The etiology of AKI in HCT recipients is multifactorial and can be attributable to the effects of high-dose chemotherapy, TBI, ATGAM, nephrotoxic drugs and anti-infectives, sepsis, hypotension, viral infections, TA-TMA, or intravenous contrast dyes used for imaging studies.
In allogeneic transplant recipients, this list is lengthened to include hepatic veno-occlusive disease and administration of calcineurin inhibitors (tacrolimus or cyclosporine) given for the prevention and treatment of GVHD.[14
] Development of AKI increases the transplant related mortality in both allogeneic and autologous HCT. Zagar et. al. showed that the post transplant mortality increased with worsening degree of renal impairment. In their study, mortality was greater than 80% in patients who required hemodialysis. Moreover, patients who survived were at an increased risk for development of chronic kidney disease (CKD) [7
Among patients with SSc, the incidence of AKI is frequently underestimated since serum creatinine is a less robust marker of renal function in these patients, presumably due to renal vasculopathy and decreased muscle mass due to scleroderma.[19
] It is currently unknown if the combination of SSc and HCT magnifies the risk of subsequent renal complications.
In a European phase I/II study of autologous SCT in SSc, 5 (12%) of 41 patients were reported to have scleroderma-related renal impairment before transplant, but only 1 experienced significant deterioration of serum creatinine at one year after transplant. Although there was a 10% rise in the final serum creatinine over baseline, the authors did not find a significant correlation between baseline renal function and survival.[20
] Similar results were noted by other European investigators who found that renal function remained stable after autologous HCT for SSc.[21
] Of note, most patients transplanted for autoimmune disease in Europe do not receive TBI for lymphoablation.
In the U.S pilot trial of high-dose cyclophosphamide, ATGAM, TBI and autologous HCT, 6 (patient number 6–11) of 34 (18%) patients developed some degree of AKI.[10
] Renal events occurred within 3 months of transplantation and no late renal abnormalities were noted. Two patients required dialysis and died due to complications of hospitalization. A third patient required dialysis for 21 months, and at 6 years post transplant was dialysis independent with a serum creatinine of 2.4 mg/dL. Because of an apparent increased incidence of AKI in the pilot U.S. autologous transplant trial when compared to the European study, kidney shielding with limitation to 200 cGy renal transmission was instituted for the subsequent randomized SCOT trial. Other measures adopted in the SCOT trial to minimize nephrotoxicity include the routine administration of ACE-I through day 60 post transplant, ie, through the time patients receive glucocorticoids. Use of captopril as an ACE-I is not recommended in recipients of HCT because the sulfa moiety in this agent has been associated with neutropenia. Aggressive control of blood pressure (to below 110/80 mmHg), restricted use of glucocorticoids, prohibition of intravenous contrast and close monitoring of renal function including urinary protein/creatinine ratios are also standard. It is notable that to date only 2 of the transplant recipients in the SCOT trial have developed transient renal complications after autologous HCT and both individuals survive with normal renal function.
As shown in , AKI can develop in patients with SSc in the absence of HCT. Scleroderma renal crisis is estimated to occur in up to 19% of patients with SSc.[1
] It is more common in individuals with diffuse cutaneous scleroderma and is rare in patients with limited disease. The majority of patients with SRC present within 5–6 years of their initial diagnosis of scleroderma and classically manifest malignant hypertension (90% of patients), microangiopathic hemolytic anemia (MAHA, 43% of patients), and central nervous system abnormalities (11% of patients). However, 10% of individuals with SRC may present with normal blood pressure readings (so-called normotensive renal crisis).[23
] The etiology of SRC is poorly understood, but renal vascular intimal proliferation, vascular hyper-reactivity, decreased cortical blood flow, and activation of the renin–angiotensin–aldosterone axis have all been implicated.[24
] The primary treatment of SRC is ACE inhibition, given even in the presence of AKI. With ACE-I administration, the 1- year mortality of SRC has dramatically decreased from 76% to 15%.[26
] Glucocorticoid administration, particularly at high-doses (i.e., prednisone ≥ 15 mg/day or equivalent), has been postulated to trigger the onset of SRC.[25
] However, in the appropriate clinical setting (i.e., Rodnan skin hardening score ≥20 and large joint contractures) even lower doses of prednisone (mean 7.4 mg daily) have been associated with SRC. Multivariate regression analysis demonstrated that clinical characteristics rather than prednisone use was more important in predicting the development of SRC.[29
] Therefore, if systemic steroids are used in patients with SSc, the renal function and blood pressure must be monitored carefully. The use of prophylactic ACE-I is controversial but should be considered in this particular clinical situation.
Patients undergoing allogeneic HCT appear at further risk for developing renal abnormalities due to administration of calcineurin inhibitors and high-dose corticosteroids for the prevention or treatment of GVHD.[31
] Both individuals with SSc who underwent allogeneic transplantation are included in this review; no significant renal complications were observed during 7 months of cyclosporine treatment in one patient. In the other patient (patient # 5), SRC was temporally associated with the administration of 2 mg/kg/day of prednisone. However, the patient died 18 months after allogeneic HCT due to complications of chronic GVHD while tolerating long-term calcineurin inhibitors without significant renal dysfunction.[11
] Based on this limited experience, it is not possible to conclude that there is/is not an increased risk of renal dysfunction in SSc subjects with calcineurin inhibitors.
Inclusion of TBI in the conditioning regimen for patients with malignant diseases has been implicated in the development of CKD, TA-TMA, hemolytic uremic syndrome (HUS) and radiation nephritis. [8
] In a recent study, the risk of developing AKI after haploidentical allogeneic transplantation was similar in the TBI and non-TBI group, however, the group that received TBI in the conditioning regimen was more likely to develop CKD.[8
] Clinical features of HUS and TA-TMA may be indistinguishable from that of radiation nephritis which may also present with hypertension, anemia, edema, proteinuria, hematuria and elevated serum creatinine.[33
] Post transplant TTP or TA-TMA has been reported in 0.51 to 74% of patients undergoing allogeneic HCT [35
] and in 0.13% to 0.25% in individuals undergoing autologous HCT [39
]. TA-TMA appears to be distinct from idiopathic TTP because of different causative events and a higher mortality [40
]. TA-TMA is usually not associated with deficiency of ADAMTS 13 activity (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) or with the presence of inhibitory antibodies.[41
] Moreover, TA-TMA does not usually respond to plasma exchange.[42
] The clinical distinctions among TA-TMA, TTP and normotensive SRC in the absence of ADAMTS 13 determinations can be problematic. For example, the clinical findings in patient # 2 in our series were attributed to normotensive SRC, but the patient was also treated for TTP with plasma exchange and had a successful outcome.
In either setting of SSc or HCT, AKI may also be due to the development of TTP. Classic TTP is a relatively rare syndrome characterized by a pentad of acute kidney injury, thrombocytopenia, MAHA, neurologic abnormalities, and fever. These signs and symptoms result from microvascular platelet clumping.[43
] Left untreated, TTP is often rapidly fatal, whereas prompt initiation of plasma exchange can be lifesaving.[45
] Several publications have reported cases of the coexistence of TTP with SSc[47
] True TTP in individuals with SSc may mimic SRC; while radiation nephritis, MAHA, and drug induced nephrotoxicity may also contribute to the differential diagnosis of post transplant AKI. Features which help distinguish TTP from SRC have been detailed by Manadan et. al. and are summarized in .[47
] Laboratory testing for ADAMTS-13 (vWF cleaving protease) and plasma concentration of ultra-large von Willebrand factor multimers may provide additional clarifying information but are not rapidly available in most institutions. Therefore, if there is clinical suspicion of TTP treatment with plasma exchange should be initiated early as delays can prove life-threatening. Plasma exchange can be discontinued if ADAMTS-13 activity is normal.
Distinguishing Between TTP and SRC*