Tatsumi Moriya

Glomerular hyperfiltration and increased glomerular filtration surface are associated with renal function decline in normo- and microalbuminuric type 2 diabetes

The prevalence of glomerular hyperfiltration in type 2 diabetic patients varies widely. Here we studied whether glomerular hyperfiltration in diabetic nephropathy in type 2 patients is related to renal structural changes and predicts the functional development of diabetic nephropathy. Thirty normo- or microalbuminuric type 2 diabetic patients having a renal biopsy were followed every 6 months for a mean of 6.2 years. The glomerular filtration rate (GFR) at the time of biopsy, determined by iohexol clearance, correlated with filtration surface per glomerulus, but no other quantitative microscopic morphometric parameter. The filtration surface was positively associated with the decrease in GFR during the first year but not associated in subsequent years following the renal biopsy. The GFR showed a statistically significant linear decrease in 9 of the 30 patients; however, slopes of the regression lines were almost zero in 11 patients. The GFR increased and decreased in a parabolic manner in two patients. Seven of the nine patients with a statistically significant decline in renal function did not show any appreciable worsening of albuminuria, while two patients developed persistent proteinuria. Thus, in renal biopsy-proven normo- or microalbuminuric type 2 diabetic patients, glomerular hyperfiltration is closely associated with an increased glomerular filtration surface. An elevated GFR predicts its subsequent decline, which may occur without worsening of albuminuria.

Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study.

The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study previously showed that treatment with telmisartan, an angiotensin II receptor blocker, effectively reduced the transition from incipient to overt nephropathy in Japanese type 2 diabetic patients. However, that large study included both normotensive and hypertensive patients. In the present post hoc analysis, we aimed to assess whether or not telmisartan elicits beneficial effects on the progression of microalbuminuria in normotensive patients. We randomized 163 microalbuminuric (urinary albumin-to-creatinine ratio: UACR of 100 to 300 mg/g creatinine) normotensive type 2 diabetic patients to treatment with telmisartan (40 or 80 mg once daily) or placebo over 52 weeks. The patients treated with either dose of telmisartan showed lower transition rates from microalbuminuria to overt nephropathy compared to the placebo group. In addition, more patients on telmisartan reverted to normoalbuminuria (UACR<30 mg/g creatinine): 15.5% of the 40 mg group, 19.6% of the 80 mg group, and 1.9% of the placebo group. In normotensive patients treated with telmisartan, changes in UACR were not significantly correlated with changes in blood pressure. Side effects did not differ among the groups. The present study demonstrates that telmisartan prevents the progression of microalbuminuria (in some cases induces remission of albuminuria) in normotensive Japanese patients with type 2 diabetes. Telmisartan is shown to be safe and well tolerated in these patients.

Analysis and a long-term follow up of ketosis-onset Japanese NIDDM patients

It has been reported that excessive intake of sugar-containing soft drinks results in diabetic ketoacidosis (DKA) or ketosis (DK) in obese patients with non-insulin dependent diabetes mellitus (NIDDM). We describe the clinical characteristics and results of long-term follow-up for 24 newly-diagnosed patients with acute-onset NIDDM presenting with DKA or DK. A history of excessive intake of sugar-containing soft drinks was found in 19 (Group A); serious non-diabetic illnesses were found in 5 (Group B). The range of patient ages in Group A was 16 to 57 years while all patients in Group B were 60 years or older. In Group A, no patient was positive for autoantibodies, specific HLAs for Japanese insulin dependent diabetes mellitus, or mutation of the beta-3-adrenergic receptor gene. The body mass indices (BMIs) at onset and admission and serum C-peptide immunoreactivities at admission and discharge were significantly higher in patients in Group A than in patients Group B. In conclusion, we reconfirmed that excessive intake of sugar-containing soft drinks is one of the contributing factors in DKA or DK-onset NIDDM patients. We found no autoimmune mechanism involved in the pathogenesis and that a polymorphism in the beta-3-adrenergic receptor gene could be associated with the development of soft-drink ketosis.

The telmisartan renoprotective study from incipient nephropathy to overt nephropathy - rationale, study design, treatment plan and baseline characteristics of the incipient to overt : Angiotensin ii receptor blocker, telmisartan, investigation on type 2 diabetic nephropathy (INNOVATION) study

We planned the INNOVATION study to determine whether telmisartan, an angiotensin-2-receptor blocker, delays the progression of renal disease from incipient nephropathy to overt nephropathy in hypertensive or normotensive Japanese patients with type 2 diabetes mellitus. The INNOVATION study is a randomized, double-blind, placebo-controlled trial. Eligible patients must have incipient nephropathy (defined as a urinary albumin to creatinine ratio of 100-300 mg/g creatinine) and a serum creatinine concentration of < 1.5 mg/dl for men and < 1.3 mg/dl for women. Patients who need treatment with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors are excluded. Eligible patients are randomly assigned to three groups: telmisartan titrated to 40 mg; telmisartan titrated to 80 mg; or placebo. The primary endpoint is the time from baseline visit to first detection of overt nephropathy (defined by a urinary albumin to creatinine ratio that is > 300 mg/g creatinine and 30% higher than the baseline on at least two consecutive visits). A total of 1855 patients have been enrolled from 160 study centres. In 527 randomized patients (28.4% of the enrolled patients), mean (SD) urinary albumin to creatinine ratio and serum creatinine concentration at baseline were 173.3 (47.2) mg/g creatinine and 0.78 (0.19) mg/dl. Sixty-eight per cent of the patients had hypertension at baseline. Mean (SD) systolic and diastolic blood pressures at baseline were 137.1 (14.6) and 77.5 (10.3) mmHg. The INNOVATION study will determine whether telmisartan, an angiotensin II receptor blocker, provides clinical benefits in hypertensive or normotensive patients with diabetes mellitus and diabetic nephropathy.

Glomerular structural changes and structural-functional relationships at early stage of diabetic nephropathy in Japanese type 2 diabetic patients.

Details of renal structural changes and structural-functional relationships at the early stage of diabetic nephropathy (DN) in type 2 diabetes are not well known. The present review focuses on these topics from previous studies using light and electron microscopic morphometric analysis. Glomerular hypertrophy, one of the histological changes in DN, is present in type 2 as well as in type 1 diabetic patients. However, mechanisms of increased glomerular size might be different from those in type 1 diabetes. Other typical glomerular changes, glomerular basement membrane thickening and mesangial expansion, are present in normoalbuminuric type 2 diabetic patients as a group. However, these parameters are similar between normo- and microalbuminuric patients. Renal structural-functional relationships cannot be seen in type 2 diabetic patients and therefore urinary albumin might not be a reliable indicator for glomerular structural changes in type 2 diabetic patients. Although previous reports showed reversibility of advanced diabetic glomerulosclerosis in type 1 diabetes by 10 years of strict glycemic control, there is no report regarding histological reversibility by therapeutic interventions in type 2 diabetic patients. In addition, it is unclear whether DN lesions are concordant or discordant with diabetic retinopathy grade in type 2 diabetes. From this information, renal structural changes or structural-functional relationships in type 2 diabetic patients might be heterogeneous and different from those in type 1 diabetic patients. Careful longitudinal study of renal structure and function including serial renal biopsy at the early stage of DN in type 2 diabetes is necessary.

Association Between Remission of Macroalbuminuria and Preservation of Renal Function in Patients With Type 2 Diabetes With Overt Proteinuria

OBJECTIVE Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking. RESEARCH DESIGN AND METHODS A total of 211 T2DM patients with albuminuria ≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated. RESULTS During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12–0.76]). CONCLUSIONS Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.

Renal histological heterogeneity and functional progress in normoalbuminuric and microalbuminuric Japanese patients with type 2 diabetes.

Background and objectives Renal histological injury patterns in type 2 diabetes are heterogeneous. We compared renal histological injury patterns using renal biopsy findings with renal function and followed up renal functional changes in normoalbuminuric and microalbuminuric patients with type 2 diabetes to determine whether renal function progresses according to injury patterns. Design, setting, participants, and measurements We examined 111 patients with type 2 diabetes with percutaneous renal biopsy (78 men, 52±11 years old, 59 normoalbuminuria, 52 microalbuminuria) and followed up 37 cases for 11 years. Light microscopy of tissues revealed renal injury patterns as: category I (CI), normal or near-normal structure; category II (CII), typical diabetic glomerulopathy; category III (CIII), atypical (disproportionately severe tubulointerstitial/vascular damage with no/mild glomerulopathy). Results There were 29 CI, 62 CII, and 20 CIII patients. CII patients had a higher frequency of chronic kidney disease (CKD) G3-4, while the injury pattern distribution was not different among the albuminuria stages. The mean glomerular volume and volume fraction of cortical interstitium were larger than those of controls. The arteriolar hyalinosis index was larger in CII and CIII, while the percent global glomerular sclerosis was larger in CKD G3-4 compared with CKD G1-2. Renal function at follow-up was decreased in CII and CIII compared with the baseline estimated glomerular filtration rate (eGFR), while the GFR decline rate was faster in CII. Conclusions In normoalbuminuric and microalbuminuric patients with type 2 diabetes, loss of GFR could indicate typical diabetic glomerulosclerosis and a high frequency of global glomerular sclerosis. Urinary biomarkers identifying histological patterns of renal injury are necessary because GFR decline rates differed according to histological injury patterns.

Loss of glomerular anionic sites and the development of albuminuria in rats with streptozotocin-induced diabetes.

Examination was made of changes in the anionic sites of the glomerular basement membrane (GBM) in rats with streptozotocin (STZ)-induced diabetes by the immersion method of polyethyleneimine (PEI). PEI particles in GBM of diabetic rats significantly decreased from the 1st through the 8th week. Urinary albumin excretion in diabetic rats significantly increased at the 2nd but not earlier week. Insulin treatment effectively prevented decrease in PEI particles in STZ-injected rats. In rats with STZ-induced diabetes, initial renal alteration was disturbance of the charge barrier, followed by the development of albuminuria. Continued deterioration of anionic sites and possibly additional disturbance of size barrier were considered responsible for the development of albuminuria. Insulin treatment appears to prevent the loss of anionic sites of GBM.

Diabetic Retinopathy and Microalbuminuria Can Predict Macroalbuminuria and Renal Function Decline in Japanese Type 2 Diabetic Patients: Japan Diabetes Complications Study

OBJECTIVE To examine the interactive relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetic patients and to elucidate the role of DR and microalbuminuria on the onset of macroalbuminuria and renal function decline. RESEARCH DESIGN AND METHODS We explored the effects of DR and microalbuminuria on the progression of DN from normoalbuminuria and low microalbuminuria (<150 mg/gCr) to macroalbuminuria or renal function decline in the Japan Diabetes Complications Study (JDCS), which is a nationwide randomized controlled study of type 2 diabetic patients focusing on lifestyle modification. Patients were divided into four groups according to presence or absence of DR and MA: normoalbuminuria without DR [NA(DR−)] (n = 773), normoalbuminuria with DR [NA(DR+)] (n = 279), microalbuminuria without DR [MA(DR−)] (n = 277), and microalbuminuria with DR [MA(DR+)] (n = 146). Basal urinary albumin-to-creatinine ratio and DR status were determined at baseline and followed for a median of 8.0 years. RESULTS Annual incidence rates of macroalbuminuria were 1.6/1,000 person-years (9 incidences), 3.9/1,000 person-years (8 incidences), 18.4/1,000 person-years (34 incidences), and 22.1/1,000 person-years (22 incidences) in the four groups, respectively. Multivariate-adjusted hazard ratios of the progression to macroalbuminuria were 2.48 (95% CI 0.94–6.50; P = 0.07), 10.40 (4.91–22.03; P < 0.01), and 11.55 (5.24–25.45; P < 0.01) in NA(DR+), MA(DR−), and MA(DR+), respectively, in comparison with NA(DR−). Decline in estimated glomerular filtration rate (GFR) per year was two to three times faster in MA(DR+) (−1.92 mL/min/1.73 m2/year) than in the other groups. CONCLUSIONS In normo- and low microalbuminuric Japanese type 2 diabetic patients, presence of microalbuminuria at baseline was associated with higher risk of macroalbuminuria in 8 years. Patients with microalbuminuria and DR showed the fastest GFR decline. Albuminuria and DR should be considered as risk factors of renal prognosis in type 2 diabetic patients. An open sharing of information will benefit both ophthalmologists and diabetologists.

Renal structure as an indicator for development of albuminuria in normo- and microalbuminuric type 2 diabetic patients

Baseline glomerular structure in microalbuminuric (MA) and proteinuric Caucasian type 2 diabetic patients predicted progressive glomerular filtration rate decline while baseline urinary albumin excretion (UAE) did not. Little is known about whether or not renal structure at the early stages of diabetic nephropathy (DN) in type 2 diabetic patients can predict further functional development of DN. Baseline renal structure and function and follow-up data of renal function were examined in 17 type 2 diabetic patients (11 men, 45+/-7 (mean+/-S.D.) years old) with known diabetes duration 11+/-8 years without definable renal disease other than DN. Six patients showed normoalbuminuria (NA), 11 microalbuminuria (MA), and were followed up for 6.4+/-1.8 years after the baseline renal biopsy. Light and electron microscopic morphometric analyses provided quantitative glomerular and tubulointerstitial structural changes. No statistically significant difference was observed in hemoglobin A1c (HbA1c) values or mean blood pressure (MBP) between baseline and follow-up, even though the number of patients placed on antihypertensive drugs increased from 3 to 7. Follow-up UAE was not significantly different from the baseline UAE although 13 of 17 cases showed an increase. Baseline UAE did not correlate with the follow-up UAE or morphometric measures. Glomerular basement membrane width and volume fraction of the mesangium and mesangial matrix positively correlated with follow-up UAE. In NA and MA Japanese type 2 diabetic patients, baseline renal structural measures are more reliable indicators for the development of UAE than baseline UAE.