Risk factors for kidney stone disease recurrence: a comprehensive meta-analysis

Kidney stone disease (KSD) is a common issue with a high health care burden that affects the quality of life among the global population. The incidence rate of nephrolithiasis increases annually, estimated to be 14% in England and 10.1% in the United States [1, 2]. Its etiology is multifactorial and includes age, sex, geography, climate, race, dietary, genetic factors and so on [3]. Approximately half of the patients with nephrolithiasis will undergo a second episode of renal colic within 10 years [4]. More than 10% of patients could experience more relapses [5]. The probability of symptomatic stone recurrence in children reached 50% within 3 years [6]. Additionally, the recurrence rate of urinary calculi in patients with specific stone mineral compositions and morphologies can even be up to 82.4% [7].

The recurrence of KSD varies greatly among different patients. Some patients have nephrolithiasis only once, while others have frequent recurrences. Although preventive measures such as diet and drugs have been implemented and have achieved significant results, the effectiveness of these interventions is still limited [8, 9]. Identifying risk factors for relapse of KSD can help clinicians develop better preventive intervention plans for patients.

Existing studies have only summarized limited risk factors for KSD recurrence [10, 11]. Nevertheless, KSD recurrence is likely associated with several different risk factors. When multiple risk factors are present, systematic evaluation is positive for individualized treatment. In addition, the relationships reported in the existing studies between some known risk factors and kidney stone recurrence are inconsistent [12]. Thus, the aim of this meta-analysis was to comprehensively explore various potential risk factors for the recurrence of KSD.

This study comprehensively and systematically analyzed the association between various risk factors and the recurrence of KSD. We identified 12 risk factors for predicting the recurrence of KSD. Personal history of nephrolithiasis is vital for identifying the incidence of recurrence. Approximately half of the patients with asymptomatic nephrolithiasis will have symptoms when stones pass during the first stone formation [57]. The 5-year recurrence rate of patients with first-time symptomatic stones is approximately 20% [41]. This rate increases with each additional KSD episode [25].

White race seem to be at a higher risk for KSD than African Americans [68]. Interestingly, our results indicated that Caucasians may undergo more recurrences of KSD than other race patients. It is not exactly known why KSD has a greater recurrence rate in Caucasian, probably because of genetic factors [5]. Thus, clinicians need to take racial differences into account when developing strategies for kidney stone prevention for patients. Younger age may also reflect a genetic component that leads to the early presentation of stones and their recurrence [41].

Family history is associated with a high incidence of KSD, which may also be related to genetic factors. A recent meta-analysis identified 20 nephrolithiasis-associated loci, including CYP24A1, DGKD, DGKH, WDR72, GPIC1, and BCR locus which were predicted to affect vitamin D metabolism and calcium-sensing receptor signaling respectively [69]. Patients with a personal history of KSD, whether symptomatic or asymptomatic, also had an increased risk of recurrence. The recurrence rate increases with each additional kidney stone episode [70]. Furthermore, nonobstructing stones are independent predictors for symptomatic recurrence [41]. If these nonobstructing stones are not treated with surgery, they can pass in the future, become obstructive and then lead to recurrence of symptoms [71].

Obesity, diabetes, hypertension and hyperlipidemia are commonly considered the main clinical characteristics of metabolic syndrome [45]. Metabolic syndrome is related to many kinds of chronic diseases. Epidemiological survey points out that the prevalence of metabolic syndrome is increasing which affects almost a quarter of European population [72]. It is also considered to elevate the rate of nephrolithiasis formation [73]. The KSD patients with higher BMI are easier to experience recurrence in our study as well. A meta-analysis containing 13 cohort studies clarified that relative risk of kidney stones for a 5-unit increment in BMI was 1.21 (1.12–1.30) [74]. In addition, hypertension was also identified as a risk factor for KSD recurrence. This is an important finding because the mechanism of hypertension promoting renal stone formation and recurrence remains unclear. Only a few studies have examined the underlying mechanisms between them. Liu et al,. reported that changes in the blood pressure have a direct consequence on the urinary microbiome and this effect could promote the formation of KSD [75]. Therefore, the control and monitoring of blood pressure is necessary for prevention of KSD recurrence. This is also an important finding of this meta-analysis.

Patients requiring surgery also have a higher risk of KSD recurrence. Common surgical procedures for upper urinary calculi are multitudinous. We believe that compared with the patients receiving conservative treatment, the patients accepting surgery have more complex stone situations, including multiple stones or larger diameter of stone [27]. Pelvic or lower pole stones may contribute to the onset of symptoms in the future, as they may be the stones that have previously detached or formed from residual fragments after surgery [76]. Uric acid stone accounts for about 8% of all stone types [77]. Symptomatic recurrence rate for uric acid at 10 years was approximately 50% which is higher than calcium oxalate and hydroxyapatite stones significantly [78]. These data suggested the importance of stone composition analysis in first-time stone formers.

The American Urologic Association Guidelines and European Association of Urology Guidelines stated that 24-h urine was important for high-risk stone formers [9, 79]. Low volume and high urine concentration are both regarded as risk factors for the formation of nephrolithiasis [80]. Thus, higher fluid intake is recommended in current guidelines, but 24-h urine indexes contribution to our analysis were too weak [9, 79]. Nevertheless, patients who completed a 24-h urine test seemed to have a relatively high KSD recurrence rate. One interpretation is that the patients with more significant KSD are more likely to receive metabolic evaluation including 24-h urine [16]. Considering that the 24-h urine is only a test method, the completion of this test itself should not affect the recurrence of stones. Preventive interventions based on 24-h urine test results do not appear to be working. Considering the evidence for empirical treatment in reducing stone recurrence and the lack of evidence for management based on 24-h urine test outcomes to reduce stone recurrence, Samson et al. suggest that clinicians should consider what results are useful [19]. They questioned whether those providers interpreted 24-h urine test results or counseled patients effectively, or whether patients followed the recommendations.

Potassium citrate is generally considered a relatively safe and commonly used prophylactic for preventing stone recurrence [81]. The treatment of potassium citrate in this study did not seem to reduce the recurrence rate. This This may be related to being affected by the result from Liu et al. [40]. In their research, patients prescribed potassium citrate increased risk of recurrence. They thought that this result might be associated with confounding by indication.

To the knowledge of us, this is the largest and the most comprehensive meta-analysis to explore the risk factors on KSD recurrence. We tried our best to systematically collect and evaluate high quality researches which reported the risk factors for KSD recurrence. This is also the first meta-analysis demonstrate that hypertension, race, 24 h urine test completion, and ureterovesical junction stone are related to KSD recurrence. We are also the first to comprehensively explore the risk factor for radiographic KSD relapse.

There were still some limitations in this study. First, the data of risk factors for recurrence of KSD used in this analysis were reported directly in the articles enrolled. Part of the data were extracted from KM curves. Second, the follow-up times recorded in these enrolled articles were different. Third, only the studies reporting OR, HR or RR were enrolled. Finally, publication bias existed in two risk factors, which could influence our results. The study on this topic is currently very restricted. More well-designed studies exploring the risk factors for relapse of KSD are still required in the future.

12 risk factors including younger age, higher BMI, race of Caucasian, family history of nephrolithiasis, personal history of nephrolithiasis, suspected nephrolithiasis episode prior to first confirmed stone episode, any concurrent asymptomatic (nonobstructing) stone, hypertension, uric acid stone, pelvic or lower pole nephrolithiasis, surgery, and 24 h urine test completion were identified to be associated with relapse of KSD. Additionally, the patients with ureterovesical junction stone might have a lower risk in the relapse of KSD. These results could serve as the risk factors for constructing recurrence prediction models. It also supplied a basis for preventing the recurrence of KSD. Although all conclusions were obtained from results of this analysis directly, several risk factors should be interpreted with caution. More well-designed researches on this topic are needed.