Objectives: Our objective was to evaluate the influence of pretransplant risk factors on posttransplant anemia recovery.

Materials and Methods: This single-center obser­vational retrospective study included 80 deceased donor kidney transplant recipients who had been followed up to 16 months after kidney transplant. Time point of posttransplant anemia recovery was considered the time when hemoglobin of 11.0 g/dL was achieved and maintained for 3 consecutive monthly visits. We collected donor/transplant charac­teristics (age, sex, hypertension history, cause of death, donor kidney function, expanded criteria donor status, deceased donor score, HLA mismatch, and cold ischemia time) and recipient data (pretransplant hemoglobin, parathyroid hormone, kidney graft function, delayed graft function, acute rejection, infections, surgical bleeding, posttransplant parathyroid hormone, iron stores, and C-reactive protein and tacrolimus levels). We used univariate and multivariate Cox proportional hazards analyses and Kaplan-Meier plots to determine associations between variables and posttransplant anemia recovery rate. P < .05 was considered significant.

Results: We identified 62 deceased donors (33 male; mean age 50 ± 15.1 years) and 80 kidney transplant recipients (52 male; mean age 47.0 ± 10.6 years). Mean pretransplant hemoglobin was 11.4 ± 1.5 g/dL. Donor age, deceased donor score, pretransplant parathyroid hormone, posttransplant transferrin saturation (all P < .05), and tacrolimus level (P < .01) were significantly related to posttransplant anemia recovery. Kaplan-Meier curve identified that recipients of deceased donors below 60 years old achieved hemoglobin of 11.0 g/dL more frequently and earlier than recipients of deceased donors above 60 years old (P < .05).

Conclusions: Deceased donor age, deceased donor score, pretransplant serum parathyroid hormone, posttransplant transferrin saturation, and tacrolimus level were significantly associated with posttransplant anemia recovery rate in deceased donor kidney transplant recipients. Anemia recovery was more frequent and earlier in recipients of deceased donors below 60 years than in recipients of donors 60 years old and above.

Key words : Deceased donor score, Hemoglobin, Parathyroid hormone

Introduction

Posttransplant anemia is more prevalent in kidney transplant recipients than in patients with chronic kidney disease, assuming that they have the same glomerular filtration rate.¹ However, until now, investigations on posttransplant anemia have received less attention than investigations on anemia in chronic kidney disease patients.^2,3

Immediately after transplant, the most common causes of anemia are surgical blood loss, intensive immunosuppression, and allograft dysfunction.⁴

Iron deficiency, hyperparathyroidism, concomitant medications, and infections may also contribute to anemia. Posttransplant anemia is linked to cardio­vascular morbidity, quality of life, and patient survival.^5-7 There is increasing evidence that cor­rection of anemia is needed to maintain graft function.⁸ However, almost 50% of kidney transplant recipients have anemia 1 year after transplant.9 Influence of pretransplant factors on posttransplant anemia recovery is an underrecog­nized problem.

The aim of this study was to evaluate associations among donor, recipient, and transplant characteristics and posttransplant anemia recovery rate as well as to define whether donor age older than 60 years affects posttransplant anemia recovery.

Materials and Methods

We conducted a single-center observational retro­spective study of 80 consecutive kidney transplant recipients who underwent their first deceased-donor renal transplant at the Clinical Center of Serbia from January 1, 2010 to December 31, 2012. Recipients received renal allografts from 62 deceased donors after declaration of brain death in the same institution. The study was approved by the institutional ethics committee and conducted in accordance with the ethical guidelines of the 1975 Helsinki Declaration. All participants provided fully informed and written consent to use their medical data.

Immunosuppressive treatment included antithy­mocyte globulin, mycophenolic acid preparations, tacrolimus, and steroids. Tacrolimus was admin­istered twice daily (8 am and 8 pm). The initial dose was 0.15 mg/kg/day, and this dose was then adjusted according to the blood concentration of the drug to maintain target levels. Target ranges of tacrolimus trough blood levels were between 10 and 12 ng/mL until the end of the first month, 8 to 10 ng/mL until the end of the fourth month, 6 to 8 ng/mL from then to the end of the first year, and 4 to 6 ng/mL thereafter. Tacrolimus levels were measured during each patient visit in whole blood by chemiluminescent microparticle immunoassay using the ARCHITECT tacrolimus assay (Abbot Laboratories Diagnostics Division); levels at the time of anemia recovery specific for each patient were further analyzed. Mycophenolate mofetil dose was 1 g twice daily during the first posttransplant year and 500 mg twice daily thereafter.

Hemoglobin concentrations were measured monthly up to 16 months after kidney transplant. Anemia recovery was defined as time when hemoglobin of 11.0 g/dL was achieved for the first time and maintained for 3 consecutive months. Patients who died or returned to dialysis were not included in the study. None of the recipients received erythropoietin-stimulating agents. All patients were prescribed folic acid 5 mg daily as well as vitamin B complex pills containing 3 mg vitamin B1, 3.4 mg vitamin B2, 2 mg vitamin B6, 1 μg vitamin B12, 25 mg niacin, and 5 mg pantothenic acid.

Characteristics of donors and the transplant process, including age, sex, history of hypertension, cause of death, kidney function, HLA mismatch, and cold ischemia time, were collected. Donor serum creatinine was measured at the time of admission and kidney procurement. Donor hypertension was considered if the donor had a history of hypertension of at least 5 years. The expanded criteria donors corresponded to a well-known definition.¹⁰ Deceased donor score was calculated based on donor age, cause of death, history of hypertension, serum creatinine at the time of kidney procurement, and HLA mismatch.¹¹

Recipient data included pretransplant hemoglobin and pretransplant serum parathyroid hormone levels, kidney graft function, delayed graft function, acute rejection occurrence, posttransplant infections, surgi­cal bleeding, transfusion volume, and serum tacrolimus levels at time of anemia recovery. Serum iron and ferritin levels, transferrin saturation, C-reactive protein, and serum parathyroid hormone levels were measured 6 and 12 months after transplant. Diagnosis of acute rejection was made by allograft biopsy or based on deterioration of allograft function that had improved after high doses of corticosteroid therapy. Hemodialysis during the first 2 weeks after transplant was consistent with a definition of delayed graft function.

Statistical analyses
Data are presented as frequencies for categorical variables. All continuous variables were tested for normal distribution and are presented as means with standard deviation or medians with interquartile range. Continuous variables were compared using t test, and categorical variables were analyzed with the chi-square test. To assess variables associated with posttransplant anemia recovery rate, univariate and multivariate Cox proportional hazards analyses were performed. Results are reported as hazard ratios with 95% confidence intervals. Kaplan-Meier plots were used for comparisons of posttransplant anemia recovery rate in recipients of deceased donors above 60 and below 60 years old. P < .05 was considered significant. Statistical analysis was carried out using SPSS 20.0 software.

Results

We included 80 kidney transplant recipients (52 males) of mean age 47 ± 10.6 years with pretransplant hemoglobin level of 11.4 ± 1.5 g/dL. The most pre­valent underlying kidney diseases were hypertension (27.5%) and glomerulonephritis (26.3%), followed by polycystic kidney disease (10.0%) and tubular interstitial nephropathy (10.0%), whereas unknown and other less frequent causes accounted for 18.8% and 7.5% of patients, respectively. Mean creatinine clearance at the end of follow-up was 64.6 ± 28.7 mL/min. The percentage of recipients with hemoglobin concentration below 11.0 g/dL significantly decreased during follow-up (93.7% at the end of the first posttransplant month vs 61.2%, 32.5%, and 25.0% at the end of the third, sixth, and twelfth posttransplant months, respectively; P < .05) (Table 1).

Sixty-two deceased donors (33 male) of mean age 50 ± 15.1 years with a cerebrovascular accident as the most frequent cause of death had initial serum creatinine of 71.3 ± 18.0 μmol/L and terminal creatinine of 102.8 ± 53.5 μmol/L. History of donor hypertension was evident in 35.5% of cases, and 48.4% of donors were classified as expanded criteria donors (Table 2). Deceased donor score of donors below 60 years old was significantly lower than the same score of donors above 60 years old (7.02 ± 5.61 vs 14.21 ± 4.94; P < .01).

A statistically significant difference was not found between kidney transplant recipients whose donors were above and below 60 years old with regard to recipient age, sex, underlying kidney disease, pretransplant hemoglobin and pretransplant serum parathyroid hormone levels, HLA mismatch, cold ischemia time, delayed graft function, acute rejection, blood transfusion volume, bleeding complications during surgery, and infections (Table 3). A sta­tistically significant difference was not found between recipients whose donors were below and above 60 years old with regard to serum iron (15.17 ± 6.53 vs 13.4 ± 5.22 μmol/L), transferrin saturation (36.26 ± 15.79% vs 31.75 ± 16.31%), ferritin level (292 μg/L, interquartile range 388 μg/L, vs 340 μg/L, interquartile range 459 μg/L), and C-reactive protein (2.70 ± 2.74 vs 2.86 ± 3.32 mg/L) 6 months after transplant. No significant difference was shown between recipients of donors below and above 60 years old in serum iron (13.1 ± 4.50 vs 13.4 ± 3.66 μmol/L), transferrin saturation (30.86 ± 8.78% vs 30.31 ± 8.80%), serum ferritin (320.5 μg/L, interquartile range 394 μg/L, vs 320 μg/L, interquartile range 358 μg/L), and C-reactive protein (2.29 ± 2.50 vs 2.17 ± 2.14 mg/L) 12 months after transplant. Median values for parathyroid hormone levels of recipients whose donors were below 60 years old 6 and 12 months after transplant were 80.0 pg/mL (interquartile range 71 pg/mL) and 56.5 pg/mL (interquartile range 37 pg/mL), whereas median values for parathyroid hormone levels of recipients whose donors were above 60 years old were 103 pg/mL (interquartile range 66 pg/mL) and 64.5 pg/mL (interquartile range 54.7 pg/mL) at the same time points. Serum tacrolimus levels at time of anemia recovery were 9.2 ± 3.2 versus 8.7 ± 3.1 ng/mL (P > .05).

Only 2 recipients (1 patient of each group of those with donors less than 60 years versus donors of 60 years or older) had clinical hypothyroidism that returned to normal after therapy with levothyroxine. To identify variables significantly associated with posttransplant anemia recovery, we performed univariate Cox proportional hazard analyses. In these analyses, transplant factors (HLA mismatch, cold ischemia time, mismatch of age) and donor factors (cause of death, history of hypertension, hemoglobin, initial donor creatinine, terminal donor creatinine) were not significant predictors of posttransplant anemia recovery. Donor age (P < .05) and deceased donor score (P < .05) were significant predictors of posttransplant anemia recovery (Table 4). Among recipient factors, age, underlying kidney disease, pretransplant hemoglobin, delayed graft function, acute rejection, transfusion volume, serum iron, ferritin levels, C-reactive protein, and parathyroid hormone 6 and 12 months post­transplant were not significantly related to post­trans­plant anemia recovery. Pretransplant parathyroid hormone (P < .05), transferrin saturation 12 months post­transplant (P < .05), and serum tacrolimus level (P < .01) were significantly related to anemia recovery (Table 5).

To assess the independent association of variables with posttransplant anemia recovery, we built a multivariate model. All variables that were significantly associated with posttransplant anemia recovery rate in the univariate Cox proportional hazard analyses were considered for inclusion in the multivariate model. Accordingly, donor age, pretransplant serum parathyroid hormone, and deceased donor score were the covariables entered into the multivariate Cox proportional hazard model as pretransplant factors in addition to posttransplant anemia recovery rate, whereas transferrin saturation 12 months posttransplant and tacrolimus level were the covariables entered into the multivariate Cox proportional hazard model as posttransplant factors. Pretransplant serum parathyroid hormone remained an independent predictor of posttransplant anemia recovery (P < .05) among pretransplant factors, whereas tacrolimus level (P < .01) was associated with posttransplant anemia recovery among post­transplant factors, according to the multivariate Cox proportional hazard model (Table 6).

A statistically higher percentage of kidney transplant recipients of deceased donors below 60 years old achieved hemoglobin 11.0 g/dL according to Kaplan-Meier curve analyses (P< .05) compared with kidney transplant recipients of deceased donors above 60 years old (Figure 1).

Discussion

In this study, we examined hemoglobin values at multiple time points and defined anemia recovery as a time-varying outcome. We demonstrated a significant association between anemia recovery and pretransplant factors, such as donor age and recipient parathyroid hormone level. Therefore, this finding could underline a need for more dedicated treatment of secondary hyperparathyroidism before selection of patients for the kidney transplant wait list. For patients on the wait list, efforts should be made to comply with existing chronic kidney disease-metabolic bone disease guidelines. There is presently a significant lack of organs available for transplant, and we are forced to use kidneys of older donors, potentially aggravating posttransplant anemia. Our results suggest that more devoted monitoring and treatment of posttransplant anemia are needed in cases of recipients of donors older than 60 years.

We found that posttransplant anemia prevalence decreased from more than 90% at 1 month after transplant to 25% at the end of the first post­transplant year, which is in line with other studies that demonstrated decreasing percentage of anemic patients during the first year after kidney transplant.^12-14

Because hemoglobin levels after transplant may take a few months to stabilize, we defined post­transplant anemia recovery as a time when hemoglobin concentration of 11 g/dL was achieved for the first time and maintained for 3 consecutive months. We used this cutoff value because it is the proposed target for erythropoietin-stimulating agent therapy according to the guidelines for treatment of renal anemia.^15-17 This cutoff of 11 g/dL was also used previously to evaluate whether anemia affected renal transplant outcomes, facilitating easier comparison.⁵ The type of donor (living vs deceased) does not seem to play a role in anemia occurrence.^18,19 However, a higher donor age, in particular when above 60 years, is predictive of anemia 1 year after transplant.^20,21 Similarly, in our investigation. donor age was significant for spontaneous posttransplant anemia recovery. In addition, the plateau of hemoglobin concentration was achieved 6 months posttransplant in recipients of older donors, whereas hemoglobin concentration continuously increased until the end of follow-up in recipients of younger donors. These differences in hemoglobin trend during follow-up suggest individualization of optimal time for initiation of anemia treatment in the subgroups of recipients according to donor age. Influence of donor age on anemia recovery is more important in the framework of increasing number of kidney transplants from donors above 60 years. Significance of donor age for posttransplant anemia is also reinforced by the evidence that the association between hemoglobin concentration and creatinine clearance weaken with increasing donor age.²² Donor age correlates significantly with severity of donor chronic renal injury, which can predict posttransplant anemia irrespective of allograft function.^23,24

Deceased donor score takes into account several risk factors for graft outcome, allowing a better comprehension of their contribution posttransplant. Although deceased donor score was proposed to provide additional information on graft survival related to donor risk factors, we used it for posttransplant anemia recovery. According to our results, any single risk factor within the deceased donor score is not significant for posttransplant anemia recovery rate; however, the contribution of a single factor is strengthened by confounding factors, such as donor age, terminal creatinine, cerebro­vascular cause of death, donor hypertension, and HLA mismatch. In accordance with the results suggesting that pretransplant hemoglobin is not related to transplant outcome, the association shown between pretransplant hemoglobin and post­transplant anemia recovery was not confirmed in our study.²⁵ Our recipients with faster and all-around better recovery from anemia had lower transferrin saturation 12 months posttransplant compared with those with more sustained anemia. A possible explanation is that, during anemia recovery, accelerated erythropoiesis decreases transferrin saturation since an additional amount of iron is required to increase hemoglobin.

In chronic kidney disease patients, an increase of serum parathyroid hormone had a significant inverse relation to serum hemoglobin less than 11.0 g/dL.²⁶ An association between pretransplant serum parathyroid hormone and risk of graft failure in kidney transplant recipients was also found.²⁷ Whether an association between pretransplant serum parathyroid hormone and posttransplant anemia exists in kidney transplant recipients is still unclear. Although spontaneous resolution of secondary hyperparathyroidism after kidney transplant is possible, persistent hyperparathyroidism is more frequent. Our study found pretransplant serum parathyroid hormone to be an independent predictor of posttransplant anemia recovery, suggesting careful evaluation of pretransplant hyperparathyroidism. Taking into account the significant discrepancy in the parathyroid hormone ranges before kidney transplant, we consider our results significant for achieving a better control of posttransplant anemia recovery. Once a new kidney allograft is functional, the typical response is the improvement of secondary hyperparathyroidism. In accordance with previous results, we observed decreasing levels of parathyroid hormone within the first 12 months posttransplant, which we consider as a possible explanation for disappearance of the significant association between parathyroid hormone and anemia.²⁸

Tacrolimus is usually not believed to be signifi­cantly myelosuppressive. We consider that the main reason for the significant association of higher tacrolimus levels with faster anemia recovery was the fact that higher tacrolimus levels were maintained according to our center’s protocol in patients with immediate anemia recovery. Furthermore, tacrolimus distributes into and binds to erythrocytes. Consequently, anemia recovery will affect the whole blood concentration of tacrolimus, which may partially explain the association between higher tacrolimus levels and better anemia recovery in our study.

Conclusions

We found donor age, deceased donor score, and pretransplant parathyroid hormone to be significant predictors of posttransplant anemia recovery rate in primary deceased donor kidney transplant recipients. Among posttransplant factors, we found transferrin saturation and tacrolimus levels to be associated with recovery of anemia. However, because tacrolimus is known to have high affinity for erythrocytes, there is a need for a more dedicated approach for therapeutic drug monitoring to make the results as broadly applicable as possible. We also found anemia recovery to be more frequent and earlier in kidney transplant recipients of deceased donors below 60 years old compared with kidney transplant recipients of donors above 60 years.

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