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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 3  |  Page : 371-377
Factors Predisposing to Post-Renal Transplant Erythrocytosis: A Retrospective Study


1 Department of Renal Transplantation, University Hospital, SFAX, Tunisia
2 Laboratory of Pharmacology, University Hospital, SFAX, Tunisia

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   Abstract 

A retrospective study was conducted on 143 consecutive renal transplant recipients who had a functioning graft for three months or longer, to evaluate the prevalence of post-transplant erythrocytosis (PTE) and its potential risk factors. True PTE was defined as hematocrit (Ht) above 52% and hemoglobin (Hb) above 18 g/dl in males, and Ht above 50% and Hb above 17g /dl in females. A total of 31 patients (21.6%) developed PTE; none had any evidence of polycythemia vera (PV), or secondary polycythemia due to reduced arterial oxygen, kidney or hepatic tumors, or relative erythrocytosis due to a decrease in plasma volume by overuse of diuretics. Thirty-one non-polycythemic patients (Hb 12.9 +-1.6 g/dl) matched for sex, age and renal function were used as case controls. PTE was more common in males (p= 0.043). The majority of our patients developed PTE within the first year post-transplantation and all had excellent renal function at the time of diagnosis. Also, PTE was found to be related to duration on dialysis prior to transplantation (p= 0.0013) and acute rejection (p= 0.0031).

Keywords: Kidney, Transplantation, Erythrocytosis

How to cite this article:
Charfeddine K, Zaghdane S, Yaich S, Hakim A, Hachicha J. Factors Predisposing to Post-Renal Transplant Erythrocytosis: A Retrospective Study. Saudi J Kidney Dis Transpl 2008;19:371-7

How to cite this URL:
Charfeddine K, Zaghdane S, Yaich S, Hakim A, Hachicha J. Factors Predisposing to Post-Renal Transplant Erythrocytosis: A Retrospective Study. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Oct 14];19:371-7. Available from: http://www.sjkdt.org/text.asp?2008/19/3/371/40495

   Introduction Top


Post-transplant erythrocytosis (PTE) is a relatively common phenomenon associated with an increased risk of thromboembolism. Many underlying conditions have been linked to PTE, including acute and chronic graft rejection, [1],[2] transplant artery stenosis, [3] smoking and diabetesand more recently, the type and dose of immunosuppressive therapy, the extent of allograft function and the duration on dialysis. [5],[6] Its etiology re≠mains unclear and the most frequently sug≠gested causative factors are still a matter of controversy. Most published studies have included both patients with true erythrocy≠tosis and those with relative erythrocytosis due to a decrease in plasma volume. We have therefore conducted a retrospective study on the prevalence of true erythrocytosis after renal transplantation and looked for predis≠posing factors by comparing several varia≠bles in the PTE patients and a matched control group.


   Patients and Methods Top


A total of 143 renal transplant recipients who received a kidney between April 1994 and December 2004, with a graft that was functioning for longer than three months, were retrospectively studied until 31 Decem≠ber 2004. All patients were given prophy≠lactic therapy with anti-lymphocyte (ALG) anti-thymocyte globuline (ATG) for 10-12 days after transplantation. Maintenance immu≠nosuppression consisted of either three-drug therapy (that is, prednisone-cyclosporine≠azathioprine or prednisone-cyclosporine-my≠cophenolate (mofetil) or double therapy with prednisone-cyclosporine. Rejection episodes were treated with high dose of methyl≠prednisolone or OKT3 (muromonab-CD3 Janssen Cilag). Erythrocytosis was defined as hematocrit (Ht) above 52% and hemog≠lobin (Hb) above 18 g/dl in males, and Ht above 50% and Hb above17 g/dl in females. The control group consisted of 31 non≠polycythemic renal transplant recipients (mean Hb, 12.5 +-1.6 g/dl) who were matched for sex, age and serum creatinine levels.

Potential risk factors

The variables compared between the poly≠cythemic and control groups were native kidney diseases, proven in 24 PTE and 20 controls, nephrectomy (1 or 2) of the native kidneys, duration on dialysis (months), number of pre-transplant trans-fusions, treatment with recombinant human erythropoitein (rHuEPO) prior to transplantation, pre-transplant Hb, degree of HLA matching, acute rejection epi≠sodes, immunosuppressive therapy, iron supple≠mentation, post-transplant hypertension, treat≠ment with angiotensin converting enzyme inhibitors (ACEI) and history of smoking. Transplant artery stenosis was looked- for by colour doppler ultrasound in all patients. None of the patients had thrombocytosis, leuko≠cytosis or spleno-megaly, thus ruling out a diagnosis of policythemia vera (PV). Arterial blood gases were normal in all policy≠ themic patients.

Statistical analysis

The data are expressed as mean Ī SD and analyzed using the chi square test, Fischer test and Mann-Whitney tests.


   Results Top


True erythrocytosis developed in 31 of the 143 patients at three to 60 months post-transplantation giving a prevalence of 20.6%. [Table - 1] lists the hematology values in the PTE and control groups. PTE occurred early after transplantation and was more common in males (90%). It occurred within the first year in the majority of patients (mean: 11.3 +- 9.8 months). The peak values for Hb and Ht between patients with and without PTE were significantly different [Figure - 1],[Figure - 2] and renal function at the time of diagnosis of PTE was normal in most patients (mean serum creatinine, 1.2 mg/dl). [Table - 1] summarizes the pre-transplant demo≠graphic and clinical characteristics of the two groups. The mean age, gender distri≠bution, donor source and age, smoking history, pre-transplant hematocrit and transfusion, creatinine level at the time of discharge and pre-transplant hypertension history were all similar on comparing the PTE group to the non-PTE patients. The distribution of underlying renal disease in both groups was similar. The post trans≠plant clinical and biochemical charac≠teristics are summarized in [Table - 1]. There was no significant difference in degree of HLA matching, post-transplant hyper≠tension requiring treatment or renal artery stenosis. None of the normotensive patients developed PTE, while up to 40% of those who were hypertensive developed the condition. Finally, we found that PTE was significantly correlated with a short dia≠lysis duration and frequency of one or more acute rejection episodes.


   Discussion Top


Erythrocytosis following renal transplantation has been recognized since 1965. [1],[2],[5],[7] The published prevalence of PTE in kid≠ney transplant recipients ranges from 6.5 to 38.4%. [2],[5],[8] The major reason for the variation in the reported prevalence of the condition is varying definition used for diagnosis of erythrocytosis. In fact, most authors defined PTE as elevated Hb or Ht values, with the upper limits set at 16-18 g/dl and 50-55% respectively. Isotopic mea≠surements of red blood cell (RBC) mass and plasma volume, to exclude spurious erythrocytosis, were performed in few studies. Using hematocrit of more than 51% as the cut off point for erythrocytosis, Qunibi and his colleagues found 93 pa≠tients with PTE among 431 transplant re≠cipients (21%). [5] They noted three varia≠bles that were consistent predictors of PTE: serum creatinine level at onset of PTE; duration on dialysis; and double immuno≠suppressive therapy, which was associated with a higher probability of PTE than triple drug therapy (34% versus 10.4%). In some other studies, up to 30% of patients were diagnosed to have PTE. [9],[10] They have reported a correlation of PTE with rejection, transplant renal artery stenosis, hydro≠nephrosis and overuse of diuretics.

PTE is an early complication, with 74 % (23/31) of patients developing this com≠plication during the first year post trans≠plant. True erythrocytosis can be either primary, as in PV, or secondary due to concomitant disorders. These diagnoses were ruled out in all our patients.

PTE is considered erythrocytosis due to an unknown cause. In view of the different and contradictory published obser≠vations, the pathogenesis of PTE is pro≠bably multifactorial, and may vary from patient to patient, so that, general con≠clusions may be difficult to draw. Sti≠mulation of erythropoiesis after a success≠ful renal transplantation occurs earlier in polycythemic patients than in controls, leading to a more rapid correction of uremic anemia. We never used r-HuEPO during dialysis in PTE patients or con≠trols. On the other hand, polycythemic patients were given fewer transfusions before and after surgery, despite similar Hb levels. Patients who develop PTE re≠quire fewer blood transfusions while on dialysis, as reported three decades ago by Kun Yu et al. [11] More recently, Hb concen≠trations were found to be significantly lower in transplant patients pre-treated with r-HuEPO than in non-treated patients.

These finding suggest that PTE patients have a higher residual capacity for endo≠genous EPO production, leading to a lesser requirement of r-HuEPO, or that their erythroid precursors are abnormally sensitive to EPO.

PTE occurred primarily in males with good renal function. The highest serum creatinine at onset of PTE was 1.8 mg/dl and all patients retained their transplanted kidney during the follow-up period. Finally, HLA matching played no major role in our study.

The results on the influence of immu≠nosuppressive therapy on the frequency of PTE are conflicting. Some authors have found that PTE occurs more fre≠quently in cyclosporine-treated patients [2],[12],[13] and that azathioprine dose is an important factor. [12],[14],[15],[16],[17] These results have not been confirmed. All our patients were given cyclosporine; on the other hand, the proportion of polycythemic and control patients on two-drug or there-drug the≠rapy were similar. There was no relation≠ship between the dose of azathioprine and the development of erythrocytosis in our study. The other suggested causes of PTE include native kidney disease, the dura≠tion on dialysis, smoking habits and renal artery stenosis; in our study, only duration on dialysis played a significant role.

PTE is not always a transient compli≠cation. At least 16 patients (51.6%) had persistent high Hb levels one year or more after onset and five of them had thrombotic manifestations. Since 18 of 31 patients were started on ACEI at the time erythrocytosis was diagnosed, a true spon≠taneous remission rate could not be defined. However, some studies has shown that erythrocytosis quickly increased in 72% of the patients with PTE after withdrawal of ACEI. [12],[13],[14],[18]

PTE is not a benign disease. The inci≠dence of major thromboembolism may be as high as 24%. [2] It was 16.1% in our study but diagnosis of PTE was established very early and aggressive therapy with phlebotomies and/or ACEI was started.

Therapeutic phlebotomies have been pro≠posed to maintain a hematocrit of about 50% and thus minimize the risk of throm≠botic complications; but in our experience, this therapy does no completely prevent thromboembolism. Theophylline, a non≠selective adenosine antagonist has been shown to reduce RBC mass and to attenuate erythropoeitin production, but its side effects may limit its use. [18] ACEI and, more recently, an angiotensin anta≠gonist (AA2) have been used to treat PTE. In agreement with other authors, we found that ACEI therapy is safe and effective.[10],[11][,13],[15][,16],[18] These results suggest that there is a negative feedback between the EPO concentrations and the renin≠angiotensin system.

We conclude that PTE is slightly more common among our patients than the highest rate reported in the literature. This may be due in part to the hematocrit cut≠off point of 50-52% used in our analysis. In this regard, our finding are similar to the highest incidence reported by others authors who used looser criteria for defi≠ning erythrocytosis.

The majority of our patients developed PTE within the first year post-trans≠plantation, and all had excellent renal function at the time of diagnosis, a shorter duration on dialysis before transplantation and a higher frequency of acute rejection episodes.[19]

 
   References Top

1.Gharamani NL, Malek Hosseini, Rais≠ Jalali GA and al. Factors relating to posttransplant erythrocytosis in renal allograft recipients. Transplant Proc; 30(2):828-9.  Back to cited text no. 1    
2.Westermann MP, Jenkins IL, Dekker A, Kreutner A, Fisher B. Significance of erythrocytosis and increased erythro≠poeitin secretion after renal transplan≠tation. Lancet ;2:755-7.  Back to cited text no. 2    
3.Bacon BR, Rothman SA, Ricanati ES, Rashad FA. Renal artery stenosis with erythropoeitin after renal transplantation. Arch Intern Med ;140:1206-11.  Back to cited text no. 3    
4.Sumrani NB, Daskalakis P, Miles AM, and al. Erythrocytosis after renal trans≠plantation. A prospective analysis. ASAIO; 39:51.  Back to cited text no. 4    
5.Qunibi WY, Barri Y, Devol E, Al-Furayh O, Sheth K, Taher S. Factors predictive of post-transplant erythrocytosis. Kidney Int ;40:1153-9.  Back to cited text no. 5    
6.Einollahi B, Lessan-Pezeshki M, Nafar M, and al. Erythrocytosis after renal trans≠plantation: Review of 101 cases. Trans≠plant Proc ;37(7):3101-2.  Back to cited text no. 6    
7.Wickre CG, Norman DJ, Benisson A, Barry JM, Bennet WM. Post renal transplant erythrocytosis: A review of 53 patients. Kidney Int ;23:731-7.  Back to cited text no. 7    
8.Webb DB, Price KA, Hutton RD, Newcombe RG, Salaman JR, Orchard J. Polycythaemia following renal trans≠plantation: An association with azathioprine dosage? Am J Nephrol; 7:221-5.  Back to cited text no. 8    
9.Zeier M, Mandelbaum A, Ritz E. Hyper≠tension in the transplanted recipient. Nephron ;80:257-68.  Back to cited text no. 9    
10.Brox Alan G, Joy M, Hanley JA, St Louis G, Mongrain S, Gagnon RF. Erythro≠cytosis after renal transplantation repre≠sents an abnormality of insuline-like growth factor-I and its binding proteins. Transplantation; 66(8):3-8.  Back to cited text no. 10    
11.Kun-Yu W, Gibson TP, Freeman RM, Bonney WW, Fried W, DeGowin RL. Erytrocytosis after renal transplantation: Its occurrence in two recipients of kidneys from the same cadaveric donor. Arch Intern Med ;132:898-902.  Back to cited text no. 11    
12.Gruber SA, Simons RL, Najarian JS, et al. Post-transplant erythrocytosis and the risk of thromboembolic complications: Correlaton from a prospective randomized study of cylosorine versus azathioprine≠antithymocyte globulin. Clin Transpl;2:60.  Back to cited text no. 12    
13.Julian BA, Gaston RS, Barker CV, Krystal G, Diethelm AG, Curtis JJ. Erythro≠cytosis after withdrawal of enalapril in post-transplant erythrocytosis. Kidney Int; 46:1397-403.  Back to cited text no. 13    
14.Webb DB, Price KA, Huton RD, and al. Polycythaemia following renal trans≠plantation: An association with azathio≠prine dosage? Am J Nephrol; 7:221-5.  Back to cited text no. 14    
15.Glezerman I, Patel H, Glicklich D, Croisat H, Devarajan P. Angiotensin-converting enzyme inhibition induces death receptor  Back to cited text no. 15    
16.apoptotic pathways in erythroid precur≠sors following renal transplantation. Am J Nephrol; 23:195-201.  Back to cited text no. 16    
17.Ersoy A, Kahavecioglu S, Ersoy C, Gift A, Dielk K. Anemia due to losartan in hypertensive renal transplant recipients without post-ransplant erythrocytosis. Transplant Proc;37(7): 2148-50.  Back to cited text no. 17    
18.Augustine JJ, Knauss TC, Schulak JA, Bodziak KA, Siegel Ch, Hnicik DE. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant recipients. Am J Transplant; 4(12):2001-6.  Back to cited text no. 18    
19.Marilda M, Gentil A, Ives F. Use of aminophylline and enalapril in post trans≠plant polycythemia. Transplantation;65 (11):1461-4.  Back to cited text no. 19    

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Correspondence Address:
K Charfeddine
Department of Nephrology and Renal Transplantation, University Hospital, P.O. Box 288, SFAX-Jadida 3207 SFAX
Tunisia
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PMID: 18445895

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    Figures

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    Tables

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