After a thorough review of relevant research, we found that our study is the largest-scale population-based study to explore the relationship between KCN and subsequent CKD. We analysed 4,609 KCN patients ≥ 12 years and 27,654 matched controls. The results indicated a significantly increased risk of CKD in male KCN patients compared with controls. The study also found that KCN is an independent risk factor for CKD in the total cohort of male participants especially in male patients ≥ 40 years of age (Table 3) after accounting for age, hypertension, hyperlipidaemia, and diabetes mellitus.
To our knowledge, several studies have investigated the association between KCN and various renal disorders [24–26]. This association has been reported in case reports or small case series including Noonan’s syndrome , Alport’s syndrome , and Leber’s congenital amaurosis . Most of these renal disorders are congenital disorders involving multiple organs. These studies were also limited by small sample sizes. In contrast, our study enrolled KCN patients ≥ 12 years old and is the largest nationwide, population-based cohort study to investigate the risk of CKD following KCN in Taiwan to date.
Structures of the cornea stroma are rich in ECM composed of collagen components . The intraglomerular mesangial cells of the kidney are also embedded in an ECM matrix comprised of collagen IV, V, fibronectin, laminin, and proteoglycans . Stromal degradation and thinning is the most important feature of KCN. This ECM remodelling is due to increased levels of proteases such as MMPs . Gelatinases MMP-2 and MMP-9, which are dominant regulators of ECM formation and breakdown in the glomerulus, cleave basement membrane components, and degrade the ECM structures of kidney tissues [10, 11]. An upregulation of MMP and dysregulation of MMP/ tissue inhibitor of metalloproteinase activity have been reported in matrix remodelling in different stages of CKD and play a role in the progression of CKD [10, 11, 27]. These similar patterns of remodelling in the extra cellular matrices associated with the over-expression of proteolytic enzymes may imply a link between KCN and CKD.
Although KCN was previously characterized as a non-inflammatory condition, several recent studies have suggested that inflammatory processes play a role in the pathogenesis of KCN [28, 29]. Numerous elevated inflammatory markers, such as IL-6 and TNF-α were found in the tears of KCN patients indicating an inflammatory component in the development of KCN [17, 30]. Increased inflammatory markers may likely be the common pathophysiological mechanism of KCN and CKD. Several studies have found higher inflammatory markers, include IL-6 and TNF-α, in CKD patients compared to healthy controls. The amount of serum IL-6 and TNF-α elevated was consistent with eGFR reduction and reached its highest levels in severe CKD patients [12, 18]. This common increase in proinflammatory cytokines may explain the association KCN with subsequent CKD formation.
The observed male predominance in the subsequent development of CKD in KCN patients may be due to aldosterone related MR activation in CKD. The MR is associated with the activation of a variety of pathological processes including remodelling, fibrosis, and inflammation in CKD . Several studies have found that activation of the MR related to aldosterone may have a major impact on the progression of CKD symptoms including elevated blood pressure, proteinuria, and renal fibrosis.[21–23] Further experimental studies have demonstrated that using MR antagonist agents could slow down the progression of CKD [21–23]. Because sex hormones can act through receptors expressed in the ocular tissue, for example, the effects of androgens rely on the androgen receptors present in corneal tissue, they may be associated with various ocular pathologies. Although Clinical information about sex hormones in KCN patients is scarce, recent studies have investigated the role of hormonal changes on corneal structure in KCN patients [19, 20]. Mckay et al. reported a significant increase of salivary dehydroepiandrosterone sulphate (DHEA-S, a common precursor of androgens) in KCN patients of both genders . Rabab et al. reported in their preliminary studies that exogenous DHEA led to significant upregulation of collagen type III and cellular fibronectin suggesting that DHEA may drive human keratotic cornea towards a fibrotic change . A similar fibrotic change related to androgen or miniralocorticoid may be the link between KCN and subsequent CKD development in male patients.
It is worth noting that the increase in adjusted HR of CKD in male KCN patients is dependent on age, especially in male KCN patients ≥ 40 years who are 19.83 times more likely to develop CKD after accounting for other comorbidities (Table 3). Unlike KCN which usually occurs during puberty followed by 10–20 years of progression until it stabilises in the third to fourth decade of life, CKD is an age-dependent disease. CKD is a progressive disease that results in end-stage renal disease through pathological renal interstitial fibrosis leading to irreversible loss of renal function [8, 9]. In addition, several studies indicate that the demographics of KCN patients vary widely from 51.0 years to 63.6 years worldwide while CKD patients are usually ≥ 40 years of age [6, 32, 33]. Hence the increased risk of developing CKD in male KCN patients who are ≥ 40 years may be due to the age-dependent progressive nature of CKD.
Some studies have reported several comorbidities associated with CKD, such as hypertension, diabetes mellitus, and hyperlipidaemia [6, 7, 34]. In this study, we appraised these comorbidities in KCN patients and discovered that hypertension is the only contributing factor for CKD in male participants in both groups (Table 3). This finding is consistent with some previous studies that identified hypertension as a main risk factor for CKD [6, 7, 34]. Hypertension is a growing non-communicable disease and an important leading cause of CKD [6, 34]. Hypertension accelerates the decline of renal function regardless of aetiology . Maintaining blood pressure below 140/90 mmHg, lifestyle modification, and antihypertensive drug therapy should be advised to patients with hypertension to reduce the risk of cardiovascular events [7, 35]. This suggests that male KCN patients with hypertension should also be considered for cardiovascular monitoring to reduce the risk of subsequent CKD.
There are several strengths in our study. First, our nationwide population-based study included a large sample of KCN patients resulting in superior statistical power and precision in risk appraisal. Second, patients with visual disturbances visit ophthalmologists and patients with renal problems visit nephrologists leading to reduced misdiagnoses, and selection bias in referral centres. Third, this cohort study was conducted with longitudinal data of up to 10 years, and potential confounding bias was eliminated by adjusting for hypertension, hyperlipidaemia, and diabetes mellitus.
There are several limitations in this study. Because the medical history of each participant in the study can only be tracked back to the year 1996, we cannot confirm whether the controls had a history of KCN before January 1996. Additionally, several important sociodemographic characteristics such as alcohol consumption, tobacco smoking habits, and laboratory data including blood pressure, blood sugar, or eGFR are not available in the claim database of the National Health Research Institute. Finally, incorrect classification is possible as the diagnosis of KCN, CKD, and other comorbidities relied on ICD-9-codes.