Hypertension and Donor Age in Living-Related Kidney Transplantation

Abstract

Introduction: Post-transplantational hypertension is one of the most important factors which has negative influence on survival of a graft and a patient. The objective of this study was to evaluate the influence of donor's age on hypertension and the outcome in living-related transplantation of the kidney. Methods: The research included 52 recipients of the graft, 30 women and 22 men who received living-related kidney graft in 5 years period. In experimental group there were recipients of grafts who's donors were 55 and older, and in control group recipients of graft who's donors were younger than 55. Age and sex of the donor, glomerular filtration rate of the donated kidney, previous dialysis treatment, kidney disease and number of months after transplantation were monitored. Blood pressure was measured once a day and average monthly value was assessed. Creatinine clearance was valuated once in six months. Functional kidney graft after 60 months was considered the one with serum creatinine ≤150μmol/l. Statistical analysis included t-test, Fisher's exact test, chi-square test, Kaplan- Meier curve and multivariant logistic regresion. Results: Experimental group included 23 examinees who received grafts from donors 55 years old and above (18 men and 5 women, average age 34,86}6,54, who have been treated for 35,33}37,59 months), and control group of 29 examinees from donors younger than 55 (16 men and 13 women, average age 31,69}10,5, who have been treated for 21,03}25,59 months). Average age of the donors in experimental group was 62,43}4,10 and 45,31}5,24 in control group. Mean creatinine clearance of the donated kidneys was 47,87}10,5 ml/min in experimental group and 51,19}10,1 ml/min in the control (p=0,005). Sixty months after transplantation graft was functional in 32,69% recipients of the experimental group and in 82,75% recipients of the control group. The average systolic blood pressure in experimental group was 146}20,00 mmHg, and in the control group 129}16,00mmHg (p<0,001). Average diastolic blood pressure was 90}11,00 mmHg in experimental group, and 83}10,00 mmHg in the control (p<0,03). Conclusions: Donor age has significant influence on long-term survival of the kidney graft in the living-related transplantation. Survival of the graft in examinees without hypertension is significantly longer. Treatment of post-transplatational hypertension is one of the most important tasks in the treatment of patients with transplanted kidney.

Hypertension and Donor Age in Living-Related Kidney Transplantation

Hypertension and Donor Age in Living-Related Kidney Transplantation

Mithat Tabakovic1, Enisa Mesic1, Senaid Trnacevic1, Emir Hodzic1, Fahir Barakovic1, Denial Tulumovic1, Goran Imamovic1, Mirza Atic1, Jasmina Bosnjic2, Mustafa Tabakovic3Clinic for Internal medicine, Clinical University Medical Center Tuzla, Bosnia and Herzegovina1 Clinic for Pulmonary Diseases and Tuberculosis, Tuzla, Bosnia and Herzegovina2Clinic for Cardiovascular Diseases, Tuzla, Bosnia and Herzegovina3

ORIGINAL PAPER

SUMMARY

Introduction: Post-transplantational hypertension is one of the most important factors which has negative inuence on survival of a gra and a patient. The objective of this study was to evaluate the inuence of donorsage on hypertension and the outcome in living-related transplantation of the kidney. Methods: The research included 52 recipients of the gra, 30 women and 22 men who received living-related kidney gra in 5 years period. In experimental group there were recipients of gras whos donors were 55 and older, and in control group recipients of gra whos donors were younger than 55. Age and sex of the donor, glomerular ltration rate of the donated kidney, previous dialysis treatment, kidney disease and number of months aer transplantation were monitored. Blood pressure was measured once a day and average monthly value was assessed. Creatinine clearance was valuated once in six months. Functional kidney gra aer 60 months was considered the one with serum creatinine 150mol/l. Statistical analysis included t-test, Fishers exact test, chi-square test, Kaplan Meier curve and multivariant logistic regresion. Results: Experimental group included 23 examinees who received gras from donors 55 years old and above (18 men and 5 women, average age 34,866,54, who have been treated for 35,3337,59 months), and control group of 29 examinees from donors younger than 55 (16 men and 13 women, average age 31,6910,5, who have been treated for 21,0325,59 months). Average age of the donors in experimental group was 62,434,10 and 45,315,24 in control group. Mean creatinine clearance of the donated kidneys was 47,8710,5 ml/min in experimental group and 51,1910,1 ml/min in the control (p=0,005). Sixty months aer transplantation gra was functional in 32,69% recipients of the experimental group and in 82,75% recipients of the control group. The average systolic blood pressure in experimental group was 14620,00 mmHg, and in the control group 12916,00mmHg (p<0,001). Average diastolic blood pressure was 9011,00 mmHg in experimental group, and 8310,00 mmHg in the control (p<0,03). Conclusions: Donor age has signicant inuence on long-term survival of the kidney gra in the living-related transplantation. Survival of the gra in examinees without hypertension is signicantly longer. Treatment of post-transplatational hypertension is one of the most important tasks in the treatment of patients with transplanted kidney.

Keywords: kidney transplantation, age of donor, gra survival, patient survival

1. INTRODUCTION

Post-transplantational hypertension in kidney graft recipients is one of the most important factors which has negative inuence on survival of a graft and a patient. Correlation between blood pressure and long-term function of graft survival is high signicant (1), and prevalence of post-transplantational hypertension is high and variation is between 60% and 85% (2). Renal artery stenosis, native kidneys, immunosuppressive therapy, especially calcineurin inhibitors (cyclosporine and tacrolimus), corticosteroids, graft malfunction, recurrent or de novo kidney disease, genetic predisposition of donor and recipient are most frequent reasons for post-transplantational hypertension in patients with kidney graft.

2. OBJECTIVE

The objective of this study was to evaluate the inuence of donors age on hypertension and the outcome in living-related transplantation of the kidney.

3. METHODS

The research included 52 recipients of the graft , 30 women and 22 men who received living-related kidney graft in ve years period. Examinees were divided in experimental and control group. In experimental group there were recipients of grafts whos donors were 55 and older, and in control group-recipients of graft whos donors were younger than 55. All donors were psychophysical healthy adult persons. Upper age was not limited. Kidney with less glomerular ltration rate (measured with radioisotope renogram methodTc99m DTPA) was taken from donors. After transplantation we used triple imunosupressive therapy which included corticosteroids, azathioprine or mycophenolate mofetil and cyclosporine.

In all kidney graft recipients were monitored age and sex of the donor, glomerular ltration rate of the donated kidney, previous dialysis treatmant, primary kidney disease and number

of months after transplantation. Blood pressure were measured once a day and average monthly value were assessed. All graft recipients were assessed every one or two months (blood glucose level, lipids, blood cell count, blood urea nitrogen, creatinine, uric acid concentration, proteins, electrolytes, bilirubins, transaminases, urin, quantitative proteinuria, creatinine clearance by Cockrofts formula (3) , kidney graft ultrasound, eye fundus and chest radiography).

Cyclosporine blood level were measured once monthly by uorescence polarization immunoassay (AxSTYM). The outcome in living-related kidney transplatation after 60 months was dened as: functional kidney graft (serum creatinine 150 mol/l), chronic graft nephropathy, other grafts malfunction reasons (glomerulonephritis de novo, infective complications, postoperative complications), terminal graft insufficiency with return on hemodialysis and letal outcome with afunctional or functional kidney graft.

Numeral datas are presented as measure of central values, arithmetic median and measure of dispersion, standard deviation. For hypothesis testing between two independent groups we used t-student test and Fishers exact test. For hypothesis testing of difference frequency (distribution) assessed parametres we used chi-square test. Survival of patients and grafts is presented by Kaplan-Meier curve (4). For all examinees in both groups were compared results of assessed paramtres with the outcome of transplantation after 60 months. For risk assessment we used Odds ratio with 95% condence interval.

For analysis of potential risk factors inuence on function of kidney graft survival we made logistic regression analysis. Independent variable was serum creatinine level, and risk factor variable high blood pressure of recipient. Cross relation risk points on measure of corelation between function of kidney graft survival and inuence of mentioned risc factors between experimental and control group. Potential risk factors used for multivariant logistic regression were age over 55 years and hypertension of recipients.

4. RESULTS

Most frequent primary kidney disease were chronic glomerulonephritis

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Hypertension and Donor Age in Living-Related Kidney Transplantation

Parametres: Control group

n =29

Experimental groupn = 23 Pvalue

Age (years) 31.80

10.50

34.90 6.60 0.210

Sistolic pressure (mmHg) 129.00

16.00

146.00 20.00 0.001*

Diastolic pressure (mmHg) 83.00

10.00

90.00 11.00 0.031*

Average sistolic pressure 131.00

13.00

142.00 13.00 0.031*

Average diastolic pressure 85.00

10.00

92.00 8.00 0.015*

Legend: parametres are presented as middle value X SD. P- signicant level *signicant level p < 0.05.

Table 1. Comparision of blood pressure in control and experimental group.

in 15 (65%) recipients in experimental and 14 (48,72%) in control group. Diabetes mellitus was register in two recipients in control group (6,89%), and in experimental group there were no diabetes mellitus. Kidney graft recipients were treated by almost same average dose of cyclosporine, 2,22 ml in experimental and 2,26 ml in control group.

Average age of recipients was 33,27 years. In age from 30 to 39 there were 25 (48%) recipients, 15 in age from 20 to 29 years (28%), six in age from 40 to 49 and three in age from 10-19 and from 50 to 59 years. Mother was donor in 22 (42,4%), father in 15 (28,8%), brother in 7 (13,5%), sister in 6 (11,5%) and other family members in 2 cases (3,8%). Total average age of the donors was 51,4 (9,7), in experimental group 62,43 (4,10) years (55-72 years), and in control gruop 45,31 (5,24) years. We did not conrm statistical significant dierence in age of recipients in experimental and control group. Average creatinine clearance value of donated kidney was 47,87 (10,5) in experimetal and 51,19 (10,1) ml/min in control gruop, what is statistical significant dierence (p=0,005).

From total 23 kidney graft recipients in experimental group there were 18 males (78,26%) and five females (21,74%), average age 34,86 (6,54), which had previous hemodialysis for 35,33 (37,59) months. Sixty months after transplantation graft was functional in 17 (32,69%) recipients, chronic graft nephropathy had ve (21,73%), three recipients were returned on hemodialysis treatment (13,04%), and four patients has died (17,39%). In one case we conrmed de novo glomerulonephritis (4,34%) over the biopsy. Average serum creatinine value of recipients in experi-

mental group after 60 months was 279 (224,00) mol/l.

From 29 examinees in control group, 16 were males (55,17%), and 13 were females (44,83%), average age 31,69 (10,9), which had previous hemodialysis for 21,03 (25,59) months. Sixty months after transplantation kidney graft was functional in 24 recipients (82,75%), three (10,34%) recipients were returned on hemodialysis treatment and two patients has died (6,89%). Average serum creatinine value of recipients in control group 60 months after transplantation was153,00 (48,00) mol/l.

We confirmed statistical significant difference between groups in sistolic and diastolic blood pressure values (table 1), but we did not register statistical significant dierence in glucose blood level, cholesterol and tryglicerides levels and hematocrit value.

According the prospects, there is statistical significant difference in creatinine blood level between the groups (p=0,005).

Difference of frequency high average sistolic pressure apperance between experimental and control gruops is not random (p=0,011). It means that there is corelation between high average sistolic presure and age of the donor.

Same conclusion we

get over Fishers exact test (p=0,006). We have calculated OR=5,38 (95% CI: 1,41-21,75), which means that chances for appearance of high sistolic pressure, are at least 1,41 times higher in experimental, than in control group.

Dierence of frequency high average diastolic pressure in experimental and control group is also not random (p=0,013), what conrms application of Fischers exacts test (p=0,009). Odds ratio (OR) for appearance high diastolic pressure in both groups is 5,85 (95%CI: 1,39-28,65). Chances for appearance of high diastolic pressure are at least 1,39 times higher than in control group.

In analysis potential risk factors inuence on function of kidney graft survival we made logistic regression analysis. For prognosis of possibility the outcome of graft survival, dependent variable is creatinine value, and as risc factors variables are age of donor and high blood pressure of recipient. Odds ratio signify on measure of corelation between function of kidney graft survival and inuence of mentioned risc factors. If kidney donated elder person, and recipient of kidney graft has high values

GroupControl Experimental Control-censured Exp.-censured

Slika 1 (Tabakovi M). Petogodinje preivljavanje grafta u primalaca eksperimentalne i kontrolne grupe.

Months

Figure 1. Five years gra survival

Picture 1. Five years graft survival

Sistolic pressure

<=130

>130

<=130 -censured

>130 -censured

Months

Figure 2. Five years gra survival related to sistolic blood pressure

Picture 2. Five years graft survival related to sistolic blood pressure

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Hypertension and Donor Age in Living-Related Kidney Transplantation

of sistolic and diastolic blood pressure, risk for rejection is 15,58 times higher, than in case when donor is younger person and recipient has not got high values of sistolic and diastolic blood pressure. In case when donor is younger person , and recipient of kidney graft has high values of blood presure, risk for high values of blood creatinine is 3,43 times higher.

If kidney graft recipient has not got high blood pressure, and donor is elder person, risk for high values of blood creatinine is 2,45 times higher.

Kidney graft function were monitored for ve years. For interpretation of the results we used Kaplan-Meiers curve. Possibility of graft survival in recipients with creatinine values over 150 mol/l for ve years period is 72,0%. As risc factors has been analysed high values of sistolic and diastolic blood presure and there were compared with groups without these risk factors. Possibility of survival in all cases until ve years is good. (77,5%). Graft survival in recipients of both groups after 60 montha is 77,5%. Five years graft survival of recipients in experimental group is about 70%, and of recipients in control group 82%. Dierence is statistical signifcant (Figure 1).

Five years graft survival in recipients with average sistolic blood presure which is equal or less than 130 mm Hg is100 %. When average sistolic blood presure of recipient was higher than 130 mm Hg, graft survival is 50% (Figure 2).

In group of recipients with average diastolic blood presure was equal or less than 80 mm Hg graft survival after 60 months iz 96%. When diastolic blood presure was higher than 80 mm Hg graft survival is about 70 % (Figure 3).

Kidney graft survival in recipients with creatinine blod values equal or less than 150 mol/L is 100 %, and in group of recipients with creatinine blod values higher than 150 mol/L, is about 72%. Dierence is statistical signifcant (Figure 4).

5. DISCUSSION

Success of kidney transplantation is evaluate over the survival of graft and patient.

Today for calculation of grafts and patients survival most frequent utilises Kaplan-Meier method (4), for half-life calculation of graft and patient. Sur-

vival of patients presents assessment of possibility that patient will be alive in period from the date of kidney transplantation until the date of death or last medical control (5). Graft survival presents assessment of possibility that kidney graft will function in period from the date of transplantation until the date of complete loss of function and recommended hemodialysis treatment, otherwise new transplantation or until the last medical control when graft was functional or until patients death (6). Graft stops to work when patient died, no matter that it had normal function before the death.

European and American studies declaim thatpatients surviving in living-related transplantation after rst year is 83-92% (7), and after ve years 70-79% (1, 6, 8). In our serial of patients ve years survival of patients is 77,5% (9). In our study survival of patients in ve years period is 77,5%. Age of donor signicantly inuence on graft survival, no matter is it living-related or cadaveric transplantation.

Inuence of donors age on long-term graft survival is well-known for many years before. When donor is older, rate of long-term survival is lower (10). Kidney transplantation from older donors is in association with more often postpone graft function, acute rejection and early appearing of chronic graft rejection, and consequence is unsatisfactory function of kidney graft (11).

In our series of examinees ve years graft survival in recipients which has got kidney from donor elder than 55 years, were 12 % less then in recipients which has got kidney from donors younger than 55 years, what is likewise as results from the other authors. High blood pressure is important risk factor with negative inuence on function of graft survival and it appears in 80% patients after kidney transplantation , be-

cause the alterations in kidney graft, primary kidney disease or disaese of the other organs. Correlation between blood pressure and long-term survival of the kidney graft is high signicant (p<0,0001). It has been proofed that this correlation is available for measuring of blood pressure in dierent time intervals after the transplantation (1). In 60-70% recipients which has taken calcineurin inhibitors after the transplantation has developed high blood pressure, and a lot of studies showed that it is independent predictor of graft insufficiency (12). In patients with systolic blood pressure under 130 mm Hg half-time of graft survival is 14,5 years. When systolic blood pressure is 160 mm Hg half-time of graft survival is under 10 years (13). In our research we presented that in the group of recipients with average diastolic blood pressure was equal or less than 80 mm Hg, graft survival after 60 months is 96%. In the group of recipients with average diastolic blood pressure was higher than 80 mm Hg, percent of graft survival is 70%. We has also showed that in kidney graft recipients with average systolic blood pressure was equal or

Diastolic presure

<=80

>80

<=80-censured

>80-censured

Slika 3 (Tabakovi M). Petogodinje preivljavanje grafta u odnosu na dijastolni krvni tlak

Months

Figure 3. Five years gra survival related to diastolic blood pressure

Picture 3. Five years graft survival related to diastolic blood pressure

Creatinine

<=150

>150

<=150-censured

>150 censured

Slika 4 (Tabakovi M). Petogodinje preivljavanje graftodnosvrijednostkreati

Rasprava

Months

Figure 4. Five years gra survival related to blood creatinine level

Picture 4. Five years graft survival related to blood creatinine level

13

14

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Hypertension and Donor Age in Living-Related Kidney Transplantation

less than 130 mm Hg, percent of graft survival after 60 months is 100%, and when average systolic blood pressure of recipients was higher then 130 mm Hg, percent of graft survival is 50%. These results are similar as the results from the other authors (1).

Effective blood pressure control presents key of success for the improvement of long-time survival of the kidney grafts, because the therapy protects graft function and reduce risk of cardiovascular complications after transplantation. The most frequent value for monitoring of the kidney graft function is serum creatinine level, but there is no standard value in post-transplantational period.

The most frequent used serum creatinine levels is from 1,5 mg/dl or 135 mol/L (14) and 2,0 mg/dL or 180 mol/L (15). Our results demonstrate that creatinine level in control group has presented statistically significat dierence comparing to creatinin level in experimental group (p=0,005), what approved inferior graft function associated with development of high blood pressure and poorly survival of recipients who have got kidney from older donors.

6. CONCLUSIONS

Age of the donor has signicant inuence on long-term survival of the kidney graft in the living-related transplantation. If kidney donated older per-

son, and recipient of kidney graft has high sistolic and diastolic blood pressure, risk from rejection is 16 times higher, than in case when kidney donated younger donor and recipient is without hypertension. Survival of the graft in examinees without hypertension is signicantly longer. Treatment of post-transplantational hypertension is one of the most important tasks in the treatment of patients with transplantated kidney.

REFERENCES

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2. Kasiske BL, Vazquez MA, Harmon WE. Recommendations for the outpatientsurveillance of renal transplant recipients. J Am Soc Nephrol, 2000; 11: 1-86.

3. Cockroft DW, Gault MN. Prediction of creatinine clearence from creatinine. Nephron, 1976; 16: 31-41.

4. Caplan E, Meier P. Nonparametric estimatim from incomplete observation. J Am Statist Assoc, 1958; 53; 47581.

5. Anonymus. Colaborative Transplant Study Newsletter 4.University of Heidelberg, Germany, 2002.

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In: Morris PJ (ed): Kidne Transplantation; Principles and Practice. WB Saunders Company, Philadhelpia, London, New York, St Louis, Sydney, Toronto, 2000; 693 715.9. Trnaevi S, Bazardanovi M, Mei E, Tabakovi M, Hodi E, Durakovi H, Imamovi G, Tulumovi D, Hasanovi E, Halilbai A, Steininger R, Mhlbacher F. Living-Related Kidney Transplantation at University Medical Center Tuzla (abstract). European Surgery ACA Acta Chirurhgica Austriaca, 2005; 37 ( Supl. 205): p19.10. Anonymous. Collaborative Transplant Study Newsletter 5. University of Heidelberg, Germany, 1991.

11. Leai V, ukanovic Lj, Blagojevi Lazi R, Radivojevi D, Markovi V, Petroni V, Bori Z, Marinkovi J. Living related kidney donors over 60 years old. Transplant Int, 1996; 9: 109-14.

12. Mange KC, Cizman B, Jae M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA, 2000; 283: 633 -8.

13. Ponticelli C, Montagnino G, Aroldi A. Hypertension after transplantation. Am J Kidney Dis, 1993; 21 (Suppl 2): 73-8.

14. First MR, Vaidya PN, Maryniak RK, Weiss MA, Manda R, Filder JP, Penn I, Aleksander JW. Proteinuria following transplantation: Corelation with histo-pathology and outcome. Transplantation, 1984; 38: 60712.

15. Cosio FG, Falkentrain MF, Pesavento TE. et al. Patient survival data after renal transplantation II. The input of smoking. Clin Transplant, 1999; 13: 336-41.

Corresponding author: Midhat Tabakovic, MD, PhD. UKC Tuzla. Bosnia and Herzegovina.

E-mail: [email protected]

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