Impact of Blood Pressure on Risk of Graft Failure or Death Among Patients After Kidney Transplantation in a 10-Year Observational Period: A Single-Center Retrospective Analysis

Abstract

Background

Hypertension is a risk factor for graft failure and mortality among kidney transplant recipients (KTRs). The aim of the study was to examine blood pressure (BP) as a factor that contributes to graft failure or death during a 10-year observation period.

Material/Methods

The study group comprised 70 KTRs who were treated according to their clinical state. Data were collected at 1 month and 1 year after transplantation and included office and ambulatory BP monitoring (ABPM) BP values, eGFR, proteinuria, and BMI. During the observation period, 6 patients died, and 10 lost the graft, but not during the first year.

Results

Office and ABPM BP values were within normal ranges and did not differ from each other. eGRF and BMI were higher at 1 year compared to 1 month after transplantation, and proteinuria decreased. Among those who died, DBP was lower compared to those of survivors with graft failure. Proteinuria and donor age were positively correlated with BP.

Conclusions

Monitoring of BP and adequate treatment of hypertension resulting in BP values within normal values among KTRs contribute to longer survival of the graft and recipient. Older donor age and proteinuria could predict post-transplant hypertension. Low diastolic BP of the recipient could increase the risk of death among KTRs. Despite the fact that ABPM is the blood pressure measurement method of choice, appropriate standard office measurement could also be used for BP monitoring.

Background

Transplantation is currently the treatment of choice for patients with end-stage renal disease (ESRD) and is associated with reduced mortality due to many factors, including cardiovascular disease (CVD). However, the population of kidney transplant recipients (KTRs) still remains at higher risk for CVD compared to the general population [1–3]. Hypertension is one of the most common traditional risk factors for CVD in this population, with prevalence between 70% and 95% [2,4–7].

The differences in the epidemiological data regarding hypertension in KTRs derive from different cut-off values. According to the Kidney Disease Improving Global Outcomes Guidelines (KDIGO) issued in 2021, hypertension is diagnosed when office blood pressure (BP) is higher than 130/80 mmHg and ambulatory BP monitoring (ABPM) exceeds 125/75 mmHg [2,8]. These values are in line with those proposed by the American College of Cardiology/American Heart Association in 2017 [9], but they differ from those established by the European Society of Cardiology/European Society of Hypertension in 2018, in which the cut-off values were 140/90 mmHg and 130/80 mmHg for office measurement and ABPM, respectively [2,10].

Risk factors for post-transplant hypertension include recipient factors present before transplantation, such as longstanding hypertension, genetic profile, age, increased body mass index (BMI), and endocrine factors. They also include factors related to ESKD and the transplantation itself, such as the donor’s pre-transplantation hypertension, donor age, higher than recommended sodium intake, poor allograft quality, the specific donor’s genetic profile or acute or chronic allograft rejection, and immunosuppressive medications, particularly steroids [11–13]. Literature data indicate that lowering systolic BP (SBP) decreases the risk of CVD and the overall mortality among KTRs. Is has also been attributed to better kidney function and graft survival. But despite these facts, the optimal BP among KTRs is still uncertain [2,14].

The main goal of post-transplant care is to improve graft and patient survival. Hypertension is established as a risk factor that could interfere with this goal. Therefore, we aimed to evaluate blood pressure monitoring and the possible impact on graft failure (GF) or patient death during a 10-year follow-up period.

Material and Methods

The Ethics Committee of the Medical University of Warsaw, Poland, approved the experimental protocol (No. KB/101/2004). All patients were advised about the purpose of the study and gave their informed, free, written consent to participate in the study. The study group comprised 20 (n=20, 28.6%) women and 50 (n=50, 71.4%) men who had undergone kidney transplantation (Tx). The mean age of KTRs was 39.46±12.21 years. The kidney donors comprised 29 (n=29, 41.4%) women and 41 (n=41, 58.6%) men, with a mean age of 42.43±14.54 years.

The study was conducted in the Department of Immunology, Transplantology and Internal Diseases. Inclusion criteria were informed consent to participate in the study and kidney transplantation due to ESRD less than 1 month prior to study enrolment. Data including eGRF, BMI, proteinuria and data regarding BP were collected 1 month (1mTx) and 1 year (1yTx) after transplantation. The ESRD resulted from glomerulonephritis in 49 (70%) recipients, adult polycystic kidney disease (APDKD) in 8 (11.4%), hypertension in 5 (7.1%), systemic lupus erythematosus in 6 (8.6%), and diabetes mellitus type 1 in 1 (1.4%). In 1 case, the reason for ESRD was unknown. All patients were treated according to their clinical state and received antihypertensive therapy according to current KDIGO recommendations, including various groups of drugs, which were mainly beta blockers (88.2% of KTRs 1mTx and 81.2% of KTRs 1yTx), calcium channel blockers (75.4% of KTRs 1mTx and 68.1% of KTRs 1yTx), and others such as diuretics, central acting sympatholytics, alpha-1 blockers, direct vasodilators, ACE inhibitors, and imidazoline receptor agonists.

BP was measured according to KDIGO guidelines regarding standard office measurement (SO) and ABPM [8]. ABPM measurement took 24 h. BP values were automatically registered every 20 min during the day (between 6 am and 10 pm) and every 30 min during the night (between 10 pm and 6 am). Mean 24-h values of SBP and diastolic BP (DBP) were calculated, along with separate mean values of night (N) and day (D) SBP and DBP. The observational period lasted 10 years. All participants survived the first year of observation. During the next 9 years, 6 (8.57%) patients died, while another 10 patients experienced GF (total, n=16 [23%]) and were referred to a dialysis program again.

Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics 25.0. Descriptive statistics were generated using standard parameters, including percentage, mean, and standard deviation. Between-group differences were analysed using a t test for dependent groups, and for multiple measures, repeated-measures analysis of variance was used. For comparison between the 2 groups of quantitative variables, the Mann-Whitney U test was used. Fisher’s exact test was used for categorical variables.

To detect significant relationships between variables, Pearson’s methods were applied for quantitative variables. For categorical variables and quantitative variables, predictive solution Eta was applied. Cox proportional-hazards regression analysis was used to estimate the impact on GF (death or graft lost) of SBP, DBP, and the coefficient of variation (CV) of BP. Results were considered significant at P<0.05.

Results

The selected clinical parameters, eGFR, proteinuria, and BMI evaluated at 1mTx and 1yTx are shown in Table 1. eGRF and BMI significantly increased at 1yTx compared to 1mTx, and proteinuria significantly decreased.

Table 1.

eGFR (ml/min), proteinuria (g/24 hours), and BMI evaluated at 1 month (1mTx) and 1 year (1yTx) after transplantation.

	1mTx (n=70)		1yTx (n=70)		P
	M	SD	M	SD
eGFR [ml/min]	56.08	21.49	66.49	20.23	<0.001
BMI	22.59	3.35	24.42	3.42	<0.001
Proteinuria [g/24 hours]	0.22	0.59	0.05	0.16	0.019

Table 2 shows the results of SO, ABPM SBP and DBP (mean values from a 24-h period), and a comparison between these measures. All values were within normal ranges, but SBP was significantly lower at 1yTx compared to 1mTx (SO: 130.76±12.39 vs 134.67±15.05, P =0.047; ABPM: 129.67±10.67 vs 136.89±16.54, P<0.001). There were no significant differences in DBP. There were also no statistically differences between SBP and DBP measured by SO compared to mean values measured by ABPM.

Table 2.

The results of standard office BP and ABPM (mean values from 24-hour period) at 1 month after transplantation (1mTX) and 1 year after transplantation (1yTx) and comparison between these measures.

	SO (n=70)		ABPM 24h (n=70)		P
	M	SD	M	SD
SBP 1mTx	134.67	15.05	136.87	16.54	0.198
DBP 1mTx	80.67	10.99	82.55	10.52	0.109
SBP 1yTx	130.76	12.39	129.67	10.67	0.408
DBP 1yTx	80.11	842.00	80.99	7.08	0.429

Table 3 shows the mean values of ABPM SBP and DBP during the daytime (D, 6 am to 10 pm) and night (N, 10 pm to 6 am the next day) at 1mTx and 1yTx and a comparison between these measures. 1mTx SBP was higher at night compared to the day, whereas DBP did not differ. At 1yTx, both SBP and DBP were higher during the day compared to night.

Table 3.

Mean values of systolic (SBP) and diastolic BP (DBP) measured with ABPM during daytime (D, 6 am to 10 pm) and during night (N, 10 pm to 6 am the next day) at 1 month after transplantation (1mTx) and 1 year after transplantation (1yTx).

	Night (n=70)		Day (n=70)		P
	M	SD	M	SD
SBP N-D 1mTx	140.68	21.13	135.41	15.45	<0.001
DBP N-D 1mTx	84.01	13.89	82.36	10.02	0.096
SBP N-D 1yTx	126.82	13.76	131.07	10.40	<0.001
DBP N-D 1yTx	77.91	9.41	82.62	6.92	<0.001

We assessed the correlations between mean values of SBP and DBP measured by ABPM at 1mTx and 1yTx, recipient and donor age, recipient and donor sex, recipient eGFR, proteinuria, and BMI. A positive correlation was found between SBP at 1mTx and donor age (r=0.33, P=0.006), and SBP at 1yTx was positively correlated with donor age (r=0.25, P=0.034) and proteinuria (r=0.32, P=0.007). There were no correlations between other pairs of variables.

To investigate the impact of hypertension on both GF (graft failure or recipient death [RD]) and RD alone, we observed the recipients for 10 years. During this period, 6 recipients died (but not during the first year of observation), while 10 patients experienced graft lost and were referred to dialysis. The comparison between GF and survivors did not show any differences at 1mTx or 1yTx in mean values of SBP and DBP measured by ABPM, day and night ABPM SBP and DBP. The results are shown in Table 4.

Table 4.

Comparison of mean values of SBP and DBP measured by ABPM, mean values of SBP and DBP measured by ABPM during daytime (D) and night (N) at 1 month (1mTx) and 1 year after transplantation (1yTx) between those with graft failure (graft loss or death) and 10-year survivors.

	Graft failure (n=16)			Survivors (n=54)			p
	Mean range	Me	IQR	Mean range	Me	IQR
SBP 1mTx	36.19	138.47	23.65	35.30	134.84	22.08	0.878
DBP 1mTx	37.63	82.42	12.12	34.87	8.44	15.31	0.634
SBP N1mTx	35.50	14.83	25.25	35.50	138.28	33.00	1.000
DBP N1mTx	38.81	86.29	15.99	34.52	83.08	18.36	0.459
SBP D1mTx	37.13	136.20	21.73	35.02	134.42	22.37	0.716
DBP D1mTx	38.00	82.82	10.02	34.76	81.78	14.43	0.576
SBP 1yTx	33.97	127.68	16.22	35.95	129.67	14.86	0.732
DBP 1yTx	34.88	81.13	14.48	35.69	82.40	9.91	0.889
SBP N1yTx	36.50	126.30	21.60	35.20	125.75	16.38	0.823
DBP N1yTx	37.44	79.66	20.20	34.93	79.72	13.05	0.665
SBP D1yTx	34.19	128.71	16.89	35.89	131.11	13.86	0.769
DBP D1yTx	33.75	80.89	10.26	36.02	84.47	10.42	0.695

To show the potential impact of BP values on the risk of death among GF group, we compared those who lost the graft (GL) with the group of patients who died (RD). This revealed a significantly lower mean value of DBP measured by ABPM and values during day and night at 1mTx, but not after 1yTx in the RD group. The results are shown in Table 5.

Table 5.

Comparison of mean values of SBP and DBP measured by ABPM, mean values of SBP and DBP measured by ABPM during day (D) and during night (N) after 1 month after transplantation (at 1mTx) between those who died (RD) and those who lost the graft (GL).

	RD (n 6)						p
	Mean range	Me	IQR	Mean range	Me	IQR
SBP 1mTx	7.50	132.17	22.50	9.10	144.07	27.43	0.515
DBP 1mTx	5.33	76.59	9.55	10.40	87.05	14.01	0.039
SBP N, 1mTx	7.00	134.03	25.68	9.40	149.59	27.87	0.329
DBP N, 1mTx	4.33	75.29	14.07	11.00	91.99	13.19	0.007
SBP D, 1mTx	8.00	132.28	19.34	8.80	142.20	26.40	0.745
DBPD, 1mTx	5.33	77.97	7.28	10.40	85.55	15.29	0.039

We investigated the impact of mean values of SBP and DBP measured with ABPM and the CV of SBP and DBP (standard deviation/mean value) at 1mTx and 1yTx on the GF using Cox regression analysis. SBP and DBP and the CV of SBP and DBP did not influence GF.

Discussion

This single-center retrospective study shows that a 10-year graft survival rate of 77% and KTR survival rate above 90% were obtained with complex post-transplant therapy that was continuously adjusted to the clinical state and provided with holistic care, including close monitoring of BP. Survival rates differ between regions and investigated time periods [15,16]. According to the Poltransplant Bulletin [17], the 10-year survival rate among KTRs in Poland varies in from 67% to 97% depending on the transplantation center, with an average of 74%. In the USA, KTRs’ 10-year survival rate varies depending on the race and ethnicity, with a mean value exceeding 70%, while the 10-year graft survival rate is below 50%. The USA results are lower than those reported by other countries [18]. However, the number of patients included into our studies was limited, and bias is possible.

Graft survival and KTR survival depend on many factors, including appropriate BP monitoring and possible hypertension control. This is critical in terms of prevention of adverse CVD events and cerebrovascular events, target organ damage, and kidney function decline [9,19,20]. The results of SBP and DBP measured by SO and ABPM were within normal ranges according to KDIGO guidelines after receiving appropriate treatment at both 1 month and 1 year after transplantation [8]. The mean SBP values at 1 month after transplantation were higher compared to 1 year after transplantation, which was beneficial since BP targets are initially less strict in order to maintain appropriate organ perfusion and omit the risk of graft thrombosis, but beyond the first month, BP values should be controlled as in the nontransplantation patients [9].

We also observed an altered diurnal pattern of BP, but only at 1 month after transplantation, which disappeared at 1 year after transplantation, and only in SBP. Diagnosis of altered diurnal BP is critical for implementation of adequate therapy [2]. Patients were also monitored for potential selected risk factors for CVD, including hypertension. At 1 year after transplantation, proteinuria was lower than at 1 month after transplantation, thus decreasing the risk for CVD and the consequences [19,20]. However, BMI increased, which could contribute to the occurrence of hypertension.

It was previously shown that KTRs gain an average of 4.1 kg of weight during the first year after transplantation, which constitutes about 7% of their BMI. Since the majority of KTRs showed insufficient knowledge about overweight or obesity prevention and possible consequences, including hypertension, appropriate educational programs should be considered for this group of patients [21]. Another risk factor for post-transplant hypertension in KTRs is donor age [22]. We confirmed the association of donor age and the values of BP. This is especially important since donor age has increased continuously since the 1980s [23].

We did not find any differences in SBP and DBP or in the diurnal pattern between patients with GF (resulting from graft loss and patient death) and those who survived with functioning kidneys during the whole observational period. The necessity of monitoring BP is undoubted since it has already been shown that each 10-mmHg increase in SBP was associated with a 5% increase in GF and a 13% increase in mortality risk [1,24,25]. Our results could derive from the fact that both SBP and DBP were properly controlled, and the values were within normal ranges. On the other hand, Malhotra et al [14] did not confirm any thresholds at which lower BP is associated with lower risk of allograft failure or eGFR decline in a large stable group of KTRs.

It should be considered that the clinical state of post-transplant patients is complex and unique, as is the pathophysiology of post-transplant hypertension, and several factors that are different from the general population could influence the hypertension outcomes. A transplanted kidney is denervated, and the autoregulation of kidney blood flow is therefore different from that of one’s own kidneys. The association between hypertension and GF or KTR death could not be direct but rather mediated by the increased risk of de novo CVD. Each 20-mmHg increase in baseline SBP is associated with a 32% increase in subsequent CVD risk [25]. Therefore, many scientists stress the continuous need for randomized controlled trials to determine the optimal BP in KTRs and to establish guidance for optimal treatment strategies [11,14,26].

After comparing the group of KTRs who died with those who lost their grafts but survived, we found that DBP measured by ABPM was lower in those who died, but only early after transplantation. The difference disappeared by 1 year after transplantation. These results are in line with the results of Carpenter et al [25], who showed that each 10-mmHg decrease in DBP was associated with a 31% increase in CVD risk and a 31% increase in mortality risk. Such an association was not demonstrated among KTRs with DBP higher than 70 mmHg [25].

BP variability (CV,%) is a predictor of CVD and mortality in the general population [28], so we also investigated the possible impact of CV on GF, but we did not find any. Ours results are in line with the results presented by Pagonas et al [27]. It was also shown that pressure variations somehow equalize after transplantation, as it has been found that during dialysis in patients with ESRD, the variations are significantly greater than after kidney transplantation [29].

According to KDIGO guidelines [8], BP should be measured with the use of the SO method or out of office with the ABPM method. Home BP monitoring (HBPM) is advised as a complementary to the SO method. We used 2 methods. The ABPM method is preferred by KTRs because this method could be used to diagnose masked hypertension and white-coat hypertension, which are common in this group of patients, and it enables BP measurement during the day and night [2]. Interestingly, we did not find significant differences between SBP and DBP measured by the SO method compared to ABPM. The SO method is more comfortable for patients than ABPM, and although it cannot totally replace ABPM due to the reasons mentioned above, it is reliable and credible and enables BP monitoring.

Limitations

KTRs are a special group of patients with multiple diseases, who undergo complex therapy, and several factors that are different from the general population could influence the hypertension outcomes. The number of patients included into the study was limited, which could have biased the results.

Conclusions

In conclusion, close monitoring of BP and adequate treatment of possible hypertension resulting in BP values within normal and advised ranges among KTRs contribute to longer graft and recipient survival. Older donor age and proteinuria could predict post-transplant hypertension. Low diastolic BP of the recipient could increase the risk of death among KTRs. Despite the fact that ABPM is the BP measurement method of choice, appropriate standard office measurement could also be used for BP monitoring.