Hypertension is the most common risk factor for cardiovascular disease and death. About 70–80% of the patients with chronic kidney disease (CKD) have hypertension, and the prevalence of hypertension increases as glomerular filtration rate (GFR) declines, such that over 80–90% patients with end stage renal disease (ESRD) are hypertensive.1

Living donor kidney transplantation becomes an important option for ESRD treatment owing to prolonged waiting times on transplant list.2 However, after donation there is an immediate 50% reduction in GFR.3 After nephrectomy up to two-thirds of donors fulfill the criteria for CKD stage 3 depending on baseline age and renal function.4 This reduction in GFR results in increased risks of ESRD and cardiovascular diseases.5 Effect of unilateral nephrectomy on blood pressure (BP) is not clear. However, a meta-analysis suggests a moderate increase of about 5mmHg in systolic BP at 10 years after donation.6 A study showed that in kidney donors; circadian rhythm of BP was disturbed as a function of GFR loss without affecting absolute levels of BP. Non-dipping of BP seemed to be the consequence of the loss of renal function.7

Renalase is a new flavoprotein secreted preferentially by the kidney (proximal tubules), which metabolizes catecholamines and may play a key role in the regulation of sympathetic tone and BP.8 Its levels are regulated by renal function, renal perfusion and plasma catecholamine levels.9 In literature, studies using the different commercial ELISA kits reported different results about the association between serum renalase levels and GFR in patients with CKD.9–12 There are several hypotheses that try to explain the discrepancy in levels of renalase when measured by western blot or different ELISA kits which were discussed in an extensive review about renalase.13 Recent studies demonstrated inverse relationship between plasma renalase and GFR in patients with CKD including renal transplant recipients.14–16 However, there are limited data about effect of the transplantation on plasma renalase and blood pressure levels in kidney donors and recipients before and after the transplantation. In this study, we hypothesize that; change in renalase levels after nephrectomy affect the blood pressure variations in donors and recipients.

The demographic and laboratory data of the study population are presented in Table 1. There were no significant differences in demographic characteristics between kidney donors and recipients. Mean serum creatinine, renalase levels, 24-h proteinuria and BP measurements were lower in healthy donors than patients with ESRD. Hemoglobin and GFR levels were higher in kidney donors than patients with ESRD. After transplantation, while the mean GFR and hemoglobin levels decreased, serum renalase levels increased in donors (Table 2). GFR was reduced by 34.9±5.7% in average from the baseline value of 115.0±9.4ml/min. Proteinuria did not change by nephrectomy. In addition, MAP levels slightly increased in donors after nephrectomy but remained within normal limits defined as SBP<140mmHg, and DBP<90mmHg. However, the night-time SBP and DBP levels increased, day-time SBP and DBP levels did not changed and the night/day ratio of MAP increased significantly by nephrectomy (Table 2). The rise in MAP after nephrectomy seemed related with night time BP elevations. In transplant recipients, while the mean GFR increased, the mean serum creatinine, serum renalase levels, and BP levels decreased after transplantation (Table 3). The night/day ratio of MAP slightly reduced in transplant recipients after transplantation (Table 3). However, we could not find any association between pre and post transplantation renalase levels and MAP levels (r=0.38, p=0.13 and r=−0.11; p=0.49 respectively), correlation analysis in whole study population showed that changes in MAP (ΔMAP) correlated with alteration in serum renalase levels (ΔRenalase) (r=0.31, p=0.0004) (Fig. 1) and change in GFR (ΔGFR) (r=−0.27, p=0.012). Similarly, we found a strong association between change in night/day ratio of MAP and ΔRenalase (r=0.35, p=0.001). ΔRenalase was also found to be inversely correlated with change in GFR (ΔGFR) (r=0.50, p=0.00057).

Fig. 1.

Correlation between change in mean blood pressure and change in serum renalase levels (r=−0.36, p=0.001) before and after transplantation.

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This study showed that kidney transplantation causes a shift in renalase levels, MAP levels and circadian pattern of BP in kidney donors and recipients. Changes in MAP and pattern of BP were associated with changes in renalase levels.

Renalase immunostaining in biopsy specimens from patients with ESRD was found clearly decreased in renal cortex.18 However, our results demonstrated that patients with ESRD have higher plasma renalase levels than healthy donors. This finding thought that high level of plasma renalase in ESRD patients may be sourced from increased extra-renal renalase production. Li G et al. showed that plasma norepinephrine levels were measured markedly higher before transplant in ESRD patients in comparison with donors.12 This finding suggested that sympathetic system was overactive in patients with ESRD. Over activated sympathetic system may have also possible role in the enhanced secretion of renalase from extra-renal sources. Renalase overproduction may be a compensate mechanism to suppress the sympathetic over activity in patients with CKD. On the other hand, transplant donors lost some glomerular function while plasma renalase levels increased after transplantation. Our findings showed that after donation, there was an immediate approximately 35% reduction in GFR in the remaining kidney. The decline in renalase clearance due to the low GFR may contribute the rise in plasma renalase levels. These findings were similar with the results of the study reported by Santaos et al. in which they showed that recovery of the renal function in transplant recipients was paralleled by a progressive decrease in plasma renalase levels and decline in glomerular function in donors was associated with increase in plasma renalase levels after transplantation.15

BP generally varies according to a circadian rhythm characterized by a reduction during sleep and an increase during wakefulness. The circadian fall in BP during sleep does not always occur in all individuals.19 Some individuals display a fall in BP during sleep (dippers) and others do not (non-dippers). Abnormal blood pressure diurnal rhythm (non-dipping) is more prevalent in patients with CKD. The underlying mechanism, however, is not clear, growing evidence indicates that sympathetic over activity may have role in development of hypertension and abnormal circadian BP variation in patients with CKD.20 In agreement with previous data,21,22 the study showed that patients with ESRD have higher MAP levels and night time BP levels compared with healthy donors. After transplantation, MAP and night time BP levels decreased in transplant recipients. There was a direct correlation between renalase decrease and decline in MAP in day and night time. This association suggested that beside the well-known factors, decreased sympathetic over activity and renalase levels due to improvement of the GFR may have role in the decline MAP and abnormal diurnal BP rhythm in patients with ESRD after transplantation. However, a study performed in heart transplant recipients could not demonstrate a link between renalase levels and sympathetic nervous system activity.23

In contrast to recipients, slightly increased MAP was measured in donors after nephrectomy. This MAP elevation mostly depends on the night time BP levels. In an earlier study Goto et al. suggested that unilateral nephrectomy disturbs the circadian rhythm of BP as a function of renal dysfunction in kidney donors.7 Our results seem parallel with the findings of Goto's study. Our results also showed that rise in night-time MAP was associated positively with increase in renalase levels in transplant donors. Both the rise in night-time MAP and plasma renalase levels in the donors after transplantation may be consequence of loss of GFR. The association between change in the plasma renalase levels and night-time MAP suggested that sympathetic over activity due to GFR decline may have role in rise in night-time MAP of donors after nephrectomy.

To the best of our knowledge, the study is the first study evaluating renalase levels and alteration in MAP and circadian rhythm of BP in transplant donors and recipients before and after transplantation. Renalase was suggested to play role in the pathogenesis of hypertension and kidney damage in general population; therefore, this connection may be established in kidney donors and recipients. However, we could not find the direct association renalase and BP levels. Our findings suggested that renalase may not have direct role on the blood pressure rise in transplant recipient and donors. However, its role may be suppressing the sympathetic system by degradation of catecholamines (noradrenalin, adrenaline and dopamine). Therefore; high plasma renalase levels may contribute blood pressure regulation indirectly due to balance the pressor effect of the catecholamines.24

Small numbers of the study population, lack of the measurement of catecholamines or sympathetic activity and lack of evaluation of renal clearance of renalase are the limitation factors of our study. The cross-sectional nature of the study also limits the ability to conclude any causal relationship between renalase, BP levels, circadian rhythm of BP and GFR.

In summary, this study showed that renalase levels are associated with change in MAP and circadian rhythm of BP in kidney transplant donors and recipients. Additionally, high levels of serum renalase were correlated with BP elevation and renal injury, presented by low levels of GFR in kidney donors. This observation is highlighted by understanding the possible pathophysiological significance of serum renalase in the development of hypertension in kidney donors. However, further prospective large-scale studies are needed to better define these observations.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None.