ACUTE KIDNEY INJURY IN PATIENTS WITH SYSTEMIC SCLEROSIS PARTICIPATING IN HEMATOPOIETIC CELL TRANSPLANTATION TRIALS IN THE UNITED STATES

doi:10.1016/j.bbmt.2010.08.003

Biol Blood Marrow Transplant. Author manuscript; available in PMC 2012 May 1.

Published in final edited form as:

Biol Blood Marrow Transplant. 2011 May; 17(5): 674–681.

Published online 2010 August 11. doi: 10.1016/j.bbmt.2010.08.003

PMCID: PMC3012135

NIHMSID: NIHMS233875

ACUTE KIDNEY INJURY IN PATIENTS WITH SYSTEMIC SCLEROSIS PARTICIPATING IN HEMATOPOIETIC CELL TRANSPLANTATION TRIALS IN THE UNITED STATES

Chitra Hosing,¹ Richard Nash,² Peter McSweeney,³ Shin Mineishi,⁴ James Seibold,⁴ Linda M. Griffith,⁵ Howard Shulman,² Ellen Goldmuntz,⁵ Maureen Mayes,⁶ Chirag R. Parikh,⁷ Leslie Crofford,⁸ Lynette Keyes-Elstein,⁹ Daniel Furst,¹⁰ Virginia Steen,¹¹ and Keith M Sullivan¹²

¹ MD Anderson Cancer Center, Houston, TX

² Fred Hutchinson Cancer Research Center, Seattle, WA

³ Rocky Mountain Cancer Center, Denver, CO

⁴ University of Michigan, Ann Arbor, MI

⁵ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

⁶ University of Texas, Houston, TX

⁷ Yale University, New Haven, CT

⁸ University of Kentucky, Lexington, KY

⁹ Rho, Inc, Chapel Hill, NC

¹⁰ University of California, Los Angeles, CA

¹¹ Georgetown University, Washington, DC

¹² Duke University Medical Center, Durham, NC

Corresponding Author: Chitra Hosing MD, Department of Stem Cell Transplantation and Cell Therapy, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030;, Email: cmhosing/at/mdanderson.org

The publisher's final edited version of this article is available at Biol Blood Marrow Transplant

Publisher's Disclaimer

Abstract

Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury and this risk may increase in patients who undergo transplantation for severe systemic sclerosis due to underlying scleroderma renal disease. Acute kidney injury after transplantation can increase transplant related mortality. To better define these risks, we analyzed 91 patients with systemic sclerosis who were enrolled in three clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation. Eleven (12%) of the 91 scleroderma patients in these studies (8 autologous, 1 allogeneic, 1 pre-transplant, 1 given intravenous cyclophosphamide on transplant trial) experienced acute kidney injury of whom eight required dialysis and/or total plasma exchange. Acute kidney injury in the 9 transplant recipients developed a median of 35 (range, 0–90) days after transplantation. Ten of 11 patients with acute kidney injury received angiotensin converting enzyme-inhibitors (ACE-I) treatment. The etiology of acute kidney injury was attributed to scleroderma renal crisis in 6 patients (including two with normotensive renal crisis), acute kidney injury of uncertain etiology in 2 patients and acute kidney injury superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died: causes of death included progression of SSc (1), multiorgan failure (1), gastrointestinal and pulmonary bleeding (1), pericardial tamponade and pulmonary complications (1), diffuse alveolar hemorrhage (1), pulmonary embolism (1), graft-versus-host disease (1) and malignancy (1). Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure and aggressive use of ACE-I may be of importance in preventing renal complications after hematopoietic cell transplantation for systemic sclerosis.

Keywords: Acute kidney injury, systemic sclerosis, scleroderma, hematopoietic cell transplant

INTRODUCTION

Acute kidney injury (AKI) has been reported in up to 26% of patients with systemic sclerosis (SSc) and scleroderma renal crisis (SRC) can develop in up to 19% of patients.[1–3] Recipients of hematopoietic cell transplantation (HCT) for hematologic malignancies can develop acute and chronic kidney injury between 1–12 months after preparative conditioning and transplantation [4–8]. The degree of renal impairment post transplantation has been shown to impact the mortality rates [9]. Therefore, patients with SSc who receive high-dose immunosuppression followed by autologous or allogeneic HCT may be at further increased risk for developing renal complications. In a pilot study of lymphoablation with a total body irradiation (TBI) containing regimen followed by CD34+ selected autologous HCT in patients with severe SSc, dramatic improvement/resolution of dermal fibrosis and stabilization/improvement of pulmonary function was observed; however, 6 (18%) of the 34 patients developed AKI.[10]

The purpose of this report is to characterize renal complications and outcomes observed in patients with poor prognosis SSc (diffuse cutaneous disease with internal organ involvement) who participated in three clinical trials of HCT in the United States and offer guidelines for prevention of AKI. Subjects in this report are derived from: the pilot study of high-dose therapy and autologous HCT (34 subjects transplanted); the ongoing randomized study of chemotherapy vs. autologous transplant in the SCOT (Scleroderma Cyclophosphamide or Transplantation) trial (55 subjects randomized to date); and a study of allogeneic HCT (2 subjects transplanted).

PATIENTS AND METHODS

From the two published studies we identified patients with severe SSc who developed AKI after undergoing autologous or allogeneic HCT.[10,11] We also identified subjects with AKI among those randomized to date on the SCOT study (www.sclerodermatrial.org). Subjects on the SCOT protocol are randomized to 12 monthly intravenous infusions of 750 mg/m² cyclophosphamide or to myeloablative conditioning followed by CD34+ selected autologous HCT. Autologous HCT patients received preparation with 120 mg/kg cyclophosphamide, 90 mg/kg antithymocyte globulin (ATGAM), and 800 cGy TBI. Total body irradiation was given in four 200 cGy fractions over 2 days with lung shielding to 200 cGy pulmonary transmission. Subjects enrolled on the SCOT trial also received kidney shielding to 200 cGy renal transmission.[12] Patients given ATGAM received methyl-prednisolone 0.5 mg/kg/day from day +6 through day +21 post transplant and then tapered through day +37 to reduce allergic reactions to ATGAM and damage to organs. Allogeneic transplant recipients were prepared with ATGAM, busulfan and cyclophosphamide followed by cyclosporine and methotrexate for graft-versus-host disease (GVHD) prophylaxis.[11] AKI was defined as an abrupt (within 48 hours) reduction in kidney function denoted as an absolute increase in serum creatinine of more than or equal to 0.3 mg/dl or a percentage increase in serum creatinine of more than or equal to 150% (1.5-fold) from baseline. Information on urine output was not available. [13] Staging of AKI is detailed in Table 1. Results were analyzed as of August 4, 2009. All patients participating in these trials gave informed consent as per standards of local institutional review.

Table 1

Classification/staging system for acute kidney injury^*

RESULTS

Thirty-four individuals with SSc were enrolled in the pilot study of autologous transplantation.[10] To date the SCOT trial has randomized 28 patients to SCT and 27 patients to monthly intravenous cyclophosphamide. In the third study, two patients underwent allogeneic transplantation.[11] Among the 91 patients with severe SSc treated on these three trials, 11 subjects (12%) developed significant AKI. Of the 64 subjects who underwent an allogeneic or autologous transplant, 9 subjects (14%) developed AKI. Six of eleven subjects who developed AKI were on the pilot study of autologous HCT, four subjects were enrolled on the SCOT study (1 subject randomized to the cyclophosphamide arm, 1 subject underwent granulocyte-colony stimulating factor induced hematopoietic cell mobilization but did not receive preparative conditioning or transplantation, 2 received autologous HCT), and 1 subject received an allogeneic HCT.

Characteristics of the 11 patients developing AKI are given in Table 2. Patients 1–4 were from the randomized SCOT protocol, patient 5 was from the allogeneic study, and patients 6–11 were from the autologus transplant pilot study. All subjects received angiotensin converting enzyme inhibitors (ACE-I) to prevent or treat SRC except one subject (patient number 10) because he was not hypertensive. After developing AKI, 3 patients underwent plasma exchange for presumed diagnosis of transplant associated –thrombotic microangiopathy (TA-TMA)/thrombotic thrombocytopenic purpura (TTP) and 7 patients required hemodialysis. The final diagnosis was SRC in 6 patients (normotensive SRC in 2), AKI of uncertain etiology in 2 patients and AKI superimposed on SRC in 3 patients. The diagnosis was based on clinical and laboratory data. Renal tissue was available for histopathological evaluation in 2 subjects (subject number 6 and 8). At last follow-up, 3 of the 11 patients are alive, 1 of who remains on dialysis (patient number 1). Surviving patients are 7, 31 and 72 months post transplant. Two patients died while on dialysis. All others were able to come off dialysis. Eight of the 11 patients died: causes of death included progression of SSc (1), multiorgan failure (1), gastrointestinal and pulmonary bleeding (1), pericardial tamponade and pulmonary complications (1), diffuse alveolar hemorrhage (1), pulmonary embolism (1), graft-versus-host disease (1) and malignancy (1). None of the deaths were directly attributable to AKI.

Table 2

Patient Characteristics

Figure 1 depicts the renal pathology in patient 6. Myointimal proliferation of arterioles and venules as well as abnormalities in the glomerular capillaries which included thickening and collapse of the walls and widening of the subendothelial spaces were present. There was also marked interstitial fibrosis associated with tubular atrophy. Autopsy kidney sections from patient 8, (Figure 2) showed widespread arterial and arteriole myointimal thickening with mucoid degeneration. The thickened myointimal layers within the interlobular and afferent arterioles contained fibrinoid material. There were multiple foci of segmental cortical necrosis with sclerosis of glomeruli. Remaining glomeruli showed loss of capillary loops with necrosis of endothelium These vascular changes were consistent with scleroderma vasculopathy. In addition, there was interstitial fibrosis with tubular atrophy. The alteration seen in the kidneys from both of these patients were consistent with chronic kidney injury from severe systemic sclerosis with some superimposed changes of acute kidney injury

Figure 1

PAS stained section of renal biopsy from patient 6. The glomerulus has duplication of the basement membrane (arrowhead), segmental collapse of capillary loops and mesangiolysis. An adjacent longitudinally oriented arteriole (arrow) has a small residual (more ...)

Figure 2

A and B Autopsy kidney from patient 8 with scleroderma renal crisis.

DISCUSSION

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.[14–18] 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) [7,9].

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.[21,22] 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 table 2, 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.[1–3] 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.[24,25] 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%.[26,27] Glucocorticoid administration, particularly at high-doses (i.e., prednisone ≥ 15 mg/day or equivalent), has been postulated to trigger the onset of SRC.[25,28] 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.[29,30] 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. [8,32] 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.[33,34] Post transplant TTP or TA-TMA has been reported in 0.51 to 74% of patients undergoing allogeneic HCT [35–38] 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.[43,44] Left untreated, TTP is often rapidly fatal, whereas prompt initiation of plasma exchange can be lifesaving.[45,46] Several publications have reported cases of the coexistence of TTP with SSc[47–49] 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 Table 3.[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.

Table 3

Distinguishing Between TTP and SRC^*

CONCLUSIONS

Hematopoietic cell transplantation is an increasingly applied and possibly successful treatment for selected patients with SSc and other autoimmune diseases.[50] Acute kidney injury in patients with SSc undergoing HCT may be attributable to several causes making the diagnosis and management of these patients particularly challenging. Renal shielding during TBI, close control of blood pressure, avoidance of intravenous contrast dyes or high-dose glucocorticoids and aggressive use of ACE-I may reduce the development of AKI in patients with systemic sclerosis undergoing autologous and allogeneic HCT. The reduction of acute kidney injury should result in reducing the post transplant mortality and the burden of chronic kidney disease following transplantation.

Acknowledgments

Grant Support. This work was supported in part by award AI005419 from the National Institute of Allergy and Infectious Diseases, NIH.

Footnotes

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Steen VD, Syzd A, Johnson JP, Greenberg A, Medsger TA., Jr Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. 2005;32(4):649–655. [PubMed]

2. Denton CP. Renal manifestations of systemic sclerosis--clinical features and outcome assessment. Rheumatology (Oxford) 2008;47 (Suppl 5):v54–56. [PubMed]

3. Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, Muller-Ladner U, Bocelli-Tyndall C, Matucci-Cerinic M. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007;66(6):754–763. [PMC free article] [PubMed]

4. Kersting S, Verdonck LF. Stem cell transplantation nephropathy: a report of six cases. Biol Blood Marrow Transplant. 2007;13(6):638–643. [PubMed]

5. Kersting S, Dorp SV, Theobald M, Verdonck LF. Acute renal failure after nonmyeloablative stem cell transplantation in adults. Biol Blood Marrow Transplant. 2008;14(1):125–131. [PubMed]

6. Saddadi F, Najafi I, Hakemi MS, Falaknazi K, Attari F, Bahar B. Frequency, risk factors, and outcome of acute kidney injury following bone marrow transplantation at dr shariati hospital in tehran. Iran J Kidney Dis. 4(1):20–26. [PubMed]

7. Parikh CR, Coca SG. Acute renal failure in hematopoietic cell transplantation. Kidney Int. 2006;69(3):430–435. [PubMed]

8. Glezerman IG, Jhaveri KD, Watson TH, Edwards AM, Papadopoulos E, Young JW, Flombaum CD, Jakubowski AA. Chronic Kidney Disease, Thrombotic Microangiopathy and Hypertension Following T-cell Depleted Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant [PMC free article] [PubMed]

9. Zager RA, O’Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, Stewart P, Thomas ED. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis. 1989;13(3):210–216. [PubMed]

10. Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener MH, Seibold JR, Sullivan KM, Furst DE. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007;110(4):1388–1396. [PubMed]

11. Nash RA, McSweeney PA, Nelson JL, Wener M, Georges GE, Langston AA, Shulman H, Sullivan KM, Lee J, Henstorf G, Storb R, Furst DE. Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis. Arthritis Rheum. 2006;54(6):1982–1986. [PMC free article] [PubMed]

12. Craciunescu OI, Steffey BA, Kelsey cR, Larrier NA, Paarz-Largay CJ, Prosnitz RG, Chao N, Chute J, Gasparetto C, Horwitz M, Long G, Rizzieri D, Sullivan KM. Renal Shielding and Dosimetry for Patients with Severe Systemic Sclerosis Receiving Immunoablation with Total Body Irradiation on the SCOT (Scleroderma: Cyclophosphamide or Transplantation) Trial. International Journal of Radiation Oncology, Biology, Physics. 2010;05:036. [PMC free article] [PubMed]

13. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. [PMC free article] [PubMed]

14. Borg M, Hughes T, Horvath N, Rice M, Thomas AC. Renal toxicity after total body irradiation. Int J Radiat Oncol Biol Phys. 2002;54(4):1165–1173. [PubMed]

15. Van Why SK, Friedman AL, Wei LJ, Hong R. Renal insufficiency after bone marrow transplantation in children. Bone Marrow Transplant. 1991;7(5):383–388. [PubMed]

16. Kal HB, Loes van Kempen-Harteveld M, Heijenbrok-Kal MH, Struikmans H. Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation. Strahlenther Onkol. 2006;182(11):672–679. [PubMed]

17. Kal HB, van Kempen-Harteveld ML. Renal dysfunction after total body irradiation: dose-effect relationship. Int J Radiat Oncol Biol Phys. 2006;65(4):1228–1232. [PubMed]

18. Levine JM, Lien YH. Antithymocyte globulin-induced acute renal failure. Am J Kidney Dis. 1999;34(6):1155. [PubMed]

19. Wu I, Parikh CR. Screening for kidney diseases: older measures versus novel biomarkers. Clin J Am Soc Nephrol. 2008;3(6):1895–1901. [PubMed]

20. Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, Fibbe WE, Farge D, Gluckman E, Locatelli F, Martini A, van den Hoogen F, van de Putte L, Schattenberg AV, Arnold R, Bacon PA, Emery P, Espigado I, Hertenstein B, Hiepe F, Kashyap A, Kotter I, Marmont A, Martinez A, Pascual MJ, Gratwohl A, Prentice HG, Black C, Tyndall A. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001;60(6):577–584. [PMC free article] [PubMed]

21. Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, Larghero J, Gluckman E, Preijers FW, van Dijk AP, Bax JJ, Roblot P, van Riel PL, van Laar JM, Farge D. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008;67(1):98–104. [PubMed]

22. Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, Peter HH, Breedveld FC, Fibbe WE, Black C, Denton C, Koetter I, Locatelli F, Martini A, Schattenberg AV, van den Hoogen F, van de Putte L, Lanza F, Arnold R, Bacon PA, Bingham S, Ciceri F, Didier B, Diez-Martin JL, Emery P, Feremans W, Hertenstein B, Hiepe F, Luosujarvi R, Leon Lara A, Marmont A, Martinez AM, Pascual Cascon H, Bocelli-Tyndall C, Gluckman E, Gratwohl A, Tyndall A. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004;63(8):974–981. [PMC free article] [PubMed]

23. Haviv YS, Safadi R. Normotensive scleroderma renal crisis: case report and review of the literature. Ren Fail. 1998;20(5):733–736. [PubMed]

24. Teixeira L, Mahr A, Berezne A, Noel LH, Guillevin L, Mouthon L. Scleroderma renal crisis, still a life-threatening complication. Ann N Y Acad Sci. 2007;1108:249–258. [PubMed]

25. Teixeira L, Mouthon L, Mahr A, Berezne A, Agard C, Mehrenberger M, Noel LH, Trolliet P, Frances C, Cabane J, Guillevin L. Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients. Ann Rheum Dis. 2008;67(1):110–116. [PubMed]

26. Steen VD, Costantino JP, Shapiro AP, Medsger TA., Jr Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med. 1990;113(5):352–357. [PubMed]

27. Steen VD, Medsger TA., Jr Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 2000;133(8):600–603. [PubMed]

28. Steen VD, Medsger TA., Jr Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998;41(9):1613–1619. [PubMed]

29. DeMarco PJ, Weisman MH, Seibold JR, Furst DE, Wong WK, Hurwitz EL, Mayes M, White B, Wigley F, Barr W, Moreland L, Medsger TA, Jr, Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner SR, Andrews B, Abeles M, Clements PJ. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum. 2002;46(11):2983–2989. [PubMed]

30. Strand V. Predictors and outcomes of scleroderma renal crisis: data from the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum. 2002;46(11):2836–2837. [PubMed]

31. Miralbell R, Bieri S, Mermillod B, Helg C, Sancho G, Pastoors B, Keller A, Kurtz JM, Chapuis B. Renal toxicity after allogeneic bone marrow transplantation: the combined effects of total-body irradiation and graft-versus-host disease. J Clin Oncol. 1996;14(2):579–585. [PubMed]

32. Cheng JC, Schultheiss TE, Wong JY. Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol Phys. 2008;71(5):1436–1443. [PubMed]

33. Rabinowe SN, Soiffer RJ, Tarbell NJ, Neuberg D, Freedman AS, Seifter J, Blake KW, Gribben JG, Anderson KC, Takvorian T, et al. Hemolytic-uremic syndrome following bone marrow transplantation in adults for hematologic malignancies. Blood. 1991;77(8):1837–1844. [PubMed]

34. Krochak RJ, Baker DG. Radiation nephritis. Clinical manifestations and pathophysiologic mechanisms. Urology. 1986;27(5):389–393. [PubMed]

35. Iacopino P, Pucci G, Arcese W, Bosi A, Falda M, Locatelli F, Marenco P, Miniero R, Morabito F, Rossetti F, Sica S, Uderzo C, Bacigalupo A. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO) Bone Marrow Transplant. 1999;24(1):47–51. [PubMed]

36. Holler E, Kolb HJ, Hiller E, Mraz W, Lehmacher W, Gleixner B, Seeber C, Jehn U, Gerhartz HH, Brehm G, et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood. 1989;73(7):2018–2024. [PubMed]

37. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(8):571–575. [PubMed]

38. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lammle B, Moake JL, Richardson P, Socie G, Zeigler Z, Niederwieser D, Barbui T. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007;92(1):95–100. [PubMed]

39. Elliott MA, Nichols WL, Jr, Plumhoff EA, Ansell SM, Dispenzieri A, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ, Micallef IN, Tefferi A, Litzow M. Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin Proc. 2003;78(4):421–430. [PubMed]

40. Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs. 2009;69(2):183–198. [PubMed]

41. Vesely SK, George JN, Lammle B, Studt JD, Alberio L, El-Harake MA, Raskob GE. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102(1):60–68. [PubMed]

42. Batts ED, Lazarus HM. Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting? Bone Marrow Transplant. 2007;40(8):709–719. [PubMed]

43. Moake JL. von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin Hematol. 2004;41(1):4–14. [PubMed]

44. Hovinga JA, Studt JD, Alberio L, Lammle B. von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol. 2004;41(1):75–82. [PubMed]

45. Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol. 2000;109(3):496–507. [PubMed]

46. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589–600. [PubMed]

47. Manadan AM, Harris C, Block JA. Thrombotic thrombocytopenic purpura in the setting of systemic sclerosis. Semin Arthritis Rheum. 2005;34(4):683–688. [PubMed]

48. Nanke Y, Akama H, Yamanaka H, Hara M, Kamatani N. Progressive appearance of overlap syndrome together with autoantibodies in a patient with fatal thrombotic microangiopathy. Am J Med Sci. 2000;320(5):348–351. [PubMed]

49. Kapur A, Ballou SP, Renston JP, Luna E, Chung-Park M. Recurrent acute scleroderma renal crisis complicated by thrombotic thrombocytopenic purpura. J Rheumatol. 1997;24(12):2469–2472. [PubMed]

50. Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: Updates from Europe and the United States. European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT) Biol Blood Marrow Transplant. 2010;16:S48–56. [PMC free article] [PubMed]

51. Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73. [PMC free article] [PubMed]