Non-autoimmune primary hypothyroidism in diabetic and non-diabetic chronic renal dysfunction.

The aim of this study was to investigate the frequency and mechanisms of hypothyroidism observed in diabetic patients with advanced diabetic nephropathy, including outcomes of management for this condition. A controlled study was designed using 32 diabetic and 31 non-diabetic patients not receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) who excreted mean urinary protein greater than 0.5 g/day examined on three consecutive days during admission to our hospital. Thyroid hormones in both serum and urine, anti-thyroid antibodies, renal function and iodine concentrations in serum were measured during admission in all patients included. In particular, in patients who showed overt hypothyroidism, further studies including large-needle biopsies of the thyroid and iodine-perchlorate discharge tests were performed. All patients in the two groups revealed negative antithyroid antibody titers, and the mean serum total iodine levels did not significantly differ between the two groups. Mean serum FT4 levels significantly decreased, and the TSH level was significantly elevated in the diabetic group compared to those in the non-diabetic group (p < 0.005, p < 0.02, respectively). The frequency of overt hypothyroidism in the diabetic group (22%; 7/32) was significantly higher (p < 0.05) than that in the non-diabetic group (3.2%; 1/31). The daily urinary thyroid hormone excretion in both groups did not show any significant correlation with serum thyroid hormone levels. Seven patients who revealed overt hypothyroidism in the diabetic group showed elevated serum total iodine levels during hypothyroidal status, ranging between 177 and 561 microg/l. Also, the iodine-perchlorate discharge tests carried out in six of these patients all showed a positive discharge. After management based on iodine restriction, normalization of serum thyroid hormone levels in accordance with definite decreases in the serum total iodine level was achieved, accompanied by a significant weight reduction. In conclusion, we found a significantly high prevalence of non-autoimmune primary hypothyroidism in patients with advanced diabetic nephropathy compared to those with non-diabetic chronic renal dysfunction, which may partly relate to earlier development of oedematous status. Clinical and laboratory findings suggest that impaired renal handling of iodine resulting in an elevation of serum iodine levels, rather than autoimmune mechanism or urinary hormone loss, may play a principal role in the development of these conditions, probably through a prolongation of the Wolff-Chaikoff effect. The mechanisms by which this phenomenon develops more frequently in diabetic than in non-diabetic renal dysfunction remain to be elucidated.

Painless thyroiditis associated with severe inflammatory reactions in amyloid goiter: a case report.

We report the case of a 64-year-old woman with rheumatoid arthritis (RA) associated with high grade fever, malaise, and painless swelling of thyroid gland. Laboratory findings showed severe systemic inflammatory reactions, including increases in various cytokines such as IL-6. Gallium-67 citrate imaging revealed intense uptake in the painlessly enlarged thyroid gland. Histologically, biopsied specimens of thyroid showed diffuse amyloid infiltrations, which included amyloid A (AA) protein. Biopsies of rectum and stomach revealed similar amyloid depositions, indicating that the amyloid had a secondary origin, potentially due to RA. All clinical symptoms were relieved by intravenous pulsatile administration of methylprednisolone followed by oral prednisone, resulting in prolonged hypothyroid status. To our knowledge, this is the first case report in Japan describing painless thyroiditis with severe inflammatory reactions in amyloid goiter.

The relationship of fasting plasma glucose values and other variables to 2-h postload plasma glucose in Japanese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma glucose (FPG) values and other variables (e.g., age, sex, and BMI) to 2-h post-75-g oral glucose load glycemia (PG) in Japanese subjects. RESEARCH DESIGN AND METHODS: Subjects included 13,694 Japanese subjects between 20 and 83 years of age (10,677 men and 3,017 women) who were undergoing a 75-g oral glucose tolerance test (OGTT) during a health screening performed at our hospital. The influences of age for 2-h PG at a fixed fasting plasma glucose (FPG) level of 126 mg/dl were analyzed. Multiple linear regression analysis was performed using a model in which the dependent variable was 2-h PG using the following explanatory variables: FPG, age, sex, BMI, blood pressure, plasma cholesterol, and triglyceride (TG) levels. RESULTS: The 2-h PG at a fixed FPG of 126 mg/dl increased by 0.94 mg/dl per year in patients aged between 30 and 78 years (r = 0.68, P < 0.0001). In multiple regression, five explanatory variables (FPG, age, BMI, plasma TG levels, and systolic blood pressure levels) were all positively associated with 2-h PG. The percentages of patients with 2-h diabetes (isolated postchallenge hyperglycemia [IPH]) versus fasting plus 2-h diabetes by the World Health Organization criteria significantly (P = 0.005) increased as the patients' decades increased, whereas the impact of BMI on the percentages was significant only in young patients (P = 0.001). CONCLUSIONS: Aging was found to be the second best predictor of 2-h PG on multiple regression. Therefore, OGTT should be performed especially in elderly patients because they show IPH more frequently.

Troglitazone combination therapy in obese type 2 diabetic patients poorly controlled with alpha-glucosidase inhibitors.

The efficacy and safety of treatment with troglitazone combined with an alpha-glucosidase inhibitor, in obese type 2 diabetic patients who were previously administered alpha-glucosidase inhibitors alone, in improving glycaemic control and reducing insulin resistance were studied. Obese type 2 diabetic patients, poorly controlled with alpha-glucosidase inhibitors, were randomized to receive either oral troglitazone 200 mg twice daily (22 patients: group A) or a placebo (20 patients: group B) in addition to their usual alpha-glucosidase inhibitor. In group A, significant decreases in the mean levels of haemoglobin A1c and basal plasma insulin levels were observed 6 months after the start of combined therapy. Serum triglyceride levels significantly decreased but serum lactic acid dehydrogenase and body weight significantly increased. New systemic oedema was observed in six patients. Combined therapy with troglitazone and alpha-glucosidase inhibitors may be effective for diabetic metabolic abnormalities, although the potential development of adverse effects such as body-weight gain and systemic oedema demands vigilance.

Development of Graves' hyperthyroidism from primary hypothyroidism in a case of thyroid hemiagenesis.

We report a 42-year-old female with right thyroid hemiagenesis who initially presented with hypothyroidism and then developed hyperthyroidism. The serum titer of thyroid-stimulating antibody was weakly positive in the initial hypothyroid state, and then markedly increased along with the development of hyperthyroidism, while thyroid stimulation-blocking antibody was continuously negative throughout the observation period. Thyroid histology of biopsied specimens during the hypothyroid state demonstrated diffuse thyroiditis with mononuclear cell infiltrations; however, the histology during the hyperthyroid state showed hyperplasia in follicular epithelial cells accompanied by partial lymphocyte infiltration. This is the first case of thyroid hemiagenesis associated with a conversion from primary hypothyroidism due to Hashimoto's thyroiditis to hyperthyroidism due to Graves' disease.

Diabetic nephropathy accompanied by iodine-induced non-autoimmune primary hypothyroidism: two case reports.

We reported 2 diabetic patients with nephrotic syndrome due to advanced diabetic nephropathy complicated by non-autoimmune primary hypothyroidism. Hypothyroidism developed along with the anasarcous status. Histological examinations of the thyroid gland revealed almost normal thyroid follicles without lymphocytic infiltration. The amounts of thyroid hormone lost into the extravascular space such as in urine and ascites were not sufficient to cause hypothyroidism alone. Serum total iodine levels measured during the hypothyroidal state in both cases were definitely elevated, and the perchlorate discharge test of both cases showed positive discharge (24 and 34%, respectively). The thyroid functions normalized after iodine restriction in the first case and initiating hemodialysis in the second case, in parallel with normalization of serum total iodine levels. These findings suggest that impaired renal handling of iodine resulting in elevation of serum iodine levels, rather than an autoimmune mechanism or extravascular hormone loss, played a principal role in the development of primary hypothyroidism found in these 2 patients, probably through a prolonged Wolff-Chaikoff effect.

Three diabetic cases of acute dizziness due to initial administration of voglibose.

We observed 3 diabetic patients with intolerable dizziness followed by nausea and vomiting immediately after an initial administration of the alpha-glucosidase inhibitor, voglibose. These symptoms did not recur after discontinuation of the drug. Adverse effects as observed in these cases have not been reported previously. Since the 3 patients were relatively old (average age, 72 years old) and had various degrees of micro- and macroangiopathies, these side effects may have been associated with increased micro- and macrocirculatory disturbances in their central nervous systems through alpha-glucosidase inhibition of this agent.

Antibodies to glutamic acid decarboxylase (GAD) in non-obese Japanese diabetics without insulin therapy: a comparison of two commercial RIA kits based on recombinant and pig brain GAD.

To compare the clinical usefulness of commercial radioimmunoassay (RIA) kits based on recombinant and pig brain GAD, we measured glutamic acid decarboxylase autoantibody (GADAb) titers in 125 non-obese (body mass index < 24) Japanese diabetics without insulin therapy using two commercial RIA kits based on recombinant human (rh) GAD65 (GADAb Cosmic) and purified pig brain native GAD (RIP Anti-GAD Hoechst). The frequencies of GADAb positivity using these two RIA kits (normal ranges; < 1.3 and < 4.0 U/ml, respectively) were about 4.8 (6/125) and 3.2% (4/125), respectively. The six patients found to be positive with RIA using GADAb Cosmic demonstrated significantly higher prevalence of NIDDM in their parents (P = 0.04), lower beta-cell function estimated by intravenous glucagon loading tests (P = 0.03) and higher prevalence of progression to insulin therapy (P = 0.0001). Five of these six patients slowly progressed to insulin-requiring status within 34 +/- 11 months of follow-up evaluation, and one of these five patients progressed to a completely insulin-dependent status within 30 months from the onset of diabetes. Of these six patients, two demonstrated chronic pancreatitis, three had chronic thyroiditis, and five showed HLA DR4. Interestingly, two of the six patients demonstrated very low GADAb titers (2.3 and 2.9 U/ml), while RIP Anti-GAD Hoechst showed no positivity with the same sera. Based on the binding study after pre-incubation of unlabeled GADs, these low titrated GADAb were elucidated to be true specific reactions to rh GAD65 alone. Moreover, one of the two patients with chronic thyroiditis and HLA DR4 slowly progressed to insulin-requiring status over a period of 45 months. These findings suggest that the measurement of GADAb using a commercial assay kit with rh GAD65 may be more useful to detect non-insulin-dependent type I diabetics among non-obese patients than using a commercial kit with purified pig brain native GAD, especially among those with low GADAb titers.

Effect of calcium antagonist, manidipine hydrochloride, on renal hemodynamics and tubuloglomerular feedback in spontaneously hypertensive rats.

The effects of a calcium antagonist, manidipine, on renal hemodynamics and the tubuloglomerular feedback (TGF) mechanism were examined in 7- to 8-week-old spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar-Kyoto rats (WKYs). Manidipine, 10 micrograms/kg intravenously, reduced blood pressure only in SHRs. A greater increase in renal plasma flow occurred in SHRs, but effects on GFR were observed in both SHR and WKY rats. Filtration fraction decreased only in SHRs. The TGF response curve in SHRs was shifted to the left compared with that in WKY rats, indicating a more active TGF in hypertensive rats. Manidipine infusion produced a right and upward shift of the feedback curve in SHRs and only an upward shift in WKY rats. We conclude that manidipine corrects hyperactivity of the TGF mechanism in SHRs.

[Renal adaptations to acid-base disorders].

Alterations in acid-base status affect renal hemodynamics and tubular function. GFR is reduced both in acute acidosis and alkalosis. Tubular functional adaptation to acute acidosis includes an acceleration in proximal acidification, induced by the increase in Pco2 and luminal bicarbonate concentration and a stimulated ammonia production, induced by low pH. Alteration in distal bicarbonate reabsorption is also an important determinant of the net acid excretion. Renal functional alterations in acute alkalosis include a reduction in GFR and a stimulated bicarbonate secretion in the cortical collecting duct. Proximal acidification is almost unchanged during acute alkalosis but reportedly accelerates after at least 3 weeks of maintained alkalosis. Renal adaptation during chronic phase of acid-base disorders differs from that during the acute phase.

Renal blood flow control by tubuloglomerular feedback (TGF) in normal and spontaneously hypertensive rats--a role for dopamine and adenosine.

Following the elementary laws of hemodynamics and the functional characteristics of the renal myogenic and macula densa-mediated (TGF) vascular resistance control mechanisms, TGF-mediated changes of renal vascular resistance are amplified by cooperative changes of the myogenic mechanism. Myogenically induced changes, on the other hand, would be antagonized by TGF. Resetting of renal vascular flow resistance by alterations to the TGF mechanisms might thus be more effective than alterations to the myogenic mechanism. Dopamine and adenosine, two autacoids occurring normally in the tubular fluid, may play a key role in operating such a resetting mechanism. Dopamine and adenosine were found in proximal tubular fluid at concentrations of 10(-8) and 0.5 10(-6) M respectively. Dopamine inhibits the tubuloglomerular feedback mechanism, this inhibition is antagonized concentration-dependently by adenosine. These effects most likely occur via D1 and A1 receptors and hence by regulation of the adenyl cyclase activity in the macula densa cells. The balance between adenosine and dopamine in tubular fluid appears to be under the control of extrarenal parameters. In normal rats, high dietary salt intake, by influencing the secretion of an unknown adrenal hormone, and inhibition of Na-K-ATPase might be of importance. In spontaneously hypertensive rats unknown genetic parameters may also play a role.

Hyperreactivity of tubuloglomerular feedback in chronically salt-loaded spontaneous hypertensive rats.

In order to investigate the mechanisms of the hyperreactivity of the tubuloglomerular feedback (TGF) mechanism in spontaneous hypertensive rats (SHR) the resetting of TGF by chronic dietary NaCl loading was studied in SHR and normotensive Wistar Kyoto rats (WKY). This treatment is known to reset the TGF by an inhibitory factor in tubular fluid and not by alterations of the intrinsic characteristics of the juxtaglomerular apparatus (JGA). TGF reactivity, and its resetting, were determined by loop of Henle perfusion with artificial late proximal tubular fluid and with harvested endogenous tubular fluid respectively. Dietary effects of the high sodium intake were measured by means of the systolic blood pressure (SBP), plasma volume (PV), and renal sodium excretion. The 4-week dietary treatment had no significant influence on SBP in WKY, whereas it accelerated the rise of SBP in SHR significantly. After 1 week of treatment, PV was increased in both WKY and SHR as compared with the control groups kept on the normal diet. Whereas PV in WKY declined to control values over the next 3 weeks, SHR remained expanded. GFR was similar in all groups, whereas urinary sodium excretion was significantly increased in salt-loaded SHR and WKY. Dietary salt loading was paralleled by the appearance of a TGF-inhibiting substance in the tubular fluid in SHR and WKY. However, when assayed with artificial late proximal tubular fluid, hyperreactivity was similar in normal and salt-loaded SHR as compared with WKY. Thus, in SHR TGF hyperreactivity is maintained in spite of volume expansion and TGF resetting by a humoral factor in tubular fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure and tubuloglomerular feedback mechanism in chronically salt-loaded spontaneously hypertensive rats.

Experiments were performed to qualitatively characterize the effects of tubuloglomerular feedback (TGF) inhibition by chronic salt loading on salt sensitivity of blood pressure in spontaneously hypertensive rats (SHR). After two weeks of salt loading, systolic blood pressure (SBP) was significantly exacerbated and plasma volume (PV) was expanded in salt-loaded SHR compared with those in control SHR (SBP: 182 +/- 1 vs. 159 +/- 2 mm Hg; PV: 4.38 +/- 0.06 vs. 4.04 +/- 0.03 ml/100 g body wt, respectively). Plasma volume of WKY was also but only transiently expanded by salt loading, whereas plasma volume expansion in SHR had persisted over the entire dietary treatment period. TGF activity was assessed as the maximal reduction of single nephron GFR (SNGFR) on increasing loop of Henle perfusion rate from 0 to 40 nl/min using previously collected tubular fluid from salt-loaded rats (TFs) or control rats (TFc). Maximal TGF response in salt-loaded SHR with TFs was 14.9 +/- 2.9% and 57.8 +/- 2.6% with TFc. In control SHR the responses were 16.9 +/- 2.5% with TFs and 52.7 +/- 2.9% with TFc. In salt-loaded WKY the response with TFs were 3.1 +/- 1.6% and 37.4 +/- 2.8% with TFc. And in control WKY, the response with TFs were 8.2 +/- 1.9% and 40.8 +/- 2.8% with TFc, respectively. These results indicate the TGF resetting in chronically salt-loaded SHR and WKY is caused by the activation of humoral TGF inhibitory factor. The suppression of TGF in SHR was, however, far more variable and, on average, less than in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of SUN 1165, a new antiarrhythmic agent, in renal dysfunction.

The pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg. The apparent volume of distribution at steady state was 1.48 l.kg-1, the absorption rate constant was 2.2 h-1, and plasma protein binding was 26.8% in subjects with normal renal function. These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration. The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml.min-1.1.48 m-2). Dosage adjustment of SUN 1165 is necessary in renal failure.

Attenuation of enhanced tubuloglomerular feedback activity in SHR by renal denervation.

We evaluated the effect of acute unilateral renal denervation (DNX) on the tubuloglomerular feedback (TGF) mechanism in Inactin-anesthetized hydropenic male 8- to 10-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). SHR had higher mean arterial pressure (MAP, 28%) and renal vascular resistance (RVR, 35%), whereas renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and sodium excretion were similar. DNX in SHR did not change MAP but decreased RVR (26%) and increased RBF (29%), GFR (16%), urine flow (52%), and sodium excretion (431%). DNX did not affect these in WKY. Loop of Henle perfusion with Ringer solution reduced early proximal flow rate (EPFR) in SHR more than in WKY; significantly different at a loop flow of 20 nl/min (9.8 +/- 0.7 vs. 6.5 +/- 0.7 nl/min). DNX in SHR increased the nonperfused EPFR from 25.6 +/- 1.1 to 31.7 +/- 1.3 nl/min and reduced TGF responses during perfusion at both 20 nl/min (9.8 +/- 0.7 vs. 4.4 +/- 0.7 nl/min) and 40 nl/min (14.2 +/- 1.1 vs. 10.4 +/- 0.7 nl/min). TGF sensitivity was attenuated by DNX, as indicated by reduced maximum reactivity (-0.89 +/- 0.14 to -0.36 +/- 0.07) and increased turning point (16.5 +/- 0.9 to 25.2 +/- 2.9 nl/min). TGF responses in WKY were not influenced by DNX. Sham denervation did not alter renal hemodynamics and TGF. These results indicate that renal nerves exert a tonic influence on the renal vasculature and the TGF system in SHR but not in WKY. Enhanced TGF responsiveness may be involved in volume retention and in the maintenance of hypertension in SHR.

Low serum creatinine levels in severe hepatic disease.

For five years, eight patients had abnormally low serum concentrations of creatinine. All patients presented with severe hepatic failure, which was due to fulminant hepatitis in seven patients and to advanced primary biliary cirrhosis in one patients. The serum urate (as uric acid) concentration was also low in seven patients. Endogenous creatinine clearance was increased in all patients (2.38 to 14.75 mL/s [143 to 885 mL/min]). However, inulin clearance measured in four patients was reduced (25 to 32 mL/min) and the creatinine-to-inulin clearance ratio ranged from 4.5 to 9.9. This range can be explained largely by an increased tubular secretion of creatinine related to body fluid expansion caused by a large fluid infusion. Renal function would be extremely overestimated when assessed from serum concentrations or clearance of creatinine in such patients.

Effect of angiotensin blockade and converting enzyme inhibition on renovascular hypertension: comparison between unilateral and bilateral renal artery stenosis.

The response to angiotensin II analog infusion during sodium deletion and the effects of a one-month captopril treatment were compared between 15 renovascular hypertensive patients with unilateral and 6 with bilateral renal artery stenosis. Plasma renin activity, its response to sodium depletion, and the renal vein renin ratio during sodium depletion were greater in unilateral than in bilateral stenosis. A fall in diastolic blood pressure induced by analog infusion during sodium depletion was correlated with the preinfusion plasma renin activity and with the renal vein renin ratio. Treatment with captopril showed a comparable hypotensive effect in unilateral and bilateral stenosis. The reduction in blood pressure was not correlated with the pretreatment renin levels or changes in blood pressure observed during analog infusion. Plasma renin activity rose and plasma aldosterone level fell in all patients. These results indicate that the mechanism maintaining high blood pressure is more renin dependent in unilateral than in bilateral stenosis and that the long-term effect of captopril does not depend solely on the suppression of the renin-angiotensin-aldosterone system.

The long term effects of percutaneous transluminal angioplasty for treating patients with renovascular hypertension: case studies.

Percutaneous transluminal angioplasty was performed on 10 patients with unilateral renovascular hypertension (7 with atheromatous and 3 with fibromuscular stenoses) who were then followed for an average of 42 months (range, 24 to 67 months). Dilation of the stenosis was initially successful in all patients except one who had severe atheromatous stenosis. Among patients with atheromatous disease, normotension was attained for 40, 25 and 24 months in 3 patients given no antihypertensive medication and for 67 and 55 months in 2 patients given only nicardipine. The remaining one patient had a recurrent stenosis 3 months after angioplasty. All patients with fibromuscular dysplasia have been normotensive without any hypotensive medication for more than 4 years. Plasma renin activity declined within one week after angioplasty and remained unchanged thereafter in all patients except the one case suffering from a recurrent stenosis. Renal blood flow and glomerular filtration rate remained increased after angioplasty. These results suggest that hypertension can be controlled and renal dysfunction in patients with renal artery stenosis caused by atheroma or fibromuscular dysplasia improved for long periods by percutaneous transluminal angioplasty. The antihypertensive effect obtained by this procedure was more valuable for the patients with fibromuscular dysplasia than in those with atheromatous disease.