INTRODUCTION — Posttransplant erythrocytosis (PTE) occurs in 8 to 15 percent of kidney transplant recipients and usually affects patients with well-preserved graft function [1-4]. The pathogenesis, clinical features, diagnosis, and treatment of this disorder are reviewed here. An overview of the general approach to the patient with polycythemia is presented separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)
DEFINITION — Posttransplant erythrocytosis (PTE) is defined as persistently elevated hemoglobin and hematocrit levels that occur following kidney transplantation and persist for more than six months in the absence of thrombocytosis, leukocytosis, or another potential cause of erythrocytosis [1-5]. Although the terms erythrocytosis and polycythemia are often used interchangeably, erythrocytosis is used to describe the condition of increased red blood cell mass in transplant patients.
The threshold used to define PTE is variable. Some studies have used cutoff values of hematocrit (50 to 54 percentage points) or hemoglobin (16.5 to 18 g/dL), whereas others have used a cutoff value of actual red cell mass. Some studies have used the same threshold to define PTE in both males and females, while others have used separate sex-based cutoffs [1-4,6-12]. Most clinicians use a hematocrit threshold of 51 percent (corresponding to a hemoglobin concentration of approximately 17 g/dL) for both males and females [2,6,13-20]. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Causes of absolute polycythemia'.)
EPIDEMIOLOGY — PTE occurs in 8 to 15 percent of kidney transplant recipients; a few studies have reported incidences as high as 22 percent [1-5,7]. The disparity in reported prevalence is due in part to the variably defined hematocrit thresholds used and the inclusion of transitory erythrocytosis (ie, persisting for less than six months) . Differences in immunosuppressive regimens may also contribute to disparities between centers in the reported prevalence of PTE since individual agents have variable effects on hemoglobin.
The incidence of PTE appears to be decreasing. Erythrocytosis defined as hemoglobin >17 g/dL was reported in 19 percent of those transplanted between 1993 and 1996 but only 8 percent of those transplanted between 1997 and 2005 and 7 percent of those transplanted between 2010 and 2013 [4,21]. The more widespread use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and mycophenolate in the more recently transplanted cohort are likely responsible for this trend. (See 'Treatment' below.)
RISK FACTORS — Potential risk factors associated with posttransplant erythrocytosis (PTE) include male sex, younger age, a rejection-free course, preserved glomerular filtration rate (GFR), hypertension, diuretic use, use of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and longer duration of dialysis [2,5,6,9,10,22,23]. Smoking history and diabetes have been shown to increase the risk of PTE in some [6,9], but not all, studies [4,5,11]. Almost all cases of PTE develop in transplant recipients who have retained native kidneys [5,24-27]. PTE seems to be less likely if the donor suffered from diabetes, hypertension, or cerebrovascular events .
Some patients appear to be particularly susceptible to PTE, suggesting that patient-specific factors play a role. As an example, in one report of a patient who underwent two transplants, PTE occurred after both surgeries, despite the presence of severe anemia in the intervening 12 months between transplantation of the first and second graft .
The original cause of end-stage kidney disease (ESKD) also affects the risk of PTE. Patients with polycystic kidney disease (PKD) and glomerulonephritis were more likely to develop PTE in some studies . Renal artery stenosis of the native or transplanted kidney was suggested as a risk factor for PTE in early case reports, but this has not been confirmed in subsequent studies [2,6,28,29].
PTE may be more common among recipients of simultaneous pancreas-kidney transplantation. This was suggested by a retrospective analysis of 94 simultaneous pancreas and kidney transplant recipients, 174 living-, related-donor recipients, and 53 type 1 diabetic kidney transplant recipients . Patients who received a simultaneous pancreas-kidney transplant had a higher incidence of PTE, compared with living, related kidney transplant recipients (16 versus 3 percent, respectively). There were no instances of PTE among the 53 diabetic kidney transplant recipients. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Posttransplant erythrocytosis (PTE)'.)
Risk factors for nontransplant-associated erythrocytosis, such as renal cell cancer, breast cancer, hepatocellular carcinoma, chronic obstructive pulmonary disease (COPD), cerebellar hemangiomas, uterine myomata, and pheochromocytoma, are presented elsewhere. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Causes of absolute polycythemia'.)
PATHOGENESIS — The pathogenesis of posttransplant erythrocytosis (PTE) is multifactorial and not well understood.
A number of hormonal systems and growth factors have been implicated in the pathogenesis of PTE, as discussed below.
Increased erythropoietin — Increased erythropoietin has been shown in many [24,31,32], though not all [1,13,32,33], studies. As an example, in one study, serum erythropoietin concentrations were elevated in six of seven patients with PTE .
Even among PTE patients with serum erythropoietin concentrations within normal range, the concentration may be inappropriately elevated for a given hemoglobin. In one study, the mean observed/expected serum erythropoietin ratio was elevated among 13 PTE patients compared with that of 42 kidney transplant recipients without erythrocytosis (8.6 versus 0.3, respectively) .
The demonstration of increased, or even normal, erythropoietin levels suggests that PTE may be a form of "tertiary hypererythropoietinemia," in which mechanisms that suppress erythropoietin synthesis or secretion and are normally provoked by a normal or elevated hematocrit do not function adequately [2,24].
The source of excess erythropoietin appears to be the native kidney [24,31]. This was suggested by one detailed study of three patients that demonstrated higher blood erythropoietin titers obtained by selective catheterization from the renal veins of native kidneys versus transplanted kidneys (41 versus 13 mU/mL, respectively). In one patient, erythropoietin titers and hematocrit were decreased within two weeks of bilateral native nephrectomy.
With the exception of phlebotomy, therapies that correct PTE are generally accompanied by a reduction in erythropoietin levels and/or normalization of the erythropoietin versus hematocrit relationship. (See 'Treatment' below.)
Other hematopoietic growth factors — Other hematopoietic factors, including insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding proteins, the serum-soluble stem cell factor (sSCF), and immunoglobulin A1 (IgA1), may either enhance the sensitivity to erythropoietin or directly promote erythropoiesis in patients with PTE [1,34-36]. In one study, cultured erythroid progenitors from patients with PTE were shown to have increased sensitivity to erythropoietin in vitro compared with erythroid progenitors from transplant recipients with normal hematocrits .
Increased concentrations of plasma IGF-1 and/or its major binding proteins have been demonstrated in patients with PTE compared with transplant recipients with normal hematocrits . The mechanisms underlying increased IGF-1 concentrations are not entirely clear. In vitro studies have shown an interaction between IGF-1 and angiotensin II at several levels, and clinical observations suggest that angiotenin-converting enzyme (ACE) inhibitors decrease circulating IGF-1 levels in patients with hypertension . In one series of 40 PTE patients, for example, treatment with an ACE inhibitor reduced concentrations of both erythropoietin and IGF-1 from 15.4±6.2 to 11.2±6.8 mU/mL and from 364±99 to 280±129 ng/mL, respectively . (See 'Activation of renin-angiotensin system' below.)
sSCF, which stimulates the growth of erythroid progenitor cells , has been shown to correlate with both hematocrit values and with the observed/expected erythropoietin values in PTE patients, suggesting a possible role in pathogenesis .
A number of observations have indicated that IgA1, which has been implicated in the pathogenesis of IgA nephropathy (IgAN), can also regulate erythropoiesis. First, in large cohorts of patients with chronic kidney disease, IgAN has been associated with erythrocytosis in 3.5 percent of patients . Secondly, after kidney transplantation, anemia recovery is faster in patients with IgAN. Thirdly, IgA1 from patients with IgAN and erythrocytosis increases the sensitivity of erythroid progenitors to erythropoietin. And finally, elevated hematocrit values were observed in A1 knock-in mice compared with wild-type counterparts.
Activation of renin-angiotensin system — Activation of the renin-angiotensin system (RAS) and especially angiotensin II, its active octapeptide, may contribute to PTE by acting as a direct growth factor on erythroid progenitors and stimulating erythropoietin secretion [40-42]. In this regard, activation of the angiotensin II receptor in PTE patients may enhance erythropoietin production in the graft or the native kidneys and directly activate red cell precursors in the bone marrow [14,41,43-49]. In addition, angiotensin II may induce hypoxia-inducible factor, a transcription factor that promotes the production of erythropoietin, and augment iron metabolism through alterations of iron transporters [50-52]. However, in a study with 331 consecutive transplant recipients, there was no association of polymorphic variants of the ACE, angiotensinogen, and angiotensin II receptor type 1 genes with PTE .
Nevertheless, experimental observations in genetically manipulated animals suggest an interrelationship between RAS activation and augmented erythropoiesis. In mice that carry both the human renin and angiotensinogen genes, development of hypertension is accompanied by higher hematocrit values, increased serum erythropoietin levels, and enhanced expression of erythropoietin messenger RNA. Both blood pressure and hematocrit remain normal when the two transgenes are introduced into the angiotensin II receptor null background, an observation that highlights the pivotal role of this receptor in both mediating sustained hypertension and regulating erythropoiesis. By contrast, in angiotensinogen, ACE, and angiotensin II receptor knock-out animals, lowering of blood pressure is coupled with decreased hematocrit values. In angiotensinogen and renin knock-out animals, anemia is rescued by angiotensin II infusion, an effect that is completely blocked by simultaneous administration of angiotensin II receptor blockers [46,54].
Similarly, clinical data indirectly support the role of the RAS system in erythropoiesis. As an example, erythrocytosis has been reported in patients with renin-secreting juxtaglomerular cell tumors and in patients with Bartter syndrome, a condition characterized by hyperreninemia [55,56]. RAS inactivation by ACE inhibitors and angiotensin receptor blockers (ARBs) reduces erythropoiesis but rarely causes clinically significant anemia in the vast majority of otherwise uncomplicated patients [40,57-66]. However, a significant hematocrit-lowering effect and/or anemia due to administration of ACE inhibitors or ARBs has been reported in various forms of secondary polycythemias, including high altitude polycythemia and hypoxia-associated polycythemia in patients with chronic obstructive pulmonary disease, and when the bone marrow requires all available stimuli to augment erythropoiesis, such as in patients with kidney function impairment, heart failure, or an immunosuppressed state. By contrast, increased hematocrit values and decreased need for exogenous erythropoietin administration have been reported after discontinuation of RAS inhibitors in patients with lower-risk myelodysplastic syndromes .
The mechanisms by which ACE inhibitors and ARBs inhibit erythropoiesis are incompletely defined, and some effects may not be common to both classes of drugs. As an example, ACE inhibitors, but not ARBs, cause an increase in the protein Ac-SDKP (goralatide) [44-46,68]. Goralatide inhibits multipotent hematopoietic stem cell entry into S phase and is usually metabolized by ACE, thereby diminishing erythropoiesis. However, this mechanism does not explain the effectiveness of ARBs in correcting PTE, suggesting that other mechanisms are also operative.
Some studies have shown that, among PTE patients with normal or high erythropoietin concentrations, the ACE inhibitor-induced reduction in hematocrit is associated with a fall in plasma erythropoietin concentrations, suggesting an erythropoietin-dependent mechanism [13,69]. However, ACE inhibitors are also effective among patients whose erythropoietin concentrations are initially suppressed or do not fall significantly after therapy is begun, suggesting that these agents may also act via an erythropoietin-independent mechanism [1,13,70]. Also compatible with an erythropoietin-independent mechanism is the observation that withdrawal of the ACE inhibitor in patients with PTE results in a gradual rise in hematocrit without a concurrent elevation in erythropoietin levels .
In patients with diabetes, who frequently have increased glucose reabsorption by sodium-glucose cotransporters (SGLTs), the high glucose environment in the renal tubulointerstitium may damage renal erythropoietin-producing cells and cause decreased erythropoietin secretion . Inappropriately low erythropoietin levels for the degree of anemia have been reported in patients with diabetes mellitus , and anemia develops earlier and is more severe in patients with diabetes and kidney disease than in their counterparts with nondiabetic kidney disease . Correction of diabetes in simultaneous kidney-pancreas recipients is associated with higher prevalence of PTE than in same-donor single kidney recipients (38.5 versus 7.7 percent) . Similarly, SGLT2 inhibitors, which block glucose reabsorption, may attenuate glucotoxicity and allow erythropoietin-producing cells to resume their function. Erythropoietin levels increase within weeks after treatment with an SGLT2 inhibitor, followed by increased reticulocyte count and hematocrit values that peak after two to three months . Thus, wider adoption of SGLT2 inhibitors in the treatment of kidney transplant recipients with high-normal hematocrit values may increase the incidence of PTE .
Endogenous androgens — Endogenous androgens may play a role in the development of PTE. Male sex is one of the most important risk factors for the development of PTE . Androgens directly stimulate erythroid progenitors  and indirectly promote erythropoiesis by stimulating either endogenous erythropoietin  or the RAS .
One study sought to determine whether angiogenic factors contribute to PTE . Serum vascular endothelial growth factor (VEGF) levels were measured in 13 patients with PTE, 75 untreated erythrocytosis nontransplant patients, and 21 healthy controls. The results indicated that VEGF was overproduced in advanced and untreated polycythemia vera (PV) patients and to a lesser degree in idiopathic erythrocytosis, but there was no evidence of increased VEGF in PTE and in secondary erythrocytosis. The absence of angiogenesis in PTE and its presence in PV demonstrates that the pathogenesis of these two entities is different. This might explain the relatively benign course of PTE.
CLINICAL PRESENTATION — Posttransplant erythrocytosis (PTE) usually occurs 8 to 24 months after transplantation , with hemoglobin/hematocrit levels increasing gradually over a period of months. There is no correlation between hemoglobin/hematocrit concentration and symptoms, and routine monitoring of the complete blood count is required to detect PTE.
Patients with PTE may experience symptoms such as malaise, headache, plethora, lethargy, and dizziness, though robust studies assessing the prevalence of these symptoms in the modern era of immunosuppression are lacking. Historically, thromboembolic complications (deep vein thrombosis, pulmonary embolus, thrombophlebitis, or stroke) were relatively common in untreated patients with PTE (18 percent in one study ); however, subsequent studies of patients undergoing treatment with ACE inhibitors or ARBs for PTE have shown very low rates of thrombosis [80,81]. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)
Platelet and leukocyte counts are normal, and arterial blood gases are normal in patients with PTE .
Without treatment, PTE spontaneously remits in approximately one-fourth of patients within two years and in approximately two-thirds of patients within five years from its onset . However, in some cases, PTE may persist for several years and eventually remit in the setting of deteriorating allograft function due to chronic rejection [7,30]. A retrospective single-center analysis of 4317 kidney transplants found that with appropriate management, there was no significant association between PTE and patient mortality, graft survival, or vascular thromboembolism .
DIAGNOSTIC EVALUATION — The diagnosis of posttransplant erythrocytosis (PTE) is made by the demonstration of a hemoglobin >17 g/dL and/or hematocrit >51 percent that persists for over six months after transplantation and by the exclusion of common causes of nontransplant-associated erythrocytosis, including malignancies and, in selected patients, chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA). (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Initial evaluation'.)
Confirmation of persistent erythrocytosis — The diagnosis of PTE should be suspected in any kidney transplant recipient who is found to have a hemoglobin >17 g/dL and/or hematocrit >51 percent for more than two to three months. An elevated hemoglobin/hematocrit level lasting more than six months confirms the presence of persistent erythrocytosis.
All patients with an elevated hemoglobin/hematocrit level should be evaluated for the possibility of hemoconcentration (ie, an elevation of hemoglobin/hematocrit due to a decrease in plasma volume without an increase of the red blood cell mass) as a potential cause of the abnormal elevation. In general, extracellular volume contraction leading to hemoconcentration is an acute event and is not likely to result in a sustained elevation in hemoglobin/hematocrit levels for prolonged periods of time.
Exclusion of nontransplant causes of erythrocytosis — Kidney transplant recipients who are found to have persistent erythrocytosis (see 'Confirmation of persistent erythrocytosis' above) should undergo a diagnostic evaluation to exclude nontransplant causes of erythrocytosis. In general, the diagnostic evaluation of PTE is different from that of erythrocytosis in a patient who has not received a transplant, since transplant patients receive a thorough evaluation prior to surgery, during which a baseline hemoglobin is established and longstanding pulmonary disease and congenital disorders are excluded. The evaluation focuses on acquired disorders that may contribute to erythrocytosis and for which the transplant population is at higher risk, including malignancies such as renal cell carcinoma and breast cancer:
●We obtain an ultrasound with Doppler waveform analysis of renal arteries of the native and transplanted kidney to exclude renal artery stenosis. If this study is suspicious for renovascular hypertension, further evaluation is performed. (See "Hypertension after kidney transplantation", section on 'Evaluation for transplant renal artery stenosis'.)
●We perform a kidney ultrasound to exclude an underlying renal carcinoma. This is typically performed at the same time as the ultrasound evaluation for renal artery stenosis. If the ultrasound is suspicious for malignancy, further evaluation is performed. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)
●In females, we obtain a mammogram if one has not been obtained within one year to exclude breast cancer. (See "Screening for breast cancer: Strategies and recommendations".)
●In patients with a history of hepatitis B or C virus infection who are at increased risk for hepatocellular carcinoma, we obtain a liver ultrasound and serum alfa fetoprotein (AFP) concentration to screen for hepatocellular carcinoma. (See "Epidemiology and risk factors for hepatocellular carcinoma".)
●In patients with a smoking history exceeding 20 years or a clinical history of COPD, a chest radiograph, pulmonary function tests, and arterial blood gases may be obtained as hypoxemia and COPD are common causes of nontransplant-associated erythrocytosis. However, as noted above, these tests have generally been performed prior to transplantation, and the utility of repeating this evaluation is not clear, since transplantation-associated erythrocytosis usually occurs within a few months following transplantation. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Diagnostic Evaluation'.)
●In patients with signs and symptoms suggestive of OSA (eg, daytime sleepiness; snoring, gasping, or choking during sleep), we obtain diagnostic testing for OSA. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Diagnostic evaluation'.)
We do not perform imaging studies to rule out other uncommon causes of erythrocytosis such as hemangioblastomas, pheochromocytoma, or uterine myomata unless there is an additional indication besides the presence of erythrocytosis.
We do not measure erythropoietin concentrations as part of the diagnostic evaluation of PTE. In contrast with the general population with erythrocytosis, the measurement of erythropoietin concentrations is not helpful among transplant recipients, since high and low concentrations have been demonstrated among PTE patients.
Measurement of renin-angiotensin system (RAS) activity, goralatide, or insulin-like growth factor-1 (IGF-1) concentrations are also not helpful in making the diagnosis or direct treatment and are not performed among transplant recipients.
Overview of treatment — In all kidney transplant recipients who have posttransplant erythrocytosis (PTE), we suggest treatment to lower the hemoglobin concentration. The primary goals of treatment are to control symptoms and reduce the risk of thromboembolic events (see 'Clinical presentation' above). Although there are no studies that have shown that reducing hemoglobin levels in patients with PTE is associated with an improvement in symptoms or reduction in thrombosis risk, extensive data in patients with polycythemia vera (a chronic myeloproliferative disorder associated with an elevated red blood cell mass) support this approach. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)
The optimal hemoglobin among patients with PTE is not known. We generally target a hemoglobin level <17 g/dL (hematocrit <51 percent) in both males and females. Our overall approach to therapy, which is largely consistent with the guidelines of the British Society of Haematology , is as follows:
●In all patients with PTE and a hemoglobin >17 g/dL, we suggest either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) as initial treatment. (See 'ACE inhibitors or ARBs in all patients' below.)
●In patients with PTE who have a contraindication to receiving an ACE inhibitor or ARB (eg, due to intolerance or known allergy) or in whom an ACE inhibitor or ARB is ineffective at reducing the hemoglobin concentration, we suggest therapeutic phlebotomy. (See 'Phlebotomy' below.)
We do not routinely use theophylline or an antiproliferative agent (eg, sirolimus) as initial therapy in patients with PTE. However, these agents can be considered for patients who do not respond to ACE inhibitors or ARBs or who have a contraindication to their use and who do not wish to undergo repeated phlebotomy. (See 'Less frequently used therapies' below.)
There are no data evaluating the use of aspirin in patients with PTE. However, in transplant recipients with PTE who have risk factors for coronary heart disease, we administer aspirin for primary prevention of cardiovascular events. (See "Risk factors for cardiovascular disease in the kidney transplant recipient" and "Aspirin in the primary prevention of cardiovascular disease and cancer".)
We continue therapy for PTE indefinitely since relapse of erythrocytosis is common if treatment is discontinued and because the majority of kidney transplant recipients are hypertensive and would benefit from treatment with an ACE inhibitor or ARB. In addition, ACE inhibitors and ARBs may slow the rate of progressive kidney dysfunction [2,25,84]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Patients with PTE who develop an acute thromboembolic event should be managed similarly to patients with polycythemia vera or other forms of secondary erythrocytosis who have thromboembolic complications. (See 'Patients with a thromboembolic event' below.)
ACE inhibitors or ARBs in all patients — In all patients with PTE and a hemoglobin level >17 g/dL, our preferred initial treatment is an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). These agents are effective in the majority of patients, are reasonably safe, and, among many patients, provide a necessary antihypertensive effect.
If the patient has a contraindication to receiving an ACE inhibitor or ARB (eg, due to intolerance or known allergy), we treat with therapeutic phlebotomy (see 'Phlebotomy' below). Some patients may not wish to undergo repeated phlebotomy; in such patients, theophylline or an antiproliferative agent may be an effective alternative therapy. (See 'Less frequently used therapies' below.)
Dosing of ACE inhibitors/ARBs — The choice between an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) is dependent upon patient and clinician preference; although limited data suggest that ACE inhibitors may be somewhat more effective in lowering the hemoglobin, they are more likely than ARBs to produce side effects. (See 'Evidence for ACE inhibitors/ARBs' below.)
We initiate therapy with an ARB, such as losartan at 50 mg/day. If the hemoglobin level does not decrease to <17 g/dL within four weeks or if blood pressure remains elevated, the dose may be increased to 100 mg/day. If an adequate lowering of the hemoglobin is not seen after an additional four weeks, we replace losartan with enalapril, administered at 10 to 40 mg daily, or an equivalent dose of another ACE inhibitor.
If the ACE inhibitor or ARB is effective at reducing the hemoglobin concentration, we continue the ACE inhibitor or ARB indefinitely, given that relapse is common when treatment is discontinued. Patients are subsequently monitored with a complete blood count monthly to every three months per routine monitoring for kidney transplant recipients. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)
In our experience, approximately 5 to 10 percent of patients will not respond to an ACE inhibitor or ARB; such patients are generally unresponsive to all other ACE inhibitors and ARBs. We do not use combination therapy with both an ACE inhibitor and an ARB in these patients. If an ARB or ACE inhibitor is ineffective at reducing the hemoglobin concentration at the maximum tolerated dose, we treat the patient with serial phlebotomy. In such patients, we typically continue the ARB or ACE inhibitor, particularly if hypertension is also present. If the patient does not wish to undergo repeated phlebotomy, theophylline or an antiproliferative agent may be an effective alternative therapy. (See 'Phlebotomy' below and 'Less frequently used therapies' below.)
Evidence for ACE inhibitors/ARBs — Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) [1,2,13,15,25,69,70,84-88] have been used to correct PTE. A 2007 systematic review of eight randomized trials including 231 transplant recipients showed that treatment with either an ACE inhibitor or ARB significantly lowered the hematocrit compared with control patients . Although this systematic review did not specifically include patients with PTE, in trials with at least 12 months of follow-up, the hematocrit was on average 3.5 percent lower (1.2 g/dL lower hemoglobin concentration) among patients treated with an ACE inhibitor or ARB. Based upon these findings, it is likely that most patients with PTE will achieve the target hemoglobin level with an ACE inhibitor or ARB alone, without the need for serial phlebotomy. In addition, ACE inhibitors and ARBs are associated with fewer adverse effects compared with theophylline. (See 'Theophylline' below.)
A dose-dependent decrease in hemoglobin and/or hematocrit values is observed in >90 percent of PTE patients within two to six weeks of treatment with an ACE inhibitor or ARB [1,2,13,15,16,25,69,70,84-86,90]. The nadir hematocrit is usually reached within three to six months, and the attained level remains stable with continued treatment during long-term observation [15,17,86,91,92]. If the ACE inhibitor or ARB is discontinued, the hematocrit values rise gradually over the next three months toward pretreatment levels in the majority of patients. However, erythrocytosis does not recur in a substantial fraction of patients (20 to 30 percent) who discontinue treatment [71,85].
Direct comparisons between ACE inhibitors and ARBs for the treatment of PTE are limited [33,84]. One randomized trial compared the efficacy of enalapril (10 mg/day) and losartan (50 mg/day) in 27 patients with PTE . The response rate (as defined by a >1 g/dL decrease in hemoglobin levels) was similar with both drugs (75 to 80 percent), but enalapril produced a greater reduction in hemoglobin concentration in the responders (3.3 versus 1.7 g/dL). Cessation of therapy led to a return to baseline hemoglobin levels in 10 of 13 patients. There was a trend for a slower return to baseline after discontinuation of losartan (seven versus three months for enalapril). A high frequency of relapse has also been noted in other studies .
ARBs are less commonly associated with side effects including cough and angioedema. Both ACE inhibitors and ARBs may cause kidney dysfunction, postural hypotension, hyperkalemia, and erectile dysfunction. These side effects are dose dependent and generally improve after dose reduction. Severe adverse reactions, such as angioneurotic edema or anaphylactoid reactions, have not been reported in patients with PTE [13,15,91]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)
The mechanisms underlying the ACE inhibitor-induced decrease in erythrocytes are unknown, although one study has suggested that ACE inhibitors induce apoptosis of the erythroid precursors . In addition, renin-angiotensin system (RAS) inhibition may decrease erythropoietin production and restore the observed/expected serum erythropoietin ratio toward normal range .
Phlebotomy — Therapeutic phlebotomy can be used for patients with PTE who have a contraindication to receiving an ACE inhibitor or ARB (eg, due to intolerance or known allergy) or in whom an ACE inhibitor or ARB is ineffective at reducing the hemoglobin concentration. (See 'Overview of treatment' above.)
A standard one unit phlebotomy (500 mL) should reduce the hematocrit by 3 percentage points in a normal-sized adult (eg, from 46 to 43 percent). Phlebotomy of 500 mL of blood should be performed at intervals appropriate for patient size and tolerability to achieve and maintain a target hemoglobin of <17 g/dL (hematocrit <51 percent).
Once a hemoglobin level <17 g/dL has been stably maintained, we attempt to withdraw phlebotomy while continuing treatment with an ACE inhibitor or ARB.
Excessive therapeutic phlebotomy may result in the development of iron deficiency. Iron replacement therapy should be administered cautiously with close monitoring of blood counts since it may provoke a rapid rise in the hemoglobin level.
Phlebotomy is quite effective in normalizing hematocrits and may be used chronically for PTE. This was demonstrated in a study of 12 kidney transplant recipients with PTE (defined by hemoglobin >17 g/dL or hematocrit >52 percent) who underwent phlebotomy (500 mL), repeated an average of three times within the first two weeks until hematocrit decreased below 45 percent . Phlebotomy reduced hematocrit from 54.8 percent at baseline to 44.3 percent after two weeks and 43.0 percent after six weeks.
Less frequently used therapies
Theophylline — In patients who do not respond to ACE inhibitors or ARBs or have a contraindication to their use and who do not wish to undergo repeated phlebotomy, theophylline is an effective alternative therapy. However, theophylline has a narrow therapeutic window and, even at relatively small doses, can cause side effects (such as headache, nervousness, and insomnia) and adversely affect the patient's quality of life. (See "Theophylline poisoning", section on 'Pharmacology and cellular toxicology'.)
In patients with PTE, theophylline can be administered as an extended-release oral formulation at a dose of 8 mg/kg of body weight per day . The initiation, dose titration, and monitoring of theophylline in patients with PTE are similar to that for patients receiving theophylline for the treatment of asthma. These issues are discussed in more detail elsewhere. (See "Theophylline use in asthma", section on 'Safe use of theophylline'.)
Theophylline appears to act as an adenosine antagonist in this setting, suggesting that adenosine facilitates both the release of and the bone marrow response to erythropoietin. In a prospective trial of eight patients with PTE and five normal controls, an eight week course of theophylline reduced the hematocrit from 58 to 46 percent in those with PTE and from 43 to 39 percent in the control group . Other studies found that theophylline can lower the hematocrit by 8 to 15 percent [32,95].
●Among the 10 patients who received enalapril, the hematocrit decreased from 57 to 45 percent at two months.
●Among the nine patients administered 600 mg/day of theophylline (given in two doses), the average hematocrit was reduced from 56 to 52 percent but remained above 51 percent in five.
●Nine patients did not receive medical treatment for PTE. After three months, PTE persisted in eight.
Antiproliferative agents — The use of antiproliferative agents such as mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus), mycophenolate, and azathioprine has been associated with anemia and may decrease the risk of PTE [4,70]. (See "Anemia and the kidney transplant recipient", section on 'Later (>3 months) posttransplantation'.)
In general, we do not alter the immunosuppression regimen (eg, switch one maintenance immunosuppression medication to sirolimus) to treat PTE in the absence of other indications (eg, inability to tolerate calcineurin inhibitors). However, altering the immunosuppressive regimen may be considered for patients who do not respond to ACE inhibitors or ARBs or who have a contraindication to their use, do not wish to undergo repeated phlebotomy, and do not wish to start theophylline due to perceived side effects, provided it is immunologically permissible.
In one study, PTE occurred more frequently among graft recipients treated with cyclosporine A compared with azathioprine . Another study of 214 kidney-pancreas recipients found a lower incidence of PTE among patients treated with sirolimus compared with those treated with mycophenolate mofetil (7 versus 19 percent, respectively) .
Patients with a thromboembolic event — Historically, thromboembolic complications were relatively common in untreated patients with PTE; however, studies of patients undergoing treatment with ACE inhibitors or ARBs for PTE have shown very low rates of thrombosis. (See 'Clinical presentation' above.)
There are no studies to guide the optimal treatment of patients with PTE who develop an acute thromboembolic event. In general, our approach to the management of thromboembolic complications in patients with PTE is similar to that for patients with polycythemia vera and other forms of secondary erythrocytosis who develop thromboembolic complications, as discussed separately. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)
Patients with PTE who develop a venous thromboembolic event should be treated appropriately with anticoagulation, but there are no studies that have examined the optimal anticoagulant or duration of anticoagulation in a patient with PTE and a first episode of venous thromboembolism. General management of venous thromboembolism is discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)
Patients with PTE who develop an arterial thromboembolic event (eg, stroke, limb ischemia) should be treated as described separately. (See "Initial assessment and management of acute stroke" and "Embolism to the lower extremities".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Definition – Posttransplant erythrocytosis (PTE) is defined as a hemoglobin concentration >17 g/dL and/or hematocrit >51 percentage points that occurs following transplantation, persists for more than six months, and occurs in the absence of another underlying cause. It is reported to occur in 8 to 15 percent of kidney transplant recipients. (See 'Introduction' above and 'Definition' above.)
●Clinical presentation – PTE most often occurs within the first 8 to 24 months after transplantation. Symptoms may include malaise, headache, plethora, lethargy, and dizziness. Historically, thromboembolic complications were relatively common in untreated patients with PTE; however, subsequent studies of patients undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for PTE have shown very low rates of thrombosis. Relapse is common after treatment is discontinued. (See 'Clinical presentation' above.)
●Diagnosis – The diagnosis of PTE is made by the demonstration of a hemoglobin >17 g/dL and/or hematocrit >51 percent that persists for over six months after transplantation and by the exclusion of other common causes of nontransplant-associated erythrocytosis, including malignancies and, in selected patients, chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA). (See 'Diagnostic evaluation' above.)
●Treatment – For kidney transplant recipients with PTE, we suggest treating all patients to lower the hemoglobin concentration (Grade 2B). The primary goals of treatment are to control symptoms and reduce the risk of thromboembolic events. The optimal hemoglobin among patients with PTE is not known. We generally target a hemoglobin level <17 g/dL (hematocrit <51 percent) in both males and females. Our overall approach to therapy, which is largely consistent with the guidelines of the British Society of Haematology, is as follows (see 'Overview of treatment' above):
•For all patients with PTE and a hemoglobin >17, we suggest treatment with either an ACE inhibitor or an ARB rather than phlebotomy or theophylline (Grade 2B). We generally use an ARB such as losartan at 50 mg/day. The dose may be increased to 100 mg/day if no response is observed within four weeks. Patients who do not respond to an ARB may respond to an ACE inhibitor such as enalapril, although patients who do not respond to one ACE inhibitor are generally equally unresponsive to all other ACE inhibitors, as well as ARBs. (See 'ACE inhibitors or ARBs in all patients' above and 'Evidence for ACE inhibitors/ARBs' above.)
•For patients who do not respond to ARBs or ACE inhibitors at the maximum tolerated dose, we suggest therapeutic phlebotomy rather than other therapies such as theophylline or antiproliferative agents (Grade 2B). (See 'Phlebotomy' above.)
•In general, our approach to the management of thromboembolic complications in patients with PTE is similar to that for patients with polycythemia vera and other forms of secondary erythrocytosis who develop thromboembolic complications. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel C Brennan, MD, FACP, who contributed to an earlier version of this topic review.
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