Diabetic nephropathy. Future avenue.

Diabetes mellitus has become the leading cause of ESRF in the United States. Patients with diabetic nephropathy suffer high cardiovascular morbidity and mortality. Because only 40% of diabetic patients eventually develop diabetic kidney disease, it may be possible to devise primary prevention measures targeted at the subset of patients at risk. Recently, a predisposition to hypertension, a family history of diabetic nephropathy, and a family history of CVD disease each have been associated independently with the development of diabetic renal complication in IDDM. Risk factors for macrovascular damage, including raised arterial BP, dyslipidemia, and insulin resistance, can be detected early in the course of progression to diabetic nephropathy. These risk indicators recently have been shown to be already present at the stage of normoalbuminuria in those patients who eventually will progress to microalbuminuria. Treatment of established renal disease can only delay the onset of ESRF, and lowering of microalbuminuria has been shown to retard the onset of persistent proteinuria. However, no study to date has demonstrated prevention of renal disease in these patients. The ultimate aim should, therefore, be the prevention of the transition from normoalbuminuria to microalbuminuria in individuals who are at higher risk of diabetic renal disease and CVD.     

Intracellular pH and Na+/H+ antiport activity of cultured skin fibroblasts from diabetics.

Increased leucocyte Na+/H+ antiport activity has previously been demonstrated in both hypertensive subjects and Type 1 diabetic patients with nephropathy and may indicate a predisposition to hypertension in such diabetic patients. We have studied intracellular pH and Na+/H+ antiport activity in cultured skin fibroblasts from diabetic patients with and without nephropathy, together with non-diabetic controls to assess if such differences persisted in cultured cells. Fibroblasts from diabetic patients with nephropathy were significantly more alkaline [median (range): 6.90 (6.82 to 7.07)] compared to both normoalbuminuric diabetic patients [6.81 (6.75 to 6.89)] or normal controls [6.82 (6.77 to 6.93)] (P < 0.001 for both). This was associated with a raised Na+/H+ antiport activity in cells from patients with nephropathy when intracellular pH (pHi) was clamped to pH 6.5, without any differences in the maximal transport capacity of the antiport at pHi 6.2. Using both intracellular pH and Na+/H+ antiport activity at pHi 6.5, patients with nephropathy were separated from uncomplicated subjects with a sensitivity of 92% and a specificity of 100%. In conclusion, the raised Na+/H+ antiport activity in cells from patients with diabetic nephropathy persists despite passaging in vitro, thus indicating a heritable component, and results mainly from an increased apparent affinity of the antiport for intracellular H+.     

Selective and extremely long inhibition of prolactin release in man by 1-ethyl-3-(3''-dimethylaminopropyl)-3-(6''-allylergoline-8''-beta- carbonyl)-urea-diphosphate (FCE 21336)

The effects on anterior pituitary function of FCE 21336 (1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'-beta-ca rbonyl)-urea- diphosphate), a synthetic ergoline derivative with selective dopamine agonistic properties, were studied. Circulating PRL, GH, TSH, cortisol and LH levels were determined up to 96 h after single oral doses of 50, 100, 200 and 300 micrograms of the compound to eight healthy males, and up to 168 h after single oral doses of 400 and 600 micrograms to six healthy males, according to double-blind, within subjects, experimental designs vs placebo. Vital signs, ECG, laboratory tests and the appearance of newly observed signs and symptoms were monitored. A dose-related decrease of serum PRL in comparison with both basal and post-placebo levels was observed after 200 micrograms and greater doses of the compound, with inhibition of spontaneous circadian rhythm. Maximal inhibition (PRL less than 2 ng ml-1) was observed in one out of five subjects after 200, three out of seven subjects after 300, four out of six after 400 and five out of six subjects after 600 micrograms. The effect was of rapid onset and long duration; the maximum or nearly maximum decrease was observed within 3 h after dosing as well as up to 96 h (200 and 300 micrograms) and up to 168 h (400 and 600 micrograms). No modifications of GH, TSH, LH and cortisol as well as of vital signs, ECG and laboratory tests were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)     

A screening programme for microalbuminuria at a diabetes clinic in Apulia,southern Italy

Microalbuminuria is a predictor of renal and cardiovascular disease in both type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes. We report on a screening programme for microalbuminuria at a diabetes clinic in Italy. All diabetic patients without Albustix-positive proteinuria attending the clinic between April and September 1991 were screened. Microalbuminuria was defined as a urinary albumin/creatinine ratio, on an early morning sterile urine sample, >3 in at least two consecutive urine collections. Three hundred and fifty patients, 45 (20 female, 25 female) type 1 and 305 (145 male, 160 female) type 2 diabetics, were examined. The age range was 18–42 years and 36–73 years and duration of diabetes 1–24 and 1–35 years for type 1 and type 2 diabetic patients respectively. Blood pressure, lipids, glycosylated haemoglobin, body mass index and insulin dose, where appropriate, were measured in all patients. Microalbuminuria was found in 8 (22%) of the type 1 diabetics. These patients had a longer duration of diabetes (17.5 vs 7.4 years,P<0.001), higher diastolic blood pressure (86±2.1 vs 76±2.6 mmHg,P<0.05) and an increased total serum cholesterol level (203±23 vs 180±25 mg/dl,P<0.05) compared with diabetic patients with microalbuminuria. Of the type 2 diabetic patients 95 (33%) were found to have microalbuminuria and 210 (69%) nor-moalbumiuria. The prevalence of hypertension (defined blood pressure >140/90 mmHg or antihypertensive treatment) and of dyslipidaemia (defined as total cholesterol >200 and triglycerides >170 or hypolipidaemic treatment) were significantly higher (P<0.001 and 0.01 respectively) in patients with microalbuminuria. This study shows a prevalence of microalbuminuria in type 1 and type 2 diabetic patients similar to that reported in surveys of diabetes clinic outpatients in northern Europe. The association between microalbuminuria and recognized risk factors for cardiovascular and renal disease justifies screening programmes for microalbuminuria for early detection of at-risk diabetic patients and for the implementation of preventive therapeutic measures.     

Effect of control of blood glucose on urinary excretion of albumin and beta2 microglobulin in insulin-dependent diabetes.

To study the effects of improved control of blood glucose on markers of renal glomerular and tubular function, we initially determined, by radioimmunoassay technics, urinary excretion rates of albumin and beta2 microglobulin in 17 nondiabetic subjects and in 43 insulin-dependent, clinically nonproteinuric diabetic patients. Duration of diabetes ranged from six months to 39 years, and the patients were studied while receiving conventional therapy. Mean urinary albumin excretion was significantly elevated in the diabetics, but beta2-microglobulin excretion rates were not different from those of the controls, suggesting that the increased albumin excretion was due to increased transglomerular loss of albumin. Seven patients with long-term diabetes (duration of six to 33 years), selected because of elevated albumin excretion, were studied before and during a continuous, subcutaneous insulin infusion for a period of one to three days. Urinary albumin excretion was significantly reduced during the insulin infusion, but mean beta2-microglobulin excretion did not change. Strict control of blood glucose, even in the short term, may reverse a functional renal abnormality in long-duration, insulin-dependent diabetes.     

Squamous-cell carcinoma developing within anal lichen planus

AIM: We present a case of squamous-cell carcinoma developing within perianal lichen planus. This is a chronic or recurrent cutaneous and/or mucosal dermatosis affecting less than 1 percent of the population. Neoplastic degeneration of cutaneous lichen planus is rare; only one case of squamous-cell carcinoma developing within perianal lichen planus has been described up until now in the international literature. CASE REPORT: Our case involved a 68-year-old woman with chronic, long-term lichen planus spreading all over the vulva and perianal region and the mucosa of the anal canal, where squamous-cell carcinoma developed within the perianal lichen planus. Treatment consisted of wide, circular excision of the perianal skin and mucosectomy of the anal canal up to as far as 1 cm above the dentate line. Reconstruction was performed by means of two V-Y bilateral subcutaneous flaps. CONCLUSION: Wide excision was performed not only to remove the squamous-cell carcinoma but also the lichen planus to prevent recurrence of metachronous or synchronous squamous-cell carcinoma. Follow-up at one year after surgery showed no local recurrence of either lichen planus or squamous-cell carcinoma, which suggests that surgical removal should be the therapy of choice for long-term, chronic perianal lichen planus that has proved to be resistant to medical therapy.     

LDL subclasses in IDDM patients: relation to diabetic nephropathy

Summary To answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric [AER 7 (1–19) g/min, median and range], in 46 microalbuminuric [AER 50 (20–192) g/min] and in 33 proteinuric [AER 422 (233–1756) g/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger LDL particles than non-diabetic control subjects (260 Å vs 254 Å, p<0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p<0.05 for normoalbuminuric and p<0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p<0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p<0.05 for both) was mainly due to the increment of light LDL (density 1.0212–1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles. The prevalence of atherogenic small dense LDL particles in IDDM patients with microalbuminuria and proteinuria is closely dependent on plasma triglyceride concentration.Abbreviations AER urinary album excretion rate - CETP cholesteryl ester transfer protein - IDDM insulin-dependent diabetes mellitus - CHD coronary heart disease - ApoB apolipoprotein B