Influence of deceased donor hemodynamic factors in transplant recipients renal function

Correspondence to: Ana Paula Maia Baptista. Federal University of São Paulo UNIFESP Kidney and Hypertension Hospital/Osvaldo Ramos Foundation. Rua Borges Lagoa, no 960, 6o andar. São Paulo, SP, Brazil. CEP: 04038-002. E-mail: apmbaptista@yahoo. com.br Introduction: The incidence of delayed graft function (DGF) and unsatisfactory creatinine clearance (UCC) after renal transplantation is significantly higher in Brazil, when compared with that observed in United States or Europe. Deceased donor (DD) characteristics should directly influence the occurrence of these two outcomes. Objective: This study aim to evaluate the influence of DD characteristics on DGF and UCC incidence in Brazil. Methods: DD clinical and laboratory variables were correlated with outcome's incidence. Results: We evaluated 787 DD whose organs were transplanted in 1298 patients. We noted a high prevalence of vasoactive drugs use (90.2%), hypernatremia (66.6%) and renal dysfunction (34.8%). The incidence of DGF and UCC was 60.6% and 55.2%, respectively. We observed a progressive increase in DGF risk for age groups over 30 years and for cold ischemia time (CIT) greater than 24 hours. DGF risk was two times higher in recipients of donor kidney final serum creatinine (Cr) over than 1.5 mg/dl. Hypertension and CIT over 36 hours was associated with an increasing of 82% and 99% in UCC risk, respectively. Donor age above 40 years was associated with a progressive increase in UCC risk. Conclusion: DD age, renal function, hypertension and prolonged CIT were associated with increased risk DGF and UCC. AbstrAct


IntroductIon
The need to increase the supply of kidneys for transplantation because of the high number of patients registered on the waiting list has demanded a more widespread use of organs from borderline deceased donors, which were previously discarded. 1,2][5][6] However, the increased use of borderline kidneys from deceased donors has been associated with an increased incidence of complications after transplantation, among them: delayed graft function (DGF), which occurs when there is a need for renal replacement therapy in the first week after transplantation, and poor kidney function (PKF), defined as serum creatinine above 1.5 mg/dL six months or one year after the transplant. 2,7he negative association between DGF and PKF and graft survival is well established.DGF patients have lower survival, lower graft function after recovery and higher incidence of acute rejection. 8Unsatisfactory renal function six months after transplantation was associated with a relative risk for graft loss being twice the risk of patients with serum creatinine lower than this value. 9,10or these reasons, it is necessary to identify the risk factors for DGF and PKF in order to develop interventions to reduce the occurrence of these outcomes and prevent complications.
Characteristics related to the deceased donor leading to higher incidences of these two outcomes have been thoroughly investigated. 11][14][15] In Brazil, the incidence of DGF is significantly higher than the U.S. incidence (57.3% vs. 23.5%), 2,16nd there is a lower graft survival after one year of the transplant. 1,2We still need to investigate the factors related to the deceased donor that determine a worse outcome of kidney transplantation in this country.
This study aimed at assessing the characteristics of deceased donors, associated with the incidence of DGF and PKF in a large transplant center in Brazil.

Methods
This is a retrospective study using a sequential cohort of deceased donors identified by the Organs and Tissues Search Service of the Paulista School of Medicine (SPOT-EPM) from January 1998 through December 2008.This study was approved by the local Ethics in Research Committee.
We removed from this analysis those deceased donors whose kidneys were transplanted at another transplant center; recipients aged less than 18; second kidney transplant recipients and recipients of another organ combined.The characteristics of deceased donors were extracted from the "Information About the Deceased Donor" form, completed by the SPOT-EPM and transferred to the State Transplant Central.The data about the kidney transplant recipients was obtained from medical records.
The aim of the study was to identify deceased donor risk factors associated with the development of delayed graft function (DGF) or poor kidney function (PKF) six months after transplantation.DGF was defined as the need for dialysis during the first week after transplantation.PKF six months after transplantation was defined as creatinine clearance less than or equal to 50 ml/min/1.73m 2, calculated using the Cockcroft-Gault. 17Follow-up loss was defined as the definitive transfer of the recipient for monitoring in another service.Graft loss was defined as return to dialysis or retransplantation.

StatiStical analySiS
The categorical variables were presented as absolute and relative frequencies and the numerical variables as means and standard deviations.To analyze the PKF outcome in the sixth month we used an imputation method for missing values, as follows: (1) those patients who lost the graft before the sixth month were assigned a value of zero for creatinine clearance; (2)  for patients who died or lost the follow-up we used the last reading made (creatinine) ("Last observation carried Forward") for the calculation of creatinine clearance in the sixth month.
The characteristics of the deceased donor assessed against the outcomes were: age, gender, ethnicity, cause of brain death, hypertension, diabetes mellitus, active infection, use of vasoactive drugs, length of stay in the intensive care unit, cardiac arrest during hospitalization, serum creatinine on the day of assessment (creatinine final), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), creatine phosphokinase, serum sodium, serology for hepatitis B (HBsAg), serology for hepatitis C (anti-HCV) and cold ischemia time.The association between donor characteristics and DGF and PKF outcomes were assessed using the chi-square or Fisher's exact test for categorical variables and the Student t-test for the continuous variables.In order to find the donor variables independently associated with the DGF and PKF outcomes, we used logistic regression.The adequacy of fit of this model was verified using the Hosmer and Lemeshow test.For all the statistical tests we used a significance level of 5%, with p < 0.05.We used the SPSS version 17.0 (SPSS Inc., Chicago, IL, USA) software used for analysis.

results
During the study period, we found 1,085 deceased donors whose kidneys were transplanted into 1,646 recipients in our service.We excluded 298 donors whose kidneys were allocated to 223 recipients under the age of 18 years and 125 recipients of second or third kidney transplant.We then analyzed 787 deceased donors and 1,298 kidney transplant recipients.
The average age of deceased donors was 40.2 years and stroke was the leading cause of death (54.9%).The donor maintenance parameters analysis shows that 90.2% received a vasoactive drug at the time of evaluation and 15% had had a cardiac arrest reversed (Table 1).In addition, 70% had hypernatremia (Na > 145 mEq/l); 66.6% had elevated creatinine phosphokinase and 34.8% had kidney failure (creatinine > 1.5 mg/dl) (data not shown).The kidneys were transplanted within a mean cold ischemia time of 23.2 (Table 1).
Recipients had a mean age of 46.1 years; 80.4% had hypertension, and 13.8% had diabetes mellitus.The incidence of DGF was 60.6% and the incidence of PKF was 55.2%.The mean creatinine level was 1.6 mg/dl and creatinine clearance was 46.1 ml/min/1.73m 2 in the sixth month of transplantation.The receiver survival rate was 93% and graft survival was 90.6% six months after transplantation (Table 2).5).After logistic regression analysis with multiple variables, we observed a progressive increase in the risk of developing PKF from age greater than 40 years, with arterial hypertension and cold ischemia times greater than 36 hours (Table 6).

dIscussIon
The most important observation of this study was the high incidence of outcomes assessed.In our sample, In fact, the high incidence of outcomes may have hindered the emergence of other characteristics associated with hemodynamic maintaining of deceased donors as a risk factor for DGF and PKF.Furthermore, the high prevalence of laboratory abnormalities and severe hemodynamic disorders in this study population, as described above, also masked the impact of other characteristics on outcomes.The average length of ICU stay until multiple organ extraction was 5 days, 90% of them were using vasoactive drugs at the time of evaluation and 69% were being treated for an infection.The mean serum sodium was 156.1 mg/dl and creatinine was 1.5 mg/d, valueswhich were higher than normal reference ranges.This high incidence of outcomes and risk factors analyzed reflects the poor maintenance of deceased donors in Brazil.
In this study, age over 30 years, cold ischemia time greater than 24 hours and final creatinine above 1.5 mg/dl were associated with increased risk of DGF; and only over the age of 40 years, cold ischemic time greater than 36 hours and hypertension were associated with increased risk of PKF.These variables have been classically described as risk factors for the incidence of DGF and PKF. 12,18,19ge, serum creatinine and hypertension in deceased donors are characteristics that make up the definition of expanded criteria donor. 12When donor age is greater than 50 years and combined with other risk factors such as hypertension, serum creatinine higher than 1.5 mg/dl and vascular etiology for brain death, or when over 60 years alone, ranks the deceased donor as expanded. 12To receive a kidney from a deceased donor with expanded criteria is associated with a 70% increase in the risk of graft loss, 12 and the higher incidence of DGF, compared to deceased donor transplants that do not meet this classification. 18,191][22][23] Furthermore, the transplants with longer cold ischemia time are those using kidneys from expanded criteria donors 24 -organs already associated with a higher incidence of DGF and PKF, regardless of the waiting time until transplantation.Since they are less accepted by transplant centers, kidneys from expanded donors have longer allocation times.
Interestingly, the cause of brain death did not appear as a risk factor associated with any of the outcomes assessed in this study.The cause of brain death is also a variable that plays a role in the main DGF and graft function risk assessment scores including DDS, DCE and KDRI, 12,20,25,26 besides, even alone, it is associated with DGF. 27In this study, the high incidence of stroke as a cause of death (40%) may have prevented the appearance of the effects of this risk factor in the outcomes assessed.
Although the characteristics that confer increased risk for DGF and PKF already have a clear association with outcomes in the literature, one particular factor of this study was the observation that donors under the age of 50, who are not classified as expanded criteria donors, also had a greater risk of conferring DGF and PKF.It is possible that in Brazil, where approaches concerning the management of deceased potential donors are not standardized nor prioritized in emergency care or intensive care units, only very young donors can withstand major failures in the process of hemodynamic and electrolytic management before organ extraction, thus reducing the risk of age.Perhaps the inadequate management of deceased donors interfere negatively in organ quality, yielding a greater risk of the recipient developing DGF and PKF, even when younger donors are included.
The discussion on better hemodynamic management of deceased donors and strategies for reducing the incidence of DGF and PKF is pressing and becomes more important in the current context, in which the profile of deceased donors is changing, and the contribution of expanded criteria donors, and even donors whose hearts stopped have been increasing in some countries. 1,2As previously discussed, this group of donors is associated with increased risk of DGF and PKF and graft loss.Thus, strategies to improve the quality of donors and minimize further injury to these organs should be thoroughly pursued.Therefore, interventions aimed at improving the quality of donor management before the extraction of multiple organs have been studied.
Recently, Malinoski et al. 28 studied the impact of completing a set of goals in the management of the deceased donor vis-à-vis the incidence of DGF.To have mean arterial pressure readings between 60 and 100 mmHg, central venous pressure between 4 and 10 mmHg, ejection fraction greater than 50% in lowest possible dose of vasopressors, blood pH between 7.30 and 7.45, PaO 2 /FiO 2 over 300, serum sodium between 135 and 155 mEq/l, blood glucose less than 150 and urine output between 0.5 and 3 ml/kg/h, together, at the time of family consent, were associated with a lower incidence of DGF (17.3% vs. 30.1%,p 0.007).It is noteworthy that only 14% of donors studied met all the criteria at this time.
As in the present study, the study from Malinoski et al. 28 showed that only age, serum creatinine and TIF were associated with higher risk of DGF.The authors did not analyze the risk factors for PKF, as in the present study.
Among the variables that were significantly associated with worse transplantation outcome, only two are modifiable and, therefore, liable to intervention.They are: donor creatinine level and cold ischemia time.Therefore, based on this study, we need to install measures to reduce cold ischemia time up to 24 hours and decrease levels of serum creatinine to normal limits.The reduction in donor serum creatinine implies the need for a joint action between the Organs and Tissues Search Service and intensive care physicians to optimize hydration, minimizing the need for vasoactive drugs, and improve water balance, i.e. improving the management quality of the potential organ donor.To reduce the average time of cold ischemia, agility is needed in the process of locating and calling the recipient as well as minimizing clinical and laboratory evaluation times.The investigation regarding HLA compatibility, even before crossmatch results -strategy already adopted by some transplant centers, can help reduce this time.
This study has limitations because it is a retrospective study with a long evaluation period.Between 1998 and 2008, there were changes in the approach used to manage deceased donor.In addition, the follow-up time of recipients is of only six months.This alleviates the effects of other complications occurring after transplantation, such as acute rejection or infection; however, these events may have influenced the outcomes, particularly the PKF outcome.

conclusIon
The incidence of DGF and PKF was high in this population, possibly due to inadequate management of the deceased donor.Protocols for managing these donors should be adopted by the hospital critical care units, to improve the quality of organs offered for transplantation.A prospective study should be performed, evaluating the performance of these protocols and their impact on the function and survival of transplanted organs.

tAble 1
DemOgraphic, clinical anD labOratOrial characteriSticS Of the DeceaSeD DOnOrS The patients who developed DGF received kidneys from donors with higher mean ages (41.5 vs. 38.3years, p < 0.001), higher final creatinine mean levels (1.6 vs. 1.3 mg/dl, p < 0.001) and longer mean cold ischemia time (23.9 vs. 22.2 hours, p < 0.001).The

tAble 3 cOmpariSOn
Of DemOgraphic, clinical anD labOratOrial characteriSticS Of DeceaSeD DOnOrS in functiOn Of DevelOping Or nOt DelayeD graft functiOn (Dfg) rate of hypertensive donors was higher in the group with DGF (28.5% vs. 21.1%,p=0.003),respectively(Table3).After the logistic regression analysis with multiple variables, we observed a progressive increase in the risk of developing DGF from age greater than 30 years, with the final creatinine valuesabove 1.5 mg/dl and cold ischemia times longer than 24 hours (Table4).8% vs. 47.5%, p < 0.001) and associated hypertension (33.6% vs. 15.7%,p < 0.001).The mean cold ischemia time was almost one hour higher on the recipients with PKF (23.6 vs. 22.7 hours, p = 0.028).On the other hand, CPK levels were higher in patients without PKF (1444.4 vs. 20005.5U/l, p = 0.051) in the sixth semester of transplantation (Table

tAble 5 cOmpariSOn
Of DemOgraphic, clinical anD labOratOrial characteriSticS Of DeceaSeD DOnOrS in functiOn Of the preSence Or abSence Of pOOr kiDney functiOn (pfk) in the Sixth mOnth Of tranSplant