Diabetic Renal Impairment Research Articles

Diagnostic value of α1-MG and URBP in early diabetic renal impairment.

Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30mg/g and eGFR≥90mL/min/1.73m2, n = 63) and DKD group (UACR>30mg/g or eGFR<90mL/min/1.73m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90mL/min/1.73m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.

Urine trace element disorder along with renal function injury in vitamin D deficient diabetic rats and intervention effect of 1α,25-dihydroxyvitamin D3.

Trace element metabolism disorders are often secondary to disorders of glucose metabolism in diabetes. Although 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] could ameliorate abnormal glucose metabolism in the development of diabetes, the effect on trace element metabolism is unclear. The objective of this study was to evaluate the influence of 1,25(OH)2D3 on urinary excretions of trace elements in Zucker diabetic fatty (ZDF) rats. At 6 weeks of age, male ZDF (n = 40) rats were subdivided into four groups: diabetic model (ZDF), low-dose (ZDF + VL, 2 μg/kg⋅bw), middle-dose (ZDF + VM, 8 μg/kg⋅bw) and high-dose (ZDF + VH, 16 μg/kg⋅bw) 1,25(OH)2D3 groups. Another 10 Zucker lean (ZL) rats served as a control group. All rats were given vitamin D deficient Purina #5008 chow and the intervention groups were given the corresponding dose of 1,25(OH)2D3 by gavage on alternate days for 7 weeks. Microalbuminuria (MALB) and urinary creatinine concentration were detected by a biochemical autoanalyzer. Urine trace element concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and were corrected by urinary creatinine. Throughout the intervention phase, MALB, UACR and urinary creatinine levels in the ZDF group were significantly higher than those in the ZL group, and showed a gradual increase with the prolongation of the intervention time. These changes were reversed in a dose-dependent manner after 1,25(OH)2D3 intervention (P < 0.05). Correspondingly, most of the urinary trace element excretions in the ZDF rats were significantly increased compared with the ZL group, and 1,25(OH)2D3 intervention significantly reduced the urinary copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo) levels in the ZDF rats (P < 0.05), especially in the medium and high dose groups. 1,25(OH)2D3 had improvement effects on urinary Cu, Zn, Se, and Mo excretions in ZDF rats, suggesting that it may be related to the reduction of diabetic renal impairment and renal oxidative damage.

Diagnostic potential of soluble TNF alpha receptor 1 in diabetic and hypertensive patients with renal impairment and UTI.

Background: Chronic kidney disease is one of the most common diseases. Health care workers in all countries of the world are concerned with the early detection and prevention of kidney diseases. Several novel diagnostic markers are being under investigation nowadays. Tumor necrosis factor-alpha and its receptors are examples.&#x0D; Aim: The present study was conducted to evaluate the role of tumor necrosis factor α receptor 1 (TNFR1) as a biomarker for detection of renal dysfunction.&#x0D; Materials and Methods: The study was carried out for the period from February to June 2019 and included 180 patients (their ages were between 19 and 85 years old) and were divided into 60 patients with renal impairment, 60 hemodialysis patients, and 60 patients with normal renal function (as a control group). Each group included patients with hypertension, patients with diabetes mellitus, and hypertensive- diabetic patients.&#x0D; The patients were attended to Center of Kidney Disease and Transplantation, Dialysis Unit of Baghdad Teaching Hospital – Medical City , Dialysis Unit of Tikrit Teaching Hospital and private laboratory in Samarra City.&#x0D; Urine sample was collected from each patient for bacteriological study and detection the level of TNFR1.&#x0D; Results: The most common pathogen isolated from cultured samples was Escherichia coli. Concentration of urinary TNFR1 in hypertensive and or diabetic with normal kidney function compared with hypertensive or and diabetic renal impairment did not differ statistically significant. Conclusion: Urinary level of tumor necrosis factor receptor 1 (TNFR1) is not important in the diagnosis of renal impairment with the presence of hypertension and or diabetes mellitus. Through statistical comparisons of patients with urinary tract infection (UTI) group and those without UTI group , it seems that UTI does not affect the diagnostic ability of urinary TNFR1. We recommend future studies focusing on serum level of the receptors mentioned above to test their diagnostic potential in renal impairment. In addition, investigating the effect of the immunological causes of renal impairment on the level of TNFR, both in urine and serum.

Predictors of Renal Function Decline in Chinese Patients with Type 2 Diabetes Mellitus and in a Subgroup of Normoalbuminuria: A Retrospective Cohort Study.

Risk factors related to renal function decline in type 2 diabetes mellitus (T2DM) remain uncertain. This study aimed to investigate risk factors in relation to renal function decline in patients with T2DM and in a subgroup of patients with normoalbuminuria. This study was a retrospective cohort study, which included 451 patients with T2DM aged 63 ± 14 years admitted to a tertiary hospital in Beijing, China, between April and December 2010 and followed up for 6-60 months. Endpoint was renal function decline, defined as estimated glomerular filtration rate less than 60 mL/min 1.73 m2 or at least twofold increase of serum creatinine. Cox proportional hazards analysis was used to estimate hazard ratios (HRs) for candidate risk factors of renal function decline. After a median follow-up of 3.3 years, 94 (20.8%) patients developed renal function decline. Increased age (HR, 1.045; 95% CI, 1.020-1.070), albuminuria (HR, 1.956; 95%CI, 1.271-3.011), mild renal dysfunction (HR, 4.521; 95%CI, 2.734-7.476), hyperfiltration (HR, 3.897; 95%CI, 1.572-9.663), and increased hemoglobin A1c (HR, 1.128; 95%CI, 1.020-1.249) were identified as major risk factors. Among a subgroup of 344 patients with normoalbuminuria at baseline, 53 (15.4%) patients developed renal function decline. Increased age (HR, 1.089; 95%CI, 1.050-1.129), mild renal dysfunction (HR, 4.667; 95%CI, 2.391-9.107), hyperfiltration (HR, 5.677; 95%CI, 1.544-20.872), smoking (HR, 2.886; 95%CI, 1.370-6.082), higher pulse pressure (HR, 1.022; 95%CI, 1.004-1.040), and increased fasting glucose (HR, 1.104; 95%CI, 1.020-1.194) were major risk factors. Risk factors of diabetic renal impairment in T2DM should be screened and evaluated at an early stage of diabetes. Albuminuria, mild renal dysfunction, hyperfiltration, increased blood glucose, increased pulse pressure, and smoking were all predictors for diabetic renal impairment and interventions that focus on these risk factors may reduce further decline in renal function.

Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-β1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events

Context: Naringenin, a flavonone and a nutritive antioxidant which is mostly obtained from grapefruit, orange or tomato skin, has been extensively studied due to its radical scavenging activity.Objective: The present study investigates the protective effect of naringenin on rat kidney after streptozotocin-induced diabetes.Materials and methods: Sixty male Wistar rats were divided into six groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg) in groups II, III and IV. Naringenin 5 mg/kg body weight was given to groups III and V, but 10 mg/kg was given to groups IV and VI, orally once a day for 10 weeks. After which all animals were sacrificed, and the biochemical, histopathological, immunohistochemical and apoptotic assays were conducted.Results: Naringenin treatment with 5 and 10 mg/kg significantly decreased (p < 0.05) the serum biochemical parameters, elevated tissue malondialdehyde levels and increased (p < 0.01) the reduced superoxide dismutase, catalase and reduced glutathione enzyme activities in the diabetic kidney. Diabetes-induced naringenin-treated groups showed an improved histology and revealed a significant reduction in apoptosis activity (7.2 ± 0.01 and 1.8 ± 0.05) and in expression of TGF-β1 (18.9 ± 3.4 and 10.2 ± 2.1) at a dose of 5 and 10 mg/kg, respectively. Similarly, in contrast to the diabetic group, a significant difference was observed in the IL-1 expression (15.68 ± 4.3) in 5 mg/kg and (9.85 ± 2.1) in 10 mg/kg naringenin-treated groups.Conclusion: Naringenin acts as a protective agent in diabetic renal impairment by altering oxidative stress, modulation of cytokines expression and apoptotic events.

Chronic renal impairment and DDAH2-1151 A/C polymorphism determine ADMA levels in type 2 diabetic subjects

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased levels of ADMA cause impaired vasodilation, leading to endothelial dysfunction and a higher risk for cardiovascular events. In patients with a chronic kidney disease, increased ADMA levels are reported to play a role in the pathogenesis of accelerated atherosclerosis and are an independent risk marker leading to end-stage renal disease and mortality. Circulating ADMA is metabolized by the action of dimethylarginine dimethylamino hydrolase (DDAH) and DDAH2 isoform is the most prevalent in tissues expressing endothelial NOS. DDAH and NOS are co-expressed in the same kidney regional sites supporting the hypothesis that a strict and specific regulation of intracellular ADMA levels is crucial for NO generation in the kidney. Starting from these findings, the study aims to investigate the role of DDAH2 gene promoter polymorphism at position -1151 A/C in determining the levels of ADMA in type 2 diabetic patients (T2DM) with chronic renal impairment. Three groups of carefully selected subjects of both sexes were enrolled and compared. The first group (control subjects) comprised 286 non-diabetic subjects (mean age 55.8 ± 11.4 years), the second group (T2DM uncomplicated subjects) was made up of 322 T2DM subjects without complications (mean age 64.9 ± 9.6 years) whereas the third group (T2DM CRF subjects) included 110 T2DM patients with chronic renal impairment. The rs805304 DDAH2-1151 A/C promoter polymorphism was determined by a polymerase chain reaction-restriction fragment length polymorphism approach. Results T2DM CRF subjects showed significant increased plasma levels of ADMA with respect to those of T2DM uncomplicated subjects and control subjects (0.51 versus 0.39 versus 0.37 μmol/L, P = 0.002, respectively). Analysis of variance showed an interaction between DDAH2-1151 C carrier and groups on ADMA plasma levels (F = 4.36; P < 0.05). ADMA plasma levels were also dependent on groups (F = 4.96; P < 0.01). Our work demonstrates that rs805304 DDAH2-1151 polymorphism plays a central role in determining ADMA in diabetic renal impairment, where patients with DDAH2-1151 C carriers showed the highest ADMA levels. This unfavourable genetic profile is highlighted by pathological kidney conditions such as diabetic CRF. These findings could open new insights on the pathways involving ADMA/DDAH/NOS in the development and progression of chronic renal impairment and therefore of the other micro- macrovascular diabetic complications.

Exenatide may aggravate moderate diabetic renal impairment: a case report

We write in response to a recently published paper in this journal [1] in which mainly nondiabetic patients with renal impairment, without polypharmacy, were evaluated using exenatide. The study concluded that subjects with mild to moderate renal impairment were able to tolerate the drug. However, whether this is the case for patients with Type 2 diabetes remains uncertain, and we present a case that highlights potential problems. Exenatide 5 µg b.i.d. was given to one male patient (66 years, body mass index 35.1 kg m−2) with Type 2 diabetes since 1992, who in 1995 was diagnosed with microalbuminuria. By 1998 he had developed macroalbuminuria, in 2000 his creatinine levels exceeded upper limits of normal and in 2004 he had developed renal impairment-related anaemia and metabolic bone disease. Other complications were proliferative retinopathy (diagnosed 1995), peripheral sensory neuropathy (since 1996) and gout (since 2007). Concomitant medications were losartan potassium 25 mg q.d., furosemide 40 mg b.i.d., spirinolactone 50 mg q.d., alfacalcidol 0.25 µg 3 days week–1, darbepoetin alfa 20 µg month–1, allopurinol 100 mg q.d., biphasic insulin aspart 30 b.i.d. [40–42 units (U) breakfast, 60–66 U dinner] and insulin aspart q.d. (10 U lunch). Due to non-optimal glycaemic control the patient was given exenatide (February 2008) after careful explanation that this was considered off-label use, since he was taking insulin. In the following 4 weeks the patient's creatinine levels rose (192 to 244 µmol l−1) and, correspondingly, the Cockroft–Gault [2] creatinine clearance (CrCL) was reduced (53.1 to 41.8 mg min−1, Figure 1). Reductions were also seen in HbA1c, fasting plasma glucose (respectively 7.6 to 6.8% and 7.2 to 5.1 mmol l−1) and total daily insulin dosages (by 40%). The worsening of renal impairment was not related to urinary tract infection, obstruction or dehydration, although he experienced some nausea and diarrhoea. Hence, exenatide was stopped, and within the next 2 weeks his kidney function parameters returned to pretreatment levels (creatinine 196 µmol l−1, CrCL 52.1 mg min−1). Serum creatinine levels and estimated CrCL the first year before treatment, during the 4 weeks' treatment period and the 2-week period following after exenatide 5 µg b.i.d. was discontinued (medium dashed arrow). Right y-axis indicates creatinine levels (solid curve) and the right axis the CrCL (dotted curve). CrCL, creatinine clearance In contrast with the previous report [1], we suggest that exenatide might not be well tolerated in patients with Type 2 diabetes with mild to moderate renal impairment, although it apparently seems safe in subjects without diabetes. One explanation could be that patients with Type 2 diabetes, compared with subjects without, at similar elevated creatinine levels metabolically tolerate the renal impairment poorer, hence should cautiously receive substances with primary renal elimination. This has been underscored, for example, in a study reporting level of renal function at the initiation of dialysis [3], where patients with end-stage renal disease (ESRD) caused by diabetes required this earlier than patients with ESRD due to other causes. Another possibility is that the polypharmacy associated with Type 2 diabetes, added to the above, could lead to unexpected drug–drug interactions further impairing renal function, perhaps particularly relevant for compounds affecting the renin–angiotensin system. A third, perhaps less likely explanation is that the combination of exenatide with insulin may aggravate the kidney function. Although this combination currently is not approved [4], such a combination is in fact being used in clinical practice, e.g. as reported in one retrospective analysis reporting weight loss and reductions in HbA1c[5]. Interestingly, exenatide has even been reported being used in patients with Type 1 diabetes [6]. We suggest that it is imperative to explore further the impact of exenatide in patients with Type 2 diabetes and renal impairment. Until proven safe, exenatide should be used cautiously in this patient group, especially with polypharmacy. O.E.J. has received travel grants, speaking fees, support for research and/or fees for consulting services from Novo Nordisk, Eli Lilly, GlaxoSmithKline, Sanofi Aventis, Pfizer, Takeda and Astra Zeneca, and was an employee of Novo Nordisk in 2006/2007.

Effects of benidipine, a calcium antagonist, on urinary kallikrein excretion and renal impairment in experimental diabetes

To assess the long-term effects of different antihypertensive agents on urinary protein excretion and kallikrein excretion in diabetic rats with renal impairment. Uninephrectomized streptozotocin diabetic Wistar-Kyoto rats were randomly assigned to receive vehicle, a calcium antagonist (benidipine) or an angiotensin converting enzyme inhibitor (captopril) for up to 12 weeks. Active kallikrein was determined by its kininogenase activity, and generated kinins were measured by radioimmunoassay. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin. Urinary protein excretion increased significantly in diabetic rats compared with non-diabetic rats. Urinary active kallikrein excretion was significantly reduced in diabetic rats, whereas urinary total kallikrein excretion was unchanged, resulting in a reduced percentage of active to total kallikrein compared with that in non-diabetic rats. Benidipine and captopril reduced blood pressure and attenuated the development of diabetic renal impairment in a similar manner. However, only benidipine attenuated the decreases in urinary active kallikrein excretion and the ratio of active to total kallikrein in diabetic rats. Although pathophysiological relevance of impaired urinary kallikrein activation to the development of diabetic renal impairment remains to be determined, our result might suggest a new mechanism by which calcium antagonists protect the kidney from diabetic renal impairment.

Antihypertensive and renal-protective effects of losartan in streptozotocin diabetic rats

To assess the renal benefits of a specific angiotensin II receptor antagonist, losartan, in diabetic rats with renal impairment. Uninephrectomized streptozotocin diabetic spontaneously hypertensive rats (SHR) were randomly assigned to receive vehicle, or to receive losartan or captopril, or both, intraperitoneally via osmotic minipumps for 8 weeks. Blood pressure and urinary protein excretion in the diabetic SHR increased progressively during the experimental period. Both captopril treatment and losartan treatment completely blocked the development of hypertension in diabetic SHR. Simultaneous administration of captopril and losartan did not enhance the antihypertensive effects of losartan treatment or captopril treatment. Furthermore, losartan treatment, captopril treatment and losartan + captopril treatment all significantly decreased urinary protein excretion, urinary albumin excretion and serum creatinine to the same extent. These effects were sustained for the entire experimental period and were not associated with any significant changes in body weight, urine volume, urine sugar and urinary electrolytes excretion. These results were confirmed by morphological analysis of kidneys in each group of rats. Losartan treatment, captopril treatment and losartan+captopril treatment all significantly and effectively protected against an increase in the percentage of focal glomerular sclerosis. Losartan treatment and captopril treatment both significantly attenuated the increase in heart weight: body weight ratio. The heart weight: body weight ratio in the losartan-treated group was significantly lower than in the captopril-treated group. These results indicate that hypertension could accelerate diabetic renal impairment and that losartan has antihypertensive and renoprotective effects in this rat model. They also suggest that the antihypertensive and renoprotective effects of captopril treatment in this rat model are caused mainly by inhibition of angiotensin II production rather than stimulation of the kallikrein-kinin system or of vasodilator prostaglandins. The difference in potency between losartan treatment and captopril treatment to attenuate the increase in heart weight: body weight ratio might partly explain the existence in the heart of angiotensin-forming pathways, which are not dependent on angiotensin converting enzyme.