OBJECTIVE

Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce.

RESEARCH DESIGN AND METHODS

We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), who underwent clinical renal biopsy and had follow-up data, from Japan’s nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score–matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality.

RESULTS

Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score–matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9–5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5–93.8) for the nonproteinuric group and 30.3% (95% CI 22.4–38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005).

CONCLUSIONS

Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.

Mainly based on the analysis of the data from patients with type 1 diabetes, in the clinical course of diabetic kidney disease it has long been considered that an increase of albuminuria, from normoalbuminuria (urine albumin-to-creatinine ratio ratio [UACR] <30 mg/g) to microalbuminuria (UACR 30–299 mg/g) to macroalbuminuria (UACR ≥300 mg/g), precedes the progression of renal decline (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) (13). Morphological changes known as nodular glomerular sclerosis (Kimmelstiel-Wilson nodule) have also been observed in patients with diabetes and loss of renal function (4,5). Therefore, patients with diabetes and reduced renal function are deemed to have overt proteinuria with nodular glomerular sclerosis. Recently, however, cumulative evidence from several cross-sectional studies revealed that a proportion of patients with type 2 diabetes develop progression of renal decline without proteinuria (macroalbuminuria) or even without microalbuminuria, suggesting the existence of a nonproteinuric phenotype of diabetic kidney disease defined as eGFR <60 mL/min/1.73 m2 and UACR <300 mg/g (611). Despite increasing attention, few clinical trials and longitudinal studies in type 2 diabetes include individuals without proteinuria or individuals with biopsy-proven diabetic kidney disease, and therefore their clinicopathological characteristics, renal prognosis, and all-cause mortality are very limited.

Similar to the U.S. and most countries in Europe, Japan has been suffering from the expanding trend in the continued increase of the prevalence of diabetic kidney disease that leads to end-stage renal disease (ESRD) and high mortality (1215). Commissioned by the Ministry of Health, Labour and Welfare and the Japan Agency for Medical Research and Development with a goal of better understanding and halting the pandemic of diabetic kidney disease, we established a nationwide biopsy-based cohort of diabetic kidney disease with followed-up data, including ESRD and death ascertainment. Using this nationwide cohort and propensity score–matching methods, we aimed to investigate clinicopathological characteristics, renal prognosis, and mortality in patients with the nonproteinuric phenotype of diabetic kidney disease compared with patients with the classical proteinuric phenotype of diabetic kidney disease.

Study Design and Population

This is a retrospective study of patients who underwent clinical renal biopsy performed from 1 January 1985 to 31 December 2016 and had a pathological diagnosis of diabetic kidney disease at the following 18 hospitals in Japan: Toranomon Hospital (Tokyo, Japan), Toranomon Hospital Kajigaya (Kanagawa, Japan), Kanazawa University Hospital (Ishikawa, Japan), Fujita Health University Hospital (Aichi, Japan), National Hospital Organization Chiba-East National Hospital (Chiba, Japan), Niigata University Hospital (Niigata, Japan), Tohoku University Hospital (Miyagi, Japan), University of Tsukuba Hospital (Ibaraki, Japan), Fukuoka University Hospital (Fukuoka, Japan), Dokkyo Medical University Saitama Medical Center (Saitama, Japan), Kobe University Hospital (Hyogo, Japan), Kanazawa Medical University Hospital (Ishikawa, Japan), Nagasaki University Hospital (Nagasaki, Japan), Nara Medical University (Nara, Japan), University of the Ryukyus Hospital (Okinawa, Japan), Okayama University Hospital (Okayama, Japan), St. Marianna University School of Medicine Hospital (Kanagawa, Japan), and Nagoya University Hospital (Nagoya, Japan). The indications for biopsy were 1) renal impairment and 2) urinary abnormalities, such as albuminuria, proteinuria, hematuria, or casts. The majority of patients were under the care of the above-mentioned main hospitals or satellite clinics, and they were followed until 31 December 2017. Patients were excluded if they had a diagnosis of concomitant renal disease with diabetic kidney disease, if they underwent protocol renal transplant biopsy, or if they were followed for <3 months. This study was approved by the institutional review boards of Toranomon Hospital, Toranomon Hospital Kajigaya, and Kanazawa University Hospital.

Clinical Characteristics, Laboratory Data, and Pathological Classification

Clinical characteristics at the time of biopsy were ascertained from the medical records, including the age, sex, BMI, existence of diabetic retinopathy, smoking status, use of renin-angiotensin-aldosterone system (RAAS) blockade, use of glucose-lowering agents, use of statins, use of erythropoietin-stimulating agents, systolic blood pressure, and diastolic blood pressure. With the review of legal annual health checkup, the onset of diabetes was defined as the date when patients first met one of the following criteria: a fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), a random plasma glucose ≥200 mg/dL (11.1 mmol/L), an HbA1c ≥6.5% (48 mmol/mol), or the use of glucose-lowering agents. Type 2 diabetes was defined as having diabetes onset after age 30 years and not taking insulin at the baseline visit in our hospitals. Diabetes duration was defined as the time from the date of diabetes onset to the date of renal biopsy. Smoking status was determined at the time of biopsy. The existence of diabetic retinopathy was defined as having microaneurysms, retinal dot and blot hemorrhage, or neovascularization in the retina. Data obtained closest to the date of biopsy were used for this study.

Laboratory data at the time of biopsy were also obtained from the medical records, including hemoglobin, HbA1c, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, uric acid, serum creatinine, eGFR (calculated by the MDRD study equation for Japanese [16]), and UACR. Nonproteinuric diabetic kidney disease was defined as having an eGFR <60 mL/min/1.73 m2 with a UACR <300 mg/g at the time of renal biopsy.

Renal biopsy specimens were processed for light microscopy, immunofluorescence, and electron microscopy. All biopsies were evaluated by three pathologists. If all three pathologists did not reach the same conclusion, discussion was held until consensus was reached. Patients with at least a 5-year duration of diabetes and proven glomerular basement membrane thickening on electron microscopy (glomerular basement membrane >430 nm in men or >395 nm in women [13]) were classified as having diabetic kidney disease, and other pathological findings were evaluated according to the following three classifications: the classification developed by Fioretto et al. (17), the Pathologic Classification of Diabetic Nephropathy developed by Tervaert et al. (18) on behalf of the Renal Pathology Society (RPS), and the Japanese classification of diabetic nephropathy (19).

For the Fioretto classification, diabetic kidney disease is classified as follows: category I, normal or near-normal structure with very mild mesangial expansion, tubulointerstitial or arteriolar changes, or arteriolar hyalinosis in any combination; category II, typical diabetic kidney disease featured by established diabetic lesions with balanced severity of glomerular, tubulointerstitial, and arteriolar changes; and category III, atypical patterns of renal injury featured by absent or only mild glomerular diabetic changes with disproportionately severe interstitial or arteriolar lesions. For the Tervaert (RPS) classification, diabetic kidney disease was classified as follows: class I, glomerular basement membrane thickening and only mild, nonspecific changes on light microscopy; class II, mild (IIa) or severe (IIb) mesangial expansion without either nodular lesions or global sclerosis in >50% of the glomeruli; class III, nodular lesions without global sclerosis in >50% of the glomeruli; and class IV, global sclerosis in >50% of the glomeruli. Other pathological findings evaluated were interstitial lesions (interstitial fibrosis and tubular atrophy [IFTA] [grades 0–3] and interstitial inflammation [grades 0–2]) and vascular lesions (arteriolar hyalinosis [grades 0–2] and arteriosclerosis [grades 0–2]). Patients were excluded if histological and serological data confirmed concomitant renal disease or if the biopsy was inadequate for diagnosis.

For the Japanese classification of diabetic nephropathy, diabetic nephropathy was evaluated on the basis of nine glomerular lesions (diffuse lesion [grades 0–3]; nodular lesion [grades 0–1]; subendothelial space widening [grades 0–3]; exudative lesion [grades 0–1]; mesangiolysis/microaneurysm [grades 0–1]; perihilar neovascularization [grades 0–1]; global glomerulosclerosis, collapsing glomerulopathy, and ischemic nephropathy [grades 0–1]; segmental sclerosis [grades 0–1]; and glomerulomegaly[grades 0–1]), two interstitial lesions (IFTA [grades 0–3] and interstitial cell infiltration [grades 0–3]), and two vascular lesions (arteriolar hyalinosis [grades 0–3] and intimal thickening [grades 0–3]). We also evaluated the percent glomerular sclerosis as defined by the number of total global and segmental sclerotic glomeruli per the total number of glomeruli.

Outcome Measures and Follow-Up

The primary outcome of this study was chronic kidney disease (CKD) progression, which was defined as new-onset ESRD, decrease of eGFR by ≥50%, or doubling of the serum creatinine level. ESRD was defined as initiation of hemodialysis/peritoneal dialysis, renal transplantation, or death as a result of uremia, and occurrence of ESRD was ascertained by reviewing the database of the Japanese Society for Dialysis Therapy (JSDT). Since 1968, the JSDT has kept a complete annual renal data registry (JSDT Renal Data registry) that covers patients on dialysis (20). If ESRD did not develop during follow-up, we evaluated whether there was a decrease of eGFR by ≥50% or doubling of serum creatinine. The secondary outcome of this study was all-cause mortality. The event of death was ascertained from the medical records. Patients who did not reach the outcome of interest or who were lost to follow-up were censored at their last follow-up visit.

Statistical Analyses

The study cohort was not from a clinical trial but from a real-world clinical practice; therefore, the sample size was determined by the number of patients who underwent a renal biopsy in real clinical settings. To address the imbalance of the effects of age, sex, known duration of diabetes, and baseline renal function on the outcomes of interest and to fairly compare clinical, laboratory, pathological profiles, and outcomes between nonproteinuric and proteinuric diabetic kidney disease, we matched the nonproteinuric diabetic kidney disease group with a proteinuric diabetic kidney disease group using propensity scores with a one-to-two nearest neighbor caliper width of 0.01 (maximum allowable difference in propensity scores). We calculated the propensity score for patients with nonproteinuric diabetic kidney disease and patients with proteinuric diabetic kidney disease using a logistic regression model to estimate the probability of the disease assignment on the basis of baseline variables such as age, sex, known duration of diabetes, and eGFR. In both the baseline and the propensity score–matched cohorts, differences in clinical, laboratory, and pathological profiles between nonproteinuric and proteinuric diabetic kidney disease were analyzed by Student t test or the Wilcoxon test for continuous variables, whereas the χ2 test or Fisher exact test was used for categorical variables.

Variables independently associated with nonproteinuric diabetic kidney disease were identified by multivariable logistic regression in the overall cohort. Variables that had missing values >20% were not used in the analysis.

In both the entire cohort and the propensity score–matched cohort, we constructed Kaplan-Meier curves for time-to-event end points (CKD progression and all-cause mortality), taking time 0 as the date of renal biopsy. We used a log-rank test to determine a difference in survival rate.

The incidence of CKD progression was then calculated as the number of patients who developed new-onset ESRD, decrease of eGFR by ≥50%, or doubling of the serum creatinine level during the follow-up period divided by the total follow-up in person-years. The risk of CKD progression for patients with nonproteinuric diabetic kidney disease compared with those with proteinuric diabetic kidney disease was estimated as adjusted hazard ratios (HRs) with 95% CIs by using the multivariable Cox proportional hazards model adjusted for age, sex, known duration of diabetes, and baseline eGFR. We conducted a separate interim analysis with updated variables at the 1-year and 3-year study points, comparing the risk of CKD progression between nonproteinuric and proteinuric groups that were also updated.

Results are expressed as the mean with SD or the median with interquartile range (IQR) for continuous data and as percentages for categorical data. Statistical tests were considered significant at P < 0.05 (two-sided). All statistical analyses were conducted using Stata 14.1 software (StataCorp, College Station, TX).

Between 1 January 1985 and 31 December 2016, 895 patients underwent clinical renal biopsy and had a pathological diagnosis of diabetic kidney disease in our cohort; 13 patients were excluded because of concomitant renal disease with diabetic kidney disease, protocol renal transplant biopsy, or <3 months of follow-up. We identified 526 who had an eGFR <60 mL/min/1.73 m2 at the time of biopsy. Among them, 88 had nonproteinuric diabetic kidney disease (UACR <300 mg/g), and 438 had proteinuric diabetic kidney disease (UACR ≥300 mg/g) at baseline. After propensity score matching, the nonproteinuric diabetic kidney disease group comprised 82 patients and the proteinuric diabetic kidney disease group comprised 164 patients (Supplementary Fig. 1).

Table 1 shows the clinical and pathological characteristics of the study groups before and after propensity score matching. In propensity score–matched cohorts, the blood pressure in patients with nonproteinuric diabetic kidney disease was better controlled compared with patients with proteinuric diabetic kidney disease, although patients with nonproteinuric diabetic kidney disease were less prescribed RAAS blockade. Patients with nonproteinuric diabetic kidney disease had lower total cholesterol levels and higher hemoglobin levels. For pathological characteristics, there was a difference in classification assignment for diabetic kidney disease between the nonproteinuric diabetic kidney disease group and proteinuric diabetic kidney disease group. For example, with the Fioretto classification, category I, which is normal or near-normal renal structure, was the most prevalent group (62%) in the nonproteinuric diabetic kidney disease group, whereas category II, which is typical diabetic kidney disease with balanced interstitial and arteriolar changes, was the most prevalent group (66%) in the proteinuric diabetic kidney disease group. Similar to the Fioretto classification, in the Tervaert classification, advanced diabetic kidney disease (class III or more) was observed in only 27% of patients with nonproteinuric diabetic kidney disease, whereas it was seen in 62% of patients with proteinuric diabetic kidney disease. Compared with the proteinuric diabetic kidney disease group, the nonproteinuric diabetic kidney disease group had less severe interstitial and vascular lesions.

Table 1

Baseline clinical and pathological characteristics before and after propensity score matching

Entire cohort
Propensity score–matched cohort
CharacteristicNonproteinuric (n = 88)Proteinuric (n = 438)P valueNonproteinuric (n = 82)Proteinuric (n = 164)P value
Clinical characteristics at biopsy       
 Age (years) 63 (57, 68) 61 (52, 68) 0.081 63 (56, 67) 64 (56, 70) 0.52 
 Male 61 74 0.016 66 68 0.68 
 BMI (kg/m223 (21, 25) 24 (22, 26) 0.033 23 (21, 25) 24 (22, 26) 0.098 
 Diabetes duration (years) 12 (8, 18) 13 (9, 20) 0.36 12 (8, 18) 13 (8, 21) 0.45 
 Diabetic retinopathy 62 74 0.11 62 69 0.44 
 Smoking 63 63 1.00 63 61 0.90 
 RAAS blockade 48 67 0.017 48 69 0.015 
 Glucose-lowering agents 93 86 0.28 93 90 0.57 
 Statins 31 28 0.73 31 20 0.21 
 Erythropoietin-stimulating agents 17 12 0.51 17 13 0.65 
 sBP (mmHg) 132 (120, 146) 148 (137, 164) <0.001 130 (120, 145) 146 (134, 162) <0.001 
 dBP (mmHg) 76 (68, 80) 80 (71, 90) 0.003 75 (68, 80) 80 (70, 90) 0.009 
 Hemoglobin (g/dL) 12 (11, 14) 11 (10, 13) <0.001 12 (11, 14) 11 (10, 13) 0.002 
 HbA1c (mmol/mol) 55.2 (47.5, 74.9) 50.8 (41.0, 65.0) 0.004 55.2 (47.5, 74.9) 51.9 (42.1, 67.2) 0.033 
 HbA1c (%) 7.2 (6.5, 9.0) 6.8 (5.9, 8.1) 0.004 7.2 (6.5, 9.0) 6.9 (6.0, 8.3) 0.033 
 Total cholesterol (mmol/L) 4.8 (4.0, 5.8) 5.4 (4.4, 6.5) <0.001 5.0 (3.9, 5.8) 5.4 (4.6, 6.4) 0.002 
 Triglycerides (mmol/L) 1.5 (1.1, 2.2) 1.8 (1.2, 2.4) 0.11 1.5 (1.1, 2.2) 1.7 (1.2, 2.4) 0.21 
 LDL-C (mmol/L) 2.8 (2.1, 3.4) 3.1 (2.5, 4.2) 0.081 2.8 (2.1, 3.4) 3.3 (2.6, 4.1) 0.033 
 HDL-C (mmol/L) 1.0 (0.8, 1.3) 1.1 (0.9, 1.3) 0.25 1.0 (0.8, 1.3) 1.1 (0.8, 1.5) 0.28 
 Uric acid (mg/dL) 6.8 (5.9, 7.5) 6.8 (5.9, 7.0) 0.33 6.8 (5.9, 7.5) 6.5 (5.7, 7.8) 0.90 
 eGFR (mL/min/1.73 m245 (33, 54) 36 (24, 46) <0.001 45 (33, 54) 44 (29, 50) 0.12 
 UACR (mg/g) 110 (40, 210) 2,200 (1,100, 4,000) <0.001 100 (30, 180) 2,100 (1,140, 3,570)  
 Albuminuria status* (n      
  Normoalbuminuria 19  19  
  Microalbuminuria 69  63  
  Macroalbuminuria 438  164  
 Hematuria 10 12 0.54 10 0.57 
Pathological characteristics at biopsy       
 Fioretto classification   <0.001   <0.001 
  Category I 60 17  62 17  
  Category II 23 70  20 66  
  Category III 17 13  18 17  
 Tervaert (RPS) classification   <0.001   <0.001 
  Class I 30  31  
  Class IIa 32 13  22 14  
  Class IIb 21  10 20  
  Class III 27 51  25 52  
  Class IV 10  10  
 Japanese classification       
  Glomerular lesions       
   %GS 20 (9, 54) 39 (22, 67) 0.007 16 (6, 37) 33 (17, 44) <0.001 
   Diffuse lesions   <0.001   <0.001 
    0 16  16  
    1 41 14  43 17  
    2 19 25  17 29  
    3 24 58  24 53  
   GBM doubling   <0.001   0.001 
    0 65 23  66 23  
    1 18 41  17 41  
    2 21  23  
    3 10 15  13  
   Exudative lesion 24 60 <0.001 24 61 <0.001 
   Nodular lesion 25 53 <0.001 22 54 <0.001 
   Mesangiolysis 19 49 <0.001 19 49 <0.001 
   Polar vasculosis 56 76 0.005 54 73 0.014 
   Glomerulomegaly 25 40 0.033 26 37 0.13 
  Interstitial lesions       
   IFTA   <0.001   <0.001 
    0 10  11  
    1 51 19  53 24  
    2 25 36  23 37  
    3 14 43  13 37  
   Inflammation   0.005   0.021 
    0 14  15  
    1 61 60  62 64  
    2 19 24  18 22  
    3 12  10  
  Vascular lesions       
   Arteriolar hyalinosis   <0.001   0.002 
    0 14  15  
    1 24 14  23 16  
    2 29 42  29 48  
    3 33 41  33 32  
   Arteriosclerosis   0.011   0.002 
    0 15  16  
    1 35 47  35 51  
    2 47 45  47 44  
    3   
Entire cohort
Propensity score–matched cohort
CharacteristicNonproteinuric (n = 88)Proteinuric (n = 438)P valueNonproteinuric (n = 82)Proteinuric (n = 164)P value
Clinical characteristics at biopsy       
 Age (years) 63 (57, 68) 61 (52, 68) 0.081 63 (56, 67) 64 (56, 70) 0.52 
 Male 61 74 0.016 66 68 0.68 
 BMI (kg/m223 (21, 25) 24 (22, 26) 0.033 23 (21, 25) 24 (22, 26) 0.098 
 Diabetes duration (years) 12 (8, 18) 13 (9, 20) 0.36 12 (8, 18) 13 (8, 21) 0.45 
 Diabetic retinopathy 62 74 0.11 62 69 0.44 
 Smoking 63 63 1.00 63 61 0.90 
 RAAS blockade 48 67 0.017 48 69 0.015 
 Glucose-lowering agents 93 86 0.28 93 90 0.57 
 Statins 31 28 0.73 31 20 0.21 
 Erythropoietin-stimulating agents 17 12 0.51 17 13 0.65 
 sBP (mmHg) 132 (120, 146) 148 (137, 164) <0.001 130 (120, 145) 146 (134, 162) <0.001 
 dBP (mmHg) 76 (68, 80) 80 (71, 90) 0.003 75 (68, 80) 80 (70, 90) 0.009 
 Hemoglobin (g/dL) 12 (11, 14) 11 (10, 13) <0.001 12 (11, 14) 11 (10, 13) 0.002 
 HbA1c (mmol/mol) 55.2 (47.5, 74.9) 50.8 (41.0, 65.0) 0.004 55.2 (47.5, 74.9) 51.9 (42.1, 67.2) 0.033 
 HbA1c (%) 7.2 (6.5, 9.0) 6.8 (5.9, 8.1) 0.004 7.2 (6.5, 9.0) 6.9 (6.0, 8.3) 0.033 
 Total cholesterol (mmol/L) 4.8 (4.0, 5.8) 5.4 (4.4, 6.5) <0.001 5.0 (3.9, 5.8) 5.4 (4.6, 6.4) 0.002 
 Triglycerides (mmol/L) 1.5 (1.1, 2.2) 1.8 (1.2, 2.4) 0.11 1.5 (1.1, 2.2) 1.7 (1.2, 2.4) 0.21 
 LDL-C (mmol/L) 2.8 (2.1, 3.4) 3.1 (2.5, 4.2) 0.081 2.8 (2.1, 3.4) 3.3 (2.6, 4.1) 0.033 
 HDL-C (mmol/L) 1.0 (0.8, 1.3) 1.1 (0.9, 1.3) 0.25 1.0 (0.8, 1.3) 1.1 (0.8, 1.5) 0.28 
 Uric acid (mg/dL) 6.8 (5.9, 7.5) 6.8 (5.9, 7.0) 0.33 6.8 (5.9, 7.5) 6.5 (5.7, 7.8) 0.90 
 eGFR (mL/min/1.73 m245 (33, 54) 36 (24, 46) <0.001 45 (33, 54) 44 (29, 50) 0.12 
 UACR (mg/g) 110 (40, 210) 2,200 (1,100, 4,000) <0.001 100 (30, 180) 2,100 (1,140, 3,570)  
 Albuminuria status* (n      
  Normoalbuminuria 19  19  
  Microalbuminuria 69  63  
  Macroalbuminuria 438  164  
 Hematuria 10 12 0.54 10 0.57 
Pathological characteristics at biopsy       
 Fioretto classification   <0.001   <0.001 
  Category I 60 17  62 17  
  Category II 23 70  20 66  
  Category III 17 13  18 17  
 Tervaert (RPS) classification   <0.001   <0.001 
  Class I 30  31  
  Class IIa 32 13  22 14  
  Class IIb 21  10 20  
  Class III 27 51  25 52  
  Class IV 10  10  
 Japanese classification       
  Glomerular lesions       
   %GS 20 (9, 54) 39 (22, 67) 0.007 16 (6, 37) 33 (17, 44) <0.001 
   Diffuse lesions   <0.001   <0.001 
    0 16  16  
    1 41 14  43 17  
    2 19 25  17 29  
    3 24 58  24 53  
   GBM doubling   <0.001   0.001 
    0 65 23  66 23  
    1 18 41  17 41  
    2 21  23  
    3 10 15  13  
   Exudative lesion 24 60 <0.001 24 61 <0.001 
   Nodular lesion 25 53 <0.001 22 54 <0.001 
   Mesangiolysis 19 49 <0.001 19 49 <0.001 
   Polar vasculosis 56 76 0.005 54 73 0.014 
   Glomerulomegaly 25 40 0.033 26 37 0.13 
  Interstitial lesions       
   IFTA   <0.001   <0.001 
    0 10  11  
    1 51 19  53 24  
    2 25 36  23 37  
    3 14 43  13 37  
   Inflammation   0.005   0.021 
    0 14  15  
    1 61 60  62 64  
    2 19 24  18 22  
    3 12  10  
  Vascular lesions       
   Arteriolar hyalinosis   <0.001   0.002 
    0 14  15  
    1 24 14  23 16  
    2 29 42  29 48  
    3 33 41  33 32  
   Arteriosclerosis   0.011   0.002 
    0 15  16  
    1 35 47  35 51  
    2 47 45  47 44  
    3   

Data are median (25th, 75th percentile) or percentage unless otherwise indicated. dBP, diastolic blood pressure; GBM, glomerular basement membrane; %GS, percent glomerular sclerosis defined as the number of global or segmental sclerosis glomeruli per total glomeruli; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; sBP, systolic blood pressure.

*Albuminuria status: normoalbuminuria, UACR <30 mg/g; microalbuminuria, UACR 30–299 mg/g; macroalbuminuria, UACR ≥300 mg/g.

†Fioretto classification: category I, normal or near-normal renal structure; category II, typical diabetic kidney disease; category III, atypical patterns of renal injury.

‡Tervaert (RPS) classification: class I, mild or nonspecific light microscopy changes and electron microscopy–proven GBM thickening; class IIa, mild mesangial expansion; class IIb, severe mesangial expansion; class III, nodular sclerosis (Kimmelstiel-Wilson lesion); class IV, advanced diabetic glomerular sclerosis.

Table 2 shows the association of baseline characteristics with nonproteinuric diabetic kidney disease in the overall cohort. In a multivariable logistic regression model, older age, lower systolic blood pressure, higher hemoglobin level, and higher HbA1c were significantly associated with a higher odds of nonproteinuric diabetic kidney disease.

Table 2

Baseline characteristics associated with nonproteinuric diabetic kidney disease in the overall cohort (N = 526)

Univariable
Multivariable
VariableOR (95% CI)P valueOR (95% CI)P value
Clinical parameter     
 Age (years) 1.02 (1.00–1.04) 0.06 1.05 (1.01–1.08) 0.004 
 Male (yes/no) 0.56 (0.35–0.90) 0.02   
 BMI (kg/m20.91 (0.85–0.98) 0.01   
 Diabetes duration (years) 0.98 (0.94–1.02) 0.31   
 Diabetic retinopathy (yes/no) 0.56 (0.28–1.15) 0.12   
 Smoking (yes/no) 1.00 (0.42–2.40) 0.99   
 RAAS blockade (yes/no) 0.45 (0.23–0.88) 0.02   
 Glucose-lowering agents (yes/no) 2.22 (0.51–9.72) 0.29   
 Statins (yes/no) 1.16 (0.50–2.67) 0.73   
 Erythropoietin-stimulating agents (yes/no) 1.47 (0.46–4.69) 0.52   
 sBP (mmHg) 0.95 (0.94–0.97) <0.001 0.95 (0.93–0.97) <0.001 
 dBP (mmHg) 0.97 (0.95–0.99) 0.002   
 Hemoglobin (g/dL) 1.30 (1.16–1.46) <0.001 1.22 (1.05–1.41) 0.010 
 HbA1c (%) 1.22 (1.08–1.39) 0.002 1.32 (1.11–1.56) 0.002 
 Total cholesterol (mmol/L) 0.99 (0.99–1.00) <0.001   
 Triglycerides (mmol/L) 1.00 (0.99–1.00) 0.26   
 LDL-C (mmol/L) 0.99 (0.98–1.00) 0.078   
 HDL-C (mmol/L) 0.97 (0.93–1.01) 0.16   
 Uric acid (mg/dL) 0.89 (0.73–1.08) 0.23   
 eGFR (mL/min/1.73 m21.04 (1.02–1.06) <0.001   
 Hematuria (yes/no) 0.55 (0.27–1.16) 0.16   
Histological parameters     
 Fioretto classification*     
  Category I 1.00 (Reference)    
  Category II 0.09 (0.05–0.16) <0.001   
  Category III 0.35 (0.18–0.68) 0.002   
 Tervaert classification (class ≥III) 0.26 (0.15–0.43) <0.001   
 Japanese classification     
  Glomerular lesions     
   %GS 0.97 (0.95–0.98) <0.001   
   Diffuse lesions (≥3) 0.26 (0.14–0.50) <0.001   
   GBM doubling (≥3) 1.75 (0.64–4.81) 0.28   
   Exudative lesion (yes/no) 0.21 (0.11–0.39) <0.001   
   Nodular lesion (yes/no) 0.30 (0.16–0.55) <0.001   
   Mesangiolysis (yes/no) 0.25 (0.13–0.49) <0.001   
   Polar vasculosis (yes/no) 0.40 (0.23–0.71) 0.002   
   Glomerulomegaly (yes/no) 0.52 (0.28–0.96) 0.035   
  Interstitial lesions     
   IFTA score (≥3) 0.23 (0.12–0.43) <0.001   
   Interstitial inflammation score (≥3) 0.49 (0.19–1.26) 0.14   
  Vascular lesions     
   Arteriolar hyalinosis score (≥3) 0.85 (0.51–1.41) 0.53   
   Arteriosclerosis score (≥3) 3.32 (0.78–14.2) 0.11   
Univariable
Multivariable
VariableOR (95% CI)P valueOR (95% CI)P value
Clinical parameter     
 Age (years) 1.02 (1.00–1.04) 0.06 1.05 (1.01–1.08) 0.004 
 Male (yes/no) 0.56 (0.35–0.90) 0.02   
 BMI (kg/m20.91 (0.85–0.98) 0.01   
 Diabetes duration (years) 0.98 (0.94–1.02) 0.31   
 Diabetic retinopathy (yes/no) 0.56 (0.28–1.15) 0.12   
 Smoking (yes/no) 1.00 (0.42–2.40) 0.99   
 RAAS blockade (yes/no) 0.45 (0.23–0.88) 0.02   
 Glucose-lowering agents (yes/no) 2.22 (0.51–9.72) 0.29   
 Statins (yes/no) 1.16 (0.50–2.67) 0.73   
 Erythropoietin-stimulating agents (yes/no) 1.47 (0.46–4.69) 0.52   
 sBP (mmHg) 0.95 (0.94–0.97) <0.001 0.95 (0.93–0.97) <0.001 
 dBP (mmHg) 0.97 (0.95–0.99) 0.002   
 Hemoglobin (g/dL) 1.30 (1.16–1.46) <0.001 1.22 (1.05–1.41) 0.010 
 HbA1c (%) 1.22 (1.08–1.39) 0.002 1.32 (1.11–1.56) 0.002 
 Total cholesterol (mmol/L) 0.99 (0.99–1.00) <0.001   
 Triglycerides (mmol/L) 1.00 (0.99–1.00) 0.26   
 LDL-C (mmol/L) 0.99 (0.98–1.00) 0.078   
 HDL-C (mmol/L) 0.97 (0.93–1.01) 0.16   
 Uric acid (mg/dL) 0.89 (0.73–1.08) 0.23   
 eGFR (mL/min/1.73 m21.04 (1.02–1.06) <0.001   
 Hematuria (yes/no) 0.55 (0.27–1.16) 0.16   
Histological parameters     
 Fioretto classification*     
  Category I 1.00 (Reference)    
  Category II 0.09 (0.05–0.16) <0.001   
  Category III 0.35 (0.18–0.68) 0.002   
 Tervaert classification (class ≥III) 0.26 (0.15–0.43) <0.001   
 Japanese classification     
  Glomerular lesions     
   %GS 0.97 (0.95–0.98) <0.001   
   Diffuse lesions (≥3) 0.26 (0.14–0.50) <0.001   
   GBM doubling (≥3) 1.75 (0.64–4.81) 0.28   
   Exudative lesion (yes/no) 0.21 (0.11–0.39) <0.001   
   Nodular lesion (yes/no) 0.30 (0.16–0.55) <0.001   
   Mesangiolysis (yes/no) 0.25 (0.13–0.49) <0.001   
   Polar vasculosis (yes/no) 0.40 (0.23–0.71) 0.002   
   Glomerulomegaly (yes/no) 0.52 (0.28–0.96) 0.035   
  Interstitial lesions     
   IFTA score (≥3) 0.23 (0.12–0.43) <0.001   
   Interstitial inflammation score (≥3) 0.49 (0.19–1.26) 0.14   
  Vascular lesions     
   Arteriolar hyalinosis score (≥3) 0.85 (0.51–1.41) 0.53   
   Arteriosclerosis score (≥3) 3.32 (0.78–14.2) 0.11   

Odds ratios (ORs) for CKD progression were determined for various clinical and histological characteristics by the logistic model. dBP, diastolic blood pressure; GBM, glomerular basement membrane; %GS, percent glomerular sclerosis defined as the number of global or segmental sclerosis glomeruli per total glomeruli; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; sBP, systolic blood pressure.

*Fioretto classification: category I, normal or near-normal renal structure; category II, typical diabetic kidney disease; category III, atypical patterns of renal injury.

†Tervaert (RPS) classification: class I, mild or nonspecific light microscopy changes and electron microscopy–proven GBM thickening; class IIa, mild mesangial expansion; class IIb, severe mesangial expansion; class III, nodular sclerosis (Kimmelstiel-Wilson lesion); class IV, advanced diabetic glomerular sclerosis.

Table 3 shows predictors for CKD progression in patients with nonproteinuric diabetic kidney disease. Cox proportional hazards analysis revealed low hemoglobin level, use of erythropoietin-stimulating agents, and severity of IFTA as the predictors of CKD progression in univariable analysis. The multivariable analysis revealed that only severe IFTA was associated with CKD progression.

Table 3

Predictors for CKD progression in patients with nonproteinuric diabetic kidney disease

Univariable
Multivariable
VariableHR (95% CI)P valueHR (95% CI)P value
Clinical parameter     
 Age (years) 1.03 (0.97–1.09) 0.32   
 Male (yes/no) 1.05 (0.36–3.02) 0.94   
 BMI (kg/m20.94 (0.77–1.15) 0.54   
 Diabetes duration (years) 1.02 (0.93–1.12) 0.63   
 Diabetic retinopathy (yes/no) 0.90 (0.21–3.80) 0.88   
 Smoking (yes/no) 2.23 (0.23–21.7) 0.49   
 RAAS blockade (yes/no) 0.74 (0.16–3.42) 0.70   
 Glucose-lowering agents (yes/no) 0.60 (0.07–5.42) 0.65   
 Statins (yes/no) 1.45 (0.13–16.2) 0.76   
 Erythropoietin-stimulating agents (yes/no) 14.2 (1.44–141) 0.02   
 sBP (mmHg) 1.00 (0.98–1.03) 0.85   
 dBP (mmHg) 0.99 (0.95–1.04) 0.80   
 Hemoglobin (g/dL) 0.63 (0.44–0.88) 0.007   
 HbA1c (%) 0.87 (0.63–1.19) 0.38   
 Total cholesterol (mmol/L) 0.98 (0.97–1.00) 0.008   
 Triglycerides (mmol/L) 0.99 (0.97–1.01) 0.20   
 LDL-C (mmol/L) 0.93 (0.88–0.99) 0.026   
 HDL-C (mmol/L) 0.94 (0.84–1.05) 0.25   
 Uric acid (mg/dL) 1.09 (0.62–1.94) 0.76   
 eGFR (mL/min/1.73 m20.96 (0.93–1.00) 0.039   
 UACR (mg/g) 6.67 (0.42–10.6) 0.10   
Histological parameter     
 Fioretto classification*     
  Category I 1.00 (Reference)    
  Category II 4.10 (1.26–13.4) 0.019   
  Category III 2.33 (0.68–8.00) 0.18   
 Tervaert classification (class ≥III) 2.4 (0.86–6.60) 0.095   
 Japanese classification     
  Glomerular lesions     
   %GS 1.02 (1.00–1.05) 0.11   
   Diffuse lesion (≥3) 1.33 (0.34–5.22) 0.68   
   GBM doubling (≥3) 1.14 (0.19–6.95) 0.89   
   Exudative lesion (yes/no) 0.75 (0.10–6.00) 0.79   
   Nodular lesion (yes/no) 1.75 (0.51–6.05) 0.38   
   Mesangiolysis (yes/no) 1.49 (0.32–6.90) 0.61   
   Polar vasculosis (yes/no) 1.05 (0.31–3.62) 0.94   
   Glomerulomegaly (yes/no) 1.56 (0.41–5.97) 0.51   
  Interstitial lesions     
   IFTA score (≥3) 4.05 (1.34–12.2) 0.013 14.8 (3.0–73.8) 0.001 
   Interstitial inflammation score (≥3) 0.98 (0.22–4.37) 0.98   
  Vascular lesions     
   Arteriolar hyalinosis score (≥3) 0.85 (0.29–2.47) 0.77   
   Arteriosclerosis score (≥3) NA NA   
Univariable
Multivariable
VariableHR (95% CI)P valueHR (95% CI)P value
Clinical parameter     
 Age (years) 1.03 (0.97–1.09) 0.32   
 Male (yes/no) 1.05 (0.36–3.02) 0.94   
 BMI (kg/m20.94 (0.77–1.15) 0.54   
 Diabetes duration (years) 1.02 (0.93–1.12) 0.63   
 Diabetic retinopathy (yes/no) 0.90 (0.21–3.80) 0.88   
 Smoking (yes/no) 2.23 (0.23–21.7) 0.49   
 RAAS blockade (yes/no) 0.74 (0.16–3.42) 0.70   
 Glucose-lowering agents (yes/no) 0.60 (0.07–5.42) 0.65   
 Statins (yes/no) 1.45 (0.13–16.2) 0.76   
 Erythropoietin-stimulating agents (yes/no) 14.2 (1.44–141) 0.02   
 sBP (mmHg) 1.00 (0.98–1.03) 0.85   
 dBP (mmHg) 0.99 (0.95–1.04) 0.80   
 Hemoglobin (g/dL) 0.63 (0.44–0.88) 0.007   
 HbA1c (%) 0.87 (0.63–1.19) 0.38   
 Total cholesterol (mmol/L) 0.98 (0.97–1.00) 0.008   
 Triglycerides (mmol/L) 0.99 (0.97–1.01) 0.20   
 LDL-C (mmol/L) 0.93 (0.88–0.99) 0.026   
 HDL-C (mmol/L) 0.94 (0.84–1.05) 0.25   
 Uric acid (mg/dL) 1.09 (0.62–1.94) 0.76   
 eGFR (mL/min/1.73 m20.96 (0.93–1.00) 0.039   
 UACR (mg/g) 6.67 (0.42–10.6) 0.10   
Histological parameter     
 Fioretto classification*     
  Category I 1.00 (Reference)    
  Category II 4.10 (1.26–13.4) 0.019   
  Category III 2.33 (0.68–8.00) 0.18   
 Tervaert classification (class ≥III) 2.4 (0.86–6.60) 0.095   
 Japanese classification     
  Glomerular lesions     
   %GS 1.02 (1.00–1.05) 0.11   
   Diffuse lesion (≥3) 1.33 (0.34–5.22) 0.68   
   GBM doubling (≥3) 1.14 (0.19–6.95) 0.89   
   Exudative lesion (yes/no) 0.75 (0.10–6.00) 0.79   
   Nodular lesion (yes/no) 1.75 (0.51–6.05) 0.38   
   Mesangiolysis (yes/no) 1.49 (0.32–6.90) 0.61   
   Polar vasculosis (yes/no) 1.05 (0.31–3.62) 0.94   
   Glomerulomegaly (yes/no) 1.56 (0.41–5.97) 0.51   
  Interstitial lesions     
   IFTA score (≥3) 4.05 (1.34–12.2) 0.013 14.8 (3.0–73.8) 0.001 
   Interstitial inflammation score (≥3) 0.98 (0.22–4.37) 0.98   
  Vascular lesions     
   Arteriolar hyalinosis score (≥3) 0.85 (0.29–2.47) 0.77   
   Arteriosclerosis score (≥3) NA NA   

HRs for CKD progression were determined for various clinical and histological characteristics by the Cox proportional hazards model. dBP, diastolic blood pressure; GBM, glomerular basement membrane; %GS, percent glomerular sclerosis defined as the number of global or segmental sclerosis glomeruli per total glomeruli; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; NA, not applicable; sBP, systolic blood pressure.

*Fioretto classification: category I, normal or near-normal renal structure; category II, typical diabetic kidney disease; category III, atypical patterns of renal injury.

†Tervaert (RPS) classification: class I, mild or nonspecific light microscopy changes and electron microscopy–proven GBM thickening; class IIa, mild mesangial expansion; class IIb, severe mesangial expansion; class III, nodular sclerosis (Kimmelstiel-Wilson lesion); class IV, advanced diabetic glomerular sclerosis.

Figure 1 shows the Kaplan-Meier curves for time-to-event end points in both the entire cohort and the matched cohort, taking time 0 as the date of renal biopsy. After a median follow-up of 1.8 years (IQR 0.9–3.7) from the date of renal biopsy, 297 (56%) of the 526 patients had renal events. The 5-year CKD progression-free survival was 33.2% (95% CI 28.4–38.2%) for all patients, 86.9% (95% CI 73.1–93.9%) for the nonproteinuric diabetic kidney disease group, and 24.5% (95% CI 19.8–29.5%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) (Fig. 1A). The same trend was seen in the propensity score–matched cohort: After a median follow-up of 1.9 years (IQR 0.9–5.0) from the date of renal biopsy, 124 (50%) of the 246 matched patients had renal events. The 5-year CKD progression-free survival was 46.4% (95% CI 38.7–53.6%) for all patients, 86.6% (95% CI 72.5–93.8%) for the nonproteinuric diabetic kidney disease group, and 30.3% (95% CI 22.4–38.6%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) (Fig. 1B). Similarly, for the secondary outcome (all-cause mortality), after a median follow-up of 2.7 years (IQR 1.1–5.7) from the date of renal biopsy, 55 (10%) of the 526 patients had death events. The 5-year death-free survival was 89.7% (95% CI 85.6–92.7%) for all patients, 98.4% (95% CI 89.1–99.8%) for the nonproteinuric diabetic kidney disease group, and 87.5% (95% CI 82.5–91.2%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) (Fig. 1C). The same trend was seen in the propensity matched cohort: After a median follow-up of 3.1 years (IQR 1.3–7.0) from the date of renal biopsy, 35 (14%) of the 246 matched patients had death events. The 5-year death-free survival was 88.2% (95% CI 82.0–92.3%) for all patients, 98.3% (95% CI 88.7–99.8%) for the nonproteinuric diabetic kidney disease group, and 82.6% (95% CI 73.6–88.8%) for the proteinuric diabetic kidney disease group (log-rank test P = 0.005) (Fig. 1D).

Figure 1

Renal event-free survival for the 526 patients in the entire cohort and the 164 patients in the propensity score–matched cohort. A: Kaplan-Meier curves of CKD progression-free survival in the entire cohort. B: Kaplan-Meier curves of CKD progression-free survival in the propensity score–matched cohort. C: Kaplan-Meier curves of death event–free survival in the entire cohort. D: Kaplan-Meier curves of death event–free survival in the propensity score–matched cohort. CKD progression was defined as new-onset ESRD, decreased eGFR ≥50%, or doubling of serum creatinine. Nonproteinurics were defined as patients with an eGFR <60 mL/min/1.73 m2 without proteinuria (UACR <300 mg/g); proteinurics were defined as patients with an eGFR <60 mL/min/1.73 m2 and proteinuria (UACR ≥300 mg/g).

Figure 1

Renal event-free survival for the 526 patients in the entire cohort and the 164 patients in the propensity score–matched cohort. A: Kaplan-Meier curves of CKD progression-free survival in the entire cohort. B: Kaplan-Meier curves of CKD progression-free survival in the propensity score–matched cohort. C: Kaplan-Meier curves of death event–free survival in the entire cohort. D: Kaplan-Meier curves of death event–free survival in the propensity score–matched cohort. CKD progression was defined as new-onset ESRD, decreased eGFR ≥50%, or doubling of serum creatinine. Nonproteinurics were defined as patients with an eGFR <60 mL/min/1.73 m2 without proteinuria (UACR <300 mg/g); proteinurics were defined as patients with an eGFR <60 mL/min/1.73 m2 and proteinuria (UACR ≥300 mg/g).

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Table 4 displays the comparison of CKD progression risk in the nonproteinuric diabetic kidney disease group and the proteinuric diabetic kidney disease group in the propensity score–matched cohort. The overall CKD progression incidence was significantly lower in the nonproteinuric diabetic kidney disease group (30 [95% CI 18–50] per 1,000 person-years) than in the proteinuric diabetic kidney disease group (231 [95% CI 191–278] per 1,000 person-years; crude HR 0.15 [95% CI 0.08–0.26]). After adjustment for age, sex, known duration of diabetes, and baseline eGFR, the risk of CKD progression remained lower in the nonproteinuric diabetic kidney disease cohort than in the proteinuric diabetic kidney disease cohort (adjusted HR 0.13 [95% CI 0.08–0.24]). The risk of CKD progression was consistently lower in the nonproteinuric diabetic kidney disease group than in the proteinuric diabetic kidney disease group when stratified by potential confounders such as age, sex, obesity, retinopathy, smoking status, use of RAAS blockade, hypertension, dyslipidemia, poor glycemic control, lower eGFR, and pathological findings.

Table 4

Comparison of CKD progression risk in the nonproteinuric diabetic kidney disease cohort and the proteinuric diabetic kidney disease cohort

Nonproteinuric (n = 82)
Proteinuric (n = 164)
CharacteristicEventsPYIR (95% CI)EventsPYIR (95% CI)Adjusted HR (95% CI)P value
Overall 15 498 30 (18–50) 110 477 231 (191–278) 0.13 (0.08–0.24) <0.001 
Elderly 131 31 (11–81) 48 207 232 (175–308) 0.11 (0.04–0.31) <0.001 
Male 11 349 32 (17–57) 79 318 248 (199–309) 0.13 (0.07–0.26) <0.001 
Obesity 183 27 (11–66) 41 195 210 (155–285) 0.10 (0.04–0.26) <0.001 
Diabetic retinopathy 113 44 (18–107) 38 190 200 (146–275) 0.23 (0.09–0.61) <0.001 
Smoking 80 50 (19–134) 36 172 210 (151–291) 0.15 (0.05–0.45) <0.001 
RAAS blockade 77 52 (19–138) 54 227 238 (183–311) 0.13 (0.04–0.42) <0.001 
Hypertension 229 35 (17–70) 88 336 262 (213–323) 0.14 (0.06–0.28) <0.001 
Dyslipidemia 10 449 22 (12–41) 95 397 239 (196–293) 0.10 (0.05–0.20) <0.001 
Poor glycemic control 249 28 (13–59) 44 208 212 (158–284) 0.12 (0.05–0.29) <0.001 
eGFR <45 mL/min/1.73 m2 336 18 (8–40) 48 306 157 (118–208) 0.13 (0.05–0.33) <0.001 
Fioretto classification*         
 Category I 344 20 (9–43) 16 168 95 (58–156) 0.17 (0.06–0.46) <0.001 
 Category II 70 57 (22–153) 75 244 308 (245–386) 0.17 (0.06–0.47) <0.001 
 Category III 84 47 (18–126) 19 65 291 (186–457) 0.10 (0.03–0.36) <0.001 
Tervaert classification (class ≥III) 128 47 (21–104) 66 197 335 (264–427) 0.14 (0.05–0.35) <0.001 
Nonproteinuric (n = 82)
Proteinuric (n = 164)
CharacteristicEventsPYIR (95% CI)EventsPYIR (95% CI)Adjusted HR (95% CI)P value
Overall 15 498 30 (18–50) 110 477 231 (191–278) 0.13 (0.08–0.24) <0.001 
Elderly 131 31 (11–81) 48 207 232 (175–308) 0.11 (0.04–0.31) <0.001 
Male 11 349 32 (17–57) 79 318 248 (199–309) 0.13 (0.07–0.26) <0.001 
Obesity 183 27 (11–66) 41 195 210 (155–285) 0.10 (0.04–0.26) <0.001 
Diabetic retinopathy 113 44 (18–107) 38 190 200 (146–275) 0.23 (0.09–0.61) <0.001 
Smoking 80 50 (19–134) 36 172 210 (151–291) 0.15 (0.05–0.45) <0.001 
RAAS blockade 77 52 (19–138) 54 227 238 (183–311) 0.13 (0.04–0.42) <0.001 
Hypertension 229 35 (17–70) 88 336 262 (213–323) 0.14 (0.06–0.28) <0.001 
Dyslipidemia 10 449 22 (12–41) 95 397 239 (196–293) 0.10 (0.05–0.20) <0.001 
Poor glycemic control 249 28 (13–59) 44 208 212 (158–284) 0.12 (0.05–0.29) <0.001 
eGFR <45 mL/min/1.73 m2 336 18 (8–40) 48 306 157 (118–208) 0.13 (0.05–0.33) <0.001 
Fioretto classification*         
 Category I 344 20 (9–43) 16 168 95 (58–156) 0.17 (0.06–0.46) <0.001 
 Category II 70 57 (22–153) 75 244 308 (245–386) 0.17 (0.06–0.47) <0.001 
 Category III 84 47 (18–126) 19 65 291 (186–457) 0.10 (0.03–0.36) <0.001 
Tervaert classification (class ≥III) 128 47 (21–104) 66 197 335 (264–427) 0.14 (0.05–0.35) <0.001 

Events indicate number of patients who developed CKD progression. Adjusted HR was adjusted for age, sex, known duration of diabetes, and eGFR. Obesity was defined as BMI ≥25 kg/m2. Hypertension was defined as a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. Dyslipidemia was defined as total cholesterol level ≥240 mg/dL, LDL cholesterol level ≥140 mg/dL, triglyceride level ≥150 mg/dL, or HDL cholesterol level ≤40 mg/dL. Poor glycemic control was defined by an HbA1c >7.5%. IR, incidence rate; PY, person-years.

*Fioretto classification: category I, normal or near-normal renal structure; category II, typical diabetic kidney disease; category III, atypical patterns of renal injury.

†Tervaert (RPS) classification: class I, mild or nonspecific light microscopy changes and electron microscopy–proven glomerular basement membrane thickening; class IIa, mild mesangial expansion; class IIb, severe mesangial expansion; class III, nodular sclerosis (Kimmelstiel-Wilson lesion); class IV, advanced diabetic glomerular sclerosis.

This propensity score–matched cohort study of patients with nonproteinuric diabetic kidney disease and proteinuric diabetic kidney disease demonstrates that patients with nonproteinuric diabetic kidney disease have lower systolic blood pressure and less frequent typical pathological lesions and are at a lower risk of CKD progression and all-cause mortality. From a clinical point of view, analysis of data mainly from patients with type 1 diabetes, it has been considered that the increase of albuminuria to macroalbuminuria or proteinuria reflects glomerular abnormalities and precedes and accompanies the decline of renal function (13). Recently, however, a number of cross-sectional studies dispelled this widely held belief, reporting that a proportion of patients with type 2 diabetes and CKD present with a normal range of albuminuria or only microalbuminuria, even in their late stages of CKD (defined as eGFR <60 mL/min/1.73 m2) (611). However, the clinical pictures for patients with nonproteinuria are inconsistent in these previous reports, although several features, such as female sex, hypertension, smoking, hyperglycemia, no evidence of microangiopathy (represented as diabetic retinopathy), and the use of RAAS blockade, were reported as risk factors for nonproteinuric diabetic kidney disease. These inconsistent findings may arise from the fact that patients with type 2 diabetes and CKD were clinically diagnosed as having a diabetic kidney disease. Therefore, it is possible that these patients have glomerular diseases other than diabetic kidney disease or concomitant renal disease with diabetic kidney disease. We therefore investigated a cohort with biopsy-proven diabetic kidney disease as the only glomerular disease diagnosis rather than inaccurate clinical diagnoses of diabetic kidney disease. We found that older age, lower systolic blood pressure, higher hemoglobin, and higher HbA1c are associated with nonproteinuric diabetic kidney disease. Furthermore, we conducted propensity score matching to address the imbalance of background factors such as age, sex, diabetes duration, and baseline eGFR that affect renal prognosis and mortality. We found that patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure, although they were less frequently prescribed RAAS blockade. These results are plausible because a number of studies reported that higher systolic blood pressure is associated with an increase in albuminuria (2123). The effect of RAAS blockade on albuminuria and blood pressure should be mentioned since previous studies report that RAAS blockade decreases the amount of albuminuria, and these effects are independent from changes in systemic blood pressure (2123). Thus, we did subgroup analyses to test for the effect of RAAS blockade and having hypertension on renal outcome but found that the lower renal risk in patients with nonproteinuric diabetic kidney disease was consistent across these subgroup analyses.

From a pathological perspective, the early studies of morphological changes with diabetes have been done mostly in patients with type 1 diabetes (4,2426). These studies showed specific lesions with diabetes that include diffuse lesions characterized by a thickened glomerular basement membrane and mesangial expansion, nodular lesions characterized by nodular glomerular sclerosis known as Kimmelstiel-Wilson nodule, and hyalinosis lesions characterized by an exudative/insudative lesion and fibrin cap. Especially, nodular glomerular sclerosis is believed to be a hallmark of classical diabetic nephropathy and observed in patients with longstanding diabetes and reduced renal function. Since the recognition of morphological changes with diabetes, later studies in type 1 diabetes have shown that glomerular structure components are associated with measured GFR by iothalamate or iohexol or 24-h creatinine clearance (27,28). In these studies, the structural-functional relationship became stronger in patients with reduced renal function, although most of those with reduce renal function had proteinuria. Conversely, available biopsy-based studies in type 2 diabetes, especially without proteinuria, have been limited since diabetic kidney disease has been clinically diagnosed in patients with type 2 diabetes. Only a few studies have analyzed the pathological lesions in patients with type 2 diabetes with nonproteinuric diabetic kidney disease (2931). The findings of these cross-sectional studies, however, are inconsistent. One study reported that patients with nonproteinuric diabetic kidney disease have advanced diabetic glomerular changes but well-preserved interstitial and arterial lesions. Other studies reported that patients with nonproteinuric diabetic kidney disease have less typical diabetic kidney disease but disproportionately damaged interstitial and arterial lesions. This inconsistency may arise from the timing of the biopsy; for example, the pathology in those with eGFR 55 mL/min/1.73 m2 may be different from that in those with the same backgrounds but with eGFR 20 mL/min/1.73 m2, or age and sex may affect their pathology. A number of studies reported that aging leads to various anatomical and physiological changes of the kidney (32,33). Also, female sex through hormonal changes is known as a risk factor of glomerular sclerosis and interstitial fibrosis. Again, we investigated a propensity score–matched cohort of biopsy-proven diabetic kidney disease to address these issues.

In this study, we used three different classification systems of diabetic nephropathy to try to capture the differences of pathological features between nonproteinuric and proteinuric diabetic kidney disease because each classification has its strengths and weaknesses. The Fioretto classification was developed as a basic distinction between typical and atypical diabetic nephropathy (17). This classification evaluates not only glomerular lesions but also interstitial and arteriolar lesions and classifies these into three categories based on the balance of the severity of glomerular, tubulointerstitial, and arteriolar changes. This classification enables us to see the overview of pathological lesions. On the other hand, the Tervaert (RPS) classification focuses purely on glomerular lesions, assigning classes I–V, which correspond to the severity of glomerular lesions (18). The major strength of this classification is that it was proposed by the Research Committee of the RPS as a platform for clinical use. However, the shortcoming of this classification is that it puts less emphasis on interstitial and arteriolar lesions and may not be able to capture a broad spectrum of disease severity. To overcome the shortcomings of the Tervaert (RPS) classification, the Japanese classification features detailed explanations that are not evaluated in the Tervaert classification and treats glomerular, interstitial, and arteriolar lesions equally (19). However, it is not yet ready for clinical application. In any case, with these classifications, we found that patients with nonproteinuric diabetic kidney disease had less typical pathological changes of diabetic kidney disease or less severe diabetic changes. However, these results should be interpreted with caution because the pathological classifications we used in our study were not quantitative measures but all qualitative measures. Previous quantitative studies in both type 1 and type 2 diabetes showed the structural-functional relationships independent of albuminuria, meaning that those with reduced renal function had more severe structural changes, even without albuminuria (3436). Renal samples in our study were not evaluated with quantitative measures of glomerular structure, such as mesangial fractional volume, mean glomerular volume, glomerular filtration surface density, and so on, all of which are strongly associated with GFR decline. Although the majority of those with nonproteinuria had only mild diabetic lesions with the qualitative measures in our study, it is possible that with quantitative measures, they may have had evident glomerular structural changes that could explain their reduced renal function.

In our study, we observed a decreased risk of CKD progression in patients with nonproteinuric diabetic kidney disease compared with those with proteinuric diabetic kidney disease. We also observed, however, that a proportion of patients with nonproteinuric diabetic kidney disease had CKD progression. In the absence of proteinuria, what will be a risk factor of CKD progression in these patients? Only in patients with nonproteinuric diabetic kidney disease, we performed univariable and multivariable Cox proportional hazards analyses to investigate candidate predictors for progression of CKD. Low hemoglobin level, use of erythropoietin-stimulating agents, and severity of IFTA were the only predictors of CKD progression in univariable analysis. The multivariable analysis revealed that only severe IFTA is associated with CKD progression (Table 3). Although the number of patients with nonproteinuric diabetic kidney disease was limited in this analysis, these results imply that interstitial fibrosis, which causes anemia and higher chances of being prescribed erythropoietin agents, is a key player in renal decline. These results are similar to some previous reports that demonstrated that interstitial injury plays a major role in the decline of eGFR (3739). In addition to interstitial fibrosis, quantitative glomerular structural measurements may improve predictive value. Again, the pathological classifications we used in our analysis are qualitative classifications, which are easy to implement but may not link directly to renal function in the absence of proteinuria. Quantitative structural studies have shown more precise structural-functional relationships and predictive value independent of albuminuria in patients with type 2 diabetes (35,36). We believe that future quantitative structural classifications of diabetic kidney disease may be able to better predict CKD progression in patients with type 2 diabetes and nonproteinuria.

Although our study suggests that those with nonproteinuria are at low risk for CKD progression, it is possible that patients with nonproteinuria will become proteinuric or vice versa. We observed that <10% of patients with nonproteinuria became proteinuric later and few with proteinuria became nonproteinuric. Most of the patients with nonproteinuria who became proteinuric later had a UACR near the upper limit of 300 mg/g at baseline. To be sure that the findings are consistent in updated variables, we conducted an interim analysis with updated variables at the 1-year and 3-year study time points, comparing the risk of CKD progression between the nonproteinuric and proteinuric groups that were also updated. In the fully adjusted model with age, sex, eGFR, systolic blood pressure, HbA1c, and use of RAAS blockade, the pattern of CKD progression was similar to that at baseline.

The strengths of our study are the nationwide study population in Japan over three decades, the use of biopsy-proven rather than inaccurate clinical diagnosis of diabetic kidney disease, the use of a longitudinal design rather than a cross-sectional design, the highly reliable linkage-based ESRD ascertainment, and the use of propensity score– matching methods addressing the imbalance of confounders between nonproteinuric and proteinuric diabetic kidney disease. All these design and methodological elements enabled a robust analysis of the comparison of clinicopathological backgrounds and the risk of CKD progression and mortality in patients with nonproteinuric and proteinuric diabetic kidney disease.

Several limitations of this study, however, should be mentioned. First, as with observational studies, especially with biopsy-based cohort studies, there is a possibility of confounding by indication, since the selection of the study group could have been biased by nephrologists who were interested in diabetic kidney disease or the patients might have undergone biopsy because they were suspected to have other renal diseases. Just for reference, ∼30% of our patients with a clinical diagnosis of diabetic kidney disease underwent biopsy in our institutions. Among 526 patients with biopsy-proven diabetic kidney disease, the prebiopsy clinical diagnoses were diabetic kidney disease as the only cause in 399 (76%), diabetic kidney disease plus hematuria in 54 (10%), diabetic kidney disease with rapid eGFR decline or abnormal casts in 42 (8%), and diabetic kidney disease with nephrotic-range proteinuria in 31 (6%). On the contrary, however, we believe that the accurate diagnosis of diabetic kidney disease provides a clearer picture of clinicopathological features of diabetic kidney disease. Second, biopsy results for diabetic kidney disease may vary by local site biopsy policies (40). Among 18 hospitals, 5 pursued a restricted policy, and 13 pursued an unrestricted policy. Not surprisingly, all 88 patients with nonproteinuria were from the hospitals that adopt an unrestricted biopsy policy. However, there were no statistical differences of biopsy findings among adopted biopsy policies (χ2 test P = 0.093). Third, the data of the previous renal events before the time of renal biopsy were not available to be accounted for in our analysis, which might affect and explain the risk of nonproteinuric diabetic kidney disease at the time of biopsy. However, all patients with nonproteinuric diabetic kidney disease denied at least a history of acute kidney injury or taking medications, such as nonsteroidal anti-inflammatory drugs, that would affect their renal function. Furthermore, to exclude another potential explanation for having nonproteinuric diabetic kidney disease, most of these patients were confirmed to not have renal stenosis by MRI or ultrasonography. Fourth, the study population was limited to Japanese patients with biopsy-confirmed diabetic kidney disease; hence, our findings may not be widely generalizable. We were unable to compare our results directly with other cohorts; however, we found a study from the Chronic Renal Insufficiency Cohort (CRIC) that reported the CKD progression rate for those with different baseline levels of urine albumin (41). We did a trial calculation of the CKD progression rate for those with nonproteinuria (UACR 30–299 mg/g) and proteinuria (UACR ≥300 mg/g): CKD progression rates were 39 and 213 per 1,000 person-years, respectively. The progression rates in the CRIC study were very similar to those in our study (CKD progression rates were 30 and 194 per 1,000 person-years for patients with nonproteinuria and proteinuria, respectively), despite the fact that patients in our cohort all had biopsy-proven rather than a clinical diagnosis of diabetic kidney disease. Fifth, we do not have the data on UACR before taking RAAS blockade. It is possible that the nonproteinuric group mostly comprised patients who responded well to RAAS blockade, resulting in a lower risk of CKD progression. However, we believe that this is unlikely to be a major factor since the lower renal risk was the same among those who were on RAAS blockade as among those who were not on RAAS blockade in the subgroup analyses (incidence rate 52 [95% CI 19–136] vs. 48 [95% CI 16–151] per 1,000 person-years, respectively). Sixth, the renal function measurement we used in this study was not measured GFRs obtained using iothalamate but estimates using serum creatinine, which might affect our results. Previous structural-functional studies were mostly done with measured GFR. Finally, unmeasured confounders were not fully adjusted for in our study. We identified older age, lower systolic blood pressure, higher hemoglobin level, and higher HbA1c level with higher odds of nonproteinuric diabetic kidney disease assignment. The finding that higher HbA1c is associated with nonproteinuria, in other words, with milder lesions, goes against the vast majority of the published literature. HbA1c is most widely accepted and used for monitoring long-term glycemic control in patients with diabetes; however, we acknowledge that HbA1c in patients with CKD can be influenced by many unmeasured factors. One of these factors is the dose of recombinant human erythropoietin agents (42). We believe it is possible that with more severe interstitial fibrosis, those with proteinuria were using a higher dose of recombinant human erythropoietin-stimulating agents that caused a low HbA1c level. Conversely, it is possible that with milder interstitial fibrosis, those with nonproteinuria were using less erythropoietin-stimulating agents, which had little effect on their HbA1c levels and made their HbA1c levels look higher than those in patients with proteinuria.

In conclusion, in propensity score–matched cohorts of biopsy-proven nonproteinuric diabetic kidney disease and proteinuric diabetic kidney disease, patients with nonproteinuric diabetic kidney disease had lower blood pressure with less frequent typical pathological lesions and were at lower risk of CKD progression and all-cause mortality. Further studies are warranted to confirm these findings in other cohorts.

Funding. This study was supported in part by a Ministry of Health, Labour and Welfare Grant-in-Aid for Diabetic Nephropathy and Nephrosclerosis Research (JP17ek0310003).

The funding source had no role in the study design or execution, data analysis, manuscript writing, or manuscript submission.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. M.Y., K.F., J.H., T.T., and T.W. designed the study protocol, researched data, contributed to the discussion, wrote the manuscript, and reviewed and edited the manuscript. A.H., M.S., K.Ki., T.F., K.O., Y.Y., H.K., Y.Su., H.S., N.U., S.H., Y.Ue., S.N., H.Y., T.N., K.S., K.Ko., Y.Sh., K.M., H.M., S.M., and Y.Ub. researched data, contributed to the discussion, and reviewed and edited the manuscript. T.W. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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