Objectives: Organs from brain-dead donors are the main source of allografts for transplant. Comparisons between living-donor and brain-dead donor kidneys show that the latter are more likely to demonstrate delayed graft function and lower long-term survival. This study aimed to assess the effects of various clinical and biochemical factors of donors on early- and long-term renal function after transplant.

Materials and Methods: We analyzed data from kidney recipients treated between 2006 and 2008 who received organs from brain-dead donors. Data from 54 donors and 89 recipients were analyzed.

Results: No relation was observed between donor sodium concentration and the presence of delayed graft function. Donor height was positively correlated with creatinine clearance in recipients in the 1 to 3 months after renal transplant. Donor diastolic blood pressure was negatively correlated with estimated glomerular filtration rate throughout the observation period. Donor age was negatively correlated with the allograft recipient’s estimated glomerular filtration rate throughout 4 years of observation. Donor estimated glomerular filtration rate was positively correlated with that of the recipient throughout 3 years of observation.

Conclusions: The results of this study indicate that various factors associated with allograft donors may influence graft function.

Key words : Delayed graft function, Graft survival, Renal graft

Introduction

Organs from brain-dead donors are the main source of allografts for transplant. Comparisons between living-donor and brain-dead donor kidneys show that the latter more frequently demonstrate delayed graft function (DGF) and lower long-term survival.^1-3 Brain damage leading to death causes system-wide disordered functioning. In potential organ donors, brain death has a detrimental effect on the function of organs taken for transplant. Brain-dead donors with beating hearts can have hemodynamic, hormonal, and metabolic disorders, as well as elevated inflam­matory processes. This study aimed to assess the effects of various clinical and biochemical factors occurring in donors on early- and long-term renal function after transplant.

Materials and Methods

We analyzed data from kidney recipients treated between 2006 and 2008 who received organs from brain-dead donors. All patients were transplanted in the Department of Transplantology of Pomeranian Medical University, and long-term outpatient care was delivered in the Department of Nephrology, Transplantology, and Internal Medicine of Pome­ranian Medical University. Data from 54 donors and 89 recipients were analyzed. All recipients received triple immunosuppressive therapy (tacrolimus, prednisone, and mycophenolate mofetil). Sodium concentration, creatinine concentration and clearance, central venous pressure, and systolic and diastolic blood pressure levels were assessed in brain-dead donors before organs were retrieved. We also analyzed donor age, weight, and cause of death. The causes of death were divided into 2 groups: vascular causes and cerebrovascular accidents versus others (here, mainly trauma and ischemia). In recipients, we examined early- and long-term kidney function after transplant. Early graft function was assessed as the need for hemodialysis treatment in the first week after kidney transplant. Patients who required hemodialysis during this period were diagnosed with DGF. Long-term kidney function was assessed as the level of creatinine at years 1, 2, 3, 4, and 5 after kidney transplant. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease method. We used the most common formula (4-variable Modification of Diet in Renal Disease), which estimates GFR using 4 variables: serum creatinine level, age, race, and sex.

Statistical analyses
We used Statistica 10 software (StatSoft, Kraków, Poland) for statistical analysis. Because the Shapiro-Wilk’s test showed that the distributions of most of the assessed quantitative variables were significantly different from normal (P < .05), we used nonpa­rametric Mann-Whitney U test and Spearman rank correlation test for statistical analyses. The risk of renal function loss depending on donor serum sodium concentration (≥ 155 vs < 155 mmol/L) was assessed by comparing Kaplan-Meier curves using the log-rank test. The risk of transplanted kidney rejection depending on donor serum sodium concentration was assessed using the 2-sided Fisher exact test. The relations between clearance values and nominal variables were analyzed using Mann-Whitney U test.

Results

Height
Donor height (mean of 175.1 cm, median of 176.5 cm, minimum to maximum of 163 to 190 cm) was positively correlated with creatinine clearance in recipients in the first 1 to 3 months after renal transplant: eGFR at day 1 showed P = .02, r = 0.52; eGFR at day 14 showed P = .09, r = 0.4; eGFR at day 30 showed P = .006, r = 0.62; and eGFR at month 3 showed P = .007, r = 0.6.

Diastolic blood pressure
The donor diastolic blood pressure values were negatively correlated with estimated creatinine clearance ratio (eGFR) throughout the observation period: eGFR at day 1 showed P = .02, r = -0.36; eGFR at day 7 showed P = .01, r = -0.39; eGFR at day 30 showed P = .01, r = -0.39; eGFR at month 3 showed P= .09, r = -0.26; eGFR at year 1 showed P = .03, r = -0.32; and eGFR at year 2 showed P = .02, r = -0.38.

Donor serum sodium concentration
Over a 60-month-long observation of kidney function in recipients using the log-rank test, it was shown that, in the group that received allografts from donors with sodium concentrations > 155 mmol/L, the risk of allograft function loss was significantly higher (P = .036) than in the group that received allografts from donors with sodium concentrations < 155 mmol/L (5 vs 0 cases of allograft function loss) (Figure 1). For sodium concentrations treated as a measurable variable, the hazard ratio of allograft function loss was 1.093 per 1 mmol/L(95% confidence interval, 1.010-1.184; P = .028) in the Cox proportional hazards model. No relation was observed between donor sodium concentration and the presence of DGF. At year 5 of the observation period, a negative correlation was identified with creatinine clearance at the time (P = .02). In our long-term analyses (60-mo follow-up) of recipients who received grafts from donors with sodium concentrations > 155 mmol/L, the likelihood of any type of acute renal transplant rejection was higher than in recipients of donors with sodium concentration < 155 mmol/L (30% vs 3%; P = .006, 2-sided Fisher exact test).

Age
Donor age was negatively correlated with allograft recipient eGFR throughout the 4-year observation period: eGFR at day 7 showed P = .03, r = -0.23; eGFR at day 14 showed P < .001, r = -0.35; eGFR at day 30 showed P < .001, r = -0.46; eGFR at month 3 showed P < .001, r = -0.38; eGFR at year 1 showed P < .001, r = -0.48; eGFR at year 2 showed P = .001, r = -0.39; eGFR at year 3 showed P < .001, r = -0.54; and eGFR at year 4 showed P = .002, r = -0.47.

Estimated glomerular filtration rate
Donor eGFR was positively correlated with recipient eGFR throughout 3 years of observation, and the P and r values are listed in Table 1.

Donor cause of brain death
Using the 2-sided Fisher exact test to compare 2 donor groups with a vascular versus posttraumatic or ischemic cause of death, we found that DGF was more frequent in recipients whose donors died of a vascular cause at 35% versus 7% (P = .007).

Discussion

Height
In our observation of recipient renal function, we found that donor height was positively correlated with recipient creatinine clearance in the first quarter after renal transplant. Adult height has been found to correlate positively with nephron number, with an estimated increase of 28 000 glomeruli/cm increase in height, and height was found to contribute to two-thirds of the variance in glomerular number. In 1988, Brenner and associates proposed that a small nephron number programmed during fetal devel­opment predisposed the individual to arterial hypertension and the development of chronic renal insufficiency.⁴ A reduced donor nephron number leads to a lower renal reserve and, thus, to a limited ability to adapt to renal injury. Since the proposal by Brenner and associates, investigators have been searching for various data to facilitate calculations of individual nephron numbers. Obviously, an important unfavorable factor is low birth weight; however, we did not have such information at our disposal for this study. Birth weight tends to be associated with subsequent height and therefore may be a confounder in this relation, but adult height is much more readily available than birth weight in clinical practice and therefore is useful.

Studies have shown that taller men have more nephrons.^5,6 In addition, hypertension and diabetic nephropathy are more common in shorter people.^7-9 Fewer nephrons and a lack of renal reserve can cause lower creatinine clearance in recipients during the initial period of renal injury that develops in the peritransplant period. Renal reserve is the most important factor influencing renal function during transplant. Shorter donors have fewer nephrons and hence lower renal reserve and lower creatinine clearance levels. After 1 year, creatinine clearance is no longer dependent on donor height, most likely because some of the injuries (eg, acute tubular necrosis) become subject to regeneration, whereas glomeruli demonstrate compensatory hypertrophy. The larger numbers of nephrons in the kidneys of taller donors certainly affect the long-term function of a transplanted kidney over 5 years after transplant. During this time, nephrons are damaged as a result of immune and nonimmune mechanisms. Renal reserve again becomes the most important factor influencing the function of the transplanted kidney. Unfortunately, in our study, patients were followed for only 5 years.

Diastolic blood pressure
Our analysis of the characteristics of brain-dead kidney donors showed that a higher diastolic pressure had a negative effect on both early- and long-term recipient kidney function. After aortic valves close, arterial pressure drops with the outflow of blood to the periphery. The value of arterial pressure during the diastole of the heart (ie, the diastolic blood pressure) depends on the duration of the diastole and the blood outflow pace, the latter of which is dependent on peripheral resistance. In summary, diastolic blood pressure is influenced by heart rate and peripheral vascular resistance. An elevated peripheral vascular resistance translates into an elevated renal vascular resistance. Even with small, so-called borderline, arterial hypertension, an increased renal vascular resistance is observed.

There are a number of factors in brain-dead donors that can affect elevated renal and peripheral vascular resistance. Oxidative stress is one of them. In most animal arterial hypertension models, oxidative stress is observed, with antioxidants decreasing arterial pressure. Reactive oxygen species induce a generalized and renal vasoconstriction by reducing the availability of nitric oxide.¹⁰ Reactive oxygen species also cause vasoconstriction through angiotensin II (ANG II), endothelin, and cate­cholamines.¹¹ Moreover, reactive oxygen species increase renal vascular resistance indirectly by stimulating the release of F2-isoprostane and adenosine.¹² Reactive oxygen species have also been observed to directly affect the vascular smooth muscles¹³ and to inhibit the production of vasodilators such as prostaglandin ^I2.14 Reactive oxygen species participate in the development of inflammation, mainly by stimulating nuclear factor κB (NF-κB). In arterial hypertension patients, an exacerbated inflammatory process is observed, taking the form of elevated concentrations of markers such as C reactive protein, tumor necrosis factor-alpha, interleukin (IL) 6, monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, adhesion molecules such as P-selectin, and intercellular adhesion molecule 1.15 It is not fully understood whether the exacerbated inflammation is the result or the cause of arterial hypertension. What is known is that brain cells do induce inflammatory responses.

A damaged blood-brain barrier allows cytokines to flow into the blood. Microglia induce the trans­cription of pro-IL-1B, which intracellularly trans­forms into the active form of IL-1B. This active form is released by cells after their apoptosis, lysis, or through lysosomal secretion.¹⁶ After they bind with their receptors, IL-1B induces the transcription of NF-κB and IL-6.¹⁷ When released into peripheral blood, IL-6 becomes the most important inflam­matory mediator. Furthermore, in the blood of brain-dead patients, increased levels of IL-8, IL-10, and interferon-beta have been observed.^18-20 Elevated activity of chemokines such as intercellular adhesion molecule 1, vascular cell adhesion molecule, E-selectin, P-selectin, and monocyte chemoattractant protein 1 have also been shown.¹⁸ In addition, as stated above, brain death is accompanied by an exacerbated oxidative process. Through oxidative stress and a more extensive inflammatory process, brain death causes an increase in systemic and renal vascular resistance, thus leading to growth in diastolic blood pressure. Renal vascular resistance is an acknowledged negative predictor of various renal diseases.²¹ It appears that the positive correlation between brain-dead kidney donor diastolic pressure and kidney recipient creatinine level observed in the long-term period may result from the exacerbation of processes stimulating systemic and renal vascular resistance. Diastolic blood pressure is an expression of inflammatory state and oxidative stress in the donor.

Donor serum sodium concentration
During our 60-month follow-up, we found that kidneys from donors with sodium concentrations > 155 mmol/L carried a larger risk of function loss than allografts from donors with sodium concentrations < 155 mmol/L. It is a well-known that the main cause of renal function loss is found in the process of chronic injury, taking the form of parenchymal fibrosis and tubular atrophy. Brain death is associated with a series of disorders. Diabetes insipidus is the most common endocrinologic complication resulting from disorders involving antidiuretic hormone release. This process is a result of ischemia of supraventricular and periventricular subthalamic nuclei. Kidneys are not able to concentrate urine, leading to the production of large amounts of unconcentrated urine. This causes hypernatremia (> 145 mmol/L) associated with increased plasma osmolality and hypovolemia. An indeterminable level of antidiuretic hormone is observed in 75% of brain-dead kidney donors.²² Desmopressin is the drug of choice for these cases.1

The influence of donor hypernatremia on the early- and long-term function of the transplanted kidney has not yet been well identified. The detrimental effects of donor hypernatremia on transplanted liver and heart function are well known. There is a higher percent of liver insufficiency in recipients of livers from donors with uncontrolled hypernatremia. It is assumed that hypernatremia above 155 mmol/L is one of the strongest risk factors for the loss of a transplanted liver.^23-25 One of the theories explaining the unfavorable influence of hypernatremia on transplanted liver suggests rapid changes of osmotic pressure between the extra- and intracellular spaces of a hepatocyte.²⁴ The 1-year survival rate is decreased in heart transplant recipients of donors with hypernatremia.²⁶

Kazemeyni and associates performed the only studies seeking the relation between serum sodium concentration in brain-dead donors and the function of a transplanted kidney.²⁷ They did not observe a relation between donor sodium concentration and recipient creatinine concentration 1 week after surgery. However, they found, as we did in our study, a positive correlation between donor sodium concentration and recipient creatinine concentration over a longer observation period (median of 20 mo).²⁷ The results of our study and the study by Kazemeyni and associates negate the theory that diabetes insipidus and hypernatremia damage the kidney of brain-dead donors due to hypoperfusion.

Hypoperfusion is known to lead to acute tubular necrosis, which is the main cause of DGF. In our study, donor sodium concentration did not influence early function of transplanted kidney. Roson and associates performed a study on healthy rats in which they induced hypernatremia through sodium overload. Rats were administered intravenous infusion of sodium chloride in increasing concen­trations over 2 hours, and kidneys from the rats were then retrieved for histopathologic assessment and immunohistochemical staining. The authors per­formed immunohistochemical reactions to assess transforming growth factor β1 (TGF-β1), L-smooth muscle actin, RANTES, transcription factor NF-κB, and ANG II. Light microscopy rendered no findings of histopathologic lesions. Immunohistochemical staining revealed the activation of the inflammatory process (ANG II, TGF-β1, NF-κB, L-smooth muscle actin, and RANTES), with changes becoming more profound when higher sodium concentrations were administered to the rats. The investigators suggested 2 possible mechanisms behind this response. The first one is that hypernatremia causes increased tubular sodium reabsorption (mainly in the proximal tubule), which significantly increases oxygen demand and leads to tubular ischemia. This leads to the generation of free radicals, which increase the production of ANG II and the activation of NF-κB.²⁸

Eisner and associates found similar results when studying cardiomyocytes exposed to hyperosmotic solutions, which led to the production of free radicals and the activation of NF-κB.²⁹ Similarly, in their in vitro studies on human mesangial cells, Chang and associates discovered that NF-κB was activated through an increased concentration of free radicals.30 In the second mechanism, increased plasma osmolality and cell dehydration are the main factors. Similarly to the first mechanism, this one leads to the activation of NF-kB, but without the presence of free radicals. Nuclear factor κB is a molecule activated in response to increased osmolality both in endothelial cells and in kidney interstitium.²⁸

In an in vitro study on enterocytes incubated in a hyperosmotic solution, activation of NF-κB was found to be responsible for the increased production of the proinflammatory chemokine IL-8.³¹ Other authors also identified an increased activity of NF-κB in response to elevated plasma osmolality.^32,33

It is known that NF-κB generates the production of proinflammatory factors and adhesion molecules. It also stimulates genes responsible for local ANG II production. Local ANG II synthesis in kidneys takes place in tubular epithelial cells and macrophages, and its concentration is 100- to 1000-fold higher than in plasma. Angiotensin II initiates the inflammatory cascade. It increases the synthesis of chemokines such as monocyte chemoattractant protein-1 and RANTES, cytokines such as IL-6 and TGF-β1, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Local renal ANG II is responsible for inflammatory process activation, and TGF-β1, produced as a result of an increased renal ANG II concentration, is responsible for activating mesangial myofibroblasts and transforming tubular epithelial cells into mesenchymal cells. This process starts interstitial fibrosis and tubular atrophy.^28,34 In the kidney donor, both cascade activation mechanisms can take place. Tubular ischemia due to increased sodium reab­sorption in proximal tubules is apparent in diabetes insipidus because of hypovolemia and kidney hypoperfusion. The relation between donor sodium concentration and long-term kidney function can be a result of an inflammatory process initiated by the activation of NF-κB. The activation of NF-κB is also tantamount with transcription of IL-2 on human T cells, which is the first step toward acute renal transplant rejection. The more frequent acute rejection of renal grafts from donors with sodium concentrations of > 155 mmol/L identified in this study may also stem from NF-κB activation.

Donor age
Donor age is a strong predictor of both early- and long-term renal function. This is related to the fact that the allograft is in “worse” condition with age, with the kidney more likely to have disorders of its physiologic and structural functions. These disorders involve reduced renocortical volume and increased amounts of sclerotic glomeruli, parenchymal fibrosis, and vascular sclerosis.35-38 In those who are age 60 years, glomerulosclerosis reaches 10% to 40%. This so-called glomerulopenia is the reason for lower glomerular filtration rates. Other authors have obtained similar results.^39-41

Donor creatinine levels and estimated glomerular filtration rates
With improvements in surgical technology and the development of immunosuppressive drugs, it is the native function of the kidney that is becoming one of the most important predictors of posttransplant renal function. Similar results were obtained by Jeong and associates, who observed a strong correlation between pretransplant creatinine clearance and long-term renal function after transplant.⁴² Similarly to donor age and height, this state is related to the number of active nephrons, which determines the posttransplant function of the kidney.

Cause of death
Using 2-sided Fisher exact test to compare 2 donor groups with vascular versus posttraumatic or ischemic causes of death, we found that DGF was more common in recipients whose donors died of vascular causes at 35% versus 7% (P = .007). Our results match those obtained by Marconi and associates, who identified a similar relation in his multiple factor analysis.⁴³ Because DGF affects chronic renal function, it can be stated that the donor cause of death has a direct effect on early-term and an indirect one on long-term renal function. The difference may be linked to the exacerbation of the brain death-related inflammatory process and hemodynamic, hormonal, and metabolic disorders. Moreover, patients who die of vascular causes carry other comorbidities, such as arterial hypertension, advanced atherosclerosis, and cardiac arrhythmia, which affect their renal function.

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