|Year : 2018 | Volume
| Issue : 3 | Page : 182-186
Erythrocytosis in renal transplant recipients: A single-center experience
Dhanasekaran Rajasekar, Jayachandran Dhanapriya, Thanigachalam Dineshkumar, Ramanathan Sakthirajan, Thopalan Balasubramaniyan, Natarajan Gopalakrishnan, Srinivasan Arivazhagan
Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Web Publication||28-Sep-2018|
Dr. Srinivasan Arivazhagan
Madras Medical College, Rajiv Gandhi Government General Hospital, Institute of Nephrology, Chennai - 600 003, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Posttransplant erythrocytosis (PTE) is defined as persistently elevated hemoglobin (Hb) >17 g/dl and or PCV >51% in renal transplant recipients. The incidence of PTE varies from 8% to 22%, with occasional life-threating thromboembolic complications. Our aim was to study the prevalence, risk factors, course, and complications of PTE. Materials and Methods: We conducted a cross-sectional descriptive study in 327 renal transplant recipients. Patients with Hb >17 g/dl were considered as PTE group, and others were considered as non-PTE group. The pattern of Hb, serum creatinine, mean arterial pressure (MAP) change, and requirement of anti-hypertensive medications was noted. Complications and their management were noted. Results: PTE was diagnosed in 51 (15.5%) patients with the median time of onset at 8 (95% confidence interval: 6–10) months after transplantation. During PTE, the mean highest documented Hb was 18.68 ± 0.73 g/dl. Mean Hb change had significant positive (r = 0.8493; P = 0.0156) correlation with mean MAP change. The dose of antihypertensive medications was increased more within 6 months of PTE diagnosis and decreased thereafter significantly. Thrombotic complications were observed in 5 (10.6%) patients. PTE was treated with enalapril in 35 (72.5%) patients and combination with phlebotomy in 11 (21.6%). Around 30 (58.8%) patients continued enalapril therapy to maintain the Hb. Conclusion: PTE was observed in 15.5% of renal allograft recipients. Hb change was temporally related to blood pressure in PTE patients. Both erythrocytosis and hypertension responded well to angiotensin-converting enzyme inhibitor.
Keywords: Enalapril, erythrocytosis, hemoglobin, posttransplant erythrocytosis, renal transplantation
|How to cite this article:|
Rajasekar D, Dhanapriya J, Dineshkumar T, Sakthirajan R, Balasubramaniyan T, Gopalakrishnan N, Arivazhagan S. Erythrocytosis in renal transplant recipients: A single-center experience. Indian J Transplant 2018;12:182-6
|How to cite this URL:|
Rajasekar D, Dhanapriya J, Dineshkumar T, Sakthirajan R, Balasubramaniyan T, Gopalakrishnan N, Arivazhagan S. Erythrocytosis in renal transplant recipients: A single-center experience. Indian J Transplant [serial online] 2018 [cited 2019 Feb 20];12:182-6. Available from: http://www.ijtonline.in/text.asp?2018/12/3/182/242433
| Introduction|| |
Posttransplant erythrocytosis (PTE) was first recognized by Nies et al. in renal transplant recipients in 1965. PTE is defined by the American Society of Transplantation as persistently elevated hemoglobin (Hb) >17 g/dl and or hematocrit >51% in renal transplant recipients, whereas European guidelines recommend to start treatment for erythrocytosis when PCV >52% in men and >49% in women. The important risk factors for PTE include male gender, preserved glomerular filtration rate, and retained native kidneys. Other risk factors include transplant renal artery stenosis (TRAS), hydronephrosis, autosomal dominant polycystic disease, high pretransplant Hb, low erythropoietin (EPO) requirement, short duration of maintenance dialysis, diabetes, smoking, immunosuppressive medications especially cyclosporine and rejection-free graft., The management includes enalapril, theophylline, and phlebotomy.
| Materials and Methods|| |
We conducted a cross-sectional descriptive study in 327 renal transplant recipients on regular follow-up in our institution. PTE was diagnosed when patients Hb was ≥17 g/dl and or PCV ≥51% on two occasions with 1-month interval irrespective of gender. Those patients Hb level ≥17 g/dl were included as PTE group and others as non-PTE group. All patient records were studied retrospectively for pretransplant Hb, native kidney disease, recipient and donor baseline characteristics, immunosuppression medications, rejection episodes, and new onset diabetes after transplantation (NODAT) were analyzed. During PTE, the pattern of Hb, serum creatinine, and mean arterial pressure (MAP) change along with requirement of anti-hypertensive medications and dosage changes were noted. Complications related to PTE and their management were noted. Those patients with estimated glomerular filtration rate <30 ml/min/1.73 m2, transplanted within 6 months and obstructive airway diseases were excluded from the study.
Statistical analysis was done with Medcalc statistical software Ver. 220.127.116.11 (Medcalc software company, Ostend, Belgium) and online statistical calculator (http://www.socscistatistics.com/). Data were presented as mean, median, standard deviation, and proportions. Test of significance was done by Chi-square test (2 × 2, 5 × 5 contingency table) for categorical variables and t-test/ANOVA test for continuous variables. The Pearson correlation coefficient (r) was used to test the correlation between the two variables. P < 0.05 was considered statistically significant.
| Results|| |
PTE was diagnosed in 51 (15.5%) patients of 327 posttransplant recipients with a mean follow-up of 52.9 ± 44.8 months. Baseline characteristics of PTE patients were analyzed with non-PTE patients [Table 1]. Two patients received second renal transplant. None of them were smokers. Younger age, male gender, high pretransplant Hb, and NODAT were identified as significant risk factors of PTE in univariate analysis.
|Table 1: Baseline characteristics of posttransplant erythrocytosis and nonposttransplant erythrocytosis cohorts|
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Pretransplant Hb was positively correlated with peak Hb of PTE patients (r = 0.2384; P = 0.0990), but not statistically significant. During PTE, the average high documented Hb was 18.68 ± 0.73 g/dl. The median time of onset of PTE was 8 (95% confidence interval [CI]: 6–10) months. PTE was diagnosed as early as 2 months up to 36 months' posttransplant. The median duration of PTE was 6.3 (95% CI: 5.6–8.2) months. In two patients, PTE recovered in 40 days whereas in three patients PTE was lasting for >3 years and required continuous enalapril therapy.
[Table 2] shows the relationship between mean Hb, MAP, and serum creatinine over PTE course. [Figure 1] shows the mean Hb change over the course of PTE was positively (r: 0.8493; p: 0.0156) correlated with MAP change which was statistically significant. Graft function was maintained throughout the course. The dose of antihypertensive medications was increased more within 6 months of PTE and decreased thereafter significantly. The enalapril requirement [Table 2] was increased significantly and the dose of enalapril was negatively (r = 0.7657; P = 0.5863) correlated with MAP of PTE course.
|Table 2: Changing parameters relation to posttransplant erythrocytosis course|
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|Figure 1: Correlation between mean hemoglobin and mean arterial pressure over the posttransplant erythrocytosis|
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Thrombotic complications were observed in 5 (10.6%) of PTE patients, involving lower limb deep vein thrombosis (DVT) in 2 (3.9%) and arteriovenous fistula (AVF) thrombosis in 3 (5.9%) patients. Other complications were transient ischemic attack 1 (1.9%), nonhealing lower limb ulcer 1 (1.9%), and headache and tinnitus 4 (7.8%). Brachiocephalic fistula was thrombosed within 3 months onset of PTE of two patients which was extended up to subclavian vein. Both patients were treated with phlebotomy along with heparin followed by oral anticoagulation for 6 months.
[Table 3] shows the management of PTE patients, around 35 (72.5%) of PTE patients were treated with enalapril alone. Combination of enalapril and phlebotomy was required in 11 (21.6%) patients. Without any form of treatment, PTE was resolved in 3 (5.9%) patients. More than one phlebotomy required in 2 (5.8%) patients. Phlebotomy required population were having high mean Hb (19.08 ± 0.88 g/dl) as well as high mean duration of PTE (19.47 ± 14.61 months) compared to other population which was statistically significant.
Enalapril related rise of serum creatinine >30% from baseline was observed in 3 (6.8%) patients. Symptomatic hypotension warranted the discontinuation of enalapril in 6 (13.6%) patients. PTE resolved completely and enalapril was not required in 16 (31.3%) patients. Around 30 (58.8%) patients continued enalapril therapy to maintain the normal Hb. Even with enalapril therapy, Hb was still high in 5 (9.8%) patients.
| Discussion|| |
PTE is a frequent unnotified complication in the posttransplant period and does not have any impact on graft function. In the present study, PTE was observed in 15.5% of posttransplant recipients, which is comparable to western studies,,,, but higher than the published Indian study. Good graft function is the single most definitive risk factor for PTE in all observations., In our study, all the patients maintaining good graft function (mean creatinine = 1.15 ± 0.26 mg/dl) during the onset of PTE. Blood group, native kidney disease, donor age and gender, hepatitis C virus status, living or deceased donation, rejection, and immunosuppression medications did not have any impact on the PTE occurrence in our study. The mean pretransplant Hb (8.58 ± 1.41 g/dl) was significantly associated with PTE occurrence compared to non-PTE group and also positively correlated with peak Hb. We did not analyze the pretransplant requirement of EPO which was low in PTE groups in other studies. The second transplant is a risk factor for PTE, in our study also the second transplant was done in two PTE patients. We identified younger age, male gender, and NODAT were significant risk factors for PTE in our patients. Steroids could lead to proliferation of erythroid stem cells. Calcineurin inhibitors (CNIs) augment EPO production through afferent arteriolar constriction and stimulation of erythroid precursors by inhibiting the lymphokine synthesis which may directly suppress primitive red cell precursors. Steroids and CNIs contribute to NODAT which may indirectly associated with PTE.
In our study, the median time of onset of PTE was 8 months after transplantation, which is comparable to other studies also., It was explained that the excellent graft function was achieved in the 1st year of transplantation and increased the sensitivity of EPO receptors in the 1st year of transplantation. Androgen increases erythropoiesis [Figure 2] directly by stimulating erythroid progenitors as well as indirectly by stimulating EPO release, males are more prone to develop PTE.
|Figure 2: Pathogenesis of posttransplant erythrocytosis (IGF-1: Insulin-like growth factor; IGFBP: Insulin-like growth factor Binding protein; ACE: angiotensin converting enzyme; Ac-SDKP: N-acetyl-seryl-aspartyl-lysyl-proline)|
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The median duration of PTE was 6.3 months in our study. During PTE, the mean peak, Hb was 18.68 ± 0.73 g/dl, which was treated with specific treatment. The peak Hb was positively correlated with duration of PTE. Erythrocytosis increases blood pressure by increasing the blood volume and viscosity associated with increased vascular resistance can lead to worsening of hypertension and demands the need of increase in antihypertensive medications. Furthermore, elevated RAAS can lead to erythrocytosis as well as hypertension. In our PTE group, the increasing mean Hb during the course was positively correlated significantly with the corresponding mean MAP. The persons required of anti-hypertensive medications as well as the dose of medications also increased significantly in the initial 3 months of PTE. The recent increase in the MAP with erythrocytosis, always rule out TRAS which was an established risk factor for PTE. However, in our study, five patients with TRAS never had erythrocytosis. No one had hydronephrosis of graft in our PTE group which was one of the risk factors for PTE.
The pathogenesis [Figure 2] is implicated by various factors such as the absolute or relative rise of EPO, probably by the native kidneys, increased sensitivity of erythroid precursors for EPO mediated by the increase in IGF-1, IGF-1 Binding Protein-3, and absent uremic toxins. Angiotensin-II (AT-II) activates erythroid progenitors directly and or indirectly by direct EPO release and HIF release to augment EPO production. Angiotensin-converting enzyme (ACE) increases erythropoiesis by metabolizing N-acetyl-seryl-aspartyl-lysyl-proline which is a natural inhibitor of erythroid progenitors.,
Symptoms of PTE occur because of increased viscosity and increased blood volume which include headache, tinnitus, blurring of vision, fatigue, hypertension, and thromboembolic episodes. Kidney disease improving global outcomes recommends starting treatment when Hb >17 g/dl or PCV >51%. Spontaneous resolution can occur in 20% and likely indicates worsening of allograft function. ACE inhibitors or AT-II blockers are the initial drug of choice for PTE. Phlebotomy should be done in pregnant or symptomatic PTE patients. There is no consensus regarding the Hb level to do phlebotomy in asymptomatic PTE patients, still commonly practiced if Hb is >18 g/dl in most centers. Theophylline (Adenosine A2 receptor antagonist) and native nephrectomy are also suggested to treat resistant PTE.,
Thrombotic complications were observed in 10.6% of patients, which was comparable to western studies,, but many observations did not have thrombotic complications. In our study, lower limb DVT and brachiocephalic fistula thrombosis were commonly observed within 6 months onset of PTE and both complications were treated with heparin, oral anticoagulants, enalapril, and phlebotomy. Two patients had thrombosis of brachiocephalic fistula which extended up to the subclavian vein with severe upper limb pain requiring hospitalization. No life-threatening complications were observed during PTE.
Most of the PTE patients (72.5%) were treated with enalapril alone. Enalapril decreased the mean Hb and the duration of PTE significantly compared to conservative treatment. All patients with thrombotic complications were treated with phlebotomy. Other patients were treated with phlebotomy while Hb raised >19 g/dl. Those patients who required phlebotomy (21.6%) were having a more protracted course with a long duration of PTE with high Hb and thrombotic complications compared to enalapril alone treated patients. In enalapril requiring patients, the dose was significantly increased after the 1st month of PTE. The mean enalapril dosage was negative correlated with MAP response during PTE indicates enalapril can be considered as the best anti-hypertensive medication to treat hypertension as well as to reduce Hb during the PTE course., Around 13.6% of patients developed symptomatic hypotension and required to discontinue enalapril. This can be explained by increased RAAS-related rise of BP during erythrocytosis as well as a reduction in RBC mass with enalapril therapy. Most of the PTE patients (58.8%) required enalapril to maintain the normal Hb.
| Conclusion|| |
During PTE, blood pressure and the requirement of antihypertensive medications were increased with raising Hb. Both erythrocytosis and hypertension responded well to ACE inhibitor. Hb change was temporally related to blood pressure. AVF thrombosis was a unique complication in PTE population compared to erythrocytosis in general population. Phlebotomy required in all symptomatic patients, but in asymptomatic patients, the Hb level to do phlebotomy must be defined.
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Conflicts of interest
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| References|| |
Nies BA, Cohn R, Schrier SL. Erythremia after renal transplantation. N
Engl J Med 1965;273:785-8.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
Vlahakos DV, Marathias KP, Agroyannis B, Madias NE. Posttransplant erythrocytosis. Kidney Int 2003;63:1187-94.
Hijazi F, Zand M, Demme R. Long-term management of post-transplant anemia and erythrocytosis. Graft 2001;4:307-15.
Kiberd BA. Post-transplant erythrocytosis: A disappearing phenomenon? Clin Transplant 2009;23:800-6.
Gaston RS, Julian BA, Curtis JJ. Posttransplant erythrocytosis: An enigma revisited. Am J Kidney Dis 1994;24:1-11.
Singh V, Sud K, Mittal BR, Kohli HS, Gupta KL, Sakhuja V. Postrenal transplant erythrocytosis: Risk factors and effectiveness of angiotensin receptor antagonists. Transplant Proc 2002;34:3191-2.
Einollahi B, Lessan-Pezeshki M, Nafar M, Pour-Reza-Gholi F, Firouzan A, Farhangi F, et al.
Erythrocytosis after renal transplantation: Review of 101 cases. Transplant Proc 2005;37:3101-2.
Qunibi WY, Barri Y, Devol E, al-Furayh O, Sheth K, Taher S. Factors predictive of post-transplant erythrocytosis. Kidney Int 1991;40:1153-9.
Danovitch GM, Jamgotchian NJ, Eggena PH, Paul W, Barrett JD, Wilkinson A, et al.
Angiotensin-converting enzyme inhibition in the treatment of renal transplant erythrocytosis. Clinical experience and observation of mechanism. Transplantation 1995;60:132-7.
Besarab A, Caro J, Jarrell B, Burke J, Francos G, Mallon E, et al.
Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis. Transplantation 1985;40:624-31.
Abdelrahman M, Rafi A, Ghacha R, Qayyum T, Karkar A. Post-transplant erythrocytosis: A review of 47 renal transplant recipients. Saudi J Kidney Dis Transpl 2004;15:433-9.
] [Full text]
Basri N, Gendo MZ, Haider R, Abdullah KA, Hassan A, Shaheen FA, et al.
Posttransplant erythrocytosis in renal transplant recipients at Jeddah Kidney Center, Kingdom of Saudi Arabia. Exp Clin Transplant 2007;5:607-9.
Chan PC, Wei DC, Tam SC, Chan FL, Yeung WC, Cheng IK. Post-transplant erythrocytosis: Role of erythropoietin and male sex hormones. Nephrol Dial Transplant 1992;7:137-42.
Spieker C, Barenbrock M, Tepel M, Zidek W. Long-term effect on hypertension of phlebotomy in posttransplant erythrocytosis. Transplant Proc 1992;24:2742-4.
Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 1991;17:199-205.
Khedr E, Abdelwhab S, El-Sharkawy M, Ali M, El-Saed K, Dawoud D. Post-kidney transplantation erythrocytosis and its relationship to renal artery stenosis, IGF-1, and its binding protein 3 (IGFBP-3). Dial Transplant 2009;38:166-74.
Gupta M, Miller BA, Ahsan N, Ulsh PJ, Zhang MY, Cheung JY, et al.
Expression of angiotensin II type I receptor on erythroid progenitors of patients with post transplant erythrocytosis. Transplantation 2000;70:1188-94.
Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, et al.
Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest 1996;97:839-44.
Mazzali M, Filho GA. Use of aminophylline and enalapril in posttransplant polycythemia. Transplantation 1998;65:1461-4.
Todeschini P, La Manna G, Dalmastri V, Feliciangeli G, Cuna V, Montanari M, et al.
Incidence of late deep venous thrombosis among renal transplant patients. Transplant Proc 2013;45:2666-8.
Glicklich D, Burris L, Urban A, Tellis V, Greenstein S, Schechner R, et al.
Angiotensin-converting enzyme inhibition induces apoptosis in erythroid precursors and affects insulin-like growth factor-1 in posttransplantation erythrocytosis. J Am Soc Nephrol 2001;12:1958-64.
Yildiz A, Cine N, Akkaya V, Sahin S, Ismailoğlu V, Türk S, et al
. Comparison of the effects of enalapril and losartan on posttransplantation erythrocytosis in renal transplant recipients: prospective randomized study. Transplantation 2001;72:542-4.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]