Acute renal failure in hematopoietic cell transplantation
2006; Elsevier BV; Volume: 69; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5000055
ISSN1523-1755
AutoresChirag R. Parikh, Steven G. Coca,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoHematopoietic cell transplantation is a common procedure for the treatment of malignancies and some non-malignant hematologic disorders. In addition to other transplant-related organ toxicities, acute renal failure is a common complication following transplantation. This review discusses the incidence, timing, etiologies, risk factors, and prognosis of renal failure associated with three commonly used transplantation procedures – myeloablative autologous, myeloablative allogeneic, and non-myeloablative allogeneic transplantation. It is important to note that the epidemiology and prognosis of renal failure are distinct with these three transplantation procedures. However, the common theme is that mortality increases with worsening renal failure with all three procedures. Moreover, mortality is >80% for patients with renal failure requiring dialysis. It also appears that surviving patients have an increased risk of chronic kidney disease after renal failure. The reduction of acute renal failure will have several advantages, including reducing mortality and the burden of chronic kidney disease following transplantation. Hematopoietic cell transplantation is a common procedure for the treatment of malignancies and some non-malignant hematologic disorders. In addition to other transplant-related organ toxicities, acute renal failure is a common complication following transplantation. This review discusses the incidence, timing, etiologies, risk factors, and prognosis of renal failure associated with three commonly used transplantation procedures – myeloablative autologous, myeloablative allogeneic, and non-myeloablative allogeneic transplantation. It is important to note that the epidemiology and prognosis of renal failure are distinct with these three transplantation procedures. However, the common theme is that mortality increases with worsening renal failure with all three procedures. Moreover, mortality is >80% for patients with renal failure requiring dialysis. It also appears that surviving patients have an increased risk of chronic kidney disease after renal failure. The reduction of acute renal failure will have several advantages, including reducing mortality and the burden of chronic kidney disease following transplantation. Hematopoietic cell transplantation is the only cure for advanced non-malignant and malignant hematologic disorders and some non-hematologic malignancies. Renal injury is a common complication and portends worse morbidity and mortality in these patients. Currently, three types of transplantations exist: myeloablative autologous (commonly known as autologous), myeloablative allogeneic (conventional allogeneic), and non-myeloablative allogeneic (mini-allo). The incidence, etiology, severity, and prognosis of acute renal failure vary among the three types of transplantations. Previous publications and reviews have not focused on the differences in renal failure between these three procedures.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar This review will discuss the unique characteristics of renal injury and the clinical outcomes in autologous, myeloablative, and non-myeloablative transplantation. Primarily an uncommon and unsuccessful procedure in the 1960s and 1970s, hematopoietic cell transplantation has become an effective and popular treatment since the 1980s. The annual use of all hematopoietic cell transplantations increased to a peak of nearly 55 000 worldwide in the late 1990s, and has now plateaued (www.ibmtr.org). Over the past 5 years, approximately 30 000 autologous, 15 000 myeloablative allogeneic, and 1350 non-myeloablative allogeneic transplantations are being performed annually. Some common indications for transplantation are listed in Table 1.Table 1Indications for HCT in North America (ranked by absolute number performed annually)AutologousAllogeneicMultiple myelomaAcute myelogenous leukemiaNon-Hodgkin's lymphomaAcute lymphocytic leukemiaHodgkin's lymphomaMyelodysplastic syndromeOther cancersaOther cancers include acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, germ cell tumors, ovarian cancer, small cell lung cancer, and central nervous system tumors.Non-Hodgkin's lymphomaNeuroblastomaChronic myelogenous leukemiaBreast cancerNon-malignant diseasebNon-malignant disease includes aplastic anemia, Fanconi anemia, thalassemia, sickle cell disease, congenital immune deficiencies, and inherited metabolic diseases.Chronic lymphocytic leukemiaa Other cancers include acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, germ cell tumors, ovarian cancer, small cell lung cancer, and central nervous system tumors.b Non-malignant disease includes aplastic anemia, Fanconi anemia, thalassemia, sickle cell disease, congenital immune deficiencies, and inherited metabolic diseases. Open table in a new tab There are three possible sources of hematopoietic cells: the affected patient (autologous), a sibling or unrelated donor (allogeneic), or umbilical cord blood (allogeneic). The source of hematopoietic stem cells has expanded over time. Initially, the bone marrow was the source of cells for most transplantations, hence the older term bone marrow transplant. However, recently, usage of recombinant human granulocyte colony-stimulating factor, which increases the amount of stem cells that enter the peripheral blood by approximately 1000-fold, has allowed cytopheresis techniques to become the dominant mode of stem cell harvesting. Transplantations can also be of the myeloablative or non-myeloablative type (Table 2). This differentiation is based on the 'conditioning regimen'. Myeloablation generally involves high-dose chemotherapy with or without total body irradiation. It serves to eradicate the underlying disease and to provide adequate immunosuppression to prevent rejection of the transplanted graft. Because of extensive toxicities (mucositis, nausea, vomiting, diarrhea, rash, neuropathies, pulmonary fibrosis, and hepatic veno-occlusive disease) related to myeloablative regimens, myeloablative transplantation has often been limited to younger patients (age 6020%<10%40%Conditioning regimen Radiation+/-12 Gy2 Gy Cytotoxic therapyHigh doseHigh doseLow doseDonor cellsPB (96%)PB (60%)PB (96%)BM (4%)BM (38%)Other (4%)CB (2%)GVT effectNoneMild/moderateMain effectVOD (incidence)4–7%14–54%Extremely rareTM (incidence)0–27%0–76%Extremely rarePancytopeniaShorter (∼2 weeks)Longer (∼3 weeks)Shorter (∼2 weeks)Acute GVHD (II–IV) Timing IncidenceN/AEarly (weeks)Later ProphylaxisN/A38–91%47–77%N/AMTX/CsA±PredCsA or Tac±PredChronic extensive GVHD (incidence)N/A58–71%46–73%Overall mortality 100 days∼5–20%∼20–25%∼5–15% 1 year∼25–30%∼40–45%∼35–40%Gy, Gray; PB, peripheral blood; BM, bone marrow; CB, cord blood; GVT, graft versus tumor; VOD, veno-occlusive disease; TM, thrombotic microangiopathy; GVHD, graft versus host disease; MTX, methotrexate; CsA, cyclosporine; Tac, tacrolimus; N/A, not applicable.Data from references 1, 3–11 and www.ibmtr.org. Open table in a new tab Gy, Gray; PB, peripheral blood; BM, bone marrow; CB, cord blood; GVT, graft versus tumor; VOD, veno-occlusive disease; TM, thrombotic microangiopathy; GVHD, graft versus host disease; MTX, methotrexate; CsA, cyclosporine; Tac, tacrolimus; N/A, not applicable. Data from references 1, 3–11 and www.ibmtr.org. Renal failure, for the purposes of this review, will be defined as an acute fall in glomerular filtration rate ≥50% or at least a doubling of serum creatinine. Following the seminal publication by Zager et al., renal failure has been recognized as a common and debilitating complication of transplantation.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar This initial report, representing a cohort of 272 patients with primarily hematologic malignancies who underwent transplantation (89% allogeneic, 11% autologous) at the Fred Hutchison Cancer Research Center in Seattle, WA, revealed that 53% of patients developed renal failure.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar Mean onset of renal failure occurred at 14 days. Following this publication, several additional studies confirmed a similar timing and extremely high incidence of renal failure following myeloablative allogeneic transplantation (Figure 1).3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 4.Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The differences between the incidence, features, and severity of renal failure between the three types of transplantation procedures have only recently been recognized.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar As mentioned above, elderly persons and those with comorbid conditions may be eligible for non-myeloablative transplantation. The non-myeloablative procedure usually has fewer complications than myeloablative transplantation. For example, there is a decreased incidence of cytomegalovirus infection, pulmonary toxicity, and hyperbilirubinemia, and platelet and red blood cell transfusion requirements are markedly decreased. Few reports, until the past 2 years, have focused on renal injury in the setting of non-myeloablative transplantation. We reported on two cohorts: a cohort of 253 patients undergoing non-myeloablative transplantation at four centers in the US, and a cohort of 129 patients undergoing non-myeloablative transplantation at the Fred Hutch Cancer Research Center, Seattle, WA.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar First, it is worth noting that patients undergoing non-myeloablative transplantation were older (median age 53 years); greater than 40% were over the age of 55 years. Second, given their increased age and comorbidities, those undergoing non-myeloablative transplantation had a much higher incidence of stage 2–5 chronic kidney disease (CKD) at baseline (59 versus 13% in the myeloablative group).6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Renal failure occurred in slightly more than 40% of patients within approximately a 3-month period post-non-myeloablative transplantation,6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar which is much lower than the 76% incidence in myeloablative allogeneic transplantation (weighted mean of published studies).1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 4.Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Controlling for clinical variables, the risk of developing renal failure was nearly five-fold less for non-myeloablative transplantation compared with myeloablative regimens.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar This relationship was also present for dialysis-requiring renal failure: an incidence of only 4% compared with 17% in myeloablative transplantation (Figure 1).1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 4.Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar Additionally, the onset of renal failure was later, occurring at a median time of 26–60 days (∼14 days in myeloablative transplantation).1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar The incidence of renal failure in patients undergoing autologous transplantation is much lower (22%) than in myeloablative allogeneic transplantation (Figure 1).8.Merouani A. Shpall E.J. Jones R.B. et al.Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.Kidney Int. 1996; 50: 1026-1031Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 9.Fadia A. Casserly L.F. Sanchorawala V. et al.Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis.Kidney Int. 2003; 63: 1868-1873Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar The reasons for this vast difference are two-fold. In autologous transplantation, there is no graft versus host disease (GVHD). GVHD may contribute to nephrotoxicity directly (infra vide) and indirectly (prophylaxis via calcineurin inhibitors). Second, because there are no foreign cells, more rapid engraftment occurs (resulting in less cytopenia, sepsis, and nephrotoxic antimicrobials). Several factors unique to the transplantation patient can contribute to renal injury, resulting in the high frequency and severity of renal failure in this population. Some of these factors are discussed in chronological order, beginning at the time of induction. Rapid destruction of tumor cells via high-dose radiation and chemotherapy poses risk for tumor lysis syndrome. Release of intracellular contents such as uric acid and phosphate may precipitate in renal tubules, resulting in intratubular obstruction and renal failure. Fortunately, because many are in remission at the time of transplantation and because of appropriate prophylaxis with intravenous fluids, urinary alkalization, and allopurinol, the incidence of tumor lysis syndrome in this population is quite low (approximately one in 400).2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar Owing to profound neutropenia as a result of bone marrow ablation secondary to radiochemotherapy, transplantation patients are at high risk of both bacterial and fungal sepsis. The resultant vasodilation and capillary leak following sepsis contribute to renal hypoperfusion. Cytokine-induced renal vasoconstriction, cytokine-induced intrarenal inflammation, and complement-mediated renal injury also contribute to renal failure in the setting of sepsis. Agents used to treat bacteremia and sepsis (e.g., gentamicin, amphotericin B) may also contribute to nephrotoxicity in this setting. To underscore the importance of sepsis in the development of post-transplantation renal failure, patients who developed dialysis-requiring renal failure (compared to those who maintained normal renal function) had a higher incidence of fevers (95 versus 50%) and positive blood cultures (63 versus 0%) within 48 h prior to the onset of renal insufficiency.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar Hepatic veno-occlusive disease is caused by acute radiochemotherapy-induced endothelial cell injury of hepatic venules, which results in venular thrombosis and subsequent sinusoidal and portal hypertension. Clinically, hepatic veno-occlusive disease begins as a fluid-retentive state with low urinary sodium that leads to peripheral edema and weight gain within the first few days after transplantation, mimicking the hepatorenal syndrome.10.McDonald G.B. Hinds M.S. Fisher L.D. et al.Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.Ann Intern Med. 1993; 118: 255-267Crossref PubMed Scopus (1002) Google Scholar Hepatomegaly, right upper quadrant pain, and ascites are also common features.10.McDonald G.B. Hinds M.S. Fisher L.D. et al.Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.Ann Intern Med. 1993; 118: 255-267Crossref PubMed Scopus (1002) Google Scholar Owing to the hepatocyte injury, transaminases and bilirubin become elevated. The signs and symptoms of hepatic veno-occlusive disease precede the development of renal insufficiency.2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 10.McDonald G.B. Hinds M.S. Fisher L.D. et al.Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.Ann Intern Med. 1993; 118: 255-267Crossref PubMed Scopus (1002) Google Scholar Risk factors for development of hepatic veno-occlusive disease include increasing age, pre-existing hepatic disease, fever, cytomegalovirus seropositivity, and medications (estrogen, progestin, amphotericin, methotrexate), including agents frequently used as part of conditioning regimens (busulfan and cyclophosphamide).2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 10.McDonald G.B. Hinds M.S. Fisher L.D. et al.Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.Ann Intern Med. 1993; 118: 255-267Crossref PubMed Scopus (1002) Google Scholar Overall, hepatic veno-occlusive disease occurs more commonly in myeloablative allogeneic compared to autologous transplantation (Table 2).3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 4.Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 8.Merouani A. Shpall E.J. Jones R.B. et al.Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.Kidney Int. 1996; 50: 1026-1031Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 10.McDonald G.B. Hinds M.S. Fisher L.D. et al.Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.Ann Intern Med. 1993; 118: 255-267Crossref PubMed Scopus (1002) Google Scholar The reduced incidence in autologous transplantation may be due to the absence of methotrexate, since there is no risk of GVHD, and because of more rapid engraftment. In non-myeloablative transplantation, hepatic veno-occlusive disease is non-existent, probably because of the much lower intensity of the radiochemotherapy.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Prevention for hepatic veno-occlusive disease can be moderately successful when heparin infusions and/or ursodeoxycholic acid are initiated immediately prior to induction. Recombinant human tissue plasminogen activator and an agent with pleuripotent properties, defibrotide, have been employed with mild to moderate success in the treatment of hepatic veno-occlusive disease (30–40% response rate). Several reports of this specific thrombotic microangiopathy appear in the literature over the past 25 years. Diagnosis of this disorder in transplantation patients is difficult, as this population has several reasons to have anemia, thrombocytopenia, renal dysfunction, fever, and neurological abnormalities. Repeated assessment of the peripheral smear to document microangiopathic anemia (via schistocytes) is essential. The etiology is more likely due to direct endothelial injury from calcineurin inhibitors, high-dose chemotherapy, and total body irradiation, rather than from deficiencies in von Willenbrand factor-cleaving protease. The incidence of thrombotic microangiopathy varies greatly in the literature, ranging from 0 to 74%, because of inconsistencies in diagnostic criteria.11.Roy V. Rizvi M.A. Vesely S.K. et al.Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes.Bone Marrow Transplant. 2001; 27: 641-646Crossref PubMed Scopus (99) Google Scholar In general, the incidence rate is lower in autologous transplantation and non-existent in non-myeloablative transplantation. Onset of thrombotic microangiopathy usually occurs between 20 and 99 days post-transplantation.11.Roy V. Rizvi M.A. Vesely S.K. et al.Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes.Bone Marrow Transplant. 2001; 27: 641-646Crossref PubMed Scopus (99) Google Scholar Risk factors associated with the development of thrombotic microangiopathy include veno-occlusive disease, grade II–IV acute GVHD, unrelated donor, and systemic bacterial, fungal, and viral infections.11.Roy V. Rizvi M.A. Vesely S.K. et al.Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes.Bone Marrow Transplant. 2001; 27: 641-646Crossref PubMed Scopus (99) Google Scholar Although many centers utilize plasma exchange for the treatment of transplantation-associated thrombotic microangiopathy, the response rates to treatment are significantly lower (45%) than in classical thrombotic microangiopathy (approximately 75%). The calcineurin inhibitors (cyclosporine, tacrolimus) are employed for prophylaxis against GVHD. In myeloablative allogeneic transplantation patients, they are combined with methotrexate, and are used with steroids in non-myeloablative transplantation. Both agents are potent renal vasoconstrictors and induce reductions in renal function that correlate well with serum concentrations of the drug.2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar However, in myeloablative allogeneic transplantation, cyclosporine has not been associated with the development of renal failure in several studies.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 2.Zager R.A. Acute renal failure in the setting of bone marrow transplantation.Kidney Int. 1994; 46: 1443-1458Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 12.Hingorani S.R. Guthrie K. Batchelder A. et al.Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.Kidney Int. 2005; 67: 272-277Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar This is probably due to frequent adjustments in doses for both high levels and elevations in serum creatinine. Also, because of several concurrent toxic insults occurring, it is difficult to statistically separate the contribution of cyclosporine to renal dysfunction. In non-myeloablative transplantation, cyclosporine was associated with all cases of non-dialysis-requiring renal failure, and renal function improved with dose reductions.7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar Therefore, it is likely that calcineurin inhibitors do a play a more significant role in renal failure in non-myeloablative transplantation. Adjustments in dose should be made to maintain lower levels and when renal dysfunction is present. Although not classically believed to involve the kidney, GVHD may affect the kidney through cytokine- and immune-related injury, including glomerular deposits leading to nephrotic syndrome, and tubulitis, as recognized by some authors.13.Rao P.S. Nephrotic syndrome in patients with peripheral blood stem cell transplant.Am J Kidney Dis. 2005; 45: 780-785Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Support for this theory also arises from mice that were found to have severe infiltration of their kidneys with cytotoxic T-cells during GVHD.14.Panoskaltsis-Mortari A. Price A. Hermanson J.R. et al.In vivo imaging of graft-versus-host-disease in mice.Blood. 2004; 103: 3590-3598Crossref PubMed Scopus (119) Google Scholar Although usually not statistically associated with renal failure in studies,1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar further experimental and human research is needed to establish the link, if any, between GVHD and renal disease. Renal failure following myeloablative allogeneic transplantation typically occurs after approximately 2 weeks. At this time, the patient is most vulnerable to multiple organ dysfunctions due to toxicities associated with the intense conditioning regimen, especially infections and hepatic veno-occlusive disease. Commensurate with these intuitive risks, the statistically-derived risk factors for development of renal failure in the setting of myeloablative allogeneic transplantation were hepatic veno-occlusive disease,3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 12.Hingorani S.R. Guthrie K. Batchelder A. et al.Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.Kidney Int. 2005; 67: 272-277Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar pulmonary toxicity,5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar older age,3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar amphotericin B,12.Hingorani S.R. Guthrie K. Batchelder A. et al.Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.Kidney Int. 2005; 67: 272-277Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar high-risk malignancy group,6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar and increased comorbidity score.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Factors not found to be statistically associated with an increased risk of renal failure in multivariate analyses were sex,1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar underlying disease,3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar conditioning therapy,3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar total body irradiation,5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar hypotension,1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar aminoglycoside use,5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar and related versus unrelated donors.6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Conflicting results were present among some potential risk factors. First, hyperbilirubinemia was a risk factor in one report but not another.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Second, higher serum creatinine at baseline was associated with a higher risk for renal failure in one analysis, but a lower risk in another analysis, despite the fact that both reports and authors originate from the same institution.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 12.Hingorani S.R. Guthrie K. Batchelder A. et al.Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.Kidney Int. 2005; 67: 272-277Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar The severity of renal injury following myeloablative transplantation may be augmented by the destruction of stem cells available for kidney repair by the radiochemotherapy administered with transplantation. Recovery of renal function may therefore be hampered by the absence of one or both of the following cell lines: renal adult stem cells that reside in the renal papilla that normally proliferate during times of renal injury and are involved in renal repair and/or mesenchymal stem cells (not administered during infusion of hematopoietic stem cells) that have renoprotective properties in experimental animals through currently unknown mechanisms.15.Oliver J.A. Maarouf O. Cheema F.H. et al.The renal papilla is a niche for adult kidney stem cells.J Clin Invest. 2004; 114: 795-804Crossref PubMed Scopus (445) Google Scholar, 16.Krause D. Cantley L.G. Bone marrow plasticity revisited: protection or differentiation in the kidney tubule?.J Clin Invest. 2005; 115: 1705-1708Crossref PubMed Scopus (92) Google Scholar Renal failure, as discussed above, is less severe and occurs later in non-myeloablative transplantation, probably because the milder conditioning regimen leads to less severe toxicities. The major culprit for renal failure in this population is cyclosporine insult.7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar When severe renal failure (dialysis-requiring) does occur, etiologies are typically multifactorial, involving cyclosporine plus factors such as severe GVHD, sepsis, volume depletion, hypotension, hemorrhage, and antibiotics.7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar Few studies have examined renal toxicity in solely autologous transplantation. Clinical predictors for renal failure in multivariate models included liver toxicity, lung toxicity, and sepsis in one report.8.Merouani A. Shpall E.J. Jones R.B. et al.Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.Kidney Int. 1996; 50: 1026-1031Abstract Full Text PDF PubMed Scopus (58) Google Scholar In a report involving only autologous transplantation for AL amyloidosis, the clinical predictors were cardiac involvement, bacteremia, higher melphelan dose (not a known nephrotoxin), higher urinary protein excretion, and lower creatinine clearance.9.Fadia A. Casserly L.F. Sanchorawala V. et al.Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis.Kidney Int. 2003; 63: 1868-1873Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Zager et al.1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar first noted the significant differences in mortality associated with varying degrees of renal failure in transplantation. In patients without renal insufficiency, the mortality was 17%; in patients with non-dialysis-requiring renal failure, the mortality was 37%; in patients with dialysis-requiring renal failure, the mortality was 84%. Subsequent reports confirmed that the degree of renal failure is associated with mortality (Figure 2). A meta-analysis encompassing 1211 patients undergoing myeloablative allogeneic transplantation found that the relative risk of death after renal failure was greater than two-fold higher.17.Parikh C.R. McSweeney P. Schrier R.W. Acute renal failure independently predicts mortality after myeloablative allogeneic hematopoietic cell transplant.Kidney Int. 2005; 67: 1999-2005Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar The adjusted odds of 6-month mortality with dialysis-requiring renal failure was 6.8-fold higher even after controlling for several demographic, clinical, and transplantation variables.17.Parikh C.R. McSweeney P. Schrier R.W. Acute renal failure independently predicts mortality after myeloablative allogeneic hematopoietic cell transplant.Kidney Int. 2005; 67: 1999-2005Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Finally, among the studies of myeloablative allogeneic, myeloablative autologous, or non-myeloablative allogeneic transplantation, one monumental fact transcends these categories. The mortality associated with dialysis-requiring renal failure is similarly devastating among the three types of transplantation, universally approaching or exceeding 80% (Figure 2).1.Zager R.A. O'Quigley J. Zager B.K. et al.Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.Am J Kidney Dis. 1989; 13: 210-216Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 3.Gruss E. Bernis C. Tomas J.F. et al.Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.Am J Nephrol. 1995; 15: 473-479Crossref PubMed Scopus (95) Google Scholar, 4.Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 7.Parikh C.R. Sandmaier B.M. Storb R.F. et al.Acute renal failure after nonmyeloablative hematopoietic cell transplantation.J Am Soc Nephrol. 2004; 15: 1868-1876Crossref PubMed Scopus (66) Google Scholar, 8.Merouani A. Shpall E.J. Jones R.B. et al.Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer.Kidney Int. 1996; 50: 1026-1031Abstract Full Text PDF PubMed Scopus (58) Google Scholar A potential reason for the extremely poor outcomes and survival witnessed with renal failure may be due to exacerbation of non-renal organ toxicities secondary to systemic cytokine elaboration and immune-mediated damage initiated by renal injury.18.Kelly K.J. Distant effects of experimental renal ischemia/reperfusion injury.J Am Soc Nephrol. 2003; 14: 1549-1558Crossref PubMed Scopus (350) Google Scholar Indeed, hepatic, pulmonary, and gastrointestinal toxicities increase as the severity of renal failure increases in transplantation.5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 6.Parikh C.R. Schrier R.W. Storer B. et al.Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2005; 45: 502-509Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar By 6–12 months after myeloablative allogeneic transplantation, approximately 20% of patients will develop CKD. The etiology is likely multifactorial. Renal failure certainly contributes to long-term impairment in renal function, with subsequent reductions in mean glomerular filtration rate of approximately 50% at 6 months.5.Parikh C.R. McSweeney P.A. Korular D. et al.Renal dysfunction in allogeneic hematopoietic cell transplantation.Kidney Int. 2002; 62: 566-573Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar In addition, radiation induces glomerular and interstitial injury in a dose-dependent fashion that can be abrogated by renal shielding.19.Cohen E.P. Radiation nephropathy after bone marrow transplantation.Kidney Int. 2000; 58: 903-918Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Shielding may preserve renal stem cells that reside in the papilla, thereby enabling renal repair and recovery.15.Oliver J.A. Maarouf O. Cheema F.H. et al.The renal papilla is a niche for adult kidney stem cells.J Clin Invest. 2004; 114: 795-804Crossref PubMed Scopus (445) Google Scholar In non-myeloablative transplantation, the development of CKD has not been well characterized until recently when a retrospective cohort of 122 patients undergoing the procedure between 1998 and 2002 was examined. A total of 65% had development of CKD (defined as a reduction in glomerular filtration rate of 25% or greater) and 22% experienced at least a doubling of serum creatinine within 1 year of receiving the non-myeloablative transplantation.20.Weiss A. Sandmaier B.M. Storer B. et al.Chronic kidney disease following nonmyeloablative hematopoietic cell transplantation.Am J Kidney Dis. 2006; 6: 89-94Google Scholar The greatest risk factor for CKD was acute renal failure (OR 32.8, 95% CI 4.3–250, P=0.0005). Other risk factors included prior autologous transplantation, chronic extensive GVHD, and long-term cyclosporine use. Assessment of the etiology, characteristics, incidence, severity, and prognosis of renal failure following transplantation must consider the three distinct forms of hematopoietic cell transplantation. Severe renal failure occurs with all three varieties, but the frequency increases from myeloablative autologous, to non-myeloablative allogeneic, to myeloablative allogeneic. In all three types of transplantation, mortality is clearly associated with the severity of renal injury, and it is greater than 80% when dialysis is required.
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