Pediatr Transplantation 2015: 19: E7–E10
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12406
Post-renal transplant erythrocytosis: A case report Almonte M, Velasquez-Jones L, Valverde S, Carleton B, Medeiros M. (2015) Post-renal transplant erythrocytosis: A case report. Pediatr Transplant, 19: E7–E10. DOI: 10.1111/petr.12406.
Mavel Almonte1, Luis Velasquez-Jones1, Saul Valverde1, Bruce Carleton2,3,4 and Mara Medeiros2,3,4,5 Departamento de Nefrologıa, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico, 2 Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, BC, Canada, 3 Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada, 4Child & Family Research Institute, Vancouver, BC, Canada, 5 Laboratorio de Investigacion en Nefrologıa y Metabolismo Mineral, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico 1
Abstract: PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14-yr-old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post-transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post-transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post-transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.
Key words: erythrocytosis – kidney transplantation – immunosuppression – enalapril – erythropoietin Mara Medeiros, Laboratorio de Investigacion en Nefrologıa y Metabolismo Mineral, Hospital Infantil de Mexico Federico Gomez, Dr. Marquez 162 Colonia Doctores, 06720 Mexico DF, Mexico Tel.: 52 55-5228-9917 Ext-4410 Fax: 52 55-5761-8974 E-mail: [email protected] Accepted for publication 29 October 2014
Background
Patients with chronic kidney disease often have anemia related to reduction in EPO production, iron, and nutrient deficiency, blood loss during hemodialysis, chronic inflammation, EPO resistance, among other causes (1). EPO secretion after successful kidney transplant has a peak within three days, reticulocytosis begins at one wk, anemia correction is expected within 8– 10 wk, and EPO levels decline to normal values over the next 4–8 months (2, 3). Anemia post-renal transplant shows a biphasic pattern with a high incidence in the early posttransplant period, improves during the first year, and slowly increases its prevalence over time, being related to the loss of graft function. In
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CMV, cytomegalovirus; EPO, erythropoietin; GFR, glomerular filtration rate; Hb, hemoglobin; Ht, hematocrit; PTE, posttransplant erythrocytosis; RAS, renin–angiotensin system.
children, the prevalence of anemia has been reported as 85% at one-month post-transplant and 68% at 12 months, and it increases to 82% at 60 months post-transplant (4). A subset of patients can develop PTE, defined as a persistently elevated Ht >51% or an Hb level >17 g/dL after renal transplantation (2, 5), its prevalence has been reported between 2.5 and 22%, with a clear decline over the past decade, probably due to (i) the increase in use of ACEI or ARBs, (ii) the change in immunosuppressive agents, with cyclosporine being substituted by tacrolimus, and the more intensive use of antiproliferatives (mofetil mycophenolate instead of azathioprine) (6–8). Known risk factors for PTE include male gender, presence of native kidneys with adequate erythropoiesis prior to transplantation, renal artery stenosis, and smoking (1, 6, 7). The type of immunosuppression may also be a risk factor. After the introduction of cyclosporine, an increase in the prevalence of PTE was reported in 1988 by Tatman and coworkers, 4% in E7
Almonte et al.
patients treated with azathioprine/prednisolone and 11% in cyclosporine/prednisolone-treated patients (9). Retrospective studies also mention that PTE is more frequent in cyclosporinetreated patients (10, 11), but these studies did not find statistically significant differences, perhaps due to the small sample sizes studied. Post-transplant erythrocytosis may increase the risk of thromboembolic events and should be treated to reduce Hb values below 17.5 g/dL. Spontaneous resolution can occur, and other proposed treatments have been phlebotomy (12), native kidneys nephrectomy (13), and ACEI or ARB pharmacotherapy (14–16). When managing a patient with erythrocytosis, a diagnostic pathway should be established to ensure an appropriate treatment plan is developed. The condition should be verified by a repeat blood cell count and a detailed clinical history. Patient examination should include questions aimed at determining whether any change in lifestyle (smoking, alcohol) or drug use coincides with packed cell volume increase. Other medical comorbidities such as cyanotic heart disease, lung disease, and renal artery stenosis should also be considered (17). Case report
We report the case of a 14-yr-old girl with chronic kidney disease of unknown etiology. She was managed with peritoneal dialysis for three months prior to receiving a kidney transplant from a non-related living donor in October 2011, conserving her native kidneys. The pretransplant Hb level was 11.1 g/dL and Ht 32.2%; prior to transplant, she received treatment with recombinant erythropoietin, 276 units/kg/wk for 12 wk. The immunosuppressive regimen consisted of induction with anti-CD25 antibodies and triple therapy with mycophenolate mofetil 683 mg/m2/ day, tacrolimus 0.08 mg/kg/day (to attain trough levels between 5 and 10 ng/mL), three methylprednisolone pulses 10 mg/kg/day, and then, prednisone tapered to 0.1 mg/kg/day at three months post-transplant. She was also treated for high blood pressure with amlodipine 0.13 mg/ kg/day and prophylaxis with ganciclovir IV for two weeks followed by oral valganciclovir during six months because she was high risk for CMV infection (seronegative). Twelve months after her transplant, she had an Hb level of 17.5 g/dL and Ht 53%, which exceeded the normal range but without symptoms (Fig. 1). Serum creatinine was 1 mg/dL, GFR by Schwartz formula (18), 86.9 mL/min/ E8
1.73 m², tacrolimus level was 4.1 ng/dL. Medical history reported smoking one cigarette per day, as well as passive smoking since October 2012. Pulse oximetry (SpO2) was 98%, and her echocardiogram showed a structurally normal heart. Ultrasound of the renal graft was normal, as was chest X-ray. EPO serum levels were 11.8 mIU/ mL (reference interval 2.0–14.2). She was evaluated by the hematology department, confirming post-transplant erythrocytosis of unknown origin. She had no spontaneous improvement, and at 19 months post-transplant, we decided to start treatment with enalapril 0.13 mg/kg/day due to an Hb of 17.5 g/dL and Ht 53%. Six months later, the hemoglobin was reduced to 15 g/dL and hematocrit to 44.5% (Fig. 1). Serum creatinine increased slightly to 1.2 mg/dL (GFR 74.25 mL/min/1.73 m2 BSA). Discussion
There are few reports of PTE cases in renal transplant children. Sinnassamy et al. described five patients in 1987, and they related the PTE to renal stenosis in three of them (19). Krull et al. (20) in 1992 reported a seven-yr-old patient who was unsuccessfully treated with a three-month course of theophylline and ended up with phlebotomy twice a week to lower the Hb; in the same case report, they mention having observed PTE in 6/186 pediatric patients transplanted before age 16 (3.2%). The overall PTE incidence has declined in adult patients in the past decade (8). PTE appears to result from the combined trophic effect of multiple and interrelated erythropoietic factors, including erythropoietin, angiotensin II, androgens, and IGF-1. Inadequate suppression of EPO production and
Fig. 1. Hemoglobin levels pre- and post-transplant. Enalapril was started at 19 months post-transplant (arrow).
Post-renal transplant erythrocitosis
increase in serum-soluble steam cell factor have been observed in patients with PTE (21, 22). Our adolescent patient had a steady increase in hemoglobin levels since the sixth-month posttransplant, reaching the Hb threshold of 17 g/dL for PTE diagnosis at 12 months post-transplant; the only risk factor found was smoking, EPO levels were normal, and she required EPO therapy before the renal transplant. Even though PTE can resolve spontaneously in some patients, the high blood viscosity carries with it the risk of thromboembolic and cardiovascular complications (17, 23). Among the suggested treatments are avoiding dehydration (17), phlebotomy (17), removal of the native kidneys (13), inactivation of RAS (14), and the use of adenosine receptor antagonists such as theophylline, as it reduces EPO levels (24). Inactivation of RAS by an ACE inhibitor or an angiotensin II AT1 receptor antagonist represents the most effective, safe, and well-tolerated therapeutic modality, (1) but the duration of treatment has not been specified. Angiotensin II is a growth factor for erythroid progenitors and it also regulates EPO production via angiotensin II type 1 receptor-mediated EGR1 activation by p21RAS–mitogen-activated protein kinase/ERK kinase ERK1/2 (25, 26). The ACE insertion/deletion (I/D) gene polymorphism, defined as the insertion of 287 bp in intron 16 (rs1799752, rs4340, rs13447447, or rs4646994), has been studied in several diseases (27), and the deletion allele is associated with a 65% increase in activity of the enzyme. The response to ACE inhibitors for treating proteinuric nephropathies varies depending on the I/D genotype (28, 29). There are conflicting results relating this polymorphism to PTE. Micozkadioglu et al. (30) reported that PTE was more frequent in those carrying the D/ D allele vs. the I/I allele. Kedzierska found no difference in genotype frequency between patients with or without PTE, but the D allele increased the risk for PTE (31). Kujawa-Szewieczek et al. (32) did not find any association between ACE polymorphism and the risk for PTE. Differences in the results among studies could be due to small sample sizes, genotypic and phenotypic misclassifications, and the interaction with other genes or environmental factors that have not been considered (33). As well, patients in these studies received different immunosuppressive regimens whereby the reported frequency of PTE itself is different. PTE could be an adverse drug reaction, but it is difficult to relate it to a particular drug when multiple drugs are used concomitantly.
The case presented was successfully treated with enalapril, but a reduction in GFR was observed (34). Funding M. Medeiros received a CONACYT grant 205627.
Conflict of interests
None. Authors’ contributions M. Almonte collected clinical data and helped in drafting the manuscript; L. Vel asquez-Jones and S. Valverde revised clinical data and drafted the manuscript; B. Carleton and M. Medeiros revised clinical data, analysis of the literature, and drafted the manuscript.
References 1. REINDL-SCHWAIGHOFER R, OBERBAUER R. Blood disorders after kidney transplantation. Transplant Rev (Orlando) 2014: 28: 63–75. 2. KESSLER M. Erythropoietin and erythropoiesis in renal transplantation. Nephrol Dial Transplant 1995: 10(Suppl 6): 114– 116. 3. SUN CH, WARD HJ, PAUL WL, KOYLE MA, YANAGAWA N, LEE DB. Serum erythropoietin levels after renal transplantation. N Engl J Med 1989: 321: 151–157. 4. AL-UZRI A, YORGIN PD, KLING PJ. Anemia in children after transplantation: Etiology and the effect of immunosuppressive therapy on erythropoiesis. Pediatr Transplant 2003: 7: 253– 264. 5. JULIAN BA, BRANTLEY RR Jr, BARKER CV, et al. Losartan, an angiotensin II type 1 receptor antagonist, lowers hematocrit in posttransplant erythrocytosis. J Am Soc Nephrol 1998: 9: 1104–1108. 6. VLAHAKOS DV, MARATHIAS KP, AGROYANNIS B, MADIAS NE. Posttransplant erythrocytosis. Kidney Int 2003: 63: 1187–1194. 7. MALYSZKO J, OBERBAUER R, WATSCHINGER B. Anemia and erythrocytosis in patients after kidney transplantation. Transpl Int 2012: 25: 1013–1023. 8. KIBERD BA. Post-transplant erythrocytosis: A disappearing phenomenon? Clin Transplant 2009: 23: 800–806. 9. TATMAN AJ, TUCKER B, AMESS JA, CATTELL WR, BAKER LR. Erythraemia in renal transplant recipients treated with cyclosporin. Lancet 1988: 1: 1279. 10. EINOLLAHI B, LESSAN-PEZESHKI M, NAFAR M, et al. Erythrocytosis after renal transplantation: Review of 101 cases. Transplant Proc 2005: 37: 3101–3102. 11. FANG GX, CHAN PC, CHENG IK, LI MK, WONG KK, CHAN MK. Haematological changes after renal transplantation: Differences between cyclosporin-A and azathioprine therapy. Int Urol Nephrol 1990: 22: 181–187. 12. USALAN C, ERDEM Y, CAGLAR M, et al. Effect of enalapril on exaggerated erythropoietin response to phlebotomy in erythrocytosic renal transplant patients. Nephrol Dial Transplant 1998: 13: 2884–2889. 13. FRIMAN S, NYBERG G, BLOHME I. Erythrocytosis after renal transplantation; treatment by removal of the native kidneys. Nephrol Dial Transplant 1990: 5: 969–973. 14. GASTON RS, JULIAN BA, CURTIS JJ. Posttransplant erythrocytosis: An enigma revisited. Am J Kidney Dis 1994: 24: 1–11.
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Almonte et al. 15. ESPOSITO R, GIAMMARINO A, DE BLASIO A, et al. Ramipril in post-renal transplant erythrocytosis. J Nephrol 2007: 20: 57– 62. 16. HIREMATH S, FERGUSSON D, DOUCETTE S, MULAY AV, KNOLL GA. Renin angiotensin system blockade in kidney transplantation: A systematic review of the evidence. Am J Transplant 2007: 7: 2350–2360. 17. KEOHANE C, MCMULLIN MF, HARRISON C. The diagnosis and management of erythrocytosis. BMJ 2013: 347: f6667. 18. SCHWARTZ GJ, BRION LP, SPITZER A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987: 34: 571–590. 19. SINNASSAMY P, O’REGAN S. Polycythemia in pediatric renal transplantation. Clin Nephrol 1987: 27: 242–244. 20. KRULL F, BOKENKAMP A, OFFNER G. Post-renal transplant erythrocytosis in a child. Pediatr Nephrol 1992: 6: 192–193. 21. GLICKLICH D, KAPOIAN T, MIAN H, GILMAN J, TELLIS V, CROIZAT H. Effects of erythropoietin, angiotensin II, and angiotensin-converting enzyme inhibitor on erythroid precursors in patients with posttransplantation erythrocytosis. Transplantation 1999: 68: 62–66. 22. KIYKIM AA, GENCTOY G, HOROZ M, et al. Serum stem cell factor level in renal transplant recipients with posttransplant erythrocytosis. Artif Organs 2009: 33: 1086–1090. 23. WICKRE CG, NORMAN DJ, BENNISON A, BARRY JM, BENNETT WM. Postrenal transplant erythrocytosis: A review of 53 patients. Kidney Int 1983: 23: 731–737. 24. BAKRIS GL, SAUTER ER, HUSSEY JL, FISHER JW, GABER AO, WINSETT R. Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N Engl J Med 1990: 323: 86–90. 25. KIM YC, MUNGUNSUKH O, MCCART EA, ROEHRICH PJ, YEE DK, DAY RM. Mechanism of erythropoietin regulation by angiotensin II. Mol Pharmacol 2014: 85: 898–908.
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26. VLAHAKOS DV, MARATHIAS KP, MADIAS NE. The role of the renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis 2010: 56: 558–565. 27. RIEDER MJ, TAYLOR SL, CLARK AG, NICKERSON DA. Sequence variation in the human angiotensin converting enzyme. Nat Genet 1999: 22: 59–62. 28. HAAS M, YILMAZ N, SCHMIDT A, et al. Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease. Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease. Kidney Blood Press Res 1998: 21: 66–69. 29. RUGGENENTI P, BETTINAGLIO P, PINARES F, REMUZZI G. Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies. Clin J Am Soc Nephrol 2008: 3: 1511–1525. 30. MICOZKADIOGLU H, COLAK T, AKCAY A, et al. Angiotensinconverting enzyme gene polymorphism significantly affects renal posttransplantation erythrocytosis. Transplant Proc 2004: 36: 161–163. 31. KEDZIERSKA K, KABAT-KOPERSKA J, SAFRANOW K, et al. Influence of angiotensin I-converting enzyme polymorphism on development of post-transplant erythrocytosis in renal graft recipients. Clin Transplant 2008: 22: 156–161. 32. KUJAWA-SZEWIECZEK A, KOLONKO A, KOCIERZ M, et al. Association between gene polymorphisms of the components of the renin-angiotensin-aldosteron system, graft function, and the prevalence of hypertension, anemia, and erythrocytosis after kidney transplantation. Transplant Proc 2011: 43: 2957–2963. 33. SAYED-TABATABAEI FA, OOSTRA BA, ISAACS A, VAN DUIJN CM, WITTEMAN JC. ACE polymorphisms. Circ Res 2006: 98: 1123– 1133. 34. WONG G, LIM WH, CHAPMAN JR. Questioning the myth: Benefits of renin-angiotensin system blockade in kidney transplant recipients. Transplantation 2014: 97: 271–272.
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12406
Post-renal transplant erythrocytosis: A case report Almonte M, Velasquez-Jones L, Valverde S, Carleton B, Medeiros M. (2015) Post-renal transplant erythrocytosis: A case report. Pediatr Transplant, 19: E7–E10. DOI: 10.1111/petr.12406.
Mavel Almonte1, Luis Velasquez-Jones1, Saul Valverde1, Bruce Carleton2,3,4 and Mara Medeiros2,3,4,5 Departamento de Nefrologıa, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico, 2 Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, BC, Canada, 3 Division of Translational Therapeutics, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada, 4Child & Family Research Institute, Vancouver, BC, Canada, 5 Laboratorio de Investigacion en Nefrologıa y Metabolismo Mineral, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico 1
Abstract: PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14-yr-old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post-transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post-transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post-transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.
Key words: erythrocytosis – kidney transplantation – immunosuppression – enalapril – erythropoietin Mara Medeiros, Laboratorio de Investigacion en Nefrologıa y Metabolismo Mineral, Hospital Infantil de Mexico Federico Gomez, Dr. Marquez 162 Colonia Doctores, 06720 Mexico DF, Mexico Tel.: 52 55-5228-9917 Ext-4410 Fax: 52 55-5761-8974 E-mail: [email protected] Accepted for publication 29 October 2014
Background
Patients with chronic kidney disease often have anemia related to reduction in EPO production, iron, and nutrient deficiency, blood loss during hemodialysis, chronic inflammation, EPO resistance, among other causes (1). EPO secretion after successful kidney transplant has a peak within three days, reticulocytosis begins at one wk, anemia correction is expected within 8– 10 wk, and EPO levels decline to normal values over the next 4–8 months (2, 3). Anemia post-renal transplant shows a biphasic pattern with a high incidence in the early posttransplant period, improves during the first year, and slowly increases its prevalence over time, being related to the loss of graft function. In
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CMV, cytomegalovirus; EPO, erythropoietin; GFR, glomerular filtration rate; Hb, hemoglobin; Ht, hematocrit; PTE, posttransplant erythrocytosis; RAS, renin–angiotensin system.
children, the prevalence of anemia has been reported as 85% at one-month post-transplant and 68% at 12 months, and it increases to 82% at 60 months post-transplant (4). A subset of patients can develop PTE, defined as a persistently elevated Ht >51% or an Hb level >17 g/dL after renal transplantation (2, 5), its prevalence has been reported between 2.5 and 22%, with a clear decline over the past decade, probably due to (i) the increase in use of ACEI or ARBs, (ii) the change in immunosuppressive agents, with cyclosporine being substituted by tacrolimus, and the more intensive use of antiproliferatives (mofetil mycophenolate instead of azathioprine) (6–8). Known risk factors for PTE include male gender, presence of native kidneys with adequate erythropoiesis prior to transplantation, renal artery stenosis, and smoking (1, 6, 7). The type of immunosuppression may also be a risk factor. After the introduction of cyclosporine, an increase in the prevalence of PTE was reported in 1988 by Tatman and coworkers, 4% in E7
Almonte et al.
patients treated with azathioprine/prednisolone and 11% in cyclosporine/prednisolone-treated patients (9). Retrospective studies also mention that PTE is more frequent in cyclosporinetreated patients (10, 11), but these studies did not find statistically significant differences, perhaps due to the small sample sizes studied. Post-transplant erythrocytosis may increase the risk of thromboembolic events and should be treated to reduce Hb values below 17.5 g/dL. Spontaneous resolution can occur, and other proposed treatments have been phlebotomy (12), native kidneys nephrectomy (13), and ACEI or ARB pharmacotherapy (14–16). When managing a patient with erythrocytosis, a diagnostic pathway should be established to ensure an appropriate treatment plan is developed. The condition should be verified by a repeat blood cell count and a detailed clinical history. Patient examination should include questions aimed at determining whether any change in lifestyle (smoking, alcohol) or drug use coincides with packed cell volume increase. Other medical comorbidities such as cyanotic heart disease, lung disease, and renal artery stenosis should also be considered (17). Case report
We report the case of a 14-yr-old girl with chronic kidney disease of unknown etiology. She was managed with peritoneal dialysis for three months prior to receiving a kidney transplant from a non-related living donor in October 2011, conserving her native kidneys. The pretransplant Hb level was 11.1 g/dL and Ht 32.2%; prior to transplant, she received treatment with recombinant erythropoietin, 276 units/kg/wk for 12 wk. The immunosuppressive regimen consisted of induction with anti-CD25 antibodies and triple therapy with mycophenolate mofetil 683 mg/m2/ day, tacrolimus 0.08 mg/kg/day (to attain trough levels between 5 and 10 ng/mL), three methylprednisolone pulses 10 mg/kg/day, and then, prednisone tapered to 0.1 mg/kg/day at three months post-transplant. She was also treated for high blood pressure with amlodipine 0.13 mg/ kg/day and prophylaxis with ganciclovir IV for two weeks followed by oral valganciclovir during six months because she was high risk for CMV infection (seronegative). Twelve months after her transplant, she had an Hb level of 17.5 g/dL and Ht 53%, which exceeded the normal range but without symptoms (Fig. 1). Serum creatinine was 1 mg/dL, GFR by Schwartz formula (18), 86.9 mL/min/ E8
1.73 m², tacrolimus level was 4.1 ng/dL. Medical history reported smoking one cigarette per day, as well as passive smoking since October 2012. Pulse oximetry (SpO2) was 98%, and her echocardiogram showed a structurally normal heart. Ultrasound of the renal graft was normal, as was chest X-ray. EPO serum levels were 11.8 mIU/ mL (reference interval 2.0–14.2). She was evaluated by the hematology department, confirming post-transplant erythrocytosis of unknown origin. She had no spontaneous improvement, and at 19 months post-transplant, we decided to start treatment with enalapril 0.13 mg/kg/day due to an Hb of 17.5 g/dL and Ht 53%. Six months later, the hemoglobin was reduced to 15 g/dL and hematocrit to 44.5% (Fig. 1). Serum creatinine increased slightly to 1.2 mg/dL (GFR 74.25 mL/min/1.73 m2 BSA). Discussion
There are few reports of PTE cases in renal transplant children. Sinnassamy et al. described five patients in 1987, and they related the PTE to renal stenosis in three of them (19). Krull et al. (20) in 1992 reported a seven-yr-old patient who was unsuccessfully treated with a three-month course of theophylline and ended up with phlebotomy twice a week to lower the Hb; in the same case report, they mention having observed PTE in 6/186 pediatric patients transplanted before age 16 (3.2%). The overall PTE incidence has declined in adult patients in the past decade (8). PTE appears to result from the combined trophic effect of multiple and interrelated erythropoietic factors, including erythropoietin, angiotensin II, androgens, and IGF-1. Inadequate suppression of EPO production and
Fig. 1. Hemoglobin levels pre- and post-transplant. Enalapril was started at 19 months post-transplant (arrow).
Post-renal transplant erythrocitosis
increase in serum-soluble steam cell factor have been observed in patients with PTE (21, 22). Our adolescent patient had a steady increase in hemoglobin levels since the sixth-month posttransplant, reaching the Hb threshold of 17 g/dL for PTE diagnosis at 12 months post-transplant; the only risk factor found was smoking, EPO levels were normal, and she required EPO therapy before the renal transplant. Even though PTE can resolve spontaneously in some patients, the high blood viscosity carries with it the risk of thromboembolic and cardiovascular complications (17, 23). Among the suggested treatments are avoiding dehydration (17), phlebotomy (17), removal of the native kidneys (13), inactivation of RAS (14), and the use of adenosine receptor antagonists such as theophylline, as it reduces EPO levels (24). Inactivation of RAS by an ACE inhibitor or an angiotensin II AT1 receptor antagonist represents the most effective, safe, and well-tolerated therapeutic modality, (1) but the duration of treatment has not been specified. Angiotensin II is a growth factor for erythroid progenitors and it also regulates EPO production via angiotensin II type 1 receptor-mediated EGR1 activation by p21RAS–mitogen-activated protein kinase/ERK kinase ERK1/2 (25, 26). The ACE insertion/deletion (I/D) gene polymorphism, defined as the insertion of 287 bp in intron 16 (rs1799752, rs4340, rs13447447, or rs4646994), has been studied in several diseases (27), and the deletion allele is associated with a 65% increase in activity of the enzyme. The response to ACE inhibitors for treating proteinuric nephropathies varies depending on the I/D genotype (28, 29). There are conflicting results relating this polymorphism to PTE. Micozkadioglu et al. (30) reported that PTE was more frequent in those carrying the D/ D allele vs. the I/I allele. Kedzierska found no difference in genotype frequency between patients with or without PTE, but the D allele increased the risk for PTE (31). Kujawa-Szewieczek et al. (32) did not find any association between ACE polymorphism and the risk for PTE. Differences in the results among studies could be due to small sample sizes, genotypic and phenotypic misclassifications, and the interaction with other genes or environmental factors that have not been considered (33). As well, patients in these studies received different immunosuppressive regimens whereby the reported frequency of PTE itself is different. PTE could be an adverse drug reaction, but it is difficult to relate it to a particular drug when multiple drugs are used concomitantly.
The case presented was successfully treated with enalapril, but a reduction in GFR was observed (34). Funding M. Medeiros received a CONACYT grant 205627.
Conflict of interests
None. Authors’ contributions M. Almonte collected clinical data and helped in drafting the manuscript; L. Vel asquez-Jones and S. Valverde revised clinical data and drafted the manuscript; B. Carleton and M. Medeiros revised clinical data, analysis of the literature, and drafted the manuscript.
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