Diabetic complications. Micro and macroangiopathic end-organ damage

Diabetes-associated sequelae lead to a considerable reduction in the quality of life and conspicuous increase in mortality. Subsequent damage becomes manifest in terms of macroangiopathy as coronary heart disease, peripheral arterial occlusive disease, and cerebrovascular insufficiency. Moreover, there is high risk of diabetic nephropathy, neuropathy, and retinopathy entailing the danger of developing chronic renal failure, loss of vision, or diabetic foot syndrome. Although chronic hyperglycemia constitutes a separate risk factor for macro- and microangiopathic complications, associated disorders such as arterial hypertension and hypercholesterinemia increase the mortality risk to a significant extent. Hence, in the past few years, new concepts have been developed for improving the diagnosis, therapy, and long-term care of people with diabetes to include diligent treatment of concomitant risk factors in addition to maintaining near-normal blood glucose levels. This optimized medical care can improve the quality of life and prognosis of patients with diabetes mellitus.     

SGLT2 inhibition to address the unmet needs in diabetic nephropathy

Current treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an “ideal” new drug should include primary prevention of microalbuminuria, additive/synergistic anti‐proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end‐stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium‐glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.     

Pathogenesis of diabetic nephropathy

As the increasing prevalence of diabetes reaches epidemic proportions worldwide, diabetic nephropathy and associated end‐stage renal failure will be an unavoidable major health burden to not only individuals with diabetes and their families, but also to the health systems both in developed and developing countries. Over the past decade, a large body of research has focused on diabetic nephropathy ranging from studies in molecular signaling, hemodynamic regulation and pharmaceutical intervention to clinical outcomes. It is likely that the pathophysiology of diabetic nephropathy involves a multifactorial interaction between metabolic and hemodynamic factors. Metabolic factors involve glucose‐dependent pathways, such as advanced glycation end‐products and their receptors. Hemodynamic factors include various vasoactive hormones, such as components of the renin–angiotensin system. It is likely that these metabolic and hemodynamic factors interact through shared molecular and signaling pathways, such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells and protein kinase C with associated reactive oxygen species generation. It is likely that these contributing factors cause pathological damage not only to the glomerulus, in particular podocytes, but also to the tubulointerstitium. Specific inhibitors of the various pathways are now available and these emerging pharmaceutical interventions might have potential implications for the prevention and treatment of diabetic nephropathy. The mainstay of therapy remains the achievement of optimal glycemic and blood pressure control in order to slow the progression of diabetic nephropathy. Agents that interrupt the renin–angiotensin system have been shown to be particularly useful as renoprotective agents in both hypertensive and normotensive type 1 and type 2 diabetic subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00131.x, 2011)     

The kidney in type 2 diabetes therapy

Renal and cardiovascular complications make type 2 diabetes one of the most morbid conditions in medicine. The kidney frequently gets involved in this "multi-organ disease". Of the large proportion of patients who progress with further loss of renal function, most prematurely die or end up in dialysis. Many interventions have targeted a decelerated progression of renal function loss, including metabolic control, blood pressure, and lipid management. Recently, modulation of the renin-angiotensin-aldosterone-system (RAAS) have been combined with the existing therapeutic armamentarium. RAAS inhibitors lower blood pressure and decrease albuminuria which leads to additionally protective renal and cardiovascular effects. Although this has been the success story of the last two decades, it has still made a relatively small contribution to patient welfare, since the residual risk in patients that received this optimal care remains extremely high. New treatment strategies are required that further slow the progression of renal and cardiovascular functions. Recently, several pathways have been investigated, targeting traditional risk factors such as blood pressure- and lipid-lowering strategies with unexpected results. Furthermore, novel targets and drugs have been identified. Preliminary studies on surrogate markers for renal outcome show a great potential for additive renal protection, such that in many cases hard endpoint trials are initiated. Novel interventions, which are reviewed here, include vitamin D receptor activators, RAASi with direct renin inhibitors or aldosterone antagonists, endothelin-antagonist, inflammation suppression with pentoxyfillin, MCP-1 synthesis inhibitors, or with Nrf2 agonists. Despite the current depressing situation of type 2 diabetic patients with nephropathy, new treatment options are under development to reduce the high morbidity and mortality associated with this universal ever-increasing disease threat.     

Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis

Aims/hypothesis  Glomerular hyperfiltration is a well-established phenomenon occurring early in some patients with type 1 diabetes. However, there is no consistent answer regarding whether hyperfiltration predicts later development of nephropathy. We performed a systematic review and meta-analysis of observational studies that compared the risk of developing diabetic nephropathy in patients with and without glomerular hyperfiltration and also explored the impact of baseline GFR. Methods  A systematic review and meta-analysis was carried out. Cohort studies in type 1 diabetic participants were included if they contained data on the development of incipient or overt nephropathy with baseline measurement of GFR and presence or absence of hyperfiltration. Results  We included ten cohort studies following 780 patients. After a study median follow-up of 11.2 years, 130 patients had developed nephropathy. Using a random effects model, the pooled odds of progression to a minimum of microalbuminuria in patients with hyperfiltration was 2.71 (95% CI 1.20–6.11) times that of patients with normofiltration. There was moderate heterogeneity (heterogeneity test p = 0.05, measure of degree of inconsistency = 48%) and some evidence of funnel plot asymmetry, possibly due to publication bias. The pooled weighted mean difference in baseline GFR was 13.8 ml min⁻¹ 1.73 m⁻² (95% CI 5.0–22.7) greater in the group progressing to nephropathy than in those not progressing (heterogeneity test p < 0.01). Conclusions/interpretation  In published studies, individuals with glomerular hyperfiltration were at increased risk of progression to diabetic nephropathy using study level data. Further larger studies are required to explore this relationship and the role of potential confounding variables.     

Risk markers for contrast-induced nephropathy

Radiological procedures requiring intravascular administration of iodinated contrast media are becoming a common source of an iatrogenic disease known as contrast-induced nephropathy (CIN). The treatment of established CIN is limited to supportive measures and dialysis. Therefore, identifying high-risk patients is the first step to minimize the overall risk of CIN. The purpose of this review is to describe classic and possible risk markers of CIN according to the ultimate clinical research and developments. Original publications, review articles, papers from our personal library, and guidelines on CIN were reviewed. Terms used for PubMed and Medline searches were as follows: "contrast-induced nephropathy," "radio-contrast nephropathy," "contrast nephropathy," "contrast medium-induced nephropathy," "contrast media," and "risk factors." No restriction was placed on date of publication. Preexisting renal failure, especially when secondary to diabetic nephropathy, is the most important risk marker for CIN.     

Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease?

Summary The high risk of cardiovascular disease in patients with diabetes mellitus, particularly in those with nephropathy, is not completely explained by classical risk factors. A high plasma homocysteine concentration is an independent risk factor for cardiovascular disease but information on its association with diabetes is limited. Fasting homocysteine concentrations were measured in the plasma of 165 diabetic patients (75 with insulin-dependent [IDDM]; 90 with non-insulin-dependent diabetes [NIDDM]) and 56 non-diabetic control subjects. Other measurements included the prevalence of diabetic complications, glycaemic control, lipid and lipoprotein levels, vitamin status and renal function tests. Patients with NIDDM had higher homocysteine levels than control subjects, whereas IDDM patients did not (9.2 ± 4.5 vs 7.7 ± 2 μmol/l, p < 0.01; and 7.0 ± 3 vs 7.4 ± 2 μmol/l, NS). Univariate correlations and multiple regression analysis showed albumin excretion rate to be the parameter with the strongest independent association with homocysteine. Patients with both types of diabetes and nephropathy had higher plasma homocysteine concentrations than those without nephropathy. Increases of homocysteine in plasma were related to increases in the severity of the nephropathy. Fasting hyperhomocysteinaemia was considered as the mean of the plasma homocysteine for all control subjects (7.5 ± 2.1 μmol/l) + 2 SD (cut-off =11.7 μmol/l). Nephropathy was present in 80 % of diabetic patients with fasting hyperhomocysteinaemia. In conclusion, increases in fasting homocysteine in diabetic patients are associated with increased albumin excretion rate, especially in those with NIDDM, thus providing a potential new link between microalbuminuria, diabetic nephropathy and cardiovascular disease. [Diabetologia (1998) 41: 684–693] Received: 4 August 1997 and in final revised form: 4 February 1998     

PPAR-γ agonists and diabetic nephropathy

Diabetic nephropathy is a clinical syndrome of albuminuria, declining glomerular filtration rate, and increased risk of cardiovascular disease. Multiple mechanisms have been implicated in its pathogenesis. Although current therapies appear to be effective, treatment of diabetic nephropathy remains suboptimal. This review summarizes the recently emerging evidence suggesting that peroxisome proliferator-activated receptor-γ agonists may prove to be effective therapeutic agents in the treatment of diabetic renal complications.     

Risk Factors Preceding Type 2 Diabetes and Cardiomyopathy

Type 2 diabetes (T2DM) and its complications such as cardiomyopathy, contribute significantly to morbidity and mortality worldwide. Increased adoption of westernized diets and decreased physical activity are contributing to the obesity epidemic which, in turn, increases the risk for T2DM. Other risk factors for T2DM include insulin resistance, dyslipidemia, hypertension, metabolic syndrome, and a genetic predisposition. Risk measures for assessing these factors include family history, blood pressure, body weight, waist circumference, fasting glucose, insulin, and lipid levels, and calculated indices such as BMI, HOMA, and QUIKI. Most of these risk measures routinely done in annual check-ups, should help a primary care physician in making an early diagnosis of impending diabetic condition. The underlying mechanisms of these clinical, anthropometric and biochemical risk measures may also be involved in the etiology of diabetes and its complications. Their levels and changes over time therefore, may indeed reflect the disease process. Early and continued assessment of diabetes risk, as part of patient care, will help identify individuals most likely to develop diabetes and allow for early interventions to reduce risk factors as well as delay or may even prevent disease onset. In T2DM patients, ongoing measurement of risk markers and implementation of intervention where appropriate will improve the diabetic condition, decrease risk of cardiovascular and other complications, and decrease morbidity.     

The pathogenesis of diabetic nephropathy

Between 20% and 40% of patients with diabetes ultimately develop diabetic nephropathy, which in the US is the most common cause of end-stage renal disease requiring dialysis. Diabetic nephropathy has several distinct phases of development and multiple mechanisms contribute to the development of the disease and its outcomes. This Review provides a summary of the latest published data dealing with these mechanisms; it focuses not only on candidate genes associated with susceptibility to diabetic nephropathy but also on alterations in various cytokines and their interaction with products of advanced glycation and oxidant stress. Additionally, the interactions between fibrotic and hemodynamic cytokines, such as transforming growth factor beta1 and angiotensin II, respectively, are discussed in the context of new information concerning nephropathy development. We touch on the expanding clinical data regarding markers of nephropathy, such as microalbuminuria, and put them into context; microalbuminuria reflects cardiovascular and not renal risk. If albuminuria levels continue to increase over time then nephropathy is present. Lastly, we look at advances being made to enable identification of genetically predisposed individuals.     

Albuminurie bei Diabetes mellitus

Diabetic nephropathy requires intensive treatment as it is the main reason for the morbidity and mortality resulting from diabetes mellitus. Patients with diabetic nephropathy have a significantly higher mortality rate due to cardiovascular events such as myocardial infarct or stroke. Microalbuminuria is the earliest clinical sign of diabetic renal disease and is also a marker for increased cardiovascular morbidity and mortality. Thus, its early detection allows not only for effective secondary prevention of the progression of diabetic nephropathy, but is also an indication for the implementation of an individually-tailored cardiovascular risk reduction management program. People with diabetes mellitus are high risk patients who need intensive monitoring and intensive supportive therapy.     

Combating diabetic nephropathy with drug therapy

Diabetes mellitus is the leading cause of end-stage renal disease and also increases the risk of atherosclerotic vascular disease. Hypertension amplifies both problems. Detection of microalbuminuria, a common and early manifestation of diabetic nephropathy and a marker for cardiovascular risk, permits early treatment to reduce progression of nephropathy and vascular disease in diabetes. Although optimal glycemic control is essential to reduce the risk of nephropathy, aggressive blood pressure lowering to a level of 130/80 mg Hg or below in hypertensive diabetic patients is as important as glycemic control. Initial drug therapy for nephropathy should include an angiotensin-converting enzyme inhibitor (or if contraindicated, an angiotensin receptor blocker), as several large randomized double-blinded multicenter clinical trials have demonstrated an independent renoprotective effect with renin angiotensin system inhibition. The role of advanced glycation end products in the pathogenesis of renal and vascular disease in diabetes is becoming more clearly established. However, the use of therapeutic strategies directed at blocking their effect still awaits further investigation. A multifaceted intervention program that combines optimal glycemic control, lifestyle modification/cardiovascular prevention guidelines such as lipid control and smoking cessation, with appropriate antihypertensive therapy when indicated, will prevent or delay both the occurrence and progression of diabetic nephropathy.     

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

The development of diabetic nephropathy in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus is still a huge clinical problem associated with increased morbidity and mortality. The mechanisms underlying the development of diabetic kidney disease are extremely complex and yet not completely understood. Among many potential pathogenic mechanisms responsible for the development of diabetic kidney disease, various growth factors have been suggested to be important players. In particular, growth hormone (GH)/insulin-like growth factors (IGFs), transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have measurable effects on the development of experimental diabetic kidney disease through complex intra-renal systems. Recent findings that these growth factors might initiate the early diabetic renal changes have provided insight into processes that might be relevant for future development of new drugs useful in the treatment of diabetic kidney disease. As will appear from the present review, enhanced understanding of the cellular mechanisms responsible for the development of diabetic kidney disease has already allowed the design of specific antagonists of pathophysiologically increased growth factors. Recent studies have shown that treating experimental diabetic models with such antagonists is followed by renoprotection. [Diabetologia (2000) 43: 1205–1223]     

A lethal tetrad in diabetes: hyperglycemia, dyslipidemia, oxidative stress, and endothelial dysfunction

This paper addresses the consequences of diabetes and obesity, diseases that have become epidemic in our society, particularly in the past 20 years. Specifically, it summarizes current knowledge about some of the risk factors and mechanisms for the vascular complications of diabetes. These complications can be broadly divided into microvascular disease, such as diabetic retinopathy and diabetic nephropathy, and macrovascular disease, such as accelerated atherosclerosis, and they are the main cause for morbidity and premature mortality among diabetic patients. The roles of hyperglycemia, dyslipidemia and dyslipoproteinemia, oxidative stress, and endothelial dysfunction will be considered. Finally, the "treatment gap" will be addressed. This gap refers to our failure to achieve currently accepted goals to reduce established risk factors for complications in the clinical management of diabetic patients.     

Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension

Summary Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes. [Diabetologia (1997) 40: 193–199] Received: 16 July 1996 and in revised form: 17 October 1996     

Slowing the progression of diabetic nephropathy and its cardiovascular consequences

This paper incorporates the findings from a multidisciplinary meeting on diabetic nephropathy and its renal and cardiovascular complications into a review article. The epidemic of obesity and the growing elderly population in the United States are primary drivers of a secondary epidemic of incipient type 2 diabetes mellitus and diabetic nephropathy. Current therapies aim to treat blood pressure, particularly with agents that block the renin-angiotensin system, to a target of 130/80 mm Hg. However, even lower blood pressure targets may be optimal. Control of hyperglycemia and dyslipidemia, smoking cessation, exercise, and weight loss all compliment blood pressure control and are achieved most effectively when the patient, provider, and health system are aligned with these goals. Once end-stage renal disease (ESRD) is reached, patients enter the highest cardiovascular risk-state appreciated in human medicine. Because of uniform access to care in the United States, advanced data systems, and circulatory system (intravascular) access in most patients, the ESRD population should be the future sampling frame for newer treatments tested in both prospective cohort and randomized trials. Cardiorenal risk, or the degree of excess cardiovascular risk incurred by patients with chronic kidney disease and ESRD, is a state offering considerable research opportunities for novel cardiovascular risk factors. Future studies should fully consider the possibility that improved outcomes would be achieved at a greater cost; thus, cost-effectiveness studies are essential for understanding the economic aspects of implementation. The goal of an ideal clinical trial would be ESRD prevention; however, pragmatic objectives such as a greater understanding of therapeutic toxicities should also be explored in this population.     

Sinusitis in the immunocompromised host

Sinusitis occurs in a wide range of immunocompromised hosts, including neutropenic patients, diabetic patients, patients in critical care units, and patients with HIV infection. Reversal of underlying risk factors, such as neutropenia or diabetic ketoacidosis, is essential in the treatment of fungal rhinosinusitis. Aggressive surveillance, high clinical suspicion, and early diagnosis and treatment are all critical aspects of sinusitis management. Sinusitis is increasingly recognized as the cause of occult cases of fever in critical care patients. Sinusitis in HIV-infected patients becomes more prevalent as immunosuppression worsens.     

饮食护理在糖尿病肾病行维持性血液透析患者中的临床探讨

目的探究分析在糖尿病肾病行维持性血液透析患者中做好饮食护理的临床护理效果。方法从2017年9月—2019年9月该院收治的糖尿病肾病行维持性血液透析患者中抽选108例,采用数字随机分配法将其分为两组,实验组55例,接受饮食护理联合常规护理;对照组53例仅接受常规护理。结果干预后,实验组ALB、BBC、Hb、TSF、AC、AMC等营养指标以及能量摄入情况和蛋白质摄入情况明显优于干预前,且明显优于对照组(P<0.05)。结论在糖尿病肾病行维持性血液透析患者中做好饮食护理能够加强患者营养的摄入,促进疾病治疗。