Arteriolar Hyalinosis Predicts the Onset of Both Macroalbuminuria and Impaired Renal Function in Patients with Type 2 Diabetes.

INTRODUCTION: Arteriolar hyalinosis (AH) has been shown to be associated with albuminuria and GFR. In this study, we investigated whether or not index of AH (IAH) is a predictor of the onset of macroalbuminuria and impaired renal function (eGFR <60 mL/min/1.73 m2 [eGFR <60]) in type 2 diabetic patients with early diabetic nephropathy. METHODS: The study population consisted of 35 patients with type 2 diabetes (25 men; age: 47 ± 9 years; eGFR: 92.7 ± 18.0 mL/min/1.73 m2) with normo- or microalbuminuria who underwent percutaneous renal biopsy. These patients were followed for at least 5 (18 ± 6, range: 6-28) years. The study endpoint was the onset of macroalbuminuria or eGFR <60. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. RESULTS: During the observation period, 9 out of the 35 patients progressed to macroalbuminuria, and 15 out of the 35 patients developed eGFR <60. The annual rate of eGFR decline was significantly correlated with IAH (r = -0.40, p = 0.016). Kaplan-Meier analysis demonstrated that AH was associated with a significantly higher risk of onset of macroalbuminuria and eGFR <60, and microalbuminuria is associated with the onset of macroalbuminuria but not the onset of eGFR <60. CONCLUSIONS: Aggravated AH is a histological risk factor which predicts the onset of macroalbuminuria and eGFR <60 in patients with type 2 diabetes. These findings provide novel insights into the mechanism of progression of diabetic nephropathy.

Glucose control, diabetic retinopathy, and hemodialysis induction in subjects with normo-microalbuminuric type 2 diabetic patients with normal renal function followed for 15 years.

AIMS: A high urinary albumin excretion (UAE) and low glomerular filtration rate (GFR) are risk factors for progressive renal function loss in type 2 diabetic patients. In addition, diabetic retinopathy (DR) is also a risk factor for progressive renal function decline in microalbuminuric type 2 diabetic patients. We aimed to elucidate the factors, including DR, associated with a more severe situation of diabetic nephropathy, i.e., hemodialysis (HD) induction in normo- and microalbuminuric type 2 diabetic patients without renal dysfunction. METHODS: Normo- and microalbuminuric type 2 diabetic patients with normal renal function whose GFRs had been measured by iohexol injection in 1995-1997 and had been followed for over 5 years were analyzed (n = 199). HbA1c levels was divided into HbA1c ≥ 7.0 (n = 146) and <7.0 (n = 53) groups. The UAE levels were classified as normoalbuminuria (NA, n = 114) and microalbuminuria (MA, n = 85). Seventy-two patients had DR, and 96 had hypertension. Patients were followed up for 15.7 ± 6.0 years and frequency of and duration to the HD induction were evaluated. RESULTS: During the study period, 8 patients received HD induction. There were no remarkable differences in the rates of HD induction between patients with and without HbA1c ≥7.0, microalbuminuria, DR or hypertension. A Kaplan-Meier analysis revealed that HbA1c ≥7.0 (p = 0.037) and DR (p = 0.037) were associated with a significantly higher risk of HD induction than HbA1c <7.0 and no DR, respectively while albuminuria grade and hypertension were not associated with the risk of HD induction. There was significant negative correlation between HbA1c and annual decline rate of eGFR and annual decline rate of eGFR in the patients with prepro-proliferative DR (PDR) was significantly higher than that in the patients without DR. In the multivariate analysis, HbA1c and PDR showed significant relationships with the annual decline rate of eGFR. CONCLUSIONS: It was reasonable that poorer glycemic control affected HD induction for 16 years follow-up. However, DR, especially PDR, should also be considered a substantial risk factor for HD induction although microalbuminuria and hypertension did not predict it at the early stage of diabetic nephropathy in type 2 diabetic patients with normal renal function.

Arteriolar hyalinosis is related to rapid GFR decline and long-standing GFR changes observed on renal biopsies in normo-microalbuminuric type 2 diabetic patients.

AIMS: Whether or not renal structural changes, especially arteriolar hyalinosis, are related to the rate of renal functional decline and increase in urinary albumin excretion (UAE) at the early stage of diabetic nephropathy in patients with type 2 diabetes is still unknown. Our previous study determined that arteriolar hyalinosis is an independent risk factor for low GFR. We sought to determine whether arteriolar hyalinosis is also a risk factor for rapidly progressive decline in GFR. METHODS: We evaluated 22 type 2 diabetic patients with normo- or microalbuminuria who took part in the previous study, to clarify which renal histological factors were associated with changes in UAE and the glomerular filtration rate (GFR) during 11.0 ±â€¯3.0 years of follow-up. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate the glomerular and interstitial structural changes. RESULTS: In all 22 patients, the GFR was significantly decreased from baseline to follow-up, while the UAE did not change markedly between the 2 periods. After 11 ±â€¯3 years of follow-up, the GFR was significantly lower in the rapid decliner group (annual rate of GFR decline ≥3.0%) than in the non-rapid decliner group (p = 0.017). The index of arteriolar hyalinosis (IAH) at baseline in the rapid decliners was significantly larger than in the non-rapid decliners (p = 0.015). The IAH showed a significant negative correlation with the GFR at follow-up (r = 0.50, p = 0.018) and the annual rate in the GFR decline (r = 0.47, p = 0.027) and significant positive correlations with UAE at follow-up (r = 0.46, p = 0.034) and the annual rate in the UAE increase (r = 0.57, p = 0.005). The GFR at follow-up in patients with IAH ≥2.0 was significantly decreased from baseline (p = 0.042) and significantly lower than that of the patients with IAH <2.0 (p = 0.026), which did not decrease significantly from baseline. The frequency of rapid decliners was larger in the IAH ≥2.0 than in the IAH <2.0 patients (p = 0.037). CONCLUSIONS: Aggravated arteriolar hyalinosis was a risk factor for a rapid GFR decline. This finding might reflect initial changes in early diabetic nephropathy.

Serial renal biopsies in normo- and microalbuminuric patients with type 2 diabetes demonstrate that loss of renal function is associated with a reduction in glomerular filtration surface secondary to mesangial expansion.

AIMS: The aim of the present study was to explore the relationship between changes in renal structure in patients with type 2 diabetes at an early stage of diabetic nephropathy using serial renal biopsies, and change in renal function. METHODS: The study population comprised 10 patients with type 2 diabetes with normo- or microalbuminuria at baseline. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate glomerular and interstitial structural changes. Urinary albumin excretion (UAE) and glomerular filtration rate (GFR) were measured annually. A second renal biopsy was performed after a mean of 6.1 ±â€¯2.4 years of follow-up. RESULTS: UAE, GFR, blood pressure and severity of diabetic retinopathy (DR) did not change between the baseline and follow-up. The annual decrease in the surface density of the peripheral glomerular basement membrane (GBM) (Sv[PGBM/glom]) was correlated with the rate of loss of GFR during the six-year follow-up period. The annual change in the Sv(PGBM/glom) was negatively correlated with the change in mesangial volume fraction. CONCLUSIONS: Decreases in the GFR in patients with type 2 diabetes with normo- or microalbuminuria at baseline were associated with a decreased glomerular filtration surface, as a result of mesangial expansion during a mean six years of observation. These findings confirm ongoing pathological progression of glomerulopathy despite no significant change in albuminuria or retinopathy status.

Arteriolar Hyalinosis Predicts Increase in Albuminuria and GFR Decline in Normo- and Microalbuminuric Japanese Patients With Type 2 Diabetes.

OBJECTIVE: This study investigated the association between renal histology, as assessed by morphometric analysis using light (LM) and electron (EM) microscopy, and changes in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in Japanese people with type 2 diabetes in the early stages of diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed percutaneous renal biopsies in 29 patients with type 2 diabetes (22 men, mean ± SD age 49 ± 10 years and GFR 119 ± 27 mL/min/1.73 m2, with 15 normoalbuminuric [UAE <20 µg/min] and 14 microalbuminuric [UAE 20-200 µg/min]) to clarify which histological factors were associated with changes in UAE and GFR during 8.0 ± 3.5 years' follow-up. Glomerular structural changes including mesangial volume fraction [Vv(Mes/glom)] were estimated using EM, whereas the index of arteriolar hyalinosis (IAH) score was assessed by LM. Patients underwent annual measurement of GFR using iohexol injection with simultaneous urine collections for UAE. RESULTS: Vv(Mes/glom) was negatively correlated with baseline and follow-up GFR but not with UAE. The IAH score was positively correlated with UAE and negatively correlated with GFR at follow-up, but it was not correlated with either UAE or GFR at baseline. GFR at follow-up was significantly decreased from baseline in patients with IAH scores ≥2.0 and significantly lower than in patients with IAH scores <2.0. Patients with IAH scores <2.0 showed no significant change in GFR during follow-up. CONCLUSIONS: Arteriolar hyalinosis is an additional histological predictor for albuminuria increase and GFR decline in normo- and microalbuminuric Japanese people with type 2 diabetes.

Type 2 diabetic patients with diabetic retinopathy and concomitant microalbuminuria showed typical diabetic glomerulosclerosis and progressive renal dysfunction.

AIMS: To determine whether or not diabetic retinopathy (DR) in type 2 diabetic patients can predict the renal functional decline. METHODS: We examined 32 normo-microalbuminuric type 2 diabetic patients by renal biopsy (23 men, age 49±10yrs) divided into two groups according to the presence (n=19) or absence (n=13) of DR. Electron microscopic morphometry including mesangial fractional volume [Vv(Mes/glom)] were performed and light microscopic tissues were categorized as: C1, normal/near normal renal structure; C2, typical diabetic glomerulopathy; C3, atypical injury patterns. Patients were followed up for 7.1±3.8years, and glomerular filtration rate (GFR) and urinary albumin excretion (UAE) measurements were taken annually. RESULTS: Vv(Mes/glom) was larger in DR+ than that in DR-. Vv(Mes/glom) positively correlated with the UAE if patients had DR. The patients with DR had a significant higher rate of C2 pattern compared to those in DR-. Among patients with DR and C2, GFR in microalbuminuria (n=7) decreased while GFR in normoalbuminuria (n=5) did not change during the observation. CONCLUSIONS: Type 2 diabetic patients with DR and C2 showed progressive renal dysfunction after they had microalbuminuria. DR and albuminuria should be considered to determine renal function decline in type 2 diabetic patients.

Serum monomeric α2-macroglobulin as a clinical biomarker in diabetes.

OBJECTIVE: Despite the number of potential biomarker proteins for diabetes, very few of them have proven useful as clinically beneficial indicators, because of the technical difficulties associated with their identification among highly abundant serum proteins. We attempted to identify a protein with distinguishable expression in human diabetes. METHODS: We applied a highly efficient strategy for the purification of endogenous low abundance proteins from diabetic and non-diabetic serum samples. Extracted sera were fractionated by SDS-PAGE and protein bands were isolated and analyzed by mass spectrometry using an ion-trap mass spectrometer. The identities of the proteins were confirmed by western blotting and the serum levels evaluated. RESULTS: A significantly upregulated protein in diabetic patients was identified as monomeric α2-macroglobulin. Its tetramer, another dominant circulating molecular form, was only marginally increased in diabetes. CONCLUSION: Serum monomeric α2-macroglobulin is highly expressed in many diabetic subjects. It is identical to the human 'cardiac isoform of α2-macroglobulin' described in the literature, a well-known acute phase serum biomarker protein mechanistically involved in cardiac and atherosclerotic diseases.

Glomerular hyperfiltration in non-proteinuric and non-hypertensive Japanese type 2 diabetic patients.

Glomerular hyperfiltration (GHF) may be an important factor in the initiation of glomerular damage and in predisposing diabetic patients to the later development of diabetic nephropathy (DN). Previous reports show wide range of prevalence of GHF in type 2 diabetic patients. This cross-sectional study was designed to determine the prevalence of GHF at an early stage of DN in Japanese type 2 diabetic patients and to investigate the relationships between clinical variables and GHF. We measured the glomerular filtration rate (GFR) using the plasma clearance of iohexol in 56 control subjects and 93 type 2 diabetic patients without hypertension or overt proteinuria. We used Altman's method to calculate the age-adjusted 95% reference ranges for GFR from the data of control subjects and classified GHF in type 2 diabetics from the reference ranges. Hyperfiltrators (defined as GFR > mean GFR + 1.96 S.D. of control subjects) was found in 17% patients (16/93). Other 77 patients (83%) were normofiltrators (defined as GFR< or = mean GFR + 1.96 S.D. of control subjects). GFR values, both in hyperfiltrators and normofiltrators, were 140.5 +/- 14.6 and 98.8 +/- 14.0 ml/min/1.73 m2, respectively. Age, sex, BMI, blood pressure, albumin excretion rate, and frequency of microalbuminuria did not differ between the hyperfiltrators and normofiltrators. Fasting plasma glucose and hemoglobin A1c were significantly higher in the hyperfiltrators than the normofiltrators (P<0.001 and 0.004, respectively). GHF exists among Japanese type 2 diabetic patients with no evidence of overt proteinuria or hypertension. Glycemic control might be a significant determinant of GHF in these patients.