Clinicopathological cohort study of kidney biopsy findings resulting in dialysis during long-term follow-up exceeding 30 years
Yoichi Oshima, Naoki Sawa, Masayuki Yamanouchi, Akinari Sekine, Hiroki Mizuno, Daisuke Ikuma, Yuki Oba, Noriko Inoue, Kiho Tanaka, Eiko Hasegawa, Tatsuya Suwabe, Kei Kono, Keiichi Kinowaki, Kenichi Ohashi, Yutaka Yamaguchi, Junichi Hoshino, Yoshifumi Ubara
TL;DR
This study identifies diabetic nephropathy and IgA nephropathy as the main kidney diseases leading to dialysis over a 30+ year follow-up.
Contribution
Long-term cohort analysis showing disease progression to dialysis from kidney biopsy data over more than 30 years.
Findings
Diabetic nephropathy and IgA nephropathy were the most common causes of end-stage kidney disease.
Lower eGFR, higher proteinuria, older age, and presence of DN were risk factors for early dialysis.
Benign nephrosclerosis was rarely a direct cause of end-stage kidney disease.
Abstract
Numerous kidney diseases progress to end-stage kidney disease (ESKD); however, a limited number of cohort studies have evaluated the underlying kidney diseases through kidney biopsy (KB). We retrospectively evaluated all patients who initiated dialysis at Toranomon Hospital, Japan, from 1985 to 2019, and whose underlying kidney disease had been diagnosed by KB. The data on histopathological diagnosis and various clinical characteristics were collected and analyzed for 357 patients. The most prevalent underlying diseases, which constituted the primary endpoint of this study, were diabetic nephropathy (DN; n = 100, 28.0%), IgA nephropathy (IgAN; n = 99, 27.7%), and focal segmental glomerulosclerosis (n = 34, 9.5%). Benign nephrosclerosis (BNS; n = 1, 0.3%), that is, arteriosclerosis/arteriolosclerosis without distinct glomerulopathy, was rare. As the secondary endpoint, Cox regression…
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Figure 4- —http://dx.doi.org/10.13039/100012832Okinaka Memorial Institute for Medical Research
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Taxonomy
TopicsRenal Diseases and Glomerulopathies · Chronic Kidney Disease and Diabetes · Vasculitis and related conditions
Introduction
The Japanese Society for Dialysis Therapy publishes an annual report presenting the results of a questionnaire survey conducted at dialysis facilities. A 2018 report identified diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis as the three primary cause of dialysis in Japan and noted an increasing prevalence of dialysis among older adults [1]. In this report, patients with a history of diabetes mellitus (DM) were classified as having diabetic nephropathy (DN); those with hematuria and/or nephrotic-range proteinuria were classified as having chronic glomerulonephritis; and those with hypertension accompanied by minimal proteinuria and atrophic kidneys were classified as having benign nephrosclerosis (BNS), alternatively termed arteriosclerosis/arteriolosclerosis without glomerulopathy. The United States Renal Data System, which compiles the causes of end-stage kidney disease (ESKD), reported in 2012 that underlying kidney diseases included diabetes (38%) and hypertension-related nephropathy (25%) [2]. However, it is important to note that the results of both the Japanese and US reports were based on the subjective assessments of the attending physicians rather than on kidney biopsy findings.
Studies based on the kidney biopsies have yielded significantly different results from those described above. A retrospective cohort study conducted in the UK, which included 463 patients aged > 70 years who underwent kidney biopsy, reported that vasculitis and paraproteinemia were the most prevalent diseases leading to dialysis, whereas primary glomerulonephritis was the least common [3]. This report excluded diabetic nephropathy, possibly because of the UK-specific criteria for kidney biopsy [3].
There is a paucity of studies utilizing histopathological evaluations of kidney biopsies to determine the most common underlying diseases resulting in dialysis initiation. Consequently, we conducted a retrospective cohort study of patients who underwent kidney biopsy and subsequently progressed to ESKD requiring dialysis initiation. Owing to the rigorous development of guidelines in recent years, the trend was observed by dividing the cohort into three groups according to the time periods and analyzed. Additionally, we analyzed and described the baseline clinical characteristics at the time of kidney biopsy and investigated independent risk factors associated with early dialysis initiation using multivariate Cox regression analysis. Furthermore, we analyzed the clinical characteristics of the two major causes of dialysis initiation, DN and IgAN, and compared the two groups.
Methods
Patients
In this retrospective, single-center cohort study, we examined 1382 patients who initiated dialysis and underwent kidney biopsy at our nephrology center at Toranomon Hospital, Tokyo, Japan, between January 1985 and December 2019. Patients with DM were predominantly referred to by diabetologists, whereas nondiabetic patients were referred to by general physicians or non-nephrologists. The investigators noted that all patients were of Japanese ethnicity. Our primary endpoint was to compile the underlying kidney diseases leading to ESKD, identified by kidney biopsy. The secondary endpoint was to analyze the progressive risk factors associated with a shorter time to ESKD. Subgroup analysis encompassed the following: underlying kidney diseases across the three periods, underlying kidney diseases in each age group at dialysis initiation, clinical characteristics of patients with DN among the three periods, clinical characteristics of patients with IgAN among the three periods, and comparison between DN and IgAN.
At our institution, kidney biopsies are considered for all patients upon referral. The decision to perform a kidney biopsy was made by the chief physician and nephrologist team based on the following criteria: proteinuria (≥ 0.2 g/day), hematuria (> 5 red blood cells/high-power field [HPF]), or renal dysfunction (estimated glomerular filtration rate [eGFR], < 60 mL/min/1.73m^2^). These criteria are applied to patients regardless of their DM status. In clinical practice, kidney biopsy is not performed in numerous patients, even if they meet the diagnostic criteria; for instance, patients with severe physical deformity may be unable to assume the prone position required for kidney biopsy.
Clinical data and pathological diagnosis of kidney biopsy
The following clinical data were collected from the medical records at the time of kidney biopsy: histopathological diagnosis; age; sex; and blood tests results, including serum creatinine (Cre; mg/dL) and estimated glomerular filtration rate (eGFR; calculated from Cre; mL/min/1.73m^2^), which were measured with a previously reported method [4]. Urine tests included assessment of proteinuria and hematuria (red blood cells per HPF in resuspended sediment, categorized as follows: grade 0 [< 1 red blood cell], grade 1 [1–5 red blood cells], grade 2 [6–10 red blood cells], grade 3 [11–30 red blood cells], grade 4 [> 30 red blood cells]). In addition, the data were collected on the number of days between kidney biopsy and dialysis initiation, as well as age at dialysis initiation.
Kidney biopsy specimens were analyzed using light microscopy (LM), immunofluorescence microscopy (IF), and electron microscopy (EM) using standard methodologies [5]. Kidney biopsy findings were evaluated by four pathologists. To validate the current pathological diagnosis, the specimens were re-evaluated according to the most recent pathological criteria. Concise diagnostic characteristics of the respective kidney diseases and other methods are described in the supplementary material.
The Toranomon Hospital Ethics Committee reviewed and approved the protocol (approval code 2081-B), and informed consent was obtained in the form of an opt-out option on the website. Those who opted out were not included in the study. All methods were performed in accordance with the Declaration of Helsinki.
Statistical analysis
Analyses were performed with the EZR software package (version 3.6.3). Graphs were prepared with GraphPad Prism, version 9. Continuous variables are expressed as the median and interquartile range (IQR) according to their distribution. The data were analyzed with the Shapiro–Wilk test for normality and Brown–Forsythe test for equal variances, followed by the Tukey–Kramer test or Steel–Dwass test for multiple comparisons. Mann–Whitney U test was used for comparing two groups, and a Cox proportional-hazards regression model was used for analyzing renal survival in patients with multiple risk factors. Log-rank test was used for comparing renal survival between two groups. A P value of less than 0.05 was considered statistically significant.
Results
Histological findings of underlying kidney disorders and patient characteristics
The most prevalent underlying disorders identified by kidney biopsy, the primary endpoint of this study, in the 357 patients were as follows (Table 1): DN (n = 100, 28.0%), IgAN (n = 99, 27.7%), FGS (n = 34, 9.5%), AAV (n = 19, 5.3%), MGN (n = 15, 4.2%), LN (n = 10, 2.8%), AA-Amy (n = 9, 2.5%), MPGN (n = 9, 2.5%), MNS (n = 6, 1.7%), TIN (n = 6, 1.7%), Alport (n = 5, 1.4%), LC-Amy (n = 5, 1.4%), Cryo (n = 3, 0.8%), and GBM (n = 3, 0.8%). Among the 100 patients with DN, 4 were diagnosed with type 1 DM and 96 with type 2 DM. The patient characteristics in aggregate were as follows: mean (SD) age at kidney biopsy 54.6 (15.9) years old; serum creatinine 3.3 (3.2) mg/dL; eGFR 28.0 (20.1) ml/min/1.73m^2^; proteinuria 2.9 (3.0) g/gCre; hematuria score 1.5 (1.4); HbA1c 6.2 (1.3) %; number of days from kidney biopsy to dialysis 2309 (2359) days; and age at start of dialysis 60.8 (15.3) years old (Table 2).Table 1. Number and percentage of histopathological diagnoses of kidney biopsy by respective dialysis initiation periodsPeriod 1 (1986–1999)Period 2 (2000–2009)Period 3 (2010–2019)Total35741160156DN100 (28.0%)10 (24%)51 (32%)39 (25%)IgAN99 (27.7%)15 (37%)39 (24%)45 (29%)FGS34 (9.5%)5 (12%)13 (8%)16 (10%)ANCA19 (5.3%)2 (5%)7 (4%)10 (6%)Membranous15 (4.2%)2 (5%)9 (6%)4 (3%)Lupus10 (2.8%)06 (4%)4 (3%)AA-Amy9 (2.5%)07 (4%)2 (1%)MPGN9 (2.5%)2 (5%)2 (1%)5 (3%)MNS6 (1.7%)02 (1%)4 (3%)TIN6 (1.7%)1 (2%)4 (3%)1 (1%)Alport5 (1.4%)03 (2%)2 (1%)LC-Amy5 (1.4%)01 (1%)4 (3%)Cryo3 (0.8%)01 (1%)2 (1%)anti-GBM3 (0.8%)1 (2%)1 (1%)1 (1%)BNS1 (0.3%)001 (1%)Others33 (9.2%)3 (7%)14 (9%)16 (10%)ND (n = 2), ITG (n = 1)ND (n = 4), Minimal (n = 2),Mitochon (n = 2), Gout (n = 2),IgAV (n = 1), ING (n = 1),CCE (n = 1), TMA (n = 1)ND (n = 4), ING (n = 2),Mitchon (n = 1), Gout (n = 1),IgAV (n = 1), TMA (n = 2),ANCA-neg (n = 1), UMOD (n = 1),OFD-1 (n = 1),SRC (n = 1), Obesity (n = 1)DN diabetic nephropathy, IgAN IgA nephropathy, FGS focal segmental glomerulosclerosis, ANCA antineutrophil cytoplasmic autoantibody-associated nephropathy, Membranous membranous glomerulonephritis, Lupus lupus nephritis, Amy AA amyloid A amyloidosis, MPGN membranoproliferative glomerulonephritis, MNS malignant nephrosclerosis, TIN tubulointerstitial nephritis, Alport Alport syndrome, LC-Amy light-chain amyloidosis, Cryo cryoglobulinemic glomerulonephritis, anti-GBM antiglomerular basement membrane antibody-associated glomerulonephritis, BNS benign nephrosclerosis, ND not diagnosed, Minimal minimal change disease, Mitochon mitochondria-associated nephropathy, Gout gouty nephropathy, HSP Henoch–Schonlein purpura, ING idiopathic nodular glomerulosclerosis, Cholesterol cholesterol thromboembolism, TMA thrombomicroangiopathy, ANCA-neg antineutrophil cytoplasmic autoantibody-negative crescentic glomerulonephritis, UMOD uromodulin-associated kidney disease, Hemi status post heminephrectomy, OFD-1 orofaciodigital syndrome 1 nephropathy, Sclero scleroderma nephropathy, Obesity obesity-associated nephropathyTable 2Clinical characteristics of the histopathological kidney diseasesNumber (Male/Female)Age at renal biopsySerum Cre (mg/dL)eGFR (ml/min/1.73m2)Proteinurea (g/gCre)Hematurea scoreHbA1c (%)Days from renal biopsy to dialysisAge at start of dialysisDN100(73/27)Median (IQR)57.5 (49–65)2.1 (1.5–3.4)24.2 (14.3–36.5)3.5 (1.7–7.0)1.0 (0.0–1.0)6.6 (6.0–7.8)971 (380–1928)62.6 (51.9–69.9)Mean (SD)56.5 (12.0)3.0 (2.4)27.0 (16.5)4.6 (3.8)1.1 (1.1)7.0 (1.6)1441 (1669)60.4 (12.6)IgAN99(72/27)Median (IQR)50 (39–62)1.7 (1.4–2.5)30.4 (19.0–42.9)1.6 (0.7–2.5)2.0 (1.0–3.0)5.8 (5.2–6.2)2743 (1062–4346)59.7 (46.9–71.5)Mean (SD)49.8 (15.9)2.9 (3.5)33.6 (22.3)1.9 (1.6)2.1 (1.3)5.8 (0.9)3058 (2638)58.2 (15.8)FGS34(24/10)Median (IQR)58.5 (49.8–72.0)2.0 (1.5–4.2)26.5 (12.3–34.5)2.1 (0.7–3.1)1.0 (0.0–1.0)5.8 (5.1–6.2)1739 (596–3728)65 0 (59.3–73.8)Mean (SD)58.8 (15.7)3.6 (3.9)27.0 (19.6)2.0 (1.3)0.9 (1.1)5.7 (0.6)2335 (2147)65.2 (13.8)ANCA19(2/17)Median (IQR)62.0 (58.0–79.0)4.0 (2.7–6.2)9.4 (6.5–17.7)1.0 (0.4–1.5)3.0 (1.0–4.0)5.7 (5.2–6.3)1086 (0–1773)73.3 (62.0–81.0)Mean (SD)61.9 (20.0)5.4 (4.6)15.3 (16.5)1.1 (0.8)2.7 (1.6)5.8 (0.8)1560 (2091)66.2 (18.4)Membranous15(12/3)Median (IQR)65.0 (56.0–70.0)1.5 (1.1–2.6)40.3 (19.6–58.3)4.3 (2.4–8.8)1.0 (0.0–1.0)6.8 (5.9–7.2)2321 (1001–4819)72.2 (64.0–79.7)Mean (SD)63.5 (13.6)2.3 (2.1)37.5 (21.1)5.7 (3.9)0.9 (1.1)6.7 (1.1)2943 (2301)71.5 (12.7)Lupus10(3/7)Median (IQR)45.0 (29.0–57.0)1.8 (1.1–3.9)31.4 (10.5–51.2)2.0 (0.4–3.6)1.0 (0.0–2.3)4.7 (4.4–5.5)1361 (29–3241)47.3 (40.4–60.5)Mean (SD)43.2 (17.8)2.2 (1.4)36.5 (27.1)2.1 (1.8)1.2 (1.4)4.8 (0.8)2307 (3126)49.5 (13.2)Amy AA9(1/8)Median (IQR)64.0 (61.0–68.5)2.6 (2.0–3.0)16.8 (13.4–20.3)1.5 (0.5–3.4)2.0 (1.0–3.0)5.6 (5.0–5.9)1051 (430–1967)68.0 (62.1–72.3)Mean (SD)62.9 (8.8)3.0 (1.8)17.0 (6.5)1.9 (1.6)2.0 (1.1)5.4 (0.5)1131 (763)66.0 (8.3)MPGN9(7/2)Median (IQR)41.0 (35.0–69.0)1.7 (1.4–5.2)33.6 (13.7–42.8)1.3 (0.6–5.3)0.5 (0.0–1.0)5.5 (5.1–5.7)5118 (2522–5907)58.6 (46.9–82.4)Mean (SD)49.8 (22.6)3.0 (2.8)29.3 (15.8)2.4 (2.6)0.5 (0.6)5.4 (0.3)4892 (2911)63.2 (20.7)MNS6(6/0)Median (IQR)55.0 (39.3–61.3)6.0 (2.5–9.2)8.6 (6.0–28.7)0.4 (0.1–1.5)1.0 (0.0–2.0)5.1 (4.6–5.6)1676 (185–3873)58.8 (54.0–63.2)Mean (SD)51.7 (11.0)6.1 (4.0)16.6 (17.6)0.9 (1.3)1.0 (1.2)5.1 (0.7)2332 (2872)58.1 (6.2)TIN6(1/5)Median (IQR)55.0 (47.8–61.8)3.6 (2.8–5.2)11.1 (8.9–16.5)0.2 (0.1–0.6)0.0 (0.0–1.0)5.4 (4.9–5.9)2605 (1952–5409)60.3 (54.1–77.4)Mean (SD)55.0 (9.6)4.3 (2.6)12.0 (5.3)0.3 (0.3)0.3 (0.5)5.4 (0.6)3301 (1831)64.1 (13.3)Alport5(4/1)Median (IQR)38.0 (27.5–63.5)1.5 (1.3–3.0)47.3 (15.9–55.0)0.7 (0.3–10.7)1.0 (0.0–3.0)5.7 (5.5–6.4)3066 (2616–5276)53.2 (36.3–73.0)Mean (SD)44.0 (23.1)2.0 (1.0)37.8 (20.3)4.5 (5.9)1.4 (1.7)5.9 (0.4)3770 (1967)54.3 (22.0)Amy AL5(4/1)Median (IQR)58.0 (48.5–68.0)1.0 (0.8–2.9)60.5 (23.4–67.1)5.6 (3.7–7.9)0.0 (0.0–0.0)5.1 (4.9–6.8)1412 (708–2939)58.8 (53.2–74.9)Mean (SD)58.2 (10.0)1.7 (1.4)48.3 (24.2)5.8 (2.5)0.0 (0.0)5.7 (1.1)1741 (1254)63.0 (11.9)Cryo3(3/0)Median (IQR)55.0 (46.0–75.0)1.5 (0.8–2.4)36.9 (24.8–78.4)3.0 (2.9–3.2)1.0 (1.0–4.0)5.3 (5.2–5.7)1122 (0–4341)66.9 (49.1–75.0)Mean (SD)58.7 (14.8)1.6 (0.8)46.7 (28.1)3.0 (0.2)2.0 (1.7)5.4 (0.2)1821 (2253)63.7 (13.3)GBM3(1/2)Median (IQR)76.0 (54.0–81.0)8.6 (7.5–8.9)4.5 (4.3–5.1)0.2 (0.2–0.6)4.0 (4.0–4.0)5.9 (5.2–6.2)3 (1–8)76.0 (54.0–81.0)Mean (SD)70.3 (14.4)8.3 (0.7)4.6 (0.4)0.4 (0.2)4.0 (0.0)5.7 (0.5)4 (4)70.3 (14.4)Total357Median (IQR)56.0 (44.0–66.0)2.0 (1.5–3.7)24.3 (12.6–39.2)1.9 (0.7–3.7)1.0 (0.0–3.0)6.0 (5.4–6.6)1586 (455–3196)62.0 (50.7–71.9)(231/126)Mean (SD)54.6 (15.9)3.3 (3.2)28.0 (20.1)2.9 (3.0)1.5 (1.4)6.2 (1.3)2309 (2359)60.8 (15.3)Hematuria grade: 0, < 1 red blood cell (RBC) per high-power field (HPF); 1, 1 to 5 RBCs per HPF; 2, 6 to 10 RBCs per HPF; 3, 11 to 30 RBCs per HPF; and 4, > 30 RBCs per HPF. The data are shown as median and interquartile range (IQR) and mean and standard deviation (SD)
The mean age at the time of kidney biopsy could be categorized as follows: 40 to 49 years for IgAN, LN, MPGN and Alport; 50 to 59 years for DN, FGS, MNS, TIN, LC-Amy, and Cryo; 60 to 69 years for AAV, MGN, and AA-Amy; and 70 to 79 years for anti-GBM. Renal function at the time of kidney biopsy was as follows: a mean eGFR of less than 30 mL/min/1.73m^2^ was observed in DN, FGS, AAV, AA-Amy, MPGN, MNS, TIN, and anti-GBM; and a median eGFR over 30 mL/min/1.73m^2^ in IgAN, LN, MGN, Alport, LC-Amy, and Cryo. The mean proteinuria values at the time of the kidney biopsy were as follows: less than 1 g/gCre was observed in MNS, TIN, Alport, and anti-GBM; 1 g to 3 g in IgAN, FGS, AAV, LN, AA-Amy, and MPGN; and over 3 g in DN, MGN, LC-Amy, and Cryo. A mean hematuria grade above 2.0 at the time of kidney biopsy was observed in IgAN, AAV, AA-Amy, and anti-GBM. The mean duration from kidney biopsy to dialysis initiation exceeded 2000 days in IgAN, FGS, MGN, LN, MPGN, MNS, TIN, and Alport (Table 2).
Underlying kidney diseases across the three periods: a subgroup analysis
A subgroup analysis examining the prevalence of underlying diseases across the three periods (1985 to 1999; 2000 to 2009; and 2010 to 2019) revealed that DN and IgAN were the two predominant underlying etiologies for dialysis initiation in each period (Table 1). The frequency distribution of kidney diseases remained consistent throughout the three periods.
Underlying kidney diseases in each age group at dialysis initiation: a subgroup analysis
At dialysis initiation, the predominant underlying diseases in each of the age groups were as follows (Table 3): patients aged 30 to 39 years, IgAN and DN; patients aged 40 to 49 years, IgAN, DN, LN and AAV; patients aged 50 to 59 years, DN, IgAN, FGS, LC-Amy, MNS, and MPGN; patients aged 60 to 69 years, DN, IgAN, FGS, AAV, AA-Amy and MGN; patients aged 70 to 79years, DN, IgAN, FGS, MGN, and AAV; and patients aged 80 years and older, IgAN, AAV and FGS. DN and IgAN were the two primary underlying causes of dialysis initiation in all age groups. IgAN was more prevalent than DN in patients aged < 50 years, whereas DN was more prevalent than IgAN in patients aged > 50 years and < 80 years. FGS has emerged as the third most prevalent underlying disease in patients over 50 years of age, while AAV manifests as an underlying disease in patients aged > 60.Table 3. Number of patients with the respective histopathology categorized by age group at dialysis initiationAge at induction of dialysis < 2020 = < age < 3030 = < age < 4040 = < age < 5050 = < age < 6060 = < age < 7070 = < age < 8080 = < ageNumber of cases38245165967931IgAN (n = 1)IgAN (n = 4)IgAN (n = 10)IgAN (n = 16)DN (n = 21)DN (n = 33)DN (n = 22)IgAN (n = 6)ANCA (n = 1)DN (n = 1)DN (n = 6)DN (n = 14)IgAN (n = 19)IgAN (n = 22)IgAN (n = 21)ANCA (n = 5)Mitchon (n = 1)Lupus (n = 1)FGS (n = 2)Lupus (n = 4)FGS (n = 5)FGS (n = 12)FGS (n = 8)FGS (n = 5)Alport (n = 1)Mitchon (n = 2)ANCA (n = 3)LC Amy (n = 3)ANCA (n = 5)MGN (n = 6)DN (n = 3)UMOD (n = 1)Lupus (n = 1)FGS (n = 2)MNS (n = 3)AA Amy (n = 5)ANCA (n = 5)MGN (n = 3)MPGN (n = 1)Not Dx (n = 2)MPGN (n = 3)MGN (n = 4)AA Amy (n = 3)MPGN (n = 2)OFD-1 (n = 1)Alport (n = 1)Alport (n = 2)Not Dx (n = 3)MPGN (n = 2)LC Amy (n = 1)HSP (n = 1)AA Amy (n = 1)TIN (n = 2)Lupus (n = 2)Not Dx (n = 2)Alport (n = 1)Cryo (n = 1)Not Dx (n = 2)MNS (n = 2)TIN (n = 1)anti-GBM (n = 1)Gout (n = 1)Obesity (n = 1)Gout (n = 1)Lupus (n = 1)ING (n = 1)ING (n = 1)anti-GBM (n = 1)LC Amy (n = 1)ING (n = 1)Not Dx (n = 1)MGN (n = 1)HSP (n = 1)TIN (n = 1)Gout (n = 1)TIN (n = 1)MNS (n = 1)Lupus (n * n* = 1)Cryo (n = 1)anti-GBM (* n* = 1)TMA (n = 1)MPGN (n = 1)MGN (n = 1)BNS (n = 1)ANCA-neg GN (n = 1)Sclero (n = 1)ITG (n = 1)Cholesterol (n = 1)TIN (n = 1)Minimal (n = 1)Cryo (n = 1)TMA (n = 1)Minimal (n = 1)TMA (n = 1)
Clinical characteristics of patients with DN among the three periods: a subgroup analysis
At dialysis initiation, in periods 1, 2, and 3 patients with DN had a median age of 43, 59, and 58 years, respectively; median serum Cre of 3.8, 2.1, and 1.9 mg/dL; median eGFR of 14.4, 24.5, and 28.1 mL/min/1.73m^2^; median proteinuria of 7.0, 2.5, and 4.7 g/gCre; median hematuria grade of 1, 1, and 1; and median number of days between kidney biopsy and dialysis of 240, 1273, and 1057. Patients in period 1 were significantly younger than those in periods 2 and 3, their renal function was significantly impaired, and the time to dialysis was significantly shorter (Fig. 1).Fig. 1. Comparison of clinical characteristics of patients with diabetic nephropathy at biopsy according to 3 periods of dialysis initiation (1985 to 1999, 2000 to 2009, and 2010 to 2019). (a) Age at kidney biopsy. Age was significantly lower in period 1 than in period 2. (b) Age at dialysis initiation. Age was significantly lower in period 1 than in periods 2 and 3. (c) Estimated glomerular filtration rate (eGFR) at kidney biopsy. eGFR was significantly lower in period 1 than in periods 2 and 3. (d) Proteinuria at kidney biopsy. Proteinuria was significantly lower in period 1 than in period 2. (e) Serum creatinine at kidney biopsy. Serum creatinine was significantly lower in period 1 than in periods 2 and 3. (f) Number of days between kidney biopsy and dialysis initiation. The number of days was significantly lower in period 1 than in periods 2 and 3. Median for each group is shown above each bar. *p < 0.05; ns not significant
Clinical characteristics of patients with IgAN among the three periods: a subgroup analysis
At dialysis initiation, in periods 1, 2, and 3 patients with IgAN exhibited median ages of 39, 48, and 56 years, respectively; median serum Cre levels of 1.7, 1.6, and 1.8 mg/dL; median eGFR of 28.0, 34.1, and 27.3 mL/min/1.73m^2^; median proteinuria levels of 1.8, 1.6, and 1.5 g/gCre; median hematuria grade of 2, 2; and 2; and median intervals between kidney biopsy and dialysis of 1506, 2903, and 2740 days. The age at the time of kidney biopsy was significantly higher in period 3 than in period 1 and 2, however, renal function and time to dialysis were comparable (Fig. 2).Fig. 2. Comparison of clinical characteristics of patients with immunoglobulin A nephropathy at kidney biopsy according to 3 periods of dialysis initiation (1985 to 1999, 2000 to 2009, and 2010 to 2019). (a) Age at kidney biopsy. Age was significantly lower in periods 1 and 2 than in period 3. (b) Age at dialysis initiation. Age was significantly lower in periods 1 and 2 than in period 3. (c) Estimated glomerular filtration rate (eGFR) at kidney biopsy. eGFR was similar in the 3 periods. (d) Proteinuria at kidney biopsy. Proteinuria was similar in the 3 periods. (e) Serum creatinine at kidney biopsy. Serum creatinine was similar in the 3 periods. (f) Number of days between kidney biopsy and dialysis initiation. The number of days was similar in the 3 periods. Median for each group is shown above each bar. *p < 0.05; ns not significant
Risk factors associated with reduced time to dialysis initiation: the secondary endpoint
The analysis of 14 variables in the whole cohort (n = 357) using a Cox regression model identified decreased eGFR, elevated proteinuria, advanced age, and histologically confirmed DN as independent risk factors for a shorter time to dialysis initiation (Table 4).Table 4. Coefficients of multivariate Cox regression analysis of dialysis initiation in all 357 casesVariableHazard ratioLower 95% CIUpper 95% CIp valueeGFR, 1 ml/min/1.73m^2^0.9680.9590.976 < 0.0001UP, 1 g/gCre1.1121.0641.163 < 0.0001Age, 1 year1.0141.0041.0240.005DN, yes1.6551.1402.4030.008LN, yes2.1780.9964.7650.051AA-Amy, yes1.7620.8383.7040.135MGN, yes0.5950.2851.2420.167MPGN, yes0.4760.1441.5670.222UB, 1 score0.9520.8671.0460.304Sex, 1 for male1.1340.8641.4900.365IgAN, yes1.1940.8131.7540.365FGS, yes1.1950.7561.8910.446MNS, yes0.7220.2502.0830.547AAV, yes1.1460.6092.1570.672CI confidence interval
Comparison between DN and IgAN: a subgroup analysis
When compared with the IgAN group, the DN group exhibited a higher age at the time of kidney biopsy, elevated serum Cre and proteinuria levels, reduced eGFR and hematuria grade, and a shorter interval between kidney biopsy and dialysis. Renal survival was significantly lower in the DN group than in the IgAN group. Furthermore, Cox regression analysis of time to dialysis initiation for 199 patients with DN or IgAN revealed that eGFR, proteinuria, and DN, but not age, were independent risk factors for a shorter time to dialysis (Table 5). Even when both groups were matched by the propensity score for eGFR and proteinuria, renal survival was significantly shorter in patients with DN than in those with IgAN (Fig. 3). The validity of the matched groups was confirmed by calculating standardized differences, which were approximated to zero.Table 5. Coefficient of multivariate analysis by cox regression analysis of dialysis initiation for 199 cases (DN and IgAN)VariableHazard ratioLower 95% CIUpper 95% CIp valueeGFR, 1 ml/min/1.73m20.9620.9500.974 < 0.0001UP, 1 g/gCre1.1431.0831.206 < 0.0001DN, yes1.4621.0182.0990.0398Age, 1 year0.9950.9811.0090.502UB, 1 score0.9640.8511.0910.557Sex, 1 for male1.0730.7561.5230.692CI confidence intervalFig. 3Comparison of clinical characteristics of patients with diabetic nephropathy and immunoglobulin A nephropathy in the overall time periods. Age at kidney biopsy (a), serum creatinine (b) and proteinuria (d) were significantly greater in DN group than in IgA group, whereas eGFR (c), hematuria score, and days from biopsy to dialysis (f) was significantly smaller. (g) Overall renal survival was significantly better in IgAN group when compared with DN group. (h) In groups with propensity score matched for eGFR and proteinuria showed significantly better overall renal survival in IgAN group when compared with DN group. Standardized difference between the matched groups for both eGFR and proteinuria were low enough so that the two groups were fair to compare. Median for each group is shown above each bar. *p < 0.05; **p < 0.01; ****p < 0.0001; ns not significant
Underlying kidney disease in other dialysis patients
Of the patients who did not undergo kidney biopsy, 1025 patients who initiated dialysis were identified from the medical records at the time of dialysis initiation. (1) ADPKD or polycystic kidney disease can be diagnosed based on the family history and imaging studies alone (n = 320, 31.2%). The ratio of kidney biopsy was 0%. (2) DN can also be diagnosed based on a history of DM, significant proteinuria, and diabetes-specific complications, such as retinopathy and foot gangrene (n = 285, 27.8%). The percentage of kidney biopsies performed was 26.0% (100 of 385). (3) Primary glomerulonephritis such as IgAN or FGS can be considered in patients with a long-standing history of proteinuria and hematuria at a young age. However, when the patient had a brief history of diabetes mellitus and no diabetes-specific complications, primary glomerular diseases other than diabetes may have been the direct cause of renal failure (n = 220, 21.4%). The percentage of kidney biopsies performed was 53.9% (257 of 477). (4) BNS, arteriosclerosis, or nephrosclerosis, the most commonly used term for kidney disease in Japan, is applied to elderly patients with systemic atherosclerosis, including hypertension, heart disease, low proteinuria, and small kidney size. In such cases, rather than considering the cause of renal failure to be the progression of arteriosclerosis, it was hypothesized that concurrent heart disease, liver disease, malignancy, and its treatment may contribute to the progression of renal failure (n = 48, 4.7%). The percentage of kidney biopsies performed was 2.0% (1 of 49).
Comprehensive characterization of patients with IgAN, including clinical and histological grades at kidney biopsy
The clinical and histological grade is shown in Table 6. The prevalence of segmental sclerosis is as high as 77.9%. Eighty percent of patients were classified as having clinical grade III disease (Table 6a). Although there were some missing data, no patients were observed in the combinations of clinical grade I and histological grade I or clinical grade II and histological grades II, III, and IV (Table 6b). We stratified IgAN patients into two groups based on the biopsy year (before or after 2000) (Fig. 4a), age (Fig. 4b), proteinuria (Fig. 4c), urinary blood level (Fig. 4d), and eGFR (Fig. 4e). The median of each factor was chosen to divide the patients into two groups. The group of patients biopsied after 2000 (p = 0.0128), those with lower-level proteinuria (p = 0.0101), and those with more preserved eGFR (p = 0.0007) demonstrated statistically better renal survival than their respective counterparts. Moreover, multivariate Cox regression analysis of 99 IgAN patients revealed that renal function (serum creatinine) and proteinuria were independent risk factors for early dialysis initiation in both Model 1 and Model 2 (Table 7).Table 6. Histological and clinical grade in IgAN patients. a) Number and percentage of MEST-C score, Histological and Clinical grade in IgAN patients. b) Classification according to respective Histological and clinical grades in IgAN patientsa)numberpercentMscore 07688.4%score 11011.6%Escore 08295.3%score 144.7%Sscore 01922.1%score 16777.9%Tscore 04147.7%score 11517.4%score 23034.9%Cscore 07183.5%score 11416.5%Histological gradeGrade I1214.5%Grade II2024.1%Grade III2631.3%Grade IV2530.1%AC1720.5%C6679.5%Grade I AC11.2%Grade I C1113.3%Grade II AC44.8%Grade II C1619.3%Grade III AC44.8%Grade III C2226.5%Grade IV AC78.4%Grade IV C1821.7%Clinical gradeGrade I1215%Grade II45%Grade III6680%b)Histological gradeIIIIII + IVClinical gradeI02 (3.3%)8 (13.3%)10 (16.7%)II3 (5%)003 (5%)III5 (8.3%)9 (15%)33 (55%)47 (78.7%)8 (13.3%)11 (18.3%)41 (68.3%)M mesantial score, E endothelial score, S segmental score, T tubule atrophy score, C crescent score, A acute lesion, C chronic lesionFig. 4Renal survival in subgroups of patients with IgAN (a) Renal survival in IgAN patients diagnosed by kidney biopsy prior to 2000 was statistically superior to that of patients diagnosed after 2000. (b) No statistically significant difference in renal survival was observed between IgAN patients aged ≥ 50 years and those aged < 50 years at the time of kidney biopsy. (c) Renal survival in IgAN patients with lower proteinuria (< 1.5 g/gCre) was superior to those with higher proteinuria (> 1.5 g/gCre) at the time of kidney biopsy. (d) No statistically significant difference in renal survival was observed between IgAN patients in the high-grade urinary blood group and the low-grade group. (e) Renal survival in IgAN patients with higher eGFR (> 30 ml/min/1.73 m^2^) was superior to those with lower eGFR (> 30 ml/min/1.73 m^2^) at the time of kidney biopsy. *p<0.05; *p<0.001; ns not significantTable 7Coefficients of multivariate analysis by cox regression analysis of dialysis initiation for 99 IgAN casesModel 1Hazard ratioLower 95% CIUpper 95% CIP valueAge, 1 year1.0120.99311.0310.227Cre, 1 mg/dL1.2891.1951.400 < 0.0001UP, 1 g/gCre1.1611.0031.3320.0379Urinary blood, 1 score1.0530.87641.2590.5775Sex, male0.87930.52981.5090.628Model 2Hazard ratioLower 95% CIUpper 95% CIP valueBiopsy after 2000, yes1.1730.73281.8880.5063Age, 1 year1.0110.99211.0310.2663Cre, 1 mg/dL1.2851.191.396 < 0.0001UP, 1 g/gCre1.1540.99481.3270.0494Urinary blood, 1 score1.0620.88251.2740.5179Sex, male0.86710.52141.490.5926CI confidence interval
The prevalence of cigarette smoking and hypertension
Among the patients who were initiated on dialysis, the smoking prevalence was 337 out of 1025 (35.3%) for those who had not undergone a kidney biopsy and 166 out of 357 (47.5%) for those who had undergone a kidney biopsy. Regarding hypertension, in the case of kidney biopsy, 339 of 357 patients (96%) were taking antihypertensive medication. Conversely, in the case of nonkidney biopsy, 960 of 1025 patients (97.1%) were taking antihypertensive medication.
Discussion
This retrospective cohort study elucidated histologically diagnosed kidney diseases responsible for ESKD. Tables 1, 2, and 3 describe the clinical characteristics of the study cohort. Lower eGFR, higher proteinuria, DN, and advanced age were significant risk factors for early dialysis initiation (Table 4). DN and IgAN are the two primary causes of ESKD. We analyzed the clinical characteristics of DN and IgAN and compared these two diseases at the time of kidney biopsy, as illustrated in Figs. 1, 2, and 3.
Although the number of patients on dialysis has been reported to be increasing in many countries, few studies have evaluated the underlying diseases, as confirmed by kidney biopsy, that led to dialysis initiation [1–3]. In patients with DM, accurate diagnosis of kidney histology is a crucial indicator of the future course of treatment when the kidneys are affected. Diagnosing DN using classification schemes facilitates improved communication between renal pathologists and clinicians, provides a logistical structure for prognostic and interventional studies, and enhances clinical management and efficiency. In accordance with this approach, Tervaert et al. proposed a pathologic classification of DN [6]. Furthermore, the Committee on Practical Guidance for Kidney Biopsy in Japan published a second edition of its kidney biopsy guidebook, suggesting that in patients with DM and renal complications, a kidney biopsy can provide a wide range of information, including: (1) presence of typical DN, (2) existence of arteriolar hyalinosis without typical DN, (3) presence of glomerular lesions other than DN, and (4) a mixture of these lesions [7]. Even in patients with clinical information suggesting typical DM accompanied by nephrotic-range proteinuria, retinopathy, and neuropathy, kidney biopsy provides pathological information that can inform treatment strategies to improve renal prognosis. Additional studies on kidney biopsy in DM patients support this approach [8, 9].
Previous reports have indicated that DN, chronic glomerulonephritis, and hypertension-related nephropathy are the three primary causes of dialysis initiation in Japan [1, 2] based on questionnaire surveys. The current study demonstrated that IgAN, FGS, MGN, and MPGN are types of chronic glomerulonephritis leading to dialysis. The pathogenesis of hypertension-associated nephropathy as an initiating factor in chronic kidney disease remains unclear [10, 11]. Moreover, the data presented herein suggest that BNS is not a major direct cause of ESKD in patients requiring kidney biopsy, a finding that is consistent with the study by Sumida et al., who investigated the renal prognosis of patients diagnosed with BNS by kidney biopsy [12]. In support of this, a meta-analysis examining kidney dysfunction in ten trials with 114,000 person-years in patients with nonmalignant or benign hypertension revealed that patients treated for hypertension did not exhibit a lower risk of renal dysfunction [13]. Furthermore, after 8–12 years of follow-up, intensive blood pressure control in patients with hypertension was not superior to normal blood pressure control with regard to renal function [14]. However, patients in the intensive blood pressure control group with proteinuria exceeding 0.22 g/gCre demonstrated a potential benefit of preserved renal function [14], suggesting that the underlying kidney condition, such as chronic glomerulonephritis or glomerulopathy accompanied by proteinuria, is susceptible to hypertension resulting in declined kidney function. Therefore, a combination of hypertension, chronic glomerulonephritis, and proteinuria may be a significant contributor to progressively declining kidney function, ultimately leading to dialysis initiation. As most kidney biopsies in older adults are associated with hypertension, the involvement of hypertension in the underlying kidney disease should be carefully evaluated. Indeed, a previous article reported that kidney biopsy of hypertensive patients revealed that 16% of the patients had primary nephritis, 19% FGS, 43% MNS, and 22% BNS [15]. This suggests that approximately 80% of hypertensive patients have glomerulopathy or glomerulonephritis, a potential factor for poor kidney prognosis, which are histologically distinctive from BNS.
Conversely, others studies have reported that biopsy-proven BNS was associated with poor renal prognosis, although in this particular study, 71% of participants had proteinuria with a maximum proteinuria of 5.1 g/day [16], suggesting that an underlying glomerulopathy could be present in some patients in addition to BNS. As delineated in the methodology section, BNS should present with intact glomeruli, and arterioles or arteries being the primary site of injury. Therefore, by definition, BNS does not typically manifest as proteinuria. This analysis corroborates our finding that BNS is an infrequent direct cause of ESKD in patients requiring kidney biopsy.
Although FGS in young patients has garnered significant attention regarding genetic abnormalities, its occurrence in clinical practice is infrequent, with majority FGS patients being over 50 years of age. Determining whether FGS is secondary to hypertension, or a primary disease, presents a diagnostic challenge. Similarly, ascertaining whether hypertension is secondary to FGS is equally problematic. It is well-established that FGS can develop due to numerous underlying conditions [17], thus rendering it a heterogeneous diagnosis in terms of etiology. The Columbia classification for FGS [18] provides a useful framework; however, in practice, patients often do not meet the specified criteria, resulting in a diagnosis of “not otherwise specified*”*. Future research is necessary to address this diagnostic limitation.
Several additional considerations merit further discussion in this study: the underlying kidney diseases in other dialysis patients; a more detailed characterization of IgAN patients, including clinical and histological grades at kidney biopsy; the prevalence of cigarette smoking and hypertension, both of which are factors associated with ESKD; a comparison between this study and the Japan Renal Biopsy Registry (J-RBR); a comparison between this study and previously reported [12] BNS prognoses; the potential association between FGS and BNS; complications related to kidney biopsy under the indication criteria in this study; the consistency of indication criteria for kidney biopsy throughout the study period; and the prevalence of BNS among all kidney biopsies, including patients without ESKD.
The underlying kidney diseases in other dialysis patients were also analyzed as described in the results section. ADPKD was the most prevalent renal disease, because our institution specializes in its treatment. Consequently, the distribution of diseases, excluding ADPKD, may be comparable to that of a general institution.
A more comprehensive characterization of patients with IgAN, including clinical and histological grades at kidney biopsy, was conducted as described in Table 6. Furthermore, as illustrated in Fig. 2, the time required to reach ESKD after biopsy tended to be longer in period 3 than in period 1. Since 2000, tonsillectomy and glucocorticoid pulse therapy have been implemented for IgAN at our institution, resulting in a significant improvement in the prognosis of IgAN. Notably, all 16 patients with creatinine levels exceeding 2.0 mg/dL ultimately required dialysis; however, the interval to dialysis initiation was prolonged. Nevertheless, some patients did not receive this treatment because of their advanced age. Although Fig. 4 demonstrated that patients with biopsies after 2000 obtained statistically better survival than their counterparts, Table 7 described only renal function and proteinuria were independent risk factors for early dialysis initiation. This may be due to the fact that patients with biopsies after 2000 presented with worse renal function (median serum creatinine 2.1 mg/dL vs 1.6 mg/dL) and higher-level proteinuria (median proteinuria 1.8 g/gCre vs 1.3 g/gCre).
The prevalence of cigarette smoking and hypertension, both of which are associated with ESKD, is of significant importance. As demonstrated in the results section, the prevalence of smoking was as high as 35.3% for patients who initiated dialysis. Considering that the prevalence of smoking in Japan is 16.7%, this elevated rate may be a contributing factor to the progression of renal failure. Regarding hypertension, 97% of patients who initiated dialysis were taking antihypertensive medication as demonstrated in the results section. This observation suggests that hypertension is associated with progression to ESKD, irrespective of the underlying disease. This finding indicates that treatment modalities targeting the underlying disease in addition to antihypertensive agents may be necessary.
A comparative analysis between this study and the Japan Renal Biopsy Registry (J-RBR) warrants further consideration. J-RBR compiled data on renal biopsies conducted in Japan. The data revealed that IgAN, DN, FGS, MCD, MGN, and other conditions were prevalent across all age groups, whereas AAV and BNS showed an increased incidence in elderly patients. BNS is observed in a significant proportion of elderly patients who present with low proteinuria and preserved renal function. A recent classification of nephrosclerosis into malignant nephrosclerosis and essential hypertension/arteriosclerosis was implemented for data collection. However, there is a dearth of reports on the renal prognosis for each specific disease entity, which remains an area for future investigation within the J-RBR [19–22].
Regarding a comparison between this study and previously reported [12] BNS prognoses, in 2016, Sumida et al. conducted a study of cases in which the pathologist's report described nephrosclerosis [12]. In this study, the diagnosis was made without EM in cases with predominantly LM and negative IgG and IgA test results. Subsequently, in the present study, kidney biopsy specimens were re-examined by multiple pathologists. In some instances, where the initial diagnosis of nephrosclerosis was based on a high number of global sclerosing glomeruli and a high degree of atherosclerosis, one or more focal segmental sclerosing glomeruli were newly identified. The diagnosis of FGS was reassessed in cases of partial IgM deposition by IF and foot process effacement by EM, and these cases were excluded from the BNS. Additionally, genetic testing was performed in patients with a family history of renal disease, and those diagnosed with Alport or UMOD were excluded from the BNS. Furthermore, patients with onion skin lesions were reclassified as having MNS or Sclero and excluded from BNS based on clinical features, including hyperreninemia and rapid deterioration of renal function. Because of these iterative procedures, the number of nephrosclerosis cases with a final diagnosis of arteriosclerosis (BNS) alone was reduced from the list of diseases causing dialysis induction to one. Conversely, renal prognosis of patients with BNS and reduced renal function who discontinued hospital visits was not observed. Patients who succumbed to extrarenal lesions during the course of the disease were lost to follow-up.
In addition to the aforementioned discussion concerning FGS, the potential association between FGS and BNS warrants further examination. The 34 cases diagnosed with FGS in this study excluded primary FGS, in which the primary disease, such as a hereditary condition that causes FGS, was evident. Consequently, further classification of FGS is not feasible. However, most cases diagnosed with FGS exhibit multilayered fibroelastosis of the renal arteries and are diagnosed as coexisting arteriosclerosis and arteriolosclerosis, suggesting a significant association between FGS and renal atherosclerosis. Furthermore, many patients with ESKD present with high-grade proteinuria, a characteristic that differs from BNS by definition because glomerulopathy does not occur in BNS. This observation may indicate the susceptibility of BNS patients to progress to secondary FGS.
Complications associated with kidney biopsy under the specified indications can be delineated as follows: A Silverman needle was utilized between 1985 and 1997. Subsequently, an automatic biopsy needle is used. During the former period, renal hemorrhage following kidney biopsy was prevalent; however, only one patient underwent endovascular treatment, and no patient required surgical nephrectomy. In the latter period, the incidence of renal hemorrhage after kidney biopsy decreased; nevertheless, endovascular treatment was performed in two patients. The guidelines established by the Japanese Society of Nephrology [7] stipulate that kidney biopsy in patients at high risk of hemorrhage should be conducted with informed consent within the same institution, and that renal biopsy should be performed in an institution where hemostatic treatment following renal bleeding is feasible [23] and when the patient has been provided with comprehensive explanation and consent. This protocol was approved by our hospital.
Consistent indication criteria for kidney biopsy throughout the study period was a critical consideration. This investigation demonstrated that serum creatinine levels at the time of kidney biopsy in diabetic patients were elevated in period 1 compared to those in period 3 (Fig. 1). Kidney biopsy in patients with diabetes is typically performed upon referral by a diabetologist for renal dysfunction. During period 1, numerous patients with diabetes were referred to a nephrologist for dialysis. However, in period 3, patients with diabetes were referred to nephrologists at an earlier stage of CKD to consider CKD management. Consequently, Cre values at the time of kidney biopsy in patients with diabetes decreased. Three patterns of renal involvement are observed in patients with diabetes: typical DN, nondiabetic renal involvement, and a combination of the two. Kidney biopsies were performed to differentiate between these three patterns [7, 24].
The prevalence of BNS among all kidney biopsies, including those of patients without ESKD at our institution, provides additional perspectives. During the observation period from 1985 to 2018, 6763 kidney biopsies were performed at our institution. Among these, 271 (4.0%) were diagnosed with BNS or nephrosclerosis, with no significant findings other than atherosclerosis. Among these 271 patients, one patient progressed to ESKD. Furthermore, the present analysis was based on the cases that had undergone kidney biopsy. Consequently, renal histology in cases where kidney biopsy could not be performed due to the small kidney size remains unknown. Such cases may include BNS. Sumida et al. investigated the clinical picture of BNS in a large number of cases using the J-RBR. They found that BNS was more prevalent in elderly patients with preserved renal function and low proteinuria levels. In our investigation of dialysis cases without kidney biopsy, we observed that the pathogenesis of dialysis in such patients is often influenced by extrarenal lesions, such as systemic atherosclerotic diseases, including cardiac and hepatic conditions, rather than by a gradual decline in renal function. Moreover, certain diseases can be diagnosed without kidney biopsy in cases where the procedure cannot be performed. These include ADPKD, SLE, AAV, AMY, pyelonephritis and genetic disorders such as Alport. In patients with renal failure complicated by DM, the typical histology of diabetic nephropathy can be inferred in cases of diabetic retinopathy; however, it is challenging to assess cases without retinopathy. Kwon provides a valuable reference in this regard [24]. The results of kidney biopsies in patients with diabetes revealed that diabetic nephropathy was diagnosed in 37% of cases, kidney diseases other than diabetic nephropathy in 54.3%, and complications in 8.5%.
The strength of this cohort study lies in its extensive follow-up period of 35 years, which facilitated the identification of patients who ultimately developed ESKD or who initiated dialysis. Among the diverse histological diagnoses, we were able to ascertain the kidney diseases listed in Table 1 as the causes of ESKD, indicating that these histological diagnoses at the time of kidney biopsy represent a potential risk factor for subsequent ESKD development.
The limitations of this study include its single-center design, which may introduce bias for kidney biopsy, although the indication for kidney biopsy was consistent for all patients regardless of the presence of DM, and a multicenter study is necessary to obtain a comprehensive representation of the situation. In addition, it is noteworthy that the renal tissue of patients with ESKD who presented to the hospital with atrophic kidneys were not examined, as these patients are not typically evaluated by kidney biopsy. Furthermore, it is often challenging to establish a diagnosis from kidney biopsy in patients with numerous sclerotic glomeruli and very few remaining functioning glomeruli, and the validity of the diagnosis of FGS in a few segmental sclerotic glomeruli in the absence of predominant deposition on IF or EM is questionable. Lastly, the cohort did not include patients who did not required dialysis; therefore, the interpretation of the data should take this limitation into account.
In conclusion, given that the criteria for kidney biopsy were consistent for patients with and without DM at our institution, we posit that the findings of our study provide a comprehensive representation of the nephropathy types that contribute to ESKD.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 37 KB)