Diurnal changes in urinary excretion of IgG, transferrin, and ceruloplasmin depend on diurnal changes in systemic blood pressure in normotensive, normoalbuminuric type 2 diabetic patients.

Previous studies of diabetic patients indicate that increased urinary excretion of certain plasma proteins (molecular radii <55 A), such as IgG, transferrin, and ceruloplasmin, precede the development of microalbuminuria. Moreover, increases in these urinary proteins predict future development of microalbuminuria. To clarify whether blood pressure changes influence urinary excretion of these proteins, we examined relationships between diurnal blood pressure changes measured by ambulatory blood pressure monitoring and urinary excretion of IgG, transferrin, ceruloplasmin, alpha2-macroglobulin (88 A) and albumin (36 A) measured separately during the day and night in 20 healthy controls and 26 normotensive, normoalbuminuric diabetic patients. Diurnal change in systolic blood pressure was not correlated to urinary excretion of either albumin or alpha2-macroglobulin in either diabetic patients or controls. However, statistically significant correlations between diurnal changes in systolic blood pressure and those of urinary excretion of IgG, transferrin and ceruloplasmin were found in diabetic patients but not in controls. The present findings suggest that urinary excretion of IgG, transferrin, and ceruloplasmin are more easily affected than albuminuria by systemic blood pressure changes in normoalbuminuric diabetic patients. This is supported by our previous finding that urinary excretion of IgG, transferrin and ceruloplasmin increased while albuminuria did not following enhanced glomerular filtration rate after acute protein loading, which causes increased glomerular capillary pressure due to afferent arterioles dilation, mimicking diabetic intra-renal hemodynamics. Taken together, these findings suggest that urinary excretion of IgG, transferrin, and ceruloplasmin may be more sensitive indicators of glomerular capillary pressure change than albuminuria in normoalbuminuric diabetic patients.

[An autopsy case of Ehlers-Danlos syndrome showing various types of cerebrovascular disease].

We report a 73-year-old woman with Ehlers-Danlos syndrome (EDS) and hypertension who had developed various types of cerebrovascular disease. She had suffered from cerebral hemorrhage of the left putamen at the age of 58, of the left parietal lobe at 64 and cerebral infarction of right internal capsule at 71. EDS type II or III was suggested by two times of skin biopsies. A brain CT at the age of 73 revealed a comparatively large cerebral aneurysm in the territory of the anterior cerebral artery. The patient was treated conservatively, but died due to rupture of the aneurysm. The wall of the aneurysm was made up thin collagen fibers without elastic fibers. There were other multiple small aneurysms in the cerebral arteries, but none in other organs. Deposition of acid mucopolysaccharides was noted in the media of the abdominal aorta. Finally, the present case was thought most likely to be of EDS type IV. It was suggested that one of the causes of the cerebral hemorrhage at the ages of 58 and 64 and the infarction at 71 was related to hypertension, since brain MR angiography at 71 showed no clear aneurysms. In cases of EDS, one should consider the possible formation or rupture of cerebral aneurysm even though the course is favorable.

Glycemic control reverses increases in urinary excretions of immunoglobulin G and ceruloplasmin in type 2 diabetic patients with normoalbuminuria.

To examine whether urinary excretions of plasma proteins with molecular radii of 45-55 A and different isoelectric points such as IgG (pI = 7.4) and ceruloplasmin (pI = 4.4) increase selectively in normoalbuminuric type 2 diabetic patients, urinary albumin excretion rate (AER), renal clearances of IgG, ceruloplasmin and alpha2-macroglobulin, and creatinine clearance (Ccr) were studied in timed overnight urine samples of 36 diabetic outpatients and 16 control subjects. Furthermore, to examine effect of glycemic control on these urinary protein excretions, the same analysis was performed before and after glycemic control in 17 diabetic inpatients admitted for glycemic control. Renal clearances of IgG and ceruloplasmin were significantly higher in diabetic outpatients than in the control group, whereas AER and renal clearance of alpha2-macroglobulin did not differ. Glycemic control caused significant decreases in renal clearances of IgG and ceruloplasmin, accompanied with tendency for Ccr to decrease (p = 0.055). The present results, together with our previous finding of selectively increased urinary excretions of 45-55 A sized plasma proteins in parallel with enhanced glomerular filtration rate after acute protein loading, led us to conclude that enhanced intraglomerular hydraulic pressure may cause increases in clearances of IgG and ceruloplasmin, and that this change can be reversed by strict glycemic control in normoalbuminuric diabetic patients.

Determination of optimal protein contents for a protein restriction diet in type 2 diabetic patients with microalbuminuria.

To establish the method by which the optimal dietary protein content for type 2 diabetic patients with nephropathy could be determined, dietary protein content was reduced in gradated steps and renal function was evaluated at the completion of each diet. Eight type 2 diabetic patients with microalbuminuria were examined in this study. Renal function, urinary albumin excretion rate (AER) and urinary excretion rates of prostaglandins were evaluated at the completion of each of three consecutive one-week dietary periods where the protein content was 1.2, 0.8 and 0.6 g x kg Body Weight (BW)(-1) x day(-1) on the first, second and third week, respectively. Filtration fraction (FF), AER and urinary excretion rates of prostaglandin E2 and 6-keto-prostaglandin F1alpha significantly decreased in response to reduced dietary protein content from 1.2 to 0.8 g x kg BW(-1) x day(-1). No additional decreases in FF, AER and urinary excretion rates of these two prostaglandins were obtained after the 0.6 g x kg BW(-1) x day(-1) low protein diet period. The method evaluating renal hemodynamics at the completion of several consecutive one-week dietary periods was confirmed to be useful to determine the optimal protein contents in type 2 diabetic patients with nephropathy. The result showed that the optimal protein content in type 2 diabetic patients with microalbuminuria was 0.8 g x kg BW(-1) x day(-1) and protein restriction of less than 0.8 g x kg BW(-1) x day(-1) was not necessary for patients with this stage of diabetic nephropathy. A part of reasons in which FF decreased after reduced protein content in diet may be due to decreased prostaglandins production in the kidneys.

Urinary excretion of ceruloplasmin is elevated in the subjects with "borderline glucose tolerance test".

To examine whether or not there are any renal alterations in subjects with borderline glucose tolerance and in patients with non-insulin dependent diabetes mellitus (NIDDM) classified by the criteria of Japan Diabetic Association, urinary excretions of plasma proteins including albumin, ceruloplasmin (Cerulo) and IgG were measured in timed overnight urine samples. Eighty middle-aged, non-obese, normotensive, untreated men with urinary albumin excretion rates below 20 microg/minutes, beta2-microglobulin excretion rates below 140 microg/minutes and creatinine clearance values exceeding 80 ml x min(-1) x (1.73 m2)(-1) were included in this study. Three groups were defined according to the results of 75 g oral glucose tolerance test (OGTT) as follows: D group, 10 subjects with NIDDM; B group, 40 subjects with "borderline glucose tolerance test" and N group, 30 subjects with normal glucose tolerance. The fractional clearance (theta) of Cerulo, but not albumin and IgG, was elevated in 37. 5% of the B group compared with the upper limit of that of the N group. Furthermore, theta-Cerulo and theta-IgG increased in the D group compared with those of the N and the B groups. Recently, we found that theta-Cerulo and theta-IgG increased in healthy volunteers when GFR was elevated by acute protein loading and that increase in theta-Cerulo is remarkable than increase in theta-IgG. The present result, taken together with our recent finding mentioned above, suggests that increases in theta-Cerulo and theta-IgG may not be due to an impairment of charge selectivity in the glomerular basement membrane, but due to an increase of intraglomerular hydraulic pressure.

Effects of protein meals on the urinary excretion of various plasma proteins in healthy subjects.

To examine whether hemodynamic changes in response to acute protein loadings with different protein sources cause increases in urinary excretion of plasma proteins in healthy subjects, urinary excretions of various plasma proteins with various molecular radii and isoelectric points, namely albumin (Alb), IgG, IgG4, ceruloplasmin (CRL), and alpha2-macroglobulin (A2), were measured in healthy subjects after ingestion of a beef meal or of a tuna fish meal. Significant increases in urinary excretions of the negatively charged IgG4 and CRL and of the neutrally charged IgG were found in parallel with enhanced creatinine clearances after each protein ingestion. These renal responses returned to basal levels 9 h after the test. This finding suggests that in healthy subjects, the increase in glomerular filtration rate after acute protein loading caused selective enhancement of urinary excretions of plasma proteins with a molecular radius of approximately 55 A (the radius of IgG, IgG4, and CRL), irrespective of the charge barrier of the glomerulus. The increases in these three plasma proteins may be induced by leakage via the shunt pathway in the glomerulus, as proposed earlier (see text). In contrast, increases in urinary excretions of A2 and Alb were not found. The former finding may be explained by the possibility that A2 would not pass through this pathway, since the molecular radius of A2 (88 A) is larger than that of IgG, although the latter finding may be partially explained by preferential renal tubular reabsorption of Alb.

Effects of short-term glycemic control, low protein diet and administration of enalapril on renal hemodynamics and protein permselectivity in type 2 diabetic patients with microalbuminuria.

To determine whether each of glycemic control (GC), low protein diet (LPD) or administration of angiotensin converting enzyme inhibitor (ACEI) has beneficial effects on diabetic nephropathy through the different mechanisms, changes in charge and size selectivity of glomerulus and renal hemodynamics were analyzed in microalbuminuric type 2 diabetic patients after additive combination therapy (first period: GC only, second period: GC-LPD, third period: GC+LPD+ACEI). To detect improvement of the impairments of glomerular charge selectivity and size selectivity, changes in the ratio of the renal clearance of two plasma proteins with similar molecular radii and different isoelectric points (pIs) (ceruloplasmin and IgG: CRL/IgG) and changes in the ratio of the renal clearance of two plasma proteins with similar pIs and different molecular radii (alpha2-macroglobulin and albumin: alpha2/Alb) were examined before and after each therapy. Creatinine clearance decreased significantly in the first and third periods although slight but not significant decrease was detected in the second period. Filtration fraction was significantly decreased only in the third period. Although renal clearances of Alb, IgG and CRL were decreased in periods of all three therapies, that of alpha2-macroglobulin with a large molecular radius was decreased significantly only after the third therapy. Neither CRL/IgG nor alpha2/Alb changed during these three therapies. These findings suggest that each of three short-term therapies consisting of GC, GC+LPD and GC+LPD+ACEI, reduced proteinuria in microalbuminuric type 2 diabetic patients not through the improvement of renal size and charge selectivities, but through improvement of renal hemodynamics.

[Favorable prognosis in a case of recurrent cerebral infarctions caused by chronic disseminated intravascular coagulation due to ovarian carcinoma].

We report a 53-year-old woman who developed a cerebral infarction in the left middle cerebral artery area. Although she did not have a hemorrhagic tendency, the results of her examination showed a chronic disseminated intravascular coagulation (DIC) and a left ovarian carcinoma. Gabexate mesilate (FOY) and nafamostat mesilate (FUT) were not effective for her DIC. One month after admission, she had another cerebral infarction in the right posterior cerebral artery area. She was treated by heparin sodium and her chronic DIC improved. Then, she was operated on for ovarian carcinoma; the histologic finding was clear cell adenocarcinoma. No recurrence of DIC nor cerebral infarction was observed postoperatively. Patients with cerebral infarctions caused by chronic DIC due to ovarian carcinoma have been reported in the literature, but few patients had a favorable prognosis such as the present case. Heparin therapy appears to be the treatment of choice for chronic DIC rather than FOY or FUT, if there is no hemorrhagic tendency. When a patient with DIC develops cerebral infarction, one should always investigate for possible malignant tumors.

[Clinical features of anterior inferior cerebellar artery territory infarcts--a study of ten patients].

Clinical features of the anterior inferior cerebellar artery (AICA) territory infarcts were investigated in ten patients, ranging in age from 38 to 76 years. In all patients, there were MR images of infarction located in the area supplied by the AICA. The lesion was on the left side in 6 patients and right side in 4. The lesion of brain stem including the middle cerebellar peduncle was found in 7 patients and that extended to the cerebellum was in 3 patients. The main ipsilateral neurological signs were the VII and VIII cranial nerves palsy and cerebellar ataxia. The V and VI cranial nerves palsy. Horner's syndrome, and dysphagia were also present. The main contralateral sign was superficial sensory disturbance, but no hemiplegia. The underlying pathology included chiefly hyperlipidemia, hypertension, and diabetes mellitus. Cerebral angiography was performed in 8 patients, most of which was observed severe arteriosclerosis suggesting poor hemodynamics in the vertebral and basilar arteries. The prognosis was relatively good, but the VII, VIII, and V cranial nerves palsy and contralateral superficial sensory disturbance remained as the sequelae. As mentioned above, there were various neurological findings and MR images in AICA territory infarcts. Especially there were some patients whose lesion extended to the upper medulla and neurological findings were similar to the Wallenberg syndrome. It is important that one investigates not only axial slices but also coronal slices of MR image to estimate the extension of AICA territory infarct.