doubling	33% vs. 10% (3 month)^a
Myeloablative allo⁴⁹ (cyclo 200-450 ng/mL)	2007	Retro	363	93%/50%	1%	HTN, ICU admission	40	Parikh^b	64% vs. 36% (6 month)
Myeloablative allo⁵⁰	2005	Pro	147	36%	NA	Amphotericin, SOS	33	Doubling	NA
Myeloablative allo⁵¹	2003	Retro	97	100%/78%	21%	SOS, aGVHD 3-5	NA	Bearman	90% vs. 18% Grade 3 vs. Grade 1-2
Myeloablative allo⁵² (cyclo 350-450 ng/mL)	2002	Retro	88	92%/69%	36%	Ventilator, SOS	16	Parikh^b	59% vs. 42% (6 month)
Myeloablative allo⁵³ (cyclo <200 ng/mL)	2002	Pro	66 (peds)	21%	0%	SOS, CSA toxicity, foscarnet	4 weeks	Doubling	14% vs. 10%
Myeloablative allo⁵⁴ (cyclo 150-450 ng/mL)	2000	Pro	180	79%	9%	NA	NA	Doubling or creatinine >2	NA
Myeloablative allo⁵⁵ (cyclo <300 ng/mL)	1998	Retro	142 (peds)	34%	0%	High baseline Scr, unrelated or non-HLA matched donor	6 weeks	Doubling	17% vs. 10% (3 month)^a
Myeloablative allo⁵⁶	1998	Pro	329	82%	15%	NA	NA	Doubling	NA
Myeloablative allo⁵⁷	1988	Pro	64	64%	NA	NA	21	Doubling	73%
Reduced Intensity Allogeneic
RIC allo²⁹	2010	Retro	62	29%/11%	NA	(aGVHD, SOS or sepsis composite), incomplete HLA-matching	38	AKIN	61% vs. 14%
RIC allo²⁵ (cyclo 200-300 ng/mL)	2009	Retro	188	52%/14%	4%	Methotrexate, >3 courses of previous chemo, DM, aGVHD grade 3-5	31	Parikh^b	47% vs. 26% (1 year)
RIC allo²⁶ (cyclo 180-380 ng/mL)	2008	Retro	82	54%/40%	5%	NA	37 (mean)	RIFLE	39% vs. 3% (3 month)^a 58% vs. 43% (5 year)
RIC allo⁵⁸ (cyclo 200-400 ng/mL)	2008	Retro	150	94%/33%	0%	Absence of vascular disease, higher GFR, grade III-IV aGVHD	37	Parikh-based^b	37% vs. 16% (1 year)
RIC allo⁴² (cyclo 500-600 ng/mL)	2008	Retro	409	58%	2%	NA	NA	Doubling or dialysis	NA
RIC allo⁵⁹ (cyclo 200-400 ng/mL)	2007	Pro	26	38%/23%	4%	NA	35	Parikh^b	40% vs. 6% (3 month)^a
RIC allo³⁸ (cyclo <500 ng/mL)	2004	Retro	253	90%/40%	4%	Ventilation	60	Parikh^b	46% vs. 30% (1 year)
Myeloablative Autolo
Myeloablative auto³⁴	2010	Retro	62	14%	8%	NA	38	AKIN	NA
Myeloablative auto⁶⁰	2008	Pro	68	22%	9%	NA	NA	NA	7%
Myeloablative auto⁶¹	2003	Pro	173	21%	5%	Melphalan dose, bacteremia, proteinuria, lower baseline CrCl	7	Scr >1 mg inc or doubling to >1.5	NA
Myeloablative auto⁶²	1996	Retro	232	56%/21%	3%	Sepsis, lung toxicity, liver toxicity/SOS	NA	Parikh^b	9% vs. 4%
^a3 month indicates 100 day follow-up ^bParikh-Schrier criteria: Grade 0 = <25% decline in baseline GFR; Grade 1 = Increase in Scr <2-fold from baseline with a decrease in GFR >25% but <50% of baseline; Grade 2 = >2-fold increase in serum creatinine without need for dialysis; Grade 3 = >2-fold increase in serum creatinine and need for dialysis.
AKI, acute kidney injury; allo, allogeneic; Retro, retrospective; NA, not available; AKIN, Acute Kidney Injury Network; Pro, prospective; Scr, serum creatinine; CrCl, creatinine clearance; CKD, chronic kidney disease; peds, pediatrics; cyclo, cyclosporine (target level); SOS, sinusoidal obstruction syndrome; aGVHD, acute graft-versus-host disease; HTN, hypertension; ICU, intensive care unit; CSA, cyclosporine; HLA, human lymphocyte antigen; RIC, reduced intensity conditioning; chemo, chemotherapy; DM, diabetes mellitus; RIFLE, risk, injury, failure, loss, end-stage renal disease; GFR, glomerular filtration rate; auto, autologous; inc, increase.

TABLE 38.5 Studies Comparing Multiple Hematopoietic Cell Transplant Modalities

Type of Conditioning

Year/Design

AKI Criteria

Total AKI (%)

Severe AKI (%)

Dialysis (%)

Mortality (%)

RIC

Auto

RIC

Auto

RIC

Auto

RIC

Auto

MA vs. RIC vs Auto³⁹

2010/Prospective

141/69/48

R/A/P

MA vs. RIC⁶³

2010/Retrospective

60/36

Parikh

–

MA vs. RIC¹⁴

2005/Retrospective

149/129

Parikh

100

–

MA vs. RIC⁴³

2010/Retrospective

149/58

RIFLE

–

MA vs. Auto⁶⁴

2010/Prospective

292/86

Doubling

–

MA vs. Auto⁶⁵,⁶⁶

2008/Retrospective

90/50

–

MA vs. Auto⁶⁷

2006/Prospective

22/25

Parikh

–

MA vs. Auto⁶⁸

1995/Retrospective

183/92

Doubling/Scr>2

–

MA vs. Auto⁴⁴

1989/Retrospective

241/31

Doubling

–

N, number of subjects; AKI, acute kidney injury; MA, myeloablative allogeneic; RIC, reduced intensity conditioning allogeneic; Auto, myeloablative autologous; R/A/P, RIFLE (risk, injury, failure loss, end-stage renal disease), AKIN (acute kidney injury network), Parikh (Parikh AKI classification system); NA, not available.

Nonmyeloablative Allogeneic

Given the older age, poorer performance status, and increased comorbidities in those patients selected for RIC, a higher incidence of AKI than is seen with myeloablative transplant might be expected. Instead, when compared directly, RIC has consistently been associated with equal¹⁴,⁴³ or reduced rates of AKI.³⁹,⁶³ Overall, the reported incidence is similar to myeloablative, ranging from 17% to 94% with a weighted mean of 65%. However, severe AKI is less common, occurring in a weighted mean of 30% of recipients. Reflecting this, the need for dialysis is lower and has been noted in 0% to 5% of patients.¹⁴,²⁵,²⁶,²⁹,³⁸,³⁹,⁴³,⁵⁸,⁵⁹,⁶³ Comparing the two modalities concurrently, myeloablative HCT was associated with an odds ratio (OR) of 4.8 for AKI.¹⁴ Because the level of posttransplant immunosuppression and the rate of GVHD are similar between the two regimens, it appears to be the milder preconditioning regimen that reduces the incidence and severity of AKI. A gentler chemoradiation procedure alleviates both direct nephrotoxicity as well as damage indirectly caused by myeloablative associated SOS, infection, and thrombotic microangiopathy (TMA).³⁸ The median onset of AKI in RIC studies ranges from 17 to 60 days with a weighted mean of 46 days. This is 2 weeks later than in myeloablative, again reflecting the lesser role of conditioning toxicity in the etiology of RIC associated AKI. The onset of AKI is fairly evenly distributed over the first 3 months but subsequently tapers off significantly.²⁵,³⁸ As with myeloablative allogeneic HCT, there has been little agreement between studies on independently significant risk factors for AKI following RIC HCT, with only aGVHD²⁵,⁵⁸ noted in multiple studies.

An additional contribution to the discordant incidence and severity of AKI in MA and RIC may lie in the recipient’s capacity to repair conditioning mediated tubular injury. Hematopoietic stem cells have shown the capacity to differentiate into renal tubular cells and home to the site of injury after ischemic renal insults.⁶⁹,⁷⁰ It is possible such cells may contribute to the repair and regeneration of damaged tubular cells and thus mitigate AKI. Renoprotective activity of stem cell lineages has been documented in ischemically injured kidneys,⁷¹,⁷² as well as with cisplatin-induced toxicity.⁷³,⁷⁴ It is possible obliteration of endogenous stem cells in myeloablative regimens contributes to the higher observed rates of AKI.

Myeloablative Autologous

Although autologous transplants outnumber allogeneic worldwide,⁶,⁷ comparatively few studies have investigated renal outcomes following this procedure.²⁹,³⁵,⁴⁰,⁴⁴,⁵⁸,⁵⁹,⁶¹,⁶²,⁶³,⁶⁴ The incidence of AKI after myeloablative autologous HCT is significantly lower than in either myeloablative allogeneic or RIC, ranging from 7% to 56%, with a weighted mean of 30%. Severe AKI occurs in a weighted mean of 19% of recipients. Dialysis is required following 0% to 9% of transplants.²⁹,³⁵,⁴⁴,⁵⁸,⁵⁹,⁶¹,⁶³ Few studies have evaluated the timing of AKI onset following autologous transplantation. The lower incidence of AKI occurs despite an older patient population and the corresponding prevalence of more comorbidities.⁸,⁹,³⁹,⁶⁷ This paradoxical outcome is due to several factors. First, autologous recipients receive comparatively mild chemoradiation conditioning regimens, thus affording protection from many conditioning associated complications. Second, autologous recipients by definition cannot suffer from acute or chronic GVHD, both of which expose the kidney to direct and indirect damage. Correspondingly, there is no need to treat autologous recipients with calcineurin inhibitors to prevent or treat GVHD and these patients are thus spared the risk of calcineurin inhibitor nephropathy (CIN). Third, associated with the milder conditioning and lack of GVHD, SOS and TMA are much less common.¹³,³⁸,⁷⁵ Finally, there is more rapid engraftment without foreign cells, shortening neutropenia, lessening sepsis, and minimizing exposure to nephrotoxic antimicrobials.⁶⁴ No risk factors have been found across studies to independently associate with AKI following autologous HCT.

General Risk Factors

Chronic Kidney Disease

CKD is a well-established risk factor for AKI in the setting of potential kidney insults with nephrotoxins such as radiocontrast media⁷⁶ and aminoglycosides.⁷⁷ Surprisingly, the inverse has been found in multiple studies of HCT. Zager assessed the relationship in 3,325 patients between pretransplant eGFR and renal function at 1 year following HCT.⁷⁸ Outcomes included both “renal functional impairment,” defined as a 25% reduction in eGFR from baseline, as well as absolute change. A striking inverse correlation was seen between baseline function and 25% decrease, r = 0.92, and absolute decrease, r = 0.97. The authors speculate it may be a form of acquired cytoresistance as seen in several animal models.⁷⁹,⁸⁰,⁸¹,⁸²,⁸³,⁸⁴ Although not universally noted,⁵⁵ a similar finding of elevated pretransplant GFR as a risk factor for AKI has been found in several RIC³⁸,⁵⁸ and myeloablative allogeneic studies.⁵⁰ Although the concept of ischemic preconditioning to prevent AKI is intriguing,⁸⁵,⁸⁶ some part of the effect in this setting is likely due to the utilized AKI definitions in that the
absolute change required for doubling of serum creatinine is less in patients with lower baselines, with the same following for GFR, and thus those patients with preserved baseline function require smaller changes to meet AKI criteria.

TABLE 38.6 Risk Factors Independently Associated with Acute Kidney Injury Following Hematopoietic Cell Transplant

*Risk Factors*	MA	Autologous	RIC
SOS/liver toxicity	6 (8)^a	1 (1)	– (0)
Cyclosporine use/toxicity	3 (7)	– (0)	1 (0)
Ventilator use	2 (2)	1 (1)	– (0)
aGVHD	2 (8)	– (0)	2 (2)
Amphotericin	2 (6)	– (1)	– (0)
Hyperbilirubinemia	2 (5)	– (0)	– (0)
Diminished baseline renal function	2 (7)	– (1)	– (0)
Sepsis/septic shock	1 (5)	1 (1)	– (0)
Hypertension	1 (3)	– (0)	– (0)
ICU admission	1 (1)	– (0)	– (0)
Unrelated donor/incomplete HLA-match	1 (9)	– (0)	1 (4)
Foscarnet	1 (2)	– (0)	– (0)
Age	1 (7)	– (2)	1 (3)
Methotrexate	– (3)	– (0)	1 (1)
Diabetes mellitus	– (0)	– (0)	1 (1)
(GVHD, sepsis, SOS) composite	– (0)	– (0)	1 (1)
>3 cycles of prior chemotherapy	– (0)	– (0)	1 (1)
Absence of vascular disease	– (0)	– (9)	1(1)
High baseline GFR	– (0)	– (0)	1 (1)
Bacteremia	– (0)	1 (0)	– (0)
Melphalan	– (0)	1 (0)	– (0)
Proteinuria	– (0)	1 (0)	– (0)
^aNumber of studies with statistically significant increased risk of AKI (number of studies where risk factor has been evaluated for independent association).
AKI, acute kidney injury; HCT, hematopoietic cell transplantation; MA, myeloablative allogeneic; RIC, reduced intensity conditioning allogeneic; SOS, sinusoidal obstruction syndrome, aGVHD, acute graft-versus-host disease; ICU, intensive care unit; GFR, glomerular filtration rate.

Genetics

SNPs in genes associated with the urea cycle (CPSI) and hemochromatosis (HFE) have been shown to influence susceptibility to SOS.⁸⁷,⁸⁸,⁸⁹,⁹⁰ Additionally, donor-recipient genotype combinations in the killer immunoglobulin-like receptors (KIRs) present on NK and some T cells are important determinants of aGVHD.⁹¹ Finally, the presence of the DD allele in the ACE gene may slow the decline in creatinine clearance in the year following HCT.⁹²

Additional Markers of Kidney Injury

Despite the tremendous incidence of AKI documented in these studies, they are likely to be significantly underestimating the true occurrence of kidney injury following HCT. As is widely recognized in nephrology, serum creatinine is a poor and insensitive marker for kidney function. Due to renal functional reserve and tubular creatinine secretion, serum creatinine can remain in the normal range even when the glomerular filtration rate (GFR) has fallen to 50% of baseline. In addition to actual changes in GFR, creatinine levels are also influenced by body weight, race, age, gender, muscle mass, protein intake, and drugs. In HCT patients in particular, given the severity of their disease, it is common to see significant weight loss, loss of muscle mass, and decreased protein intake.

^99mTc-DTPA was used to sequentially measure GFR in pediatric patients post-HCT.⁴⁷ GFR fell precipitously from baseline at 30 and 100 days but rebounded somewhat by 180 days. The estimated GFR utilizing creatinine was significantly higher than ^99mTc-DTPA measured GFR. N-acetyl-β-D-glucosaminidase (β-NAG), a biomarker of tubular damage,⁹³ was significantly elevated at 30 days but returned to baseline by 180 days. Near ubiquitous early elevation in urinary α-1 microglobulin and β-NAG and a decrease in phosphate reabsorption after conditioning indicated rampant tubular damage.²⁸ After 2 years, although only 5% of the children had inulin measured GFR <90 mL/min, approximately 40% maintained elevated urinary α-1 microglobulin levels or decreased phosphate reabsorption. Based on these more sensitive markers it appears nonspecific tubular damage in the peritransplant period is ubiquitous and recovery is often incomplete, even if subclinically so.

Additional novel markers may assist in ascertaining the true incidence of injury. Cystatin C, a low molecular weight protein (13kDa) synthesized by all nucleated cells, freely crosses the glomerular filtration barrier and is almost completely reabsorbed by the cells of the proximal tubule. Cystatin C has demonstrated superior diagnostic sensitivity for the detection of AKI compared with creatinine.⁹⁴ Cystatin-C has retrospectively been assessed as a marker for post-HCT kidney dysfunction.⁴⁵ Although noting a strong inverse correlation between cystatin C and estimated GFR, the authors did not compare the ability of cystatin C and creatinine to detect AKI. A significantly higher rate of worsening of preexisting chronic kidney disease (CKD) was found during the first year post-HCT in patients with a pretransplant cystatin C level ≥0.90 mg per L relative to patients with levels below this cutoff.

In the context of validating the results of a urine proteomic study of novel markers predictive of clinical AKI, an AKI-specific peptide panel was assessed in 31 patients undergoing allogeneic HCT, 13 of whom developed AKI.⁹⁵ Although absolute peptide levels differed from those of patients studied in an intensive care unit (ICU) setting, the panel showed excellent discriminatory ability with an area under the receiver operating curve (AUC) of 0.90, a sensitivity of 94%, and a specificity of 82% to predict AKI as defined by a rise in serum creatinine of ≥50% within 48 hours.

ETIOLOGIES OF ACUTE KIDNEY INJURY

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