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Aims/hypothesis: There is currently insufficient evidence to recommend a low-protein diet for type 2 diabetic patients with diabetic nephropathy. We assessed whether a low-protein diet could prevent the progression of diabetic nephropathy., Methods: This was a multi-site parallel randomised controlled trial for prevention of diabetic nephropathy progression among 112 Japanese type 2 diabetic patients with overt nephropathy. It was conducted in Japan from 1 December 1997 to 30 April 2006. The participants were randomly assigned using a central computer-generated schedule to either low-protein diet (0.8 g kg(-1) day(-1)) and normal-protein diet (1.2 g kg(-1) day(-1)), and were followed for 5 years. The participants and investigators were not blinded to the assignment. The primary outcomes were the annual change in estimated GFR and creatinine clearance, the incidence of doubling of serum creatinine and the time to doubling of baseline serum creatinine., Results: The study was completed by 47 (84%) of 56 participants in the low-protein diet group and 41 (73%) of 56 participants in the normal-diet group. During the study period, the difference in mean annual change in estimated GFR between the low-protein diet and the normal-protein diet groups was -0.3 ml min(-1) 1.73 m(-2) (95% CI -3.9, 4.4; p = 0.93). The difference in mean annual change in creatinine clearance between the low-protein diet and the normal-protein diet groups was -0.006 ml s(-1) 1.73 m(-2) (95% CI -0.089, 0.112; p = 0.80). A doubling of serum creatinine was reached in 16 patients of the low-protein group (34.0%), compared with 15 in the normal-protein group (36.6%), the difference between groups being -2.6% (95% CI -22.6, 17.5; p = 0.80). The time to doubling of serum creatinine was similar in both groups (p = 0.66)., Conclusions/interpretation: It is extremely difficult to get patients to follow a long-term low-protein diet. Although in the low-protein group overall protein intake was slightly (but not significantly) lower, it did not confer renoprotection., Clinical Trial Registration: ClinicalTrials.gov NCT00448526., Funding: Research grant from the Ministry of Health, Labour and Welfare of Japan.

Erythropoietin (EPO) is reported to be mainly produced by renal peritubular interstitial cells. Serum levels of EPO may provide new information on the tubulointerstitial lesions in patients with diabetic nephropathy. We determined EPO, hemoglobin (Hb), and Hb x EPO in 63 diabetic patients who showed normo-, micro- or macroalbuminuria with normal or reduced renal function (creatinine clearance, Ccr, > or = 60 ml/min or < 60 ml/min). In addition, we followed up Ccr during a mean of 26 months in 13 patients with overt nephropathy and normal renal function. The following results were obtained: (1) Hb, EPO, and Hb x EPO values gradually decreased along with advancing stages of nephropathy, and (2) 6 patients with rapidly decreasing renal function showed significantly lower initial EPO and Hb x EPO values than 7 patients without it (p < 0.01). We conclude that EPO and Hb x EPO values may be a new marker predicting future chronic renal failure in diabetic overt nephropathy.

We determined serum levels of type IV collagen 7S (IV 7S) in 73 (23 with normoalbuminuria, 21 with microalbuminuria, 17 with macroalbuminuria, and 12 primarily affected by nondiabetic renal disease (NDRD)) and 24 (10 with only macroangiopathy and 14 with retinopathy and macroangiopathy) diabetic patients to see whether IV 7S can be a useful index for differentiating early or overt diabetic nephropathy from NDRD in micro- or macroalbuminuric diabetics. IV 7S was significantly elevated in diabetic patients with micro-or macroalbuminuria compared to those with normoalbuminuria and healthy controls (p < 0.001). On the contrary, all 12 diabetic patients with micro- or macroalbuminuria due to NDRD showed normal or low IV 7S level. IV 7S was significantly higher in diabetic patients with both retinopathy and macroangiopathy than in those with only macroangiopathy (p < 0.001). We conclude that IV 7S levels may be a useful index to differentiate diabetic early or overt nephropathy from NDRD, especially nephrosclerosis, in micro- or macroalbuminuric diabetics.

The aim of this study is to elucidate the clinical significance of estimating renal size in non-insulin-dependent diabetes mellitus (NIDDM). Renal size was compared in 57 NIDDM patients with persistent normoalbuminuria [group I; 19 cases, albumin excretion rate (AER) < 20 micrograms/min], microalbuminuria (group II; 24 cases, AER = 20-200 micrograms/min), or macroalbuminuria (group III; 14 cases, AER > 200 micrograms/min). Three groups were matched for age and diabetes duration. Renal size was estimated using drip-infusion pyelography according to Simon's method (mean kidney length/height of second lumbar spine and disc; renal ratio, RR). Thirteen patients with persistent microalbuminuria (10 normotensive and 3 hypertensive) were traced during at least 3 years. Angiotensin-converting enzyme inhibitor (enalapril) was used in 11 cases. The results are as follows: (1) Renal size in groups II (RR, 3.47 +/- 0.28; cited as mean +/- SD) and III (3.62 +/- 0.32) significantly increased compared with that in group I (3.26 +/- 0.20) (p < 0.01 and p < 0.001, respectively). No statistical differences could be detected between groups II and III. (2) As a whole, good metabolic (glycosylated hemoglobin, HbA1) and hemodynamic (systolic blood pressure, SBP) control was achieved during the last 12 months (HbA1, 8.4% +/- 0.9%; SBP, 122 +/- 8 mm Hg). There was no significant correlation between RR and creatinine clearance, HbA1, SBP, or diastolic blood pressure during the first and last 12 months. Initial RR significantly correlated with AER during the last 12 months (r = 0.651, p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

The pathogenesis of the nodular lesion in diabetic glomerulosclerosis is described in association with fibrils. Thirteen diabetic patients with glomerular nodular lesions and 9 diabetics without the nodules were examined by electron microscopy using periodic acid-thiocarbohydrazide-silver proteinate staining. In cases of nodular glomerulosclerosis, abundant fibrillar structures mixed with electron-dense material were detected within the nodule and the mesangial matrix. They were also occasionally observed along the subendothelial space of the glomerular capillary walls. On the cross-section, these fibrils, including the lucent periphery, were 34 nm wide. Immunohistologically, collagen V and collagen VI were detected in nodular lesions. In contrast, in cases of the diffuse type of glomerulosclerosis, the widened mesangium was composed of dense material, which resembled the original mesangial matrix. The above fibrils were not detected in the mesangium. These findings suggest that the accumulation of the peculiar fibrils in the glomerular mesangium is a major pathogenic factor in the formation of Kimmelstiel-Wilson nodules.

The present study demonstrates the relationship between urinary albumin excretion rate (AER) and renal structural changes in patients with non-insulin-dependent diabetes mellitus (NIDDM) without clinical proteinuria. Resting AER in 30 control subjects and 67 NIDDM patients were 10.4 +/- 4.8 (mean +/- SD) micrograms/min (range 4.3-21.1 micrograms/min) and 26.4 +/- 32.3 micrograms/min (range 0.4-155 micrograms/min), respectively. Persistent normoalbuminuria (less than 20 micrograms/min) and microalbuminuria (20-200 micrograms/min) were found in 43 (Group A) and 24 (Group B) diabetics. There were significant differences in age, diabetes duration, and frequency of retinopathy (background and proliferative) as well as that of proliferative retinopathy between Groups A and B, but not in the other clinical parameters such as body mass index, HbA1, Ccr, or systolic and diastolic blood pressure (SBP, DBP). When compared with 11 normoalbuminuric patients of similar age and equal diabetes duration to those in Group B, the sole difference in clinical parameters was the existence of proliferative retinopathy in Group B. Renal structural changes were investigated by light microscopy in 14 people in Group A and 13 people in Group B, and additionally in 5 NIDDM patients with both macroalbuminuria (greater than or equal to 200 micrograms/min) and normal or nearly normal renal function (Group C). The diffuse glomerular lesion (Gellman's classification) was grade I or II in A, II or III in B, and III in C.(ABSTRACT TRUNCATED AT 250 WORDS)