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0RESULTS OF A STUDY OF THE ACETYLATION PHENOTYPE AS A CRITERIA FOR PROGNOSIS OF THE IMMEDIATE AND LONG-TERM PERIOD AFTER RELATED KIDNEY TRANSPLANTATION
1Bakhritdinov F.Sh., 2Ibadov R.A., 3Matkarimov Z.T., 4Komilova D.N., 5Elmurodova N.B.
1,2,3,4,5Republican Specialized Scientific and Practical Medical Center of Surgery named after
Academician V. Vakhidov https://doi.org/10.5281/zenodo.12684857
Abstract. The results of this paper demonstrate the significance of the acetylation phenotype in predicting the course of the immediate and long-term period following kidney transplantation (KT). The data revealed that the rapid acetylation phenotype of the donor and recipient affected the long-term survival of the kidney transplant, leading to a significant and rapid decrease in recipient's creatinine and urea levels within the first day after transplantation.
Keywords: kidney transplantation, acetylator status, rapid and slow type of acetylation.
Introduction. Taking into account limited epidemiological estimates according to the WHO, from 5 to 10 million people die annually from various kidney pathologies. This indicates an increased incidence of CKD [8].
Today, chronic kidney disease has gone beyond the scope of a nephrological problem and became a multidisciplinary and social problem that requires an integrated, coordinated approach to solving it on the part of executive authorities, healthcare system, medical institutions and doctors of various specialties. [1,5].
End-stage chronic renal failure requires renal replacement therapy, including hemodialysis, peritoneal dialysis and KT. [2].
The role of acetylation processes involving N-acetyltransferase (NAT) in the biotransformation of drugs has recently been examined. The activity of genetically determined processes of acetylation and oxidation manifests itself in the form of metabolic polymorphism according to bimodal (slow and rapid PhAc) distributions. A method has been developed for predicting the risk of complications after kidney transplantation, taking into account the determination of N-acetyltransferase activity and verified features of the relationship between acetylation phenotypes of donor-recipient pairs. [3].
In clinical practice, acetylation and oxidation statuses are also used as phenotypic markers in assessing predisposition to certain diseases [4,6,7].
Materials and methods. The study was conducted on 39 recipients after related KT, taking into account the acetylation phenotypes of both donors and recipients.
59% of recipients had a rapid acetylation phenotype.
41% of recipients had a slow acetylation phenotype.
Pic.1 shows the distribution of recipients by acetylation phenotypes (PhAc) and donor-recipient pairs depending on the combination of their acetylation phenotypes.
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Slow PhAc
Pic. 1. Distribution of recipients by F PhAc and donor-recipient pairs according to the
relationship of their PhAc
The rapid donor phenotype and the rapid recipient phenotype were combined in 38.5% of cases (group I).
The rapid phenotype of the donor and the slow phenotype of the recipient were combined in 15.4% of cases (group II).
The slow phenotype of the donor and the rapid phenotype of the recipient were combined in 20.5% of cases (group III).
The slow donor phenotype and the slow recipient phenotype were combined in 25.6% of cases (group IV).
Pic. 2 shows that in the study groups there were no statistically significant differences in initial creatinine levels (P>0.05). However, in the postoperative period, recipients in group I experienced a significant and rapid decrease in creatinine levels. For example, on the first day after surgery, the creatinine level was 218.8±14.2 |imol/l. While in group II this figure was higher and amounted to 332.3±29.5 ^mol/l (p<0.05). Groups III and IV also had higher creatinine levels after surgery: 286.4 ± 14.6 ^mol/L for group III and 373.2 ± 15.4 ^mol/L for group IV (P < 0.01).
On the 5th day after surgery, the creatinine level in group I was 95.2±6.4 |imol/l, and was significantly lower than in the other groups (p<0.05). Group IV, which combined slow PhAc from both the donor and recipient sides, had relatively higher creatinine levels throughout the study period.
Regarding urea (Pic. 3), the initial differences between the groups were not statistically significant (p>0.05). However, already on the first day after surgery, the urea level decreased significantly to 11.4±0.9 mmol/l in group I, while in group II this figure was 16.2±0.8 mmol/l (p <0.05).
Before operation
1 000 s s 800 1 ^mol/l
At the time of discharge 600 400 200 0 1'st day after operation
5'th day after —Gfi^r— Group II 3'd day after operation Group III Group IV
Pic.2. Dynamics of creatinine values (pmoM) after related KT depending on the acetylation
phenotype
Before operation
At the moment of discharge
mmol/L
1'st day after operation
5'th day after operation
3'd day after operation
Group I Group II Group III Group IV
* - P<0.05 (between groups I and II) Pic. 3. Dynamics of urea levels (mmol/l) after related kidney transplantation
A further decrease in urea occurred with approximately the same dynamics in all groups, while the urea level remained within the normal range (P>0.05) at the time of discharge.
As for GFR (glomerular filtration rate), it is one of the key indicators of kidney graft function. From Pic. 4 it can be seen that recipients in groups I and III had significantly better GFR indicators already on the 3rd day after surgery compared to the other groups, and averaged 57.2±1.8 ml/min and 46.5 ±0.9 ml/min (p<0.05). At the time of discharge, GFR in group I was 98.4±2.7 ml/min, in group II - 89.2±1.1 ml/min, in group III - 93.5±1.7 ml/min, and in group IV - 74.3±1.3 ml/min.
At the moment of discharge
3'd day after operation
Before operation
0 10 20 30 40 50 60 70 80 90 100
■ Group IV ■ Group III ■ Group II ■ Group I
Pic. 4. Dynamics of GFR indicators (ml/min) after related KT
When analyzing the dynamics of daily diuresis in recipients in the study groups, positive dynamics were revealed without a significant difference. For example, in group I, daily diuresis increased from 342.4±16.3 ml to 5450.4±320.8 ml on the 1st day after surgery. In group II, daily diuresis also increased from 327.5±4.2 ml to 3780.7±132.6 ml (p<0.05). Group III showed an increase in daily urine output from 333.5 to 4530.8±160.4 ml. Group IV remained relatively stable in this parameter (Pic. 5).
By the time recipients were discharged, daily diuresis was approximately equal in all groups, and the difference was not statistically significant.
Changes in the main biochemical parameters of the blood, reflecting the function of the transplanted kidney, were observed in groups I and III. A lower prevalence of delayed graft function resulted in a lower demand for hemodialysis in these groups.
Our study provides valuable information on the relationship between the acetylator status of the donor and recipient, as well as the nature of the post transplantation period after related kidney transplantation. Our results suggest that a rapid acetylator status in the recipient may
facilitate more rapid normalization of transplanted kidney function but is also associated with an increased risk of acute rejection.
Before operation 6 000
5 000
4 000
3 000
2 000
1 000
0
At the moment of
discharge
1'st day
after operation
5'th day
after operation
3'd day after operation
Group I Group II — Group III — Group IV
Pic. 5. Dynamics of daily diuresis after related kidney transplantation
Table 1 shows the immediate results of related KT in relation to the functional activity of the graft and KT in recipients, depending on the PhAc of the recipients and the combination of PhAc of the donor-recipient pair.
Table 1
The immediate results of related KT depending on the PhAc of the recipient and the combination of PhAc of the donor-recipient pair
Graft with primary function Acute rejection Delayed graft function Systemic complications
Group I (n=15) 15 (100%) 4 (26,7%) 0 (0,0%) 2 (13,3%)
Group II (n=6) 4 (66,7%) 0 (0,0%) 2 (33,3%) 0 (0,0%)
Group III (n=8) 7 (87,5%) 1 (12,5%) 1 (12,5%) 0 (0,0%)
Group IV (n=10) 2 (20%) 0 (0,0%) 8 (80%) 0 (0,0%)
Recipient's PhAc
Rapid PhAc (n=23) 22 (95,7%) 5 (21,7%) 1 (4,3%) 2 (8,7%)
Slow PhAc (n=16) 6 (37,5%) 0 (0,0%) 10 (62,5%) 0 (0,0%)
Thus, among recipients with rapid PhAc, primary graft function was observed in 95.7% (22 out of 23) cases, delayed graft function in 4.3% (1 out of 23), and acute rejection in 21.7% (5 out of 23). Among recipients with slow PhAc, primary graft function was observed in 37.5% (6 of 16) cases, and delayed function was observed in 62.5% (10 of 16) cases. There were no cases of acute rejection.
In all 15 (100%) cases of group I, the functional activity of the graft was assessed as primary functioning, however, in the period from 4 to 6 weeks of the post-transplant period, acute rejection was noted in 4 (26.7%) cases, which required pulse therapy. Delayed graft function was detected in 2 (33.3%) recipients of group II, 1 (12.5%) of group III and 8 (80%) of group IV.
Also, among the significant complications in recipients of group I, 2 (13.33%) cases of systemic complications due to acute kidney transplant rejection were recorded.
On the other hand, a slow acetylator status in the recipient may mean slow recovery of renal function, but with less risk of delayed graft function.
The status of the donor as an acetylator is also a factor in these relationships. The combination of the rapid acetylator status of the donor and recipient raises the possibility of unforeseen complications, such as acute rejection.
The survival table provided can be looked at with this factor in mind, as one of the factors influencing kidney graft survival after related KT. From the data presented in the graphical picture, in the context of the acetylation phenotype, we can attempt to interpret it.
Group I (rapid donor phenotype and rapid recipient phenotype). At 6, 12, 24 and 36 months, graft survival remains high (100%). However, at 48 and 60 months, survival rate begins to decline to 57.3%. This may indicate that at longer intervals after transplantation, the rapid acetylation phenotype (both donor and recipient) may influence long-term graft survival, with a lower rate than other groups.
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Group I (n=15) Group II (n=6) Group III (n=8) Group IV (n=10)
73,2% 73,2%
63,3% 63,3%
57,3% 57,3%
6
12
24 36 48
After KT, months
60
Pic. 6. Assessment of kidney graft survival depending on the acetylation phenotype
0
Group II (rapid donor phenotype and slow recipient phenotype). At 48 and 60 months after KT, graft survival decreased to 63.3%, which may indicate the influence of the slow donor phenotype on long-term survival.
Group III (slow donor phenotype and rapid recipient phenotype). At 36 months, graft survival decreased slightly (87.5%). However, at 48 and 60 months, survival also decreases to 73.2%, but this is higher than in groups I and II.
Group IV (slow donor phenotype and slow recipient phenotype). At 48 and 60 months, survival remains high (87.5%), which may indicate that the combination of slow phenotypes on both sides has high long-term graft survival.
The acetylation phenotype of the donor and recipient may influence long-term renal graft survival after related KT, according to the interpretation of the data.
Our results appear encouraging, and may serve as a starting point for further research, including a larger number of observations. It is important to understand the role of acetylator status in related renal transplantation to optimize the prevention and treatment of complications.
Discussion. Identifying groups of patients at different risk of complications after kidney transplantation may be useful, allowing to predict more accurately about their outcomes and take the appropriate medical precautions.
The results showed that a rapid acetylator status in the recipient and a slow acetylator status in the donor may contribute to a more rapid normalization of the function of the transplanted kidney.
The study highlights the need for further investigation into the role of acetylator status in kidney transplantation. These results could help improve the prevention and treatment of complications after kidney transplantation, which is critical for improving the results of this type of surgery. The study is an important step in this direction and may serve as a starting point for future studies with larger patient groups, despite the limited sample size.
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