In the present study, we showed that higher UA levels may be associated with long-term post-donation adverse events and negative effects on eGFR in living donors. There are only a few short-term studies available that discuss the correlation between preoperative UA levels and postoperative renal function.(26-28) Cho et al.(27) concluded that a 1 mg/dl increase in the preoperative UA level was associated with a 1.7-fold higher risk of eGFR decline (>25%) at 6 months after donation in females. However, this trend was not observed in males. Similarly, Bravo et al.(28) demonstrated the association of high UA levels (>4.5 mg/dl) with the decrease in eGFR at 6 months and 1 year after donation in females only. However, Kulah (26) showed that these associations were also applicable to males. This author found that UA levels higher than 6 mg/dl in males and 5 mg/dl in females were associated with high Cr levels (>1.4 mg/dl in males and >1.3 mg/dl in females) at 6 months post-surgery. The present study corroborated these prior studies and, furthermore, extended them by demonstrating the long-term impact of baseline UA levels on adverse events related to the decline in renal function irrespective of sex.
Although higher UA had a negative impact on the postoperative eGFR recovery within the 5 years after donation in the present study, other factors such as BMI, BP, HbA1c, and LDL-C were found to be unrelated to the poor recovery of renal function. Nevertheless, hypertension,(41-43) hyperglycemia,(44, 45) and dyslipidemia (46, 47) have been reported to be associated with a decline in renal function in the general population. This discrepancy might be explained by the fact that a donor loses 50% of the renal function immediately after the nephrectomy. This sudden decline in renal function could affect UA excretion, which would certainly lead to higher UA levels.(48, 49) After living donation, UA levels increased by 15% (4.6 mg/dl to 5.3 mg/dl) at 6 months in a prior multi-center study(50) and by 20% (from 4.9 mg/dl to 5.8 mg/dl) at 1 year in the present study.
Based on the existing literature, we speculate that the sudden increase in UA after living donation might result in the poor recovery of renal function through endothelial dysfunction,(9) inflammation, vasoconstriction,(10, 11) and increased COX-2 expression (12), which may eventually lead to hypertension,(51, 52) hyperglycemia, and dyslipidemia.(53, 54) In fact, prior studies have suggested that hyperuricemia is associated with the occurrence of hypertension(51, 52) and dyslipidemia(53, 54) in the non-CKD population. In the CKD population, a randomized control study revealed that a 1 mg/dL increase in the UA level was associated with a 17% increased risk of all-cause mortality (HR = 1.17) and a 16% increased risk of cardiovascular disease mortality (HR = 1.16).(55) A meta-analysis suggested that a 1 mg/dl increase in UA level was correlated with the incidence of hypertension (relative risk = 1.15).(56) In addition, a Japanese cohort study showed that with every 1 mg/dL increase in the serum UA levels, there was a 19% increased risk for developing hypertension (odds ratio = 1.19, 95% CI: 1.11–1.27).(57) The present study also revealed that the cumulative incidence of adverse events, except for the prescription for hyperuricemia, was significantly different between the high and low UA groups (p = 0.047, log-rank test). Although the population in the present study was different from the CKD population in previous studies, we have provided new insight into the possible impact of an immediate increase in UA levels on new-onset hypertension and hyperlipidemia after donation.
Similarly, in the CKD population, a sudden cessation of anti-hyperuricemia drugs (such as allopurinol) is known to induce renal and endothelial dysfunction.(58) Furthermore, the withdrawal of anti-hyperuricemia drugs in patients with mild hyperuricemia results in the worsening of hypertension and the acceleration of the rate of kidney function loss.(52) As noted above, living donors face a similar situation to patients with a sudden withdrawal of anti-hyperuricemia drugs through the sudden increase in the UA levels. Given the difference in the baseline characteristics between living donors and the CKD population, more studies are needed to find ways to mitigate the risk of adverse events for living donors after donation.
We set the arbitrary cutoff value for the UA level according to the distribution in the present study. This cutoff value (5.5 mg/dl) was slightly lower than the standard value for patients with asymptomatic hyperuricemia. While the Japanese Society of Gout and Nucleic Acid Metabolism has suggested that the cutoff value for serum UA be 7.0 mg/dl regardless of sex and age,(36) the American College of Rheumatologists and the American College of Physicians did not provide any recommendation regarding the cutoff and treatment.(31, 32, 34, 35) In recent years, asymptomatic hyperuricemia has also emerged as a target for the treatment of various conditions. The optimal UA levels associated with the lowest development of cardiometabolic diseases were suggested as <5 mg/dL for men and 2–4 mg/dL for women.(33) Also, in an Italian cohort study, patients with mild hyperuricemia (4.6–5.5 mg/dl) had higher cardiovascular mortality (HR = 1.98, 95% CI: 1.22–3.23) than those with low UA levels (1.8–4.5 mg/dl).(30) Given these emerging results, our cutoff of 5.5 mg/dl seemed reasonable. However, further large randomized trials are warranted to elucidate the potential effect and treatment of asymptomatic hyperuricemia in living donors.
HbA1c was not associated with either adverse events or reduced eGFR. Normal HbA1c may not affect postoperative renal functions. A previous Japanese study at a single center reported that prediabetic donors without diabetic complications who showed an abnormal pattern in the 75 g oral glucose tolerance test did not develop ESRD after donation in the long-term.(59) Another study reported that although donors with impaired fasting glucose (100–125 mg/dL) could preserve their renal functions, a high proportion of them developed diabetes mellitus (15.56%) within 10 years after donation.(60) In our study, while 97.8% (179/183) of donors had non-diabetic HbA1c (<6.5%), 61.2% (112/183) of the donors had prediabetic HbA1c (5.6–6.5%). The postoperative eGFR did not differ between the normal and prediabetic or diabetic HbA1c donors. Our study corroborated previous studies and suggested that, in addition to the abnormal fasting glucose, prediabetic HbA1c may also not be associated with postoperative renal functions at 5 years after donation.
Other clinical parameters, apart from HbA1c, were found to predict the postoperative incidence of adverse events in the present study. Higher BMI (>22 or 25 kg/m2), higher BP (>130 mmHg), and higher LDL-C levels (>120 mg/dl) were associated with a greater occurrence of adverse events. These thresholds can be conceived as pre-disease status. The Japan Society for the Study of Obesity has defined obesity as a BMI of >25 kg/m2.(61) A Japanese cohort study demonstrated a reverse-J pattern for all-cause mortality, and the lowest risk of total mortality was observed in patients with a BMI of 21–27 kg/m2.(62) The American Heart Association guidelines for hypertension (2017) has revised the definition of BP for hypertension by lowering the threshold from 140/90 mmHg to 130/80 mmHg.(63) A randomized trial showed that intensive systolic BP control (<120 mmHg) resulted in lower all-cause mortality (HR = 0.73; 95% CI: 0.60–0.90).(64) The Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017 suggested that patients with a high risk of diabetes mellitus, CKD, non-cardiogenic cerebral infarction, or peripheral arterial disease should control LDL-C levels at <120 mg/dl as the primary preventive measure for dyslipidemia.(65) These active interventions for pre-disease status have become more important in recent years. The present study showed that this pre-disease status had a negative impact on the incidence of lifestyle-related diseases after living donation, but not on the renal function itself.
Most of the donors (92.0%) were comprehensively followed up for 5 years in the present study. The Japanese Society for Clinical Renal Transplantation and the Japan Society for Transplantation reported in a follow-up survey in 2018 that 20.9% of Japanese living kidney donors’ data could be aggregated by web-based methods and 79.5% of them were properly followed up for 5 years after donation.(66) The United Network for Organ Sharing and Organ Procurement and Transplantation Network mandates a 2-year follow-up after donation.(67) The study that used data from the Scientific Registry of Transplant Recipients showed that only 43% of centers in the United States met the 6-month, 1-year, and 2-year living donor follow-up criteria.(68) An additional clinical study on the safety of American living donors reported that 85.3% of donors could not be properly assessed due to the cessation of follow-up or lack of data.(69) This report also showed a high possibility that non-surgical adverse events occurred more than 2 years after donation.(69) Given the results of these studies, both the follow-up rate and period of the present study were sufficient to show reliable results. Furthermore, the present study highlighted the importance of long-term follow-up for the safety of living kidney donors.
There are some limitations to this study. First, this was a single-center retrospective study with a relatively small sample size, and only 44 adverse events were observed. This limited number of events may not be adequate to support meaningful multivariable analyses. In the present study, most of the living donors were limited to Japanese living in a single prefecture. Analysis of multiethnic and heterogeneous populations should be considered in further studies. Second, although de novo prescriptions are regarded as hard outcomes, both the timing and indication of the prescriptions are dependent on individual doctors. Living donors generally hesitate to take a new medication because they think they do not require it. Therefore, it is likely that the incidence rate in the present study was underestimated.