Advanced Diabetic Kidney Disease Research Articles

The role of endothelial biomarkers in predicting damp-heat syndrome in diabetic kidney disease

To explore the role of endothelial biomarkers in predicting damp-heat syndrome in diabetic kidney disease (DKD). A total of 183 patients with DKD were divided into 3 groups: the early DKD group, established DKD group, and advanced DKD group. All patients were classified according to traditional Chinese medicine (TCM) syndrome type, and clinical indexes were collected for statistical analysis. A total of 183 DKD patients were included in this study. Fibroblast growth factor 23 (FGF23), chitinase-3-like protein 1 (CHI3L1), endocan, tumor necrosis factor receptor 1 (TNFR1), secretory leukocyte protease inhibitor (SLPI), and vascular endothelial growth factor A (VEGF-A) were increased in advanced DKD. FGF23, CHI3L1, endocan, SLPI, and TNFR1 showed a negative correlation with estimated glomerular filtration rate (eGFR), while they had a positive correlation with 24 h urine protein. After adjusting for age, gender, diabetes duration, body mass index (BMI), hemoglobin, glucose, uric acid, 24 h urine protein, cholesterol, triglyceride, low-density lipoprotein, and hemoglobin A1c (HbA1c), the multiple regression analysis showed that FGF23, endocan, TNFR1, and SLPI significantly correlated with eGFR. FGF23, endocan, TNFR1, and SLPI are elevated in advanced DKD compared with early stage, and they may take part in the pathogenesis and progression of DKD. Our study provides useful biomarkers for predicting the appearance of damp-heat syndrome, including FGF23, endocan, TNFR1, and SLPI.

Insulin Resistance in Early and Advanced Diabetic Kidney Disease

Background: Insulin resistance (IR) is commonly seen in diabetic kidney disease (DKD) and could contribute to the progression of renal disease and cardiovascular risk. In this study, we aim to measure homeostasis model assessment IR (HOMA-IR) in DKD and see the effect of advancing kidney disease on HOMA IR. Material and Methods: We recruited 120 subjects with type 2 diabetes mellitus and divided them into people without kidney disease (controls; n = 20), early DKD (n = 40), and advanced DKD (n = 60). Biochemical tests including fasting plasma glucose and fasting serum C-peptide were done in 120 subjects. IR was calculated by the HOMA model in 109 subjects. Data were presented as median (interquartile range [IQR]). Univariable and multivariable analysis was done. Results: Median of HOMA-IR in the control group was 2.0 (IQR: 1.5–2.8; n = 20), early DKD group was 2.3 (1.8–2.9; n = 37), and advanced DKD group was 3.67 (1.6–3.9; n = 52). P = 0.03 indicated a significant increase in the HOMA IR with advancing kidney disease. Conclusion: In patients with DKD, with advancing kidney disease, there was a significant increase in the HOMA IR, a marker of IR. IR is a modifiable metabolic risk factor, and if it is managed by novel therapeutic ways, it might improve clinical outcomes in DKD.

FcER1: A Novel Molecule Implicated in the Progression of Human Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a key microvascular complication of diabetes, with few therapies for targeting renal disease pathogenesis and progression. We performed transcriptional and protein studies on 103 unique blood and kidney tissue samples from patients with and without diabetes to understand the pathophysiology of DKD injury and its progression. The study was based on the use of 3 unique patient cohorts: peripheral blood mononuclear cell (PBMC) transcriptional studies were conducted on 30 patients with DKD with advancing kidney injury; Gene Expression Omnibus (GEO) data was downloaded, containing transcriptional measures from 51 microdissected glomerulous from patients with DKD. Additionally, 12 independent kidney tissue sections from patients with or without DKD were used for validation of target genes in diabetic kidney injury by kidney tissue immunohistochemistry and immunofluorescence. PBMC DKD transcriptional analysis, identified 853 genes (p < 0.05) with increasing expression with progression of albuminuria and kidney injury in patients with diabetes. GEO data was downloaded, normalized, and analyzed for significantly changed genes. Of the 325 significantly up regulated genes in DKD glomerulous (p < 0.05), 28 overlapped in PBMC and diabetic kidney, with perturbed FcER1 signaling as a significantly enriched canonical pathway. FcER1 was validated to be significantly increased in advanced DKD, where it was also seen to be specifically co-expressed in the kidney biopsy with tissue mast cells. In conclusion, we demonstrate how leveraging public and private human transcriptional datasets can discover and validate innate immunity and inflammation as key mechanistic pathways in DKD progression, and uncover FcER1 as a putative new DKD target for rational drug design.

S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease.

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

Could serum zonulin be an intestinal permeability marker in diabetes kidney disease?

Zonulin is a protein associated with the tight junction complex opening at the intestinal epithelium, previously linked to obesity, cardiovascular diseases, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, its role in CKD has not been totally elucidated. This study aimed to evaluate zonulin levels in subjects with diabetic kidney disease (DKD). This case-control study included two cases groups: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2; 2) Albuminuric T2DM cases: diabetic patients with urinary albumin excretion (UAE) >30mg/g creatinine, but with eGFR>60ml/min/1.73m2. Two control groups were also included: 1) T2DM controls: patients with T2DM without impaired kidney function; 2) Non-T2DM controls: subjects without T2DM and normal renal function. Serum levels of zonulin were measured by ELISA. Eighty-six individuals were included. Zonulin levels was different among study groups (P = 0.003). T2DM controls presented higher zonulin levels than non-T2DM controls [(131.35 (83.0–170.5) vs. 87.25 (54.7–111.8), P = 0.018] and advanced DKD cases [63.72 (45.03–106.0); P = 0.007]. Zonulin showed a positive correlation with eGFR (r = 0.222; P = 0.040), total cholesterol (r = 0.299; P = 0.034), LDL (r = 0.258; P = 0.021), and negative with albuminuria (r = -0.243; P = 0.024) and body fat (r = -0.271; P = 0.014). In the multivariate logistic regression analyses, zonulin levels were independently associated to renal outcomes [OR 0.99 (0.98–0.99, P = 0.012)] after 5-year inclusion. In conclusion, increased zonulin levels in patients with TD2M without renal disease suggest an impaired intestinal permeability. Moreover, its association with renal outcomes could indicate its use as a disease monitoring marker. However, the mechanisms behind this association should be better understood.

MO580HYPOPROTEIC DIET SUPPLEMENTED WITH KETOANALOGUES IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE – EFFECTS ON MINERAL BONE DISORDERS

Abstract Background and Aims Dietary protein restriction is rediscussed as mainstay approach in advanced Chronic Kidney Disease (CKD), both in diabetics and non-diabetics to defer renal replacement therapy (RRT), mainly by better metabolic control; improvements in mineral bone disorders (MBD) were also suggested, but less studied in Diabetic Kidney Disease (DKD). An unicentric prospective interventional trial aimed to assess the effects of ketoanalogue-supplemented low protein diet (sLPD) on proteinuria and CKD progression (data already presented). The parameters of MBD were also evaluated. Method Adult diabetic patients (452) with stable CKD stage 4+, proteinuria&amp;gt;3g/g creatininuria and SGA A were enrolled in a run-in phase (3 mo), with LPD (0.6g/kg dry ideal bw). Those who proved adherent (92, 64% males, median age 55.7 yrs, 65% on insulin) received sLPD (Ketosteril®, 1 tablet/10kg) for 12mo. Monitoring and treatment followed the Best Practice Guidelines. The primary endpoint was proteinuria during intervention as compared to pre-enrolment. Serum levels of calcium, phosphates and iPTH were considered to assess MBD. Nutrition, inflammation (SGA, BMI, serum albumin, CRP) and compliance were safety parameters. Results In patients with advanced DKD and severe proteinuria, sLPD was associated with a 69 (63; 82) % reduction in proteinuria (data presented). Significant amelioration in MBD was noted: serum levels of calcium and phosphates were significantly ameliorated at the end of the study as compared to enrolment - 4.3 (4.2-4.9) vs 3.2 (3.1-3.5) mg/dL and 5.4 (4.9-6.1) vs 8.2 (7.8-8.9) mg/dL, respectively. Serum iPTH significantly decreased: 185 (168-212) vs 375 (354-585) pg/mL. The need for calcium supplementation decreased: 6.5 (6.0-6.7) vs 7.0 (6.8-7.3) g/day. Vitamin D was required by only 35% vs 65% of patients. Nutritional status was preserved and dietary compliance was very good throughout the study. Conclusion In patients with advanced DKD ketoanalogue supplemented low protein diet seems to be effective and safe as part of MBD management.

Advanced diabetic kidney disease complicated by acute interstitial nephritis: A case report and literature review

Currently, diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and end‑stage renal disease (ESRD) worldwide. The condition of advanced DKD is severe and is often accompanied by a number of complications, such as heart failure and pulmonary infection, requiring multiple‑drug treatment. However, any type of medicine has the potential to cause acute interstitial nephritis (AIN). In addition, as renal fibrosis in advanced DKD is already severe without taking any complications, such as AIN into account, it remains unclear whether steroidal therapy can benefit the condition. The present study describes the case of a patient with advanced DKD complicated by AIN, who was administered steroidal therapy. Ultimately, the patient's renal function partially improved. The present study also presents a brief review, discussing past experience on DKD with complications. On the whole, it is demonstrated that even patients with advanced DKD may still benefit from steroid therapy.

POS-360 MULTISCALAR DATA INTEGRATION LINKS GLOMERULAR ANGIOPOIETIN SIGNALING PATHWAY ACTIVATION WITH PROGRESSION OF DIABETIC KIDNEY DISEASE

Diabetes is the primary cause of chronic kidney disease (CKD) worldwide. Current clinical parameters lack specificity or sensitivity in predicting diabetic kidney disease (DKD) progression. Our study aims to identify prognostic biomarkers and understand the molecular mechanisms underlying the association of biomarkers and DKD progression through plasma proteomic and kidney transcriptomic data integrative analysis. Two subgroups of patients from the C-PORBE (Clinical Phenotyping Resource and Biobank Core) were used as discovery and validation cohorts (Table 1 & Figure 1). Baseline plasma samples were measured using SOMAscan Assay 1.3k. Cox proportional model was applied to identify proteins associated with progression, defined as composite event of developing ESRD or loss > 40% of baseline eGFR. Lasso cox was used to establish marker panel. C statistic and likelihood ratio (LR) test were used to evaluate additive value. Pathway Interaction, Reactome and Netpath databases were used for pathway query. Pathway score was calculated using the z score method. Single-cell RNAseq data analysis was processed according to the KPMP single cell protocol.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To identify circulating biomarkers associated with DKD progression, we applied cox proportional model on over 1300 plasma proteins and identified 84 of them are significantly associated with a composite endpoint of ESRD or 40% baseline eGFR reduction. A lasso cox-based machine learning procedure identified three biomarkers (EGFR, ANGPT2 and CLEC4M) that significantly improved the prediction of progression on top of the clinical model, including age, sex, race, eGFR and uACR (LR test p=0.003). This significant improvement was validated in the validation cohort (Table 2). ANGPT2 was significantly associated with outcome in both cohorts. To understand the mechanisms underlying the association between circulating ANGPT2 and DKD progression, we investigated the kidney-specific Angiopoietin-Tek signaling pathway by compiling a 21 gene-set through public database queries and transcriptomic data-driven approach. An Angiopoietin-Tek pathway activation score was calculated using this 21-gene-set for C-PROBE patients with overlapping transcriptomic, proteomic and longitudinal outcome data available. A significant positive association was observed between circulating ANGPT2 and Angiopoietin-Tek score in the glomerular compartment (r=0.39, p=0.03), but not in tubulointerstitium. The ANGPT2-Tek pathway score is significantly higher in progressors compared to non-progressors in C-PROBE (p=0.04). Consistent with a compartment-specific regulation of the pathway, TEK receptor showed maximal expression in glomeruli compared to tubulointerstitium with expression in glomerular endothelial cells. In two publicly available transcriptomic datasets derived from patients with DKD confirmed the association of ANGPT2-Tek signaling pathway activation with advanced DKD. We identified and validated a panel of three biomarkers (ANGPT2, EGFR, and CLEC4M) that exhibited significantly improved predictive performance for DKD progression when combined with the clinical model. Using comprehensive bioinformatic analysis, a kidney glomerular signaling cascade underlying the association of circulating ANGPT2 and DKD progression was identified providing a rational to target the ANGPT2-TEK signaling pathway in patients with DKD.

Ketoanalogue supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study

Metabolism dysregulation and protein energy wasting occur in patients with chronic kidney disease (CKD) and are associated with poor survival, especially in patients prior to starting dialysis. Accumulating evidence indicates that dietary supplementation with ketoanalogues (KAs, a mixture of branched-chain amino acids) exerts a variety of beneficial effects for patients with CKD. However, the role of KAs in diabetic kidney disease (DKD), one of the major causes of CKD, is still controversial. The aim of this study was to explore the impact of KA supplements on survival in patients with stage 5 DKD who have not yet started dialysis (DKD-5-ND). We analyzed a nationwide cohort retrieved from the National Health Insurance Research Database in Taiwan to study the long-term impact of KA supplements in patients with DKD-5-ND. We enrolled 15,782 incident pre-dialysis DKD patients between January 1, 2004 and December 31, 2007. Landmark analysis was used to eliminate immortal bias, and overlap weighting was used to balance differences between the KA users and nonusers in the beginning. The primary study endpoint was all-cause mortality, and the occurrence of permanent dialysis (presenting the end-stage renal disease, ESRD) and major adverse cardiovascular events (MACEs) was also evaluated. All patients were followed for five years or until death. The prevalence of KA usage in the DKD-5-ND patients was 6.3%. The 5-year all-cause mortality rate in the KA users was lower than that in the nonusers (34.7% vs 42.7%). After adjusting for known covariates, the KA users still had a lower risk of mortality (adjusted hazard ratio [aHR]: 0.73, 95% confidence interval [CI]: 0.66-0.82). In addition, the incidence of ESRD was also slightly lower among the KA users (90.9% for users vs 91.2% for nonusers, adjusted cause-specific hazard ratio [aCSHR]: 0.65, 95% CI: 0.61-0.69), and the occurrence of MACEs was lower (adjusted incidence rate ratios [aIRR]: 0.76, 95% CI: 0.67-0.86). Although the all-cause mortality was higher among patientsolder than 70 years (60.5% for KA users vs 46.5% for nonusers) the risk reduction seemed prominent among older patients (aHR: 0.65, 95% CI: 0.56-0.76 for patients aged ≥70 years; aHR: 0.82, 95% CI: 0.71-0.96 for patients aged<70 years). The reduction in risks of mortality was consistent in subgroup analysis and sensitivity tests. The use of KA supplements seemed to be beneficial for patients with DKD-5-ND; further in-depth analysis of using KA for these patients is warranted.

Low-salt low-protein diet and blood pressure control in patients with advanced diabetic kidney disease and heavy proteinuria.

To assess the associations between effects of low salt, low protein diet supplemented with keto-analogues (sLPD)-on salt intake, blood pressure (BP) and cardiovascular events (CVEs) in patients with advanced diabetic kidney disease (DKD) and heavy proteinuria. Prospective, single-center study (total duration of 15months), enrolling 92 patients with advanced DKD (median eGFR 11.7ml/min) and heavy proteinuria (median 4.8g/g creatininuria). The intervention consisted in a low salt-low protein (0.6g/kg-day) diet (sLPD) under intensive nutritional counselling, and adjustment of antihypertensive therapy. The endpoints of this sub-analysis were a salt intake ≤ 5g/day, a mean blood pressure (MAP) ≤ 97mmHg, corresponding to KDIGO target of 130/80mmHg, and the rate of CVEs. Salt intake decreased with 2.5g/day and the proportion of patients reaching the salt intake endpoint increased with 58%. A salt intake ≤ 5g/day was associated with a reduced MAP, BMI, proteinuria, fractional excretion of sodium, and eGFR, suggesting a salt-related volume contraction but was not related to protein intake. Mean arterial pressure decreased with 13mmHg. MAP ≤ 97mmHg was associated with lower proteinuria, salt, and protein intake, but the contribution of salt intake cannot be differentiated from that of protein intake. CVEs occurred in 20% of patients and were independently related to a lower age and MAP, and increased comorbidities. eGFR only minimally declined and no renal adverse events were noted. sLPD was nutritionally safe. The multifactorial personalized intervention allowed a stable MAP reduction to KDIGO recommended levels (≤ 97mmHg), related to the decrease in salt and protein intake. However, BP lower than 130/80mmHg increased the cardiovascular but not the renal risk in heavy proteinuric patients with advanced DKD. 0341507433: NCT03415074. Registered 02/02/2015 in US National Library of Medicine, ClinicalTrials.gov (NCT).

NOS3 rs1799983 and rs2070744 polymorphisms and their association with advanced chronic kidney disease and coronary heart disease in Canarian population with type 2 diabetes.

Different polymorphisms of the endothelial nitric oxide synthase gene (NOS3) have been related to diabetic kidney disease. To evaluate the association between advanced diabetic chronic kidney disease (ACKD) and the rs1799983 and rs2070744 poymorphisms of NOS3 in a population from the Gran Canaria island. Cross-sectional case-control study. Polymorphisms were genotyped in 152 subjects with ACKD secondary to type 2 diabetes [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2], 110 subjects with type 2 diabetes for 20 or more years since diagnosis without ACKD (eGFR ≥45 mL/min/1.73m2 and albumin/creatinine ratio <300 mg/g and/or 24-h urinary albumin excretion <300 mg) and 292 healthy controls. Association between both polymorphisms and established coronary heart disease (CHD) was also analyzed in both groups with diabetes. A greater proportion of homozygous individuals for the risk allele C of rs2070744 was found among subjects with ACKD. Association between ACKD and rs2070744 was observed in a recessive genetic model, both for comparison to subjects with diabetes but no ACKD [OR 2.17 (95% CI: 1.17-4.00), p=0.014] and for comparison to healthy controls [OR 1.61 (1.03-2.52), p=0.036]. The frequency of the C allele was significantly higher among subjects with CHD, but only in the group with ACKD. No associations were found for rs1799983. NOS3 rs2070744 is associated with ACKD in population with type 2 diabetes from Gran Canaria. A link between this genetic variant and CHD in Canarian subjects with type 2 diabetes could be restricted to cases with ACKD.

Coagulation, Protease-Activated Receptors, and Diabetic Kidney Disease: Lessons from eNOS-Deficient Mice.

Endothelial nitric oxide synthase (eNOS) dysfunction is known to exacerbate the progression and prognosis of diabetic kidney disease (DKD). One of the mechanisms through which this is achieved is that low eNOS levels are associated with hypercoagulability, which promotes kidney injury. In the extrinsic coagulation cascade, the tissue factor (factor III) and downstream coagulation factors, such as active factor X (FXa), exacerbate inflammation through activation of the protease-activated receptors (PARs). Recently, it has been shown that the lack of or reduced eNOS expression in diabetic mice, as a model of advanced DKD, increases renal tissue factor levels and PAR1 and 2 expression in their kidneys. Furthermore, pharmaceutical inhibition or genetic deletion of coagulation factors or PARs ameliorated inflammation in DKD in mice lacking eNOS. In this review, we summarize the relationship between eNOS, coagulation, and PARs and propose a novel therapeutic option for the management of patients with DKD.

Dipeptidyl-Peptidase 4 Inhibitors did not Improve Renal Endpoints in Advanced Diabetic Kidney Disease

The efficacy of dipeptidyl-peptidase 4 inhibitors (DPP4is) in advanced diabetic kidney disease (DKD) is unknown. We investigated whether DPP4is confer renal protective benefits in DKD patients. We conducted a retrospective cohort study between 2012 and 2018 in Taiwan. We only included type 2 diabetes patients with estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73 m2 and urine albumin to creatinine ratio between 300 and 5,000 mg/g. Patients with DPP4i prescriptions were selected as cases, while non-DPP4i users served as controls. We followed these patients until the presence of composite primary renal endpoints, which was defined by the earliest occur-rence of clinical renal outcomes. A total of 522 patients were included in the analysis, comprising 273 patients with a DPP4i prescription who were selected as cases and 249 patients without DPP4i prescription who were assigned as controls. Median follow-up duration for DPP4i users and nonusers was 2.2 years and 3.4 years, respectively. At baseline, the mean glycated hemoglobin levels for DPP4i users and nonusers were 8.1% and 8.3%, respectively. Among patients with DPP4i prescriptions, there was no reduction in composite primary renal outcome, with a crude hazard ratio (HR) of 1.50 (95% confidence interval [CI], 0.95 to 2.36). Similar results were observed for the risk of persistent eGFR <15 mL/min/1.73 m2, with a HR of 1.68 (95% CI, 0.90 to 3.13), doubling of serum creatinine level, with a HR of 1.05 (95% CI, 0.15 to 7.45), and end-stage renal disease, with a HR of 0.87 (95% CI, 0.14 to 5.19). DPP4i prescription did not reduce the risk of composite renal endpoints in DKD patients. BMI = body mass index; CI = confidence interval; CVOT = cardiovascular outcomes trial; DPP4i = dipeptidyl-peptidase 4 inhibitor; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = glycated hemoglobin; HR = hazard ratio; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2D = type 2 diabetes; UACR = urine albumin to creatinine ratio.

Monitoring and management of hyperglycemia in patients with advanced diabetic kidney disease.

Diabetes mellitus is the leading cause of end-stage renal disease, and uncontrolled hyperglycemia is directly related to the increased mortality in this setting. As kidney function decreases, it becomes more challenging to control blood glucose since the risk of hypoglycemia increases. Decreased appetite, changes in glycaemia homeostasis, along with reduced renal excretion of anti-hyperglycemic drugs tend to facilitate the occurrence of hypoglycemia, despite the paradoxical occurrence of insulin resistance in advanced kidney disease. Thus, in patients using insulin and/or oral anti-hyperglycemic agents, dynamic adjustments with drug dose reduction or drug switching are often necessary. Furthermore, in addition to consider these pharmacokinetics alterations, it is of utmost importance to choose drugs with proven cardio-renal benefits in this setting, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. In this review, we summarize the indications and contraindications, titration of doses and side effects of the available anti-hyperglycemic agents in the presence of advanced diabetic kidney disease (DKD) and dialysis, highlighting the risks and benefits of the different agents. Additionally, basic renal function assessment and monitoring of glycemic control in DKD will be evaluated in order to guide the use of drugs and define the glycemic targets to be achieved.

ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE - EXECUTIVE SUMMARY.

Introduction: COVID-19 is now a global pandemic affecting millions of people Patients on dialysis are at an increased risk to COVID-19 infection due to their exposure in the health care setting Strategies for infection control and prevention are also being implemented in the dialysis units because of the increased risk of virus transmission within the unit Objective: Describe the different measures and strategies done to mitigate the spread of COVID-19 outbreak in a hospital based dialysis centre Methods: Review of the epidemic course with contact tracing was done from March 14 to May 14, 2020 in the dialysis unit of a tertiary hospital Results: Of 167 haemodialysis patients, 20 were considered COVID-19 suspects Eight tested positive-2 were traced to be exposed with the first confirmed case, 2 were handled by a COVID-19 infected healthcare worker (HCW) who was asymptomatic at time of contact while 2 asymptomatic patients tested positive during mass screening Two of 67 HCWs tested positive were exposed to patients Key interventions during the course of the outbreak included: mass testing of patients and HCWs after identifying 6 patients and 2 HCWs infected with COVID-19 using nasopharyngeal/oropharyngeal swabs by RT-PCR;dialysis of COVID-19 confirmed and suspected cases in isolation rooms separate from the dialysis unit (instead of cohorting);provision of adequate protective personal equipment for HCWs and surgical masks for all patients, environmental disinfection especially in the waiting area with strict social distancing and screening for signs and symptoms at the entrance of the unit Conclusion: Infection control strategies are needed to manage the spread of COVID-19 in dialysis centres These infection prevention measures should be implemented at the first indication of transmission in the area and should be maintained for the duration of the pandemic and until the area show no more reports of transmission

Randomized trial of an intensified, multifactorial intervention in patients with advanced-stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan).

Aims/IntroductionWe evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD).Materials and MethodsThe Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population.ResultsThe IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups.ConclusionsThe risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease.

P0929LOW PROTEIN DIET, BLOOD PRESSURE CONTROL AND NATRIURESIS IN PATIENTS WITH ADVANCED DIABETIC KIDNEY DISEASE AND HEAVY PROTEINURIA

Abstract Background and Aims Recent data suggest the possibility to optimize blood pressure control by low protein diet (LPD) in patients with diabetic kidney disease (DKD). We aimed to assess the effects of a low protein diet (LPD) supplemented with keto-analogues on urinary sodium excretion and blood pressure control. Method Prospective, uni-center study with a total duration of 15 months.The study was conducted in a tertiary Nephrology Clinic and included a total of 92 diabetic patients with advanced CKD (eGFR &amp;lt; 30 mL/min) and heavy proteinuria (&amp;gt; 3 g/g creatininuria). Intervention consisted in a LPD (0.6 g/kg-day) supplemented with keto-analogues of essential amino acids with nutritional counselling and adjustment of antihypertensive therapy. The primary efficacy parameter was proteinuria during intervention as compared to pre-enrolment. Blood pressure (BP), urinary sodium excretion, eGFR and blood glucose control were secondary end-points. Results Mean arterial pressure (MAP) decreased from baseline (Bs) to end of study (EOS) with -11 (-17 to -7) mmHg despite a reduction with 22% of patients needing antihypertensive medication. Independent predictors of a lower than median MAP (90mmHg) were a lower protein intake (HR 0.00 (0.00; 0.04; p=0.002), treatment with furosemide (HR 1.06 [1.06; 3.85]; p=0.03) but not with angiotensin-aldosterone system inhibitors (RAASi) [HR 0.17 (0.17; 0.90); p=0.03)] and was not influenced by natriuresis. Natriuresis decreased from 130 (121-135) to 80 (71-86) mmol/day (p&amp;lt;0.0001). A lower than median natriuresis (100mmol/day) was directly related to proteinuria [HR 0.0003 (0.00; 0.004); p=&amp;lt;0.0001], eGFR [HR 0.0001 (0.00; 0.14); p=0.01] and to diuretic therapy [0.21 (0.05; 0.83); p=0.03] but not to protein intake. Cardiovascular events were observed in 20% of patients and their occurrence was related to a lower MAP [0.97 (0.95; 0.99}; p=0.001]. No renal adverse were noted and the diet was nutritionally safe. Conclusion A low protein diet supplemented with ketoanalogues of essential amino acids on top of anti-hypertensive therapy (mostly loop diuretics) allows for a good control of blood pressure, unrelated to natriuresis in heavy proteinuric patients with advanced DKD.

506-P: Hepatic Fibrosis but Not Steatosis Is Associated with Diabetic Kidney Disease in Nonobese Patients with Type 2 Diabetes

Background: Recent studies investigated the association between nonalcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) but the results are inconclusive. Here we aimed to investigate the effect of obesity on the association between NAFLD and DKD in a large cohort of participants with T2DM. Methods: In this cross-sectional study, a total of 3,439 patients (1,710 men and 1,729 women) with T2DM were recruited from the Seoul Metabolic Syndrome cohort between 2003 and 2016. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. Advanced fibrosis was defined as FIB4 index ≥ 1.45. DKD was defined as an estimated glomerular filtration rate (eGFR) of &amp;lt; 60 mL/min/1.73 m2. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Results: The mean age was 57.4 ± 10.3 years and duration of diabetes was 7.7 ± 7.1 years. Two hundred and fifty subjects (7.3%) had DKD and 1869 (54.3%) subjects had NAFLD. The prevalence of DKD were 7.0%, 4.5% and 11.9% in no-NAFLD group, liver steatosis only group and advanced fibrosis group respectively (p&amp;lt;0.001). Advanced fibrosis was independently associated with an increased risk of DKD (odds ratio [OR] 1.75; 95% confidence interval [CI] 1.08-2.86; p = 0.034) compared to no NAFLD after adjustment for potential confounders in patients with BMI &amp;lt; 25 kg/m2. However, the association between advanced fibrosis and DKD was not significant in those with BMI ≥ 25 kg/m2. There was no significant associated between hepatic steatosis without advanced fibrosis with DKD regardless of obesity status. Conclusion: This study suggests that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of DKD in non-obese patients with T2DM. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None.

Combined effect of diabetic retinopathy and diabetic kidney disease on all-cause, cancer, vascular and non-cancer non-vascular mortality in patients with type2 diabetes: A real-world longitudinal study.

Aims/IntroductionWe assessed the relationship between diabetic retinopathy (DR) and/or diabetic kidney disease (DKD) according to their severity and all‐cause, cancer, vascular and non‐cancer non‐vascular mortality in real‐world patients with type 2 diabetes.Materials and MethodsA total of 1,902 patients with type 2 diabetes were enrolled from 1995 to 1999 and followed to 2017. At baseline, DR was diagnosed in 374 patients, DKD in 529, vision‐threatening DR in 123 and advanced DKD in 287. Patients were classified by the status of DR and DKD. Multivariate Cox regression analysis was carried out.ResultsThere were 266 deaths during a median follow‐up period of 18.6 years. Among these, 92 were from cancer, 78 were from vascular causes and 82 were from non‐cancer non‐vascular causes. DR and/or DKD predicted all‐cause, vascular and non‐cancer non‐vascular mortality, but not cancer mortality. Similarly, vision‐threatening DR and/or advanced DKD predicted all‐cause, vascular and non‐cancer non‐vascular mortality, but not cancer mortality. Hazard ratios for all‐cause, vascular and non‐cancer non‐vascular mortality were highest in the DR(+)DKD(+) group, and higher in the DR(−)DKD(+) and the DR(+)DKD(−) groups than in the DR(−)DKD(−) group. The results for vision‐threatening DR and advanced DKD were similar. The interaction for non‐cancer non‐vascular mortality, but not all‐cause and vascular mortality, between DR and DKD and between vision‐threatening DR and advanced DKD might be significant.ConclusionsDR and DKD may be jointly and independently associated with all‐cause, vascular and non‐cancer non‐vascular mortality, but not cancer mortality, according to their severity in real‐world patients with type 2 diabetes.

ACE Inhibitor Benefit to Kidney and Cardiovascular Outcomes for Patients with Non-Dialysis Chronic Kidney Disease Stages 3-5: A Network Meta-Analysis of Randomised Clinical Trials.

BackgroundThe advantages of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular events (CVEs) and delaying end-stage kidney disease (ESKD) in patients with chronic kidney disease (CKD) is well-known. However, the efficacy and safety of these agents in non-dialysis CKD stages 3–5 patients are still a controversial issue.MethodsTwo investigators (Yaru Zhang and Dandan He) independently searched and identified relevant studies from MEDLINE (from 1950 to October 2018), EMBASE (from 1970 to October 2018), and the Cochrane Library database. Randomised clinical trials in non-dialysis CKD3–5 patients treated with renin-angiotensin system (RAS) inhibitors were included. We used standard criteria (Cochrane risk of bias tool) to assess the inherent risk of bias of trials. We calculated the odds ratio (OR) and 95% confidence interval (CI) for each outcome by random-effects model. A 2-sided p value < 0.05 was considered statistically significant, and all statistical analyses were performed using STATA, version 15.0. This network meta-analysis was undertaken by the frequency model.ResultsForty-four randomised clinical trials with 42,319 patients were included in our network meta-analysis. ACEIs monotherapy significantly decreased the odds of kidney events (OR 0.54, 95% CI 0.41–0.73), cardiovascular events (OR 0.73, 95% CI 0.64–0.84), cardiovascular death (OR 0.73, 95% CI 0.63–0.86) and all-cause death (OR 0.77, 95% CI 0.66–0.91) when compared to placebo. According to the cumulative ranking area (SUCRA), ACEI monotherapy had the highest probabilities of their protective effects on outcomes of kidney events (SUCRA 93.3%), cardiovascular events (SUCRA 77.2%), cardiovascular death (SUCRA 86%), and all-cause death (SUCRA 94.1%), even if there were no significant differences between ACEIs and other antihypertensive drugs, including calcium channel blockers (CCBs), β-blockers and diuretics on above outcomes except for kidney events. ARB monotherapy and combination therapy of an ACEI plus an ARB showed no more advantage than CCBs, β-blockers and diuretics in all primary outcomes. In the subgroup of non-dialysis diabetic kidney disease patients, no drugs, including ACEIs or ARBs, significantly lowered the odds of cardiovascular events and all-cause death. However, ACEIs were still better than other antihypertensive drugs including ARBs in all-cause death but not ARBs in cardiovascular events according to the SUCRA. Only ARBs had significant differences in preventing the occurrence of kidney events compared with placebo (OR 0.82, 95% CI 0.72–0.95). Both ACEI/ARB monotherapy and combination therapy had higher odds of hyperkalaemia. ACEIs had 3.81 times higher odds than CCBs (95% CI 1.58–9.20), ARBs had 2.08–5.10 times higher odds than placebo and CCBs and combination therapy of an ACEI and an ARB had 4.80–24.5 times higher odds than all other treatments. Compared with placebo, CCBs and β blockers, ACEI therapy significantly increased the odds of cough (OR 2.90, 95% CI 1.76–4.77; OR 8.21, 95% CI 3.13–21.54 and OR 1.80, 95% CI 1.08–3.00). There were no statistical differences in hypotension among all comparisons except ACEIs versus placebo.ConclusionsAlthough ACEIs increased the odds of hyperkalaemia, cough and hypotension, they were still superior to ARBs and other antihypertensive drugs and had the highest benefits for the prevention of kidney events, cardiovascular outcomes, cardiovascular death and all-cause mortality in non-dialysis CKD3–5 patients. In patients with advanced diabetic kidney disease, ACEIs were superior to ARBs in lowering risk of all-cause death but not in kidney events and cardiovascular events.Electronic supplementary materialThe online version of this article (10.1007/s40265-020-01290-3) contains supplementary material, which is available to authorized users.