Urinary KIM-1 has been considered to be a biomarker for tubulointerstitial damage and repair and is not detected in severely damajged tubules . Inconsistent results about the relationships between urinary KIM-1 and clinical parameters in IgAN have been derived by previous studies. The earliest study on the correlation between urinary KIM-1 and IgAN was made by Van Timmeren et al. . The authors studied 102 patients with various kinds of kidney diseases including IgAN and found that urinary KIM-1 correlated negatively with renal function but not with proteinuria. However, there were only 10 patients with IgAN in that study. Subsequent studies focusing on patients with various stages of IgAN got different results [16, 18]. In the current study, we found no correlation between urinary KIM-1 and proteinuria, as well as between urinary KIM-1 and renal function for IgAN patients with normotension, normal renal function and mild proteinuria, and the proportion of patients with elevated urinary KIM-1 was lower than previous studies [16, 18]. We speculated that the heterogeneity of the selected patients might contribute to the differences of the results.
Oxford classification is the first specially-designed pathological system for evaluating the prognosis of IgAN. Among all 4 variables, tubular atrophy/interstitial fibrosis has been indicated to have the most predictive value by different validation studies [10–12]. In the current study, the patients with elevated urinary KIM-1 had more severe tubulointerstitial injury (5/18 patients with elevated urinary KIM-1 had T1 score, while no patient with normal urinary KIM-1 had T1 score). Although no difference of the response to treatment between patients with and without elevated urinary KIM-1 was observed during a short-term follow-up, it seems that the long-term prognosis of the patients with elevated urinary KIM-1 should be paid more attention.
Although KIM-1 is a sensitive and specific biomarker for the tubulointerstitial damage, elevated urinary KIM-1 can be observed not only in the kidney diseases characterized mainly by tubulointerstitial damage, but also in that characterized exclusively by globular damage (such as minimal change disease) . In these diseases, tubulointerstitial damage should be due to reabsorption of protein. So urinary KIM-1 is a marker of the disease activity, however when tubules and interstitium are extremely damaged, KIM-1 will disappear. In the current study, significant correlation between urinary KIM-1 and crescent formation was found in patients with mild IgAN. Previous studies indicated more than 20% of IgAN patients could be found to have crescents on the initial biopsy [24–26]. Poor prognosis of crescentic IgAN has been generally recognized by clinicians . Coexistence of the cellular, fibrocellular and fibrous crescents reflects the process of slow progression of IgAN. Although crescent formation was not demonstrated to be an independent risk factor of ESRD in the Oxford classification, the significance of crescent formation in IgAN should not be neglected, because patients with rapidly progressive kidney failure were excluded when developing the Oxford classification.
IgAN is a kind of glomerulopathy and the tubular/interstitial injury should emerge following the glomerular injury. The chronic glomerular damage causes local microcirculation barrier, and then causes kidney ischemia and damages the tubules and interstitium. Although no correlation between crescents and urinary KIM-1 was found in 18 patients with crescentic IgAN, the urinary KIM-1 level of these patients was higher than that of patients with mild IgAN and the tubular/interstitial injury was much more severe (72% patients with crescentic IgAN were of T2 score). Thus, we speculated that crescents formation might be able to cause tubular/interstitial injury and then induce the expression of KIM-1 indirectly. It was noteworthy that for patients with mild IgAN, it was the fibrous crescent not the cellular crescent that correlated with urinary KIM-1. Fibrillation of crescents means the acute damage of glomeruli turn to be chronic and irreversible, and the microcirculation of interstitium will be injured inevitably. Thus, the correlation between fibrous crescents and urinary KIM-1 found in patients with mild IgAN might be a reflection of the ischemic injury of tubules and interstitium caused by the irreversible glomerular damage.
Although the exact reason is still unclear, previous studies indicated that vascular lesions in IgAN were very common [27, 28]. Since vascular lesions can influence the blood supply to the glomeruli, tubules and interstitium and cause more damage to the glomerular and tubulointerstitial tissues, it might also influence the expression of KIM-1. In the current study, no significant difference of the incidence of vascular lesions between patients with and without elevated urinary KIM-1 was found. However, since the p-value of the comparison had reached 0.057, we thought that the result might be reversed when the number of patients could be enlarged enough.
There are some limitations to the present study. First, According to Oxford classification, the histologic lesions of biopsy of patients with clinically mild IgAN were relatively small. The proportion of patients with T1 was low and no patient was found to be with T2. This might have an influence on the analysis of the relationship between urinary KIM-1 and the tubulointerstitial injury. Second, urinary KIM-1 was measured at a single time-point and it is unclear whether the level of urinary KIM-1 fluctuates on different occasions. Finally, since the time of follow-up is short, we could not judge the long-term outcome of these patients at present. A large-scale analysis with a long time follow-up is warranted.