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Review on pathophysiology and treatment of diabetic kidney disease
Abstract
Diabetes is the leading cause of chronic kidney disease, which in the Thailand is the most common cause of end stage renal disease (ESRD) requiring dialysis. Patients with diabetic kidney disease (DKD) are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes. The development of DKD is determined by environmental and genetic factors. This review focuses on the latest published data dealing with mechanisms and treatment of DKD. DKD has several distinct phases of development of the disease and hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney disease. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage: nonenzymatic glycosylation that generates advanced glycosylation end products, activation of protein kinase C, and acceleration of the polyol pathway. Oxidative stress also seems to be a theme common pathway. These derangements, along with hemodynamic changes, activate various cytokines and growth factors such as vascular endothelial growth factor, transforming growth factor-beta2 Interleukin 1 (IL 1), IL-6 and IL-18. Current renoprotective treatments for DKD include optimization of glycemic, blood pressure, lipid and weight control blockade of the renin-angiotensin system, salt and protein restriction. Multiple intensive interventions reduce cardiovascular events as well as nephropathy by about half when compared with a conventional multifactorial treatment.
... Hemodynamic changes increase systemic and intra-glomerular pressure, thereby stimulating vasoactive hormone pathways, while metabolic changes contribute to mesangial cell expansion, mesangial cell apoptosis, and structural changes. These pathways converge ultimately, leading to inflammation, endothelial dysfunction, and fibrosis [8]. ...
... Oxidative stress is also contributed from hyperglycemiainduced AGEs production in the later stages of non-enzymatic glycation of sugar and protein, by the process called Maillard reaction [11]. Hyperglycemia-induced oxidative stress mediates DNA damage, lipid peroxidation, mitochondrial dysfunction, and infiltration of inflammatory cells, progressing to renal cell damage [8]. ...
The global burden of diabetic kidney disease (DKD) is escalating, and it remains as a predominant cause of the end-stage renal disease (ESRD). DKD is associated with increased cardiovascular disease and morbidity in all types of diabetes. Prediction of progression with albuminuria and eGFR is challenging in DKD, especially in non-proteinuric DKD patients. The pathogenesis of DKD is multifactorial characterized by injury to all components of the nephron, whereas albuminuria is an indicator of only glomerular injury. The limits in the diagnostic and prognostic value of urine albumin demonstrate the need for alternative and clinically significant early biomarkers, allowing more targeted and effective diabetic treatment, to reduce the burden of DKD and ESRD. Identification of biomarkers, based on multifactorial pathogenesis of DKD can be the crucial paradigm in the treatment algorithm of DKD patients. This review focuses on the potential biomarkers linked to DKD pathogenesis, particularly with the hope of broadening the diagnostic window to identify patients with different stages of DKD progression.
... However, the hallmark of established DN is persistent albuminuria, with coexisting retinopathy and no evidence of alternative kidney disease [87]. Practically, DN is a clinical syndrome in DM patients characterized by persistent albuminuria (>300 mg/day or >200 μg/min) at 2 out of 3 examinations within 3-6 months, a progressive decrease in GFR, and hypertension [90]. ...
... The rate of decline in renal function after DN varies between patients and is influenced by additional factors, including blood pressure and glycemic control [128]. Faster development can occur at heavier degrees of albuminuria and hypertension [90]. The presence of retinopathy is also a predictor of faster DN progression [13]. ...
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting A1c < 7%, and <130/80 mmHg. Regression of albuminuria remains an important therapeutic goal. However, there are problems in diagnosis and treatment of nonproteinuric DN (NP-DN), which does not follow the classic pattern of DN. In fact, the prevalence of DN continues to increase, and additional therapy is needed to prevent or ameliorate the condition. In addition to conventional therapies, vitamin D receptor activators, incretin-related drugs, and therapies that target inflammation may also be promising for the prevention of DN progression. This review focuses on the role of inflammation and oxidative stress in the pathogenesis of DN, approaches to diagnosis in classic and NP-DN, and current and emerging therapeutic interventions.
... The increased excretion of albumin, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking are some of the key risk factors that contribute to the development and progression of DN (5,6). The diagnosis of DN is made in the laboratory based on the presence of albuminuria over a prolonged period of time and a gradual decline in glomerular filtration rate (GFR) (7). However, albuminuria has a number of drawbacks, such as a high degree of variability and a low degree of sensitivity, and the level of albuminuria sometimes cannot correctly reflect the particular situation of DN (8). ...
Previous studies have found that the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) exerts its biological effects on the progression of diabetic nephropathy by sponging microRNAs and affecting the gene transcription of downstream molecules. In this study, the primary emphasis is placed on the functions that MALAT1 plays in relation to the pathophysiology of diabetic nephropathy as well as the processes that underlie these roles. In addition, the usage of this long noncoding RNA as a possible biomarker or therapeutic target for diabetic nephropathy will be discussed.
... (4) In the absence of active intervention, DN will progress to ESRD within 6~7 years. The decline rate of renal function varies among DN patients and is influenced by albuminuria, blood pressure, and BG [72,73]. The models in the 9 studies were all early DN models, 2~3 of which focused on the ability of PF to effectively reduce BUN and Scr and improve the renal function-related clinical indicators. ...
Background
Paeoniflorin (PF), the main active glucoside of Paeonia Lactiflora, has many pharmacological activities, such as inhibition of vasodilation, hypoglycemia, and immunomodulation. Although the current evidence has suggested the therapeutic effects of PF on diabetic nephropathy (DN), its potential mechanism of action is still unclear.
Purpose
A systematic review and meta-analysis of the existing literature on paeoniflorin treatment in DN animal models was performed to evaluate the efficacy and mechanism of PF in DN animal models.
Methods
The risk of bias in each study was judged using the CAMARADES 10-item quality checklist with the number of criteria met varying from 4 / 10 to 7 / 10, with an average of 5.44. From inception to July 2022, We searched eight databases. We used the Cochrane Collaboration’s 10-item checklist and RevMan 5.3 software to assess the risk of bias and analyze the data. Three-dimensional dose/time-effect analyses were conducted to examine the dosage/time-response relations between PF and DN.
Results
Nine animal studies were systematically reviewed to evaluate the effectiveness of PF in improving animal models of DN. Meta-analysis data and intergroup comparisons indicated that PF slowed the index of mesangial expansion and tubulointerstitial injury, 24-h urinary protein excretion rate, expression of anti-inflammatory mediators (mRNA of MCP-1, TNF-α, iNOS, and IL-1 β), and expression of immune downstream factors (P-IRAK1, TIRF, P-IRF3, MyD88, and NF-κBp-p65). Furthermore, modeling methods, animal species, treatment duration, thickness of tissue sections during the experiment, and experimental procedures were subjected to subgroup analyses.
Conclusion
The present study demonstrated that the reno-protective effects of PF were associated with its inhibition on macrophage infiltration, reduction of inflammatory mediators, and immunomodulatory effects. In conclusion, PF can effectively slow down the progression of DN and hold promise as a protective drug for the treatment of DN. Due to the low bioavailability of PF, further studies on renal histology in animals are urgently needed. We therefore recommend an active exploration of the dose and therapeutic time frame of PF in the clinic and in animals. Moreover, it is suggested to actively explore methods to improve the bioavailability of PF to expand the application of PF in the clinic.
... DKD was previously known as diabetic nephropathy (DN) and is defined as elevated urine albumin excretion, decreased glomerular filtration rate (GFR), or both [17]. The clinical phase of DKD is generally divided into five stages in most guidelines characterized initially by GFR and albuminuria based on the classification and staging of chronic kidney disease (CKD) [18,19]. Morphologically, the thickening of the glomerular basement membrane, the expansion of the mesangium, glomerulosclerosis, and podocyte injury are typically revealed in kidney biopsies [20][21][22]. ...
Vitamin D is a hormone involved in many physiological processes. Its active form, 1,25(OH)2D3, modulates serum calcium–phosphate homeostasis and skeletal homeostasis. A growing body of evidence has demonstrated the renoprotective effects of vitamin D. Vitamin D modulates endothelial function, is associated with podocyte preservation, regulates the renin–angiotensin–aldosterone system, and has anti-inflammatory effects. Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide. There are numerous studies supporting vitamin D as a renoprotector, potentially delaying the onset of DKD. This review summarizes the findings of current research on vitamin D and its role in DKD.
... или >200 мкг/мин.) в двух из трёх определений в течение 3-6 месяцев, прогрессирующее снижение скорости клубочковой фильтрации (Скф) и артериальная гипертония [36]. распространённость диабетической нефропатии в зависимости от стадии составляет 29-61%, согласно результатам рандомизированного клинического исследования (рки) ukpDs (united kingdom prospective Diabetes study) 64 [37]. ...
The review presents the prevalence of both type 2 diabetes mellitus (type 2 DM) and its microvascular complications among patients with coronary heart disease (CHD), and CHD among patients with carbohydrate metabolism disorders. It is shown, that the prognosis of patients with CHD and type 2 DM, especially in the presence of microvascular complications, is extremely unfavorable, and is characterized by a significant increase in the risk of cardiovascular death, myocardial infarction, stroke, terminal stage of the chronic kidney disease and visual impairment. It was noted, that despite the successes achieved in the treatment of CHD, type 2 DM and its microvascular complications, there is a high risk of total, cardiovascular mortality and hospitalizations associated with cardiovascular diseases. In type 2 DM, especially in the presence of microvascular complications and comorbid pathology, special pathogenetic mechanisms of thrombotic risk and bleeding have been identified. Based on large randomized clinical trials, the review evaluated the efficacy and safety of various antithrombotic strategies in patients with stable СРВ, type 2 DM in the presence of microvascular complications and comorbid pathology.
... Inoltre, è noto come l'IRC peggiori notevolmente gli outcome dei pazienti con DM: sia il DM che l'IRC sono considerati tra i principali fattori di rischio CV. La definizione classica di DKD prevede che in un soggetto con diabete di tipo 1 o di tipo 2 sia presente un'albuminuria persistente (>300 mg/24 h o ACR >300 mg/g), confermata in almeno due determinazioni e/o riduzione del GFR (<60 ml/min), frequentemente associata a retinopatia diabetica, in assenza di segni di altre forme di malattia renale 34 . La DKD si sviluppa con una latenza molto variabile, ma la sua prevalenza aumenta con l'aumentare della durata del DM. ...
Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.
... (4) In the absence of active intervention, DN will progress to ESRD within 6~7 years. The decline rate of renal function varies among DN patients and is influenced by albuminuria, blood pressure, and BG [72,73]. The models in the 9 studies were all early DN models, 2~3 of which focused on the ability of PF to effectively reduce BUN and Scr and improve the renal function-related clinical indicators. ...
... Diabetes mellitus is a multi-systemic metabolic disorder affecting body organs such as kidney, testis, liver, heart, eyes and the brain to a varying degree depending on the severity and chronicity of the persistent hyperglycemia (Fowler, 2008;Satirapoj, 2010;Forouhi and Wareham, 2019). ...
Diabetes Mellitus (DM) is a leading pan-systemic endocrine disorder with attendant high morbidity and mortality owing to its deleterious effects on vital body organs caused by untreated chronic hyperglycemia, attendant oxidative stress and glycation processes. The present study is designed to investigate possible protective role and mechanism(s) of action 125-500 mg/kg/day of Morinda lucida aqueous stem bark extract (MLASE) on renal and hepatic functions in alloxan-induced hyperglycemic rats for 8 days. Forty-two alloxan-induced hyperglycemiic male Wistar rats were randomly allotted to Groups II-VI and orally treated with 10 ml/kg/day distilled water, 5 mg/kg/day glibenclamide, 125 mg/kg MLASE, 250 mg/kg MLASE, and 500 mg/kg/day MLASE, respectively. Group I normal rats served as untreated control and were orally treated with 10 ml/kg of distilled water, all under same sham-handling. Blood samples were taken for measurement of fasting blood glucose, renal and hepatic function profile. Liver and kidney tissue samples were taken for determination of the activities of oxidative stress markers such as malondialdehyde (MDA), reduced glutathione (GSH), and glutathione peroxidase (GPx), catalase (CAT) and superoxidase dismutase (SOD). Results showed that intraperitoneal injection with 120 mg/kg of alloxan in cold 0.9% normal saline reliably and significantly induced a steadily sustained hyperglycemia which were ameliorated by short-term oral treatment with 125-500 mg/kg/day of MLASE, dose dependently, similar to that ameliorated by the standard antihyperglycemic drug, glibenclamide. Similarly, MLASE significantly mitigated against derangements in the measured renal and hepatic function parameters as well as oxidative stress induced by alloxan-induced hyperglycemia. In conclusion, results of this study showed the protective role of 125-500 mg/kg/day of MLASE in chronic hyperglycemia-associated renal and hepatic dysfunctions which was mediated via antioxidant and free radical scavenging activities of MLASE.
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p=0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1–83.6%], p=0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1–26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [−18.6–0.4%] per year in the captopril-treated group (p=0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (−6.4 [−10.2–−2.5] vs −1.4 [−5.3–2.6] ml · min−1 · 1.73 m−2, p=0.07). Baseline albumin excretion rate (p<0.0001) and glycated haemoglobin (p=0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p=0.02) and serum cholesterol level (p=0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.
The Diabetes Control and Complications Trial has demonstrated that intensive diabetes treatment delays the onset and slows the progression of diabetic complications in subjects with insulin-dependent diabetes mellitus from 13 to 39 years of age. We examined whether the effects of such treatment also occurred in the subset of young diabetic subjects (13 to 17 years of age at entry) in the Diabetes Control and Complications Trial. One hundred twenty-five adolescent subjects with insulin-dependent diabetes mellitus but with no retinopathy at baseline (primary prevention cohort) and 70 adolescent subjects with mild retinopathy (secondary intervention cohort) were randomly assigned to receive either (1) intensive therapy with an external insulin pump or at least three daily insulin injections, together with frequent daily blood-glucose monitoring, or (2) conventional therapy with one or two daily insulin injections and once-daily monitoring. Subjects were followed for a mean of 7.4 years (4 to 9 years). In the primary prevention cohort, intensive therapy decreased the risk of having retinopathy by 53% (95% confidence interval: 1% to 78%; p = 0.048) in comparison with conventional therapy. In the secondary intervention cohort, intensive therapy decreased the risk of retinopathy progression by 70% (95% confidence interval: 25% to 88%; p = 0.010) and the occurrence of microalbuminuria by 55% (95% confidence interval: 3% to 79%; p = 0.042). Motor and sensory nerve conduction velocities were faster in intensively treated subjects. The major adverse event with intensive therapy was a nearly threefold increase of severe hypoglycemia. We conclude that intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy and nephropathy when initiated in adolescent subjects; the benefits outweigh the increased risk of hypoglycemia that accompanies such treatment. (J PEDIATR 1994;125:177-88)
