The revised version 2018 of the nationwide web-based registry system for kidney diseases in Japan: Japan Renal Biopsy Registry and Japan Kidney Disease Registry

The J-RBR/J-KDR collects clinical data and pathological diagnoses of patients from the collaborative institutes in Japan. These data are registered via the web page of the J-RBR/J-KDR (Fig. 1) utilizing the system of Internet Data and Information Center for Medical Research (INDICE) in the University Hospital Medical Information Network (UMIN). The essential points of this revision are described below.

The clinical diagnoses of the patients are selected from the list shown in Fig. 1, which includes urinary abnormalities, acute nephritic syndrome, chronic nephritic syndrome, rapidly progressive nephritic syndrome, nephrotic syndrome, acute kidney injury (AKI), chronic kidney dysfunction, and others. These clinical diagnoses are defined by current related guidelines or WHO classification [26,28‐31]. The revised system of the J-RBR/J-KDR 2018 allows the registration of multiple clinical diagnoses for each case in case of overlapping clinical symptoms e.g., an MCD case demonstrated with acute kidney injury. A new category for urinary abnormalities was added to describe the patients whose biopsy was followed by asymptomatic mild hematuria and/or proteinuria.

In this revision, we added more items for detailed pathological classification of several glomerular diseases, such as the Oxford Classification [32‐34] and Japanese Histological Grade [35] for IgA nephropathy, the Columbia Classification for FSGS [36], the International Society of Neurology and the Renal Pathology Society (ISN/RPS) classification for Lupus nephritis [37], the International Study of Kidney Disease in Children (ISKDC) classification for Henoch-Schönlein purpura nephritis [38], and the European Vasculitis Study Group (EUVAS) classification for ANCA-associated vasculitis [39].

In patients who received immunosuppressive treatment before biopsy, laboratory data at biopsy may be modified by the treatment. Information on the treatment status including whether the case is a new onset one or relapsed one will also be collected. The “baselines” for collecting clinical data are defined as follows (Fig. 1). Regarding the cases in which immunosuppressive treatment started or strengthened within 1 month prior to biopsy, the time just before the initiation of treatment is considered to be the baseline. In the cases in which immunosuppressive treatment started or strengthened more than 1 month prior to biopsy, the time of biopsy is considered as the baseline. In the cases in which immunosuppressive treatment started or strengthened within 1 month prior to biopsy but the data just before the treatment were not available, the time of biopsy is considered to be the baseline.

The clinical diagnoses in the revised system enable to describe the clinical status of the patients more accurately based on the following modifications. First, the revised J-RBR/J-KDR allows the selection of all clinical diagnoses that are appropriate for the patients from the 8 listed items. Although the clinical indications for kidney biopsy vary [6], we sometimes experience patients who have multiple clinical symptoms that lead to biopsy. For example, 20–30% of the patients with MCD were reported to have demonstrated AKI [42]. If only one clinical diagnosis is registered in such cases, both the clinical diagnoses, nephrotic syndrome and AKI, could be underestimated. Second, the items indicating abnormalities in urinalysis were added. In Japan, a nationwide annual health examination program including urinalysis screening for all community residents has been going on for over 40 years [43]. It enables early detection of urine abnormalities and early referral to a nephrologist, and it is possible that a substantial number of the patients have undergone renal biopsy due to asymptomatic hematuria and/or proteinuria. Therefore, the revised J-RBR/J-KDR 2018 can describe clinical features of such patients.

For kidney diseases, the classification system should meet the following requirements: (a) clinically significant, useful, and therapeutically relevant, (b) based on pathogenesis within current knowledge, (c) easy to use and morphologically reproducible and (d) able to provide the information for prognosis [44]. Although the terminology of kidney diseases has been mainly based upon morphology, the pathogenesis of kidney diseases has been gradually revealed in recent decades. For example, membranous proliferative glomerulonephritis (MPGN) has been recognized as a pattern of glomerular injury and indicates a grouping of the patients who share common light microscopic findings. Nowadays, the cases with dysregulation of the alternative pathway of complement in MPGN are subdivided into C3 glomerulopathy [45]. Considering these advances, a classification based on etiology and pathogenesis is more desirable [44].

In addition, the value of a registry depends on its data quality, clarity of registration method, and ease of using the collected data [46]. The WHO classification [25,26], which was the fundamental concept behind the original J-RBR/J-KDR 2007 system, embodies the idea that the pathology of kidney diseases should be comprehensively interpreted with the integration of clinical, histopathological, and pathognomonic diagnoses. However, this classification was basically weighted in favor of morphology, not pathogenesis. Further, this complicating method made difficulty in data aggregation and not all diagnoses are suitable for being expressed by this method (e.g., MCD or diabetic nephropathy). In this revised system, the most appropriate diagnosis for the patients can be selected from the diagnosis panel, and this simple method will provide high reproducibility in registration.

Most of registries for kidney diseases collect the clinical data at the time of biopsy. However, it is difficult to interpret the laboratory data of patients without information on the treatment status. For example, we cannot distinguish the patients who demonstrated non-nephrotic range proteinuria from those who showed the improvement in nephrotic syndrome as a result of immunosuppressive treatment from their laboratory data alone. The revised J-RBR/J-KDR 2018 collects the information whether the laboratory data were collected before or after starting the immunosuppressive treatment. In this revision, based on these status, different “baselines” are defined for each case and it will provide more reliable data to describe the laboratory features of kidney diseases.

The revised J-RBR/J-KDR 2018 system has several points that require further discussion. First, the borderline between the terms, “Primary (idiopathic)” and “Secondary,” in the glomerular disease is ambiguous. For example, primary MCD and FSGS are considered as a spectrum of diseases that are provoked by humoral permeability factors [47], while secondary cases indicate the presence of an identifiable etiology [48,49]. However, the identities of the permeability factors for MCD/FSGS are yet to be revealed [50]. For MN, the antibodies against potent etiological factors, such as the phospholipase A2 receptor (PLA2R) [51] and thrombospondin type-1 domain-containing 7A (THSD7A) [52], have been detected. Therefore, the classification based on the terminology of “primary” that indicates an unknown etiology may no longer make sense for patients with MN [53].

Second, this revision does not completely cover the recently reported disorders, such as tubulointerstitial nephritis with IgM-positive plasma cells [54]. Furthermore, in the near future, the newly developed technical approaches in kidney research including multi-omics analysis will probably reveal new pathogenesis for kidney diseases [55,56],therefore, it is necessary to continue the revision of the diagnosis panel with every new result.