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2003 102: 2695 doi:10.1182/blood-2003-06-1778

Chronic renal failure: a nonmalignant late effect of allogeneic stem cell transplantation François Vincent, Marie-Alyette Costa, Eric Rondeau, Gerard Sociè and Andre Tichelli

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Correspondence

To the editor: Chronic renal failure: a nonmalignant late effect of allogeneic stem cell transplantation We read with interest the excellent review by Socie` et al concerning nonmalignant late effects after allogeneic stem cell transplantation (SCT).1 However, we were surprised with the fact that renal side effects are not mentioned. Acute renal failure in the course of SCT is well described.2 It usually occurs in the first weeks after SCT. It results from infection and its subsequent treatment with nephrotoxic medications, graft-versus-host disease (GVHD), and veno-occlusive disease. Chronic renal failure following allogeneic SCT was recognized more than 15 years ago as related to the total body irradiation (TBI) used for conditioning.3 Indeed, many observations without TBI have been published. The initial chemotherapy including BCNU (1,3-bis(2chloroethyl)-1-nitrosourea), cyclophosphamide, ifosfamide, and the use of cyclosporine, tacrolimus, or methotrexate for the prophylaxis of GVHD may also play a role.4 Clinically, when anticalcineurins’ toxicity has been ruled out as the cause of chronic renal failure, the disorder may be called bone marrow transplantation nephropathy (BMTN), a form of radiation nephropathy.5 The exact incidence of BMTN is unknown. An incidence between 0.6% and 13% has been noted in adult patients. Children appear to develop this lesion slightly more commonly, with a reported incidence as high as 45%.6 The main symptoms of BMTN are closely related to hemolytic and uremic syndrome (HUS), including constant hypertension, peripheral edema, and anemia with mild thrombopenia and the possibility of schizocytes. The anemia is out of proportion to the degree of azotemia. In a personal study of 9 patients we retrieved paradoxical low levels of erythropoietin, more pronounced than those observed for an equivalent decrease in glomerular filtration rate (GFR). The rate of decline of GFR may be chronic or acute.7 Treatments such as plasma exchange or other treatments are poorly effective in the management of the acute form, leading to mortality ranging from 50% to 100%.8 The blockade of renin-angiotensin axis is the main point in the treatment of the chronic form.6 The goal of blood pressure control is not well defined. We think that low pressure, less than 130/70 mmHg, must be obtained. We preferentially use a combination of angiotensin-converting inhibitor and angiotensin II receptor blockers.

This remains to be validated. A large study concerning the prevalence of hypertension following SCT and its treatment is also needed. Despite the control of blood pressure, use of erythropoietin, and discontinuation of nephrotoxics, the evolution to chronic renal failure requiring dialysis may occur.9 Survival on dialysis therapy is often poor. Renal transplantation may be preferable.9,10 If bone marrow and kidney are from the same donor, the recipient requires little or no immunosuppression. This is of importance in view to diminish the risk of infections and malignancy. Franc¸ois Vincent, Marie-Alyette Costa, and Eric Rondeau Correspondence: Franc¸ois Vincent, Hoˆpital Tenon, 4, Rue de la Chine, 75020 Paris, France; e-mail: [email protected]

References 1. Socie´ G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. 2003;101:3373-3385. 2. Parikh CR, McSweeney PA, Korular D, et al. Renal dysfunction in allogeneic hematopoietic cell transplantation. Kidney Inter. 2002;62:566-573. 3. Chappell ME, Keeling M, Prentice HG, Sweny P. Haemolytic uremic syndrome after bone marrow transplantation: an adverse effect of total body irradiation. Bone Marrow Transplant. 1988;3:339-347. 4. Cohen EP. Renal failure after bone marrow transplantation. Lancet. 2001;357:6-7. 5. Cohen EP. Radiation nephropathy after bone marrow transplantation. Kidney Inter. 2000;58:903-918. 6. Antignac C, Gubler MC, Leverger G, Broyer M, Habib R. Delayed renal failure with extensive mesangiolysis following bone marrow transplantation. Kidney Inter. 1989;35:1336-1344. 7. Cruz DN, Perazella MA, Mahnensmith RL. Bone marrow transplant nephropathy: a case report and review of the literature. J A S N. 1997;8:166-173. 8. Roy V, Rizvi MA, Vesely SK, George JN. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplantation. 2000;27:641-646. 9. Butcher JA, Hariharan S, Adams MP, Johnson CP, Roza AM., Cohen EP. Renal transplantation for end-stage renal disease following bone marrow transplantation: a report of six cases, with and without immunosuppression. Clin Transplant. 1999;13;330-335. 10. Hamawki K, De Magalhaes-Silverman M, Bertolatus JA. Outcomes of renal transplantation following bone marrow transplantation. Am J Transplant. 2003;3:301-305.

Response: Renal and other rare late complications following allogeneic stem cell transplantation We read with interest the letter by Dr Vincent et al on chronic renal failure following allogeneic stem cell transplantation (SCT). Many reports and publications were not included in our review due to space constraints. We agree that chronic renal failure should have been mentioned among nonmalignant late effects. A few other effects including late cardiac failure and metabolic disorders are also worthy of mention. The X syndrome that associates hyperinsulinemia, glucose intolerance, hypertension, and hypertriglyceridemia has also been reported recently in long-term survivors following SCT.1 However, for all these complications not reviewed in our manuscript, we clearly lack well-designed analyses on a large cohort of patients to provide cumulative incidence rates and descriptions of risk factors.

BLOOD, 1 OCTOBER 2003 䡠 VOLUME 102, NUMBER 7

Concerning late renal failure specifically, while previous reviews2 stressed the role of irradiation and of hemolytic and uremic syndrome, other risk factors including graft-versus-host disease, drug-induced toxicity, and early onset arteriosclerosis would also be worthwhile of study. As in long-term survivors of treatment in Hodgkin disease, this might expose the patients who underwent transplantation to premature cardiovascular diseases. In the case of long-term survivors of marrow transplantation, we again would like to urge physicians to conduct life-long follow-up, especially if, as in these cases, such follow-up could lead to timely therapeutic intervention and prevent the occurrence of late death.3

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BLOOD, 1 OCTOBER 2003 䡠 VOLUME 102, NUMBER 7

CORRESPONDENCE

Gerard Socie` and Andre Tichelli, on behalf of the Late Effect Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

References 1. Socie` G. Is syndrome ”X” another late complication of bone-marrow transplantation? Lancet. 2000;356:957-958.

Correspondence: Gerard Socie`, Service de greffe de moelle, University Paris VII, Hopital Saint Louis AP-HP, 1 Avenue Claude Vellefaux, Paris Cedex 10, 75475 France; e-mail: [email protected]

2. Cohen EP. Renal failure after bone-marrow transplantation. Lancet. 2001;357: 6-7.

Members of the Late Effect Working party of the EBMT are listed in “Appendix” in the original review.4

4. Socie` G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. 2003;101:3373-3385.

3. Socie` G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. N Engl J Med. 1999;341:14-21.

To the editor: Penetrance in hereditary hemochromatosis Ajioka and Kushner1 make the point that ascertainment bias is the reason for the finding of low clinical penetrance in some studies of the incidence of hemochromatosis. They explain how they have avoided ascertainment bias in their study of hemochromatosis families by studying clinically unselected relatives homozygous for the HFE Cys282Tyr mutation and also by comparing 2 groups of probands—those presenting clinically and found to have hemochromatosis and those detected through screening of blood donors or through annual health assessment visits. For the clinical cases, the possibility of selection bias by referral to a tertiary center is acknowledged by the authors but not considered to be a source of bias. Furthermore all the “detected” probands had a transferrin saturation more than 62%. All probands were therefore selected either by disease or iron phenotype and are not representative of those in the general population who are homozygous for Cys282Tyr. The study of 10 500 blood donors from South Wales2 referred to in the “Rebuttal to Beutler”3 was not designed to determine clinical penetrance, as blood donors must declare that they are not being treated for any medical condition before giving blood. The study was designed to determine HFE genotype frequencies and iron status within the several genotype groups. Of the 72 donors homozygous for Cys282Tyr, only 60% of males and 30% of females would have been identified if the selection was based on a transferrin saturation more than 62%. After interviewing 63 of the blood donors, a surprising finding emerged— none was aware of any family history of iron overload. Since completion of the blood donor study, further work in South Wales has also confirmed our belief that the penetrance of the HFE gene is indeed low. A survey of hemochromatosis as a clinical condition in 2 health authorities (included in the blood donor survey region, population approximately 1 million) concluded that only 1.2% of adult Cys282Tyr homozygotes had received a confirmed diagnosis.4 Restricting the study to men older than 45 years, the figure rose to 2.8%. Recently, we have been able to study further the families of those blood donors homozygous for Cys282Tyr. Iron status and morbidity have been compared with families of Cys282Tyr homozygotes presenting clinically (C.A.M. et al, in preparation). Despite 32% of all female Cys282Tyr⫹/⫹ relatives and 72% of all male

Cys282Tyr⫹/⫹ relatives having both a raised transferrin saturation and serum ferritin, serious morbidity directly attributable to iron overload was low. These studies, and those reviewed by Beutler5 and Ajioka and Kushner,1 all point in the same direction. Most men and about 50% of premenopausal women who are homozygous for HFE Cys282Tyr have biochemical evidence of iron accumulation (raised transferrin saturation). However, this cannot simply be equated with iron overload or morbidity and is not reflected in a significant, identifiable burden of disease for health services. There have now been many reports of the frequency of homozygosity for Cys282Tyr in patients with diabetes, cardiac disease, liver disease, and arthritis. With the exception of hepatoma, there is no increase in frequency in such patients.6 The urgent need is to identify the factors that, in addition to homozygosity for Cys282Tyr, cause significant iron accumulation and disease. The male blood donors from South Wales had given a mean of 1 unit per year and the female donors 0.5 units. If regular blood donation at this frequency is found to prevent morbidity in Cys282Tyr homozygotes, then a universal system of disease prevention already exists. Anne McCune and Mark Worwood Correspondence: Anne McCune, Department of Haematology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; e-mail: [email protected]

References 1.

Ajioka RS, Kushner JP. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood. 2003;101:3351-3353.

2.

Jackson HA, Carter K, Darke C, et al. HFE mutations, iron deficiency and overload in 10 500 blood donors. Brit J Haematol. 2001;114:474-484.

3.

Ajioka RS, Kushner JP. Rebuttal to Beutler. Blood. 2003;101:3358.

4.

McCune CA, Al-Jader LN, May A, et al. Hereditary haemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum Genetics. 2002;111:538-543.

5.

Beutler E. The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood. 2003;101:3347-3350.

6.

Worwood M. HFE mutations as risk factors in disease. Best Pract Res Clin Haematol. 2002;15:295-314.

Response: Morbid complications of hemochromatosis Dr McCune has misinterpreted the significance of an elevated transferrin saturation. An elevated transferrin saturation is not biochemical evidence of iron accumulation. The serum ferritin concentration is the laboratory study that most accurately reflects

an increase in liver iron stores. An elevated transferrin saturation has proved to be a remarkably reliable phenotypic marker of homozygosity for the Cys282Tyr HFE mutation. Dr McCune states that only 60% of men homozygous for the Cys282Tyr mutation