Introduction

The Japan Renal Biopsy Registry (J-RBR), the first nation-wide web-based registry of renal biopsies in Japan, was established in 2007 [1]. The renal biopsy is the gold standard for the classification and diagnosis of kidney diseases, and it provides essential information for managing the condition [2,3]. It can also provide us with information on the incidence and distribution of kidney diseases. From the 1980s, the results of renal biopsy registry studies have been reported from all over the world [4,5,6,7].

In 2009, the Japan Kidney Disease Registry (J-KDR) which includes non-biopsy cases in addition to those registered in the J-RBR was started [8]. Thereafter, the kidney diseases that do not require renal biopsy, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), could also be registered. As of December 2017, 143 nephrology centers have joined the J-RBR/J-KDR, which includes 40,369 patients in total: 37,215 biopsy cases and 3154 non-biopsy cases [9]. The cross-sectional data from the J-RBR/J-KDR have revealed the demographics of kidney diseases in Japan [10,11,12,13,14,15,16,17,18] and provided fundamental knowledge for ancillary studies [19,20,21,22,23,24].

In the original J-RBR/J-KDR 2007 system, diagnosis of the patients consists of three components: (i) a clinical diagnosis, (ii) a histological diagnosis by pathogenesis, and (iii) a histological diagnosis by histopathology (Online Resource 1) [1]. It followed the classification of glomerular diseases that was originally proposed in the 1980s by the World Health Organization (WHO) and revised in the 1990s [25,26]. This classification describes histopathological patterns of glomerular injury but does not encompass its etiology. Recently, Sethi et al. suggested a pathogenesis-based classification for glomerulonephritis [27], however, that did not include major proteinuric glomerular diseases, such as minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and tubulointerstitial diseases. Therefore, it was necessary to establish a comprehensive classification, which covers all categories of biopsy-proven kidney diseases based on their pathogenesis.

The Committee for Renal Biopsy and Disease Registry of the Japanese Society of Nephrology revised the J-RBR/J-KDR system to establish a more practical histopathological grouping and classification of the kidney diseases.

Materials and methods

Participants and data collection

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.

Fig. 1
figure 1

The main page for registration with J-RBR/J-KDR. Definitions: Urinary Abnormalities, hematuria and/or proteinuria observed prior to registration; Acute Nephritic Syndrome, A syndrome characterized by abrupt onset of macroscopic hematuria, proteinuria, hypertension, decreased glomerular filtration and retention of sodium and water [26]. Chronic Nephritic Syndrome, slowly developing renal failure accompanied by proteinuria, hematuria, and hypertension [26]. Rapidly Progressive Nephritic Syndrome, rapidly progressing renal failure within several weeks to several months that is associated with urinary findings, such as proteinuria, hematuria, red blood cell casts, and granular casts indicating glomerulonephritis [28]. Nephrotic Syndrome, both massive proteinuria (≥ 3.5 g/day) and hypoalbuminemia (serum albumin ≤ 3.0 g/dL) [29]. Acute Kidney Injury, (1) Increase serum Creatinine ≥ 0.3 mg/dL within 48 h, (2) Increase serum Creatinine ≥ 1.5 times baseline within 7 days, (3) Urine volume < 0.5 mL/kg/h for 6 h [30]. Chronic Kidney Dysfunction, Cases with eGFR < 60 mL/min/1.75m2 for more than 3 months [31]. Pulmonary involvement of ANCA-associated vasculitis/anti-GBM disease, abnormality in chest X-ray except infection or chronic obstructive pulmonary disease (COPD), alveolar hemorrhage and interstitial pneumonia. HBV, cases with prior infection or latent infection are considered as “present”. Explanations: *Patient characteristics at the “baseline”, If immunosuppressive treatment was started or strengthened more than 1 month prior to biopsy, the time of biopsy is considered to be the baseline. If immunosuppressive treatment was 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. † Status of immunosuppressive therapy at baseline, Select the status of immunosuppressive treatment at the time of “baseline”. “after finishing the treatment” indicates the status without any immunosuppressive treatment. J-RBR Japan Renal Biopsy Registry, J-KDR Japan Kidney Disease Registry, RPGN rapid progressive glomerulonephritis, CRF chronic renal failure, CKD chronic kidney disease, DM diabetes mellitus, AKI acute kidney injury, FSGS focal segmental glomerulosclerosis, ANCA anti-neutrophil cytoplasmic antibody, MPO myeloperoxidase, PR3 proteinase 3, EUVAS the European Vasculitis Study Group, GBM glomerular basement membrane, ISKDC the International Study of Kidney Disease in Children, ISN/RPS the International Society of Neurology and the Renal Pathology Society, UPCR urinary protein creatinine ratio, RBC red blood cell, HPF hyper power field, CRP C-reactive protein, NGSP the National Glycohemoglobin Standardization Program, HBV hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus

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Clinical diagnoses

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 [26,28,29,30,31]. 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.

Pathological diagnoses

  1. 1.

    Overview of the diagnosis panel


    The pathological diagnoses for registration are selected from the “Diagnosis Panel” in the web page of J-RBR/J-KDR. Clicking the button of the panel on the web page opens the list of the diagnoses as shown in Table 1. It is the main part of this revision, and constructed based on two principles. First, we tried to cover all the diagnostic names of kidney diseases including the rare ones. The panel contains 22 categories of renal diseases: 18 glomerular, 1 tubulointerstitial, 1 congenital/genetical, 1 transplant related, and 1 other, including 123 diagnostic names. In the registration process, the most appropriate diagnosis should be selected from the panel as principal diagnosis. For complex cases with multiple diagnoses, such as lupus nephritis with findings of diabetic nephropathy, additional panels for secondary diagnosis are set on the web page of the J-RBR/J-KDR.

    Second, the diagnostic names of the kidney diseases will be registered based on their pathogenesis rather than morphology. For example, a patient with MN induced by hepatitis B virus (HBV) infection is registered into the category of infection-related glomerulonephritis and not MN.

    Additional information, such as the name of specific drug that provoked drug-induced secondary MCD, may be entered in the <13. Description Box; Diagnosis> in the main page of the J-RBR/J-KDR registration (Fig. 1). This panel was reviewed by the Japanese Renal Pathology Society.

  2. 2.

    Detailed pathological classification (optional)

Table 1 List of the diagnoses in the Diagnosis Panel of the J-RBR/J-KDR
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In this revision, we added more items for detailed pathological classification of several glomerular diseases, such as the Oxford Classification [32,33,34] 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].

Clinical data

  1. 1.

    Physical measurements and laboratory data

    The revised system collects baseline clinical data (Fig. 1). The baseline is defined in the next section. The clinical variables include patient characteristics and physical measurements (age, sex, height, body weight, and systolic/diastolic blood pressure), comorbidities (hypertension, diabetes, infection of HBV, hepatitis C virus, or human immunodeficiency virus), urinary findings (qualitative testing for urinary protein, occult blood, and red blood cells, and quantitative measurement of urinary protein creatinine ratio and daily proteinuria), and blood test findings (serum creatinine, total protein, albumin, total cholesterol, CRP, and HbA1c). Estimated glomerular filtration rate (eGFR) is calculated from the patient’s age, sex, and serum creatinine level using the equations for Japanese children [40] and adults [41] at the time of analysis.

  2. 2.

    Treatment status of the “baseline”


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.

Results

The revised system of J-RBR/J-KDR came into use in January 2018. As of December 2018, the number of cases registered under the revised system had reached 2748 in the first year from 146 facilities. The total number of the cases registered in the J-RBR/J-KDR had reached 43,813 from the beginning of J-RBR in 2007.

Discussion

The J-RBR/J-KDR is a nationwide web-based registry in Japan, which has been conducted for more than 10 years, and it is one of the biggest registries for patients with kidney diseases including biopsy cases. We revised its registration system in 2018 with several strengths.

Clinical diagnoses that can represent the clinical status of the patients

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.

Classification of kidney diseases and the structure of their registry system

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.

Clinical data collection with the information of treatment status

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.

Problems requiring further discussion

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.

Conclusion and future perspectives

The revised J-RBR/J-KDR 2018 system has attempted to cover the current classification and diagnosis of kidney diseases based on pathogenesis. It can provide data of higher quality on the demographics of kidney diseases and their classifications. In addition, the revised J-RBR/J-KDR 2018 system will be a platform for standardized registration of kidney diseases, and with this platform, we expect to promote international collaborations in research.