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Query: UMLS:C0011854 (type 1 diabetes)
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Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.
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PMID:Treatment of diabetic nephropathy in its early stages. 1267 78

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.
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PMID:Diabetic autonomic neuropathy. 1271 21

In Germany, 36% of all new chronic dialysis patients have diabetic nephropathy. The majority are type 2 diabetics. Early intervention has the greatest effect. Incipient nephropathy can be diagnosed by evidence of microalbuminuria (30-300 mg albumin/g creatinine). Proteinuria on the standard test strip (>300 mg/g) indicates manifest nephropathy followed by progressive renal failure. Important cofactors for progression are hypertension, hyperglycemia, and smoking. Low normal blood pressure levels (<130/80 mmHg without and <125/75 mmHG with proteinuria) based on ACE inhibitors/AT1 blockers are the goal. Combination therapies are frequently necessary. This can often reverse microalbuminuria. Chronic renal failure requires special attention (e.g. bone metabolism, anemia, acidosis). Timely initiation of renal replacement therapy (GFR <15 ml/min) reduces morbidity and mortality. In addition to hemo- and peritoneal dialysis, early kidney and in individual cases of type 1 diabetes combined kidney/pancreas transplantation is appropriate.
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PMID:[Diagnostics and therapy of diabetic nephrology]. 1273 10

In patients with diabetes, altered diurnal blood pressure (BP) regulation (high night-to-day [N/D] ratio, or "nondipping") is associated with increases in albumin excretion and a decline in the glomerular filtration rate (GFR) by an unknown mechanism. Because it is known that renin angiotensin system (RAS) activation and defective glucose control contribute to adverse renal outcomes, we examined renal responses to high glucose and to manipulation of the RAS in adolescents (mean age 14 +/- 2 years) with uncomplicated type 1 diabetes, segregated into two groups on the basis of the presence or absence of normal N/D BP ratio. In the first experiment, renal hemodynamic comparisons were made during euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l), maintained by modified clamp techniques. The induction of hyperglycemia resulted in a significant increase in GFR and filtration fraction (FF) in the high N/D ratio group. In the second experiment, we examined the renal response to graded angiotensin II (Ang II) infusion while subjects were euglycemic and salt replete. High N/D ratio was associated with an enhanced FF response to Ang II. In the third experiment, the N/D ratio and GFR were assessed after 3 weeks of ACE inhibition. This maneuver corrected the high N/D ratio, but it had no effect on glomerular hyperfiltration. These results suggest that RAS activation does not explain the hyperfiltration state, nor can it explain the poor outcomes, at least in this population. However, the observed deleterious hemodynamic responses to high glucose and Ang II and the insensitivity to ACE inhibition may, taken together, provide an explanation for the adverse renal outcomes in patients with type 1 diabetes and high N/D ratio.
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PMID:Relationship between diurnal blood pressure, renal hemodynamic function, and the renin-angiotensin system in type 1 diabetes. 1282 50

Diabetes mellitus and hypertension are both major public health problems in our country, which co-exist frequently resulting in significant morbidity and mortality. The reported prevalence of hypertension in diabetes varies widely but is probably 1.5-2 times higher than that reported in the general population. In type 2 diabetics many are hypertensives at the time of diagnosis, while in type 1 diabetes, hypertension is predominantly associated with the development of nephropathy. Hypertension in diabetes is due to several pathophysiological mechanisms which include increased volume expansion, altered sodium homeostasis, increased peripheral vascular resistance, hyperinsulinaemia, insulin resistance, etc. The presence of hypertension in diabetic patients increases the mortality 4-5 folds, largely through coronary artery disease and stroke. It may also be an aetiological factor in the development of nephropathy and retinopathy. Treatment of hypertension in a diabetic has considerable therapeutic advantages and should be carried out vigorously. Lifestyle modifications have a useful role in the treatment of mild hypertension and have a beneficial effect on other cardiovascular risk factors. The choice of antihypertensive agents should be based on their potential impact on the metabolic abnormalities observed in diabetics. Amongst the currently available antihypertensive agents, ACE inhibitors and calcium channel blockers are the favoured agents.
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PMID:Hypertension in diabetes. 1284

Great advances in cell transplantation have been made, including the recent, remarkable success in pancreatic islet transplantation for the treatment of type 1 diabetes mellitus. Unfortunately, the transplanted cells are very susceptible to oxidative stress that cause severe damage to either allo- or xenogeneic islets upon graft in diabetic patients. Consequently, the transplanted islet functional life span is significantly shortened. The aim of this study was to examine the possible effects of antioxidants on in vitro cultured adult rat islets, and to evaluate the effects of a prolonged-release formulation, in form of cellulose acetate (CA) microspheres, on Vitamin D(3) activity. Isolated rat islets, both free and entrapped in microspheres were treated with Vitamin D(3). The effects of the vitamin were studied at 3, 6 and 9 days of in vitro cell culture. According to insulin secretory patterns, treatment with Vitamin D(3) of both free and CA entrapped microspheres, increased the insulin output as compared to untreated controls. Such positive effects were confirmed under islet static incubation with glucose at day 6. These results suggest that pancreatic islets can be advantageously treated with anti-oxidising vitamins before implantation, and speculatively, with the help of special delivery systems, throughout the islet cell life span, in the post-transplant time period.
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PMID:Multifunctional microcapsules for pancreatic islet cell entrapment: design, preparation and in vitro characterization. 1289 83

Hypertension is extremely common in patients with diabetes mellitus. In type 1 diabetes it usually signifies the onset of nephropathy. Tight control of hypertension in diabetes has shown to decrease the complications like ischaemic heart disease and renal failure thereby reducing the morbidity and mortality. Management of hypertension in diabetes include weight reduction, dietary restriction of sodium, adequate intake of potassium and calcium, regular exercise, cessation of smoking and drug therapy. Many type 2 diabetic patients require more than one drug for good blood pressure control. Even though many of the hypotensive drugs are effective in diabetic patients, ACE inhibitors have an edge over the other drugs in view of its favourable effect on the accompanying co-morbid conditions.
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PMID:Hypertension and diabetes mellitus. 1296 45

The aim of this study was to analyse the direct costs of some components of primary, secondary and tertiary prevention of the diabetic foot syndrome (cost of illness study). Information considering the costs of prevention and therapy of the diabetic foot and costs following after amputation in diabetic patients is available from international economical trials but is almost missing in the Czech Republic. The economical assessment of the most important mean of primary prevention/which is regular dispensarisation and preventive care for diabetic patients in risk of diabetic foot syndrome/is very problematic. The costs of primary prevention were calculated as the intervention costs of risk factors of diabetic foot syndrome according to the recommended daily doses and prices of the medicaments in AISLP database. Costs of hospitalisation in secondary and tertiary prevention were calculated by using bills for health insurance company in the programme Steiner-UNIS, costs for out-patient care according to ordinations (medication, aids, codes for heath insurance companies and means of diagnostic process). Costs of tertiary prevention were based on information gained from the Regional Social Authority. There were 20 patients (12 men, 8 women, age 65 +/- 12 years, 3 patients with 1. type diabetes, 17 with 2. type diabetes), involved in secondary in-patient care, 30 (20 men, 10 women, age 69 +/- 12.4 years, 2 patients with type 1. diabetes, 28 with type 2 diabetes) in out-patient care and 20 (12 men, 8 women, age 70 +/- 9.4 years, 1 patient with type 1 diabetes, 19 with type 2 diabetes) in tertiary prevention. This study proved high costs of the intervention of hyperglycaemia in type 1. diabetics, hypertension with ACE inhibitors, critical ischaemia, neuropathy. Costs of out-patient care for ulcers for eight months were 7,500.- +/- 4,400.-CK, antimicrobial treatment 1,900.-CK, in-patient care for ulcers 22,500.- +/- 6,400.-CK and amputation 22,000.- +/- 9,900.-CK. The highest costs were calculated for tertiary prevention--the first year after amputation 400,000.- CK. The study shows very high costs of tertiary prevention and suggests discussion on this topic.
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PMID:[Calculation of the costs of drugs, medical materials, certain medical procedures and social services for patients with diabetic foot syndrome]. 1450 74

The impact of polymorphisms in the genes coding for angiotensinogen (M235T), ACE (ID), and angiotensin II type 1 receptor (A(1166)-->C) on decline in GFR and doubling of s-creatinine or development of ESRD in patients with type 1 diabetes and diabetic nephropathy (DN) was tested. From 1985, all patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR ((51)Cr-EDTA). In a Cox proportional hazards model corrected for other risk factors, the D allele (ACE/ID) was associated with time to doubling of s-creatinine/ESRD (rate ratio, 1.81 per allele; 95% confidence interval, 1.09 to 3.03; P = 0.02). A new interaction hypothesis was generated demonstrating that the following variables were associated with accelerated decline in GFR: albuminuria (estimate, 2.12 ml/min per yr per 10-fold increase in albuminuria; P < 0.001), mean BP (estimate, 0.88 ml/min per yr per 10 mmHg; P = 0.02), hemoglobin A(1c) (estimate, 0.54 min/min per yr per 1%; P = 0.02), and number of M (M235T)/D (ID)/A (A(1166)-->C) alleles (estimate, 0.45 ml/min per yr per allele; P = 0.049). Number of M/D/A alleles also influenced time to doubling of s-creatinine or ESRD. In this study of patients with type 1 diabetes, the D allele of the ACE/ID polymorphism in addition to nongenetic risk factors independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies.
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PMID:Genetic variation in the Renin-Angiotensin system and progression of diabetic nephropathy. 1456 94

The incidence of diabetes as cause of end-stage renal failure (ESRF) has significantly increased, and will continue to grow during the next few years. Moreover, diabetic nephropathy is associated with elevated cardiovascular morbidity and mortality. These guidelines focus on the possible intervention strategies to prevent and treat ESRF in diabetic patients. In normoalbuminuric patients, glycated haemoglobin levels less than and equal to 7.5% is mandatory for reducing the risk of incipient nephropathy. Furthermore, blood pressure levels < 130/80 mmHg are strongly recommended. In microalbuminuric patients, glycated hemoglobin levels below 7.5% and blood pressure levels below 130/80 mmHg (120/70-75 mmHg in patients < 50 years) are recommended. Moreover, there is evidence that inhibition of the rennin-angiotensin-aldosterone system, either by angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensin II receptor antagonists (AIIRA) is able to reduce the incidence of overt nephropathy, regardless of blood pressure levels. Current guidelines recommed ACE-I as the first-choice drug in type 1 diabetes, while both ACE-I and AAIRA are considered first-choice therapy in type 2 diabetes. In proteinuric patients it is uncertain whether glycemic control affects the progression of nephropathy, which in turn is dramatically influenced by blood pressure. Optimal blood pressure levels are below 130/80 mmHg (120/70-75 mmHg in patients < 50 years). In type 1 diabetes there is consensus on the renoprotective role of ACE-1. In type 2 diabetes, two recent trials demonstrated that AIIRA are more effective than conventional therapy or calcium channel blockers in slowing down the progression of nephropathy. ACE-I are indeed recommended as first-choice drugs in type 1 diabetes while AIIRA are the first-choice agents for ESRF prevention in type 2 diabetes. Dialysis treatment should be started as soon as the creatinine clearance is reduced to about 10-15 mL/min. The choice of dialysis schedule should be individualized according to clinical and adequacy criteria (CAPD weekly Kt/V > or = 2 and single HD session Kt/V > or = 1.5). Simultaneous pancreas-kidney transplantation should be the first-choice therapeutic option in type 1 diabetes, while renal transplantation has been demonstrated to significantly improve the prognosis of type 2 diabetes patients with ESRF.
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PMID:[Guidelines for diagnosis and therapy of diabetic nephropathy]. 1466 6


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