Diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease. The pathogenesis and risk factors for the development of diabetic kidney disease are complex and multifaceted, resulting in glomerular hypertrophy, tubulointerstitial inflammation, and fibrosis. The clinical staging progresses over 5 stages from early hyperfiltration to overt nephropathy. Primary prevention like glycaemic control, control of blood pressure, treatment of dyslipidemia and lifestyle modifications have shown promising benefits. Despite widespread research, very few drugs are available to retard disease progression. More literature and research are needed to fill these lacunae. We carried out a literature search focusing on newer updates in diabetic kidney disease pathophysiology, diagnosis and management using a PubMed search through the National library of medicine using keywords “Diabetic kidney disease,” and “Diabetic nephropathy” till the year 2022. We have summarized the relevant information from those articles. Studies in diabetes kidney disease in the last few years have shown many new pathophysiological pathways and corresponding newer treatment options. A review of these updates would guide us in better patient management. It can cause damage to several organ systems, including the urinary tract. The damage to the urinary system may be due to diabetic nephropathy, primary glomerular diseases, recurrent acute pyelonephritis, renal tubular acidosis, papillary necrosis, diabetic cystopathy etc.The major cause of end-stage kidney disease (ESKD) worldwide is diabetes mellitus (DM).In 2021, the International Diabetic Federation anticipated that roughly 537 million individuals (20–79 years) are living with diabetes worldwide. India was found to be the second most prevalent nation, after China. The approximate number of diabetic adults in India is 73 million.The prevalence of microalbuminuria and macroalbuminuria among the microvascular consequences of DM is approximately 30% to 35% in both types of diabetes.–4Numerous risk factors for diabetic nephropathy can be categorized as modifiable and non-modifiable. While the former includes poor glycaemic and blood pressure control, high blood cholesterol, smoking, presence of diabetic retinopathy, use of oral contraceptives, obesity, hyperuricemia, etc, the latter consists of the male sex, positive family history for DM, the onset of Type 1 diabetes mellitus (T1 DM) before the age of 20 years, certain ethnic groups like African Americans, Mexican Americans, Pima Indians, South Asian immigrants settled in the United Kingdom etc.2. For albuminuria or low eGFR to be confirmed, two abnormal values must be taken at least three months apart.The clinical assessment of diabetic kidney disease (DKD) is based on clinical parameters such as the duration of DM and edematous illness, the presence of diabetic retinopathy (DR), and the measurement of eGFR and albuminuria. DKD is recognized clinically by a persistently high urinary albumin-to-creatinine ratio ≥ 30 mg/g and/or unrelenting reduction in eGFR < 60 mL/min/1.73 mThe American Diabetes Association (ADA) Standards of Medical Care in Diabetes 2022 recommend that screening for DKD should be performed at least once a year for patients with T1 DM beginning 5 years after diagnosis and in all patients with type 2 diabetes mellitus (T2 DM) at the first visit.Amongst patients with DM and renal involvement (in the form of proteinuria and/or failure), the following is the pattern of presentations-60% – classic Kimmelstiel–Wilson disease 13% – an atypical presentation consistent with ischemic nephropathy (shrunken kidneys with no major proteinuria)27% – had a known primary kidney disease with concomitant or superimposed diabetes.Management of DKD includes prevention of the onset of albuminuria i.e., Kidney Disease initiative: Global outcome (KDIGO) stage A1 (Primary Prevention), retarding the progression from KDIGO stage A1 to stage A2/A3 (Secondary Prevention) and treatment involved in ESKD.The most important modality for Primary Prevention is strict glycemic control in patients with Type 1 DM and adequate glycemic control in those with T2 DM. Other therapy modalities for Primary Prevention include blood pressure control, treatment of dyslipidemia, and lifestyle adjustments.The Diabetes Control and Complications Trial was the seminal study that demonstrated that strict glycemic control lowers the risk for microalbuminuria and impaired glomerular filtration rate (GFR) in patients with Type 1 DM. Patients receiving intensive therapy (mean HbA1c 7%) had a 35% to 45% lower risk for the development of microalbuminuria compared with the control group (mean HbA1c 9%).An important study in T2 DM was the United Kingdom Prospective Diabetes Study (UKPDS). The mean achieved HbA1c was 7.0% in the intense control group while it was 7.9% in the standard group. The relative risk reduction for the emergence of microalbuminuria was 24% after nine years of intensive therapy. Although the glycemic control was lost significantly earlier in the study, these patients demonstrated a reduced risk of vascular complications and a lower all-cause mortality throughout a subsequent ten-year period of follow-up.Since the UKPDS, three large trials, Action in Diabetes and Vascular Disease: Perindopril and Indapamide Modified Release Controlled Evaluation, Action to Control Cardiovascular Risk in Diabetes (ACCORD), and VA Diabetes Trial, have demonstrated that intensive control of blood sugars is of unproven benefit in patients with Type2 DM.In its 2022 guidelines, the ADA suggests a target HbA1c of 7.0% to stop or slow the progression of the microvascular consequences of diabetes, including DKD in both Type 1 and Type 2 DM patients (ADA).,10 Renin angiotensin aldosterone blockade plays an important role in hypertension control and in the prevention of the progression of DKD. ACEi decreases the production of Ang II, which is a potent vasoconstrictor, leading to lower intraglomerular pressure and reduced glomerular hypertension. They also decrease the glomerular permeability to urinary albumin leading to decreased proteinuria. ARBs act by blocking Ang II type 1 receptor. This blockade may lead to a further increase in the synthesis of Ang II which binds to intrarenal AT2 receptors, resulting in decreased blood pressure and reduced renal interstitial fibrosis.The prevention of DKD, DR, and cardiovascular disease in diabetic individuals depends on the early management of hypertension. In individuals with hypertension who also have diabetes, the first-line antihypertensive drugs are angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).,13Two key studies done in patients with T1 DM to assess the response of RAAS blockade on the advancement of both DN and DR with time, were the Renin-Angiotensin-Aldosterone System Study (RAAS) and the Diabetic Retinopathy Candesartan Trials. Both had found that with time, the progression of DR had slowed down but there was no effect on the progression of DN.The Bergamo Nephrologic Diabetes Complications Trial, which compared an ACEi versus Calcium channel blockers and found that there was less progression to the stage of microalbuminuria with the former as compared to the latter, was the landmark study that had demonstrated the beneficial effect of RAAS inhibitors in slowing the evolution of DN in patients with T2 DM.The Randomized Olmesartan and Diabetes Microalbuminuria Prevention trial, another significant study on the effect of ARBs on the development of nephropathy in T2 diabetic patients, demonstrated that an ARB could delay or prevent the onset of microalbuminuria in comparison to a placebo.In order to lower cardiovascular disease mortality and decrease the course of CKD, ADA 2022 recommends that blood pressure objectives for all normoalbuminuric diabetics be below 140/90 mm Hg. A lower blood pressure goal (130/80 mm Hg) is advised after albuminuria develops.There are few clinical studies on the effectiveness of lipid-lowering alone in preventing DN.The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid trial and the Diabetes Atherosclerosis Intervention Study have both demonstrated a slower progression to microalbuminuria.According to the Diabetes Atherosclerosis Intervention Study, fenofibrate significantly reduced the rate of progression from normoalbuminuria to microalbuminuria in T2 diabetes patients at 3 years compared to the placebo group.The Simvastatin and Fenofibrate Combination Medicine Study (ACCORD-Lipid) looked into the effects of this combination therapy. Simvastatin with fenofibrate was found to considerably slow the development of microalbuminuria in T2 DM patients as compared to the control group .Lifestyle changes such as weight reduction, exercise, and smoking cessation have been found beneficial. Dietary modification such as salt restriction  has also been recommended.It is involved in retarding the progression from KDIGO stage A1 to A2/A3. Blood pressure control is indeed the most important strategy in the treatment of DKD and prevention of the onset of KDIGO stage A2. Additionally, it advises patients with DM and hypertension who have urinary albumin-to-creatinine ratios below 300 mg/g creatinine and/or eGFRs below 60 mL/min/1.73 m2 to use ACEi or ARBs as first-line medications.Patients with urine albumin excretion of more than 30 mg per 24 hours should have a target blood pressure of 130/80 mm Hg or less, and all diabetic patients should have a target blood pressure of 140/90 mm Hg or less. Both proved that there was a reduction in the development of microalbuminuria in those patients whose blood pressure was controlled more strictly. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial (ACCORD BP) had depicted that there was no reduction in the rate of major cardiovascular events in those Type2 diabetic patients whose blood pressure was controlled more intensively (Systolic blood pressure < 120 mm Hg) as compared to those whose blood pressure BP was kept on a higher side (Systolic blood pressure < 140 mm Hg).Two landmark studies were done in patients with T2 DM, which showed the benefit of intensive blood pressure control over less stringent control were the UKPDS and the Appropriate Blood Pressure Control in Diabetes trial.It is important to note that the RAAS blockade in patients with DKD, by either ACEi or with ARBs provides renoprotection that is independent of blood pressure reduction.Virtually all studies done in Type1 diabetic patients with nephropathy were based on ACEi, not ARBs. In a meta-analysis of 12 placebo-controlled trials enrolling normotensive patients with Type1 DM and microalbuminuria treated with ACEi, there was a 60% decline in evolution to macroalbuminuria and there was also a threefold rise in regression to normoalbuminuria.The serum creatinine concentration has been seen to increase by up to 30% in proteinuric patients with renal impairment after taking RAAS blockers. If the increase in serum creatinine concentration occurs within 4 weeks of starting ACEi or ARBs and is greater than 30%, they should be stopped and this should raise the possibility of underlying renal artery stenosis. Measures to lower serum potassium levels should be used to treat hyperkalemia brought on by ACEi or ARBs rather than lowering the dose or terminating ACEi or ARBs right away.As additional antihypertensive medications, dihydropyridine calcium channel blockers such as nisoldipine, nifedipine, amlodipine, etc., may be utilized; however, these medications have not been demonstrated to reduce albuminuria or to slow the progression of the renal diseases. Some investigations have demonstrated that non-dihydropyridine calcium channel blockers, such as diltiazem and verapamil, have positive antiproteinuric effects.A low-sodium diet (<2.0 g sodium/d) may help. For lowering blood pressure and reducing proteinuria, a combination of a loop diuretic or thiazide diuretic plus RAAS blockers may be superior to either kind of treatment alone. SARAs, or selective aldosterone receptor antagonists, have also been proven to reduce proteinuria when administered alone and to increase it when combined with ACEi or ARBs. The FIDELIO-DKD trial demonstrated that finerenone therapy resulted in decreased risks of cardiovascular events and CKD progression than placebo.In T2 DM patients with DKD (A1/A2), the KDIGO 2020 suggests an individual HbA1c target range from 6.5% to 8%. An HbA1c target of 7% is advised by ADA 2022. Additionally, it indicates that lowering the HbA1c level would be advantageous if it could be done so without substantial hypoglycemia or other negative treatment side effects. Another agent, Pramlintide can be used if renal functions are normal but limited experience is available regarding its use in CKD and is therefore not recommended in this subset of patients.For T1 DM, ADA 2022, recommends multiple daily injections of prandial and basal insulin or continuous subcutaneous insulin infusion as first-line therapy. The use of sodium-glucose cotransporter 2 inhibitors (SGLT-2i), which prevent sodium and glucose uptake in the proximal tubule and cause natriuresis and glucosuria, to treat Type 1 diabetics is still relatively new. However, the National Institute for Health and Care Excellence advised the use of sotagliflozin in 2020 for T1 DM patients when insulin alone is insufficient to control glycemia. SGLT2i are relatively new drugs that have been permitted for the treatment of T2 DM. Sodium-glucose cotransporter 2 proteins are expressed in the proximal convoluted tubules of the kidney. They are responsible for approximately 90% of the filtered glucose reabsorption. Inhibition of this causes glucosuria leading to better glycaemic control. Together with glucosuria, SGLT2i also cause natriuresis leading to a better BP control. Natriuresis increases sodium delivery to the juxta-glomerular apparatus in the distal nephron, which through tubule-glomerular feedback causes afferent arteriolar constriction, thereby reducing glomerular hyperfiltration seen in diabetic nephropathy. Recently, two trials designed as cardiovascular safety studies- Empagliflozin, Cardiovascular Outcomes, and Mortality in T2 DM and Canagliflozin Cardiovascular Assessment Study, have revealed noteworthy cardiovascular risk reduction when these are used for the management of T2 DM. In these cardiovascular outcome trials, these agents were found to have positive effects on kidney outcomes, namely albuminuria reduction and a reduction in the occurrence of a composite renal outcome. In patients with T2 DM with CKD, the CREDENCE  trial showed that long-term administration of canagliflozin conferred better renal outcomes which include slower progression to ESKD. Similarly in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, the risk of sustained decline in the estimated GFR (eGFR) of at least 50%, ESKD or death from renal or cardiovascular causes was found to be significantly lower with dapagliflozin than with placebo.For Type 2 diabetics with DKD, large studies  advocate that intensive glycemic control may provide some renoprotection but does not safeguard against macrovascular complications. Thus, anti-diabetic therapy must be tailored to T2 DM. It is important to note that these agents are contraindicated in patients with an eGFR < 30 mL/min/1.73m2 (1). Long-acting GLP-1 receptor agonists  are used as the preferred second-line agents in patients with Type2 DM and CKD.Based on these studies, for T2 DM, KDIGO 2020 and ADA 2022 recommends Metformin and SGLT2i (or gliflozins) as first-line treatment modalities. The patients should be counseled regarding the potential adverse reactions or side effects e.g., diabetic ketoacidosis, urinary tract infection, volume contraction, acute kidney injury, bone fractures etc of SGLT2i. Thus, interventions aimed at improving all lipid targets are required. The largest trial performed on the role of aggressive lipid reduction in diabetes was the ACCORD Lipid trial, in which intensive lipid lowering with simvastatin and fenofibrate versus simvastatin and placebo was carried out out. The addition of fenofibrate did not affect the primary CV outcome of the trial, nor was there a difference in the incidence of ESKD or dialysis requirement. There was, however, a reduction in both microalbuminuria and overt proteinuria in the intensive group. Thus, intensive lipid lowering with simvastatin and fenofibrate may reduce proteinuria but may not prevent death or dialysis in T2 DM.In type 2 diabetics patients with non–dialysis-dependent DN, treatment with statins (dose based on creatinine clearance) provides substantial cardiovascular benefit. In the UKPDS, elevated triglycerides were independently associated with albuminuria in T2 diabetic patients Field.Dietary protein restriction may alleviate uremic symptoms in patients at or approaching ESKD. However, it is of uncertain benefit in the treatment of DN. Small trials have shown a low-protein diet (0.8 g/kg/d) to reduce proteinuria significantly with increased plasma albumin in Type 2 diabetic patients with moderately increased albuminuria.Other complications of CKD per se are to be managed according to standard guidelines.Patients who are being treated with hemodialysis and peritoneal dialysis should consume a protein intake of 1.2 and 1.3 g/kg/d respectively, with a calorie intake of 30 to 35 Kcal/kg/d, apart from the diabetic diet.,27 Timely creation of vascular access in these patients is crucial. It is recommended that it should be initiated when eGFR is 20 to 25 mL/min/1.73 m2.A diabetic patient with ESKD has multiple options for renal replacement therapy (RRT), which include Hemodialysis, Peritoneal dialysis, and Transplantation. Out of these, transplantation is the best modality. For a patient with T1 DM and ESKD, transplantation can be of three types – Kidney only, Simultaneous Pancreas with Kidney (SPKT), and Pancreas after Kidney (PAKT). Out of all these, the best results are with SPKT.,29In the past, RRT was initiated early in diabetic patients to decrease symptoms of uremia and diabetes. It is yet unknown when maintenance dialysis should start for people with ESKD. The Initiating Dialysis Early and Late research, a randomized trial that examined the impact of dialysis beginning at two distinct levels of kidney function, found no appreciable differences between the two treatment groups in terms of survival or other patient-centered outcomes. Additionally, a systematic evaluation of the literature found no differences in mortality between patients with diabetes and those without diabetes between early (higher eGFR) and late (lower eGFR) starts of RRT. Thus, regardless of the existence or lack of, RRT should begin based on the same principles in all patients. See  has been found to improve glomerular filtration and decrease proteinuria. Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activator (Bardoxolone methyl) is another anti-inflammatory agent which protects the renal tubular epithelial cells in DKD by improving redox balance and mitochondrial function and inhibiting inflammation.JAK-STAT pathway inhibitors (Baricitinib) have been found to have a noticeable effect on decreasing proteinuria, mesangial dilation, decreased podocyte density, and glomerulosclerosis. The phosphodiesterase inhibitors (Pentoxifylline and Cilostazol) have been found to have anti-inflammatory and immunomodulatory effects in DKD and were found to reduce the decline of eGFR and significantly decrease proteinuria in T2DM patients with CKD stages 3 to 4. See  were found to have a renoprotective effect. Inhibitors of advanced glycation end products have been studied in DKD stages 2 to 4. Sevelamer, a commercially used non-calcium phosphorus binder, decreased the expression of advanced glycation end products and thereby conferred a renal protective effect in DKD patients.2. Primary Prevention includes glycaemic control, control of blood pressure, treatment of dyslipidemia and lifestyle modifications. ADA 2022 recommends a target blood pressure of 140/90 mm Hg or less for all diabetic patients, and 130/80 mm Hg or less for patients with urine albumin excretion of greater than 30 mg per 24 hours. RAAS blockade in patients with DKD, by either ACEi or with ARBs provides renoprotection that is independent of blood pressure reduction. KDIGO 2020 and ADA 2022 recommend Metformin and an SGLT2i (or gliflozins) as first-line treatment modalities of DM in DKD.The overall prevalence of microalbuminuria and macroalbuminuria is around 30% to 35% in both types of diabetes. DKD is recognized clinically by a persistently high urinary albumin-to-creatinine ratio ≥ 30 mg/g and/or unrelenting reduction in eGFR < 60 mL/min/1.73 mConceptualization: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Data curation: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Formal analysis: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Investigation: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Methodology: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Project administration: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Resources: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Software: Devada Sindhu, Gaurav Shekhar Sharma.Supervision: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Validation: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Visualization: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Writing – original draft: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.Writing – review & editing: Devada Sindhu, Gaurav Shekhar Sharma, Damodar Kumbala.


Chronic kidney disease (CKD) has been one of the most common complications in type 2 diabetes mellitus (T2DM) patients. This retrospective study aimed to investigate the regional differences in the prevalence and management of CKD in T2DM inpatients from two grassroots hospitals in Beijing and Taiyuan.2).The sociodemographic status, health history, lifestyle information, biochemical parameters and drug choices of the patients were collected from the Diabetes Care Information System using a retrospective cross-sectional analysis. The presence of CKD was defined as albuminuria  and/or as a reduced estimated glomerular filtration rate  in both the Beijing and Taiyuan groups were not ideal. Patients with CKD tended to use insulin, renin–angiotensin–aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and dyslipidaemia therapy in Taiyuan than in Beijing. The actual proportion of carbohydrate, fat and protein in calories was 49.6%:35.4%:14.4% in Beijing and 61.5%:27.8%:10.8% in Taiyuan.858 patients with T2DM in Beijing and 1,085 patients with T2DM in Taiyuan were included, with a median age of 61.0 and 61.9 years, respectively. The duration of diabetes was 10.5 and 10.3 years, respectively. The prevalence of CKD in Beijing (39.2%) was significantly higher than in Taiyuan (22.4%). The overall ABC control (A = haemoglobin AThe higher prescription rates of RAAS inhibitors, SGLT-2i and dyslipidaemia therapy may underlie the fluctuations in the prevalence of CKD in Beijing or Taiyuan. Intensive insulin therapy and personal nutritional guidance, along with the extensive use of RAAS inhibitors, SGLT-2i and dyslipidaemia therapy during follow-up, can all play a positive role in the management of CKD in patients with T2DM in both Beijing and Taiyuan.The online version contains supplementary material available at 10.1186/s41043-023-00406-1. The increasing prevalence of diabetes has led to a worldwide rise in chronic kidney disease (CKD) over the last two decades. The microvascular complications in type 2 diabetes mellitus (T2DM) like diabetic nephropathy and diabetic retinopathy has been detected in more and more T2DM patients . Accordi1c [HbA1c]; B, blood pressure [BP]; and C, cholesterol) ) and protein intake was lower in both Beijing (A/R: 92.1% [70.7–115.3%]) and Taiyuan (A/R: 64.6% [52.3–84.1%]). When comparing Taiyuan to Beijing, significantly more patients had an actual carbohydrate ratio of > 60% and an actual fat ratio of < 27%. In Taiyuan, the recommended carbohydrate and fat ratio was higher in group 1 than group 2, while the protein ratio was lower. In both Beijing and Taiyuan, there was a significant difference in the recommended protein intake of 0.8, 0.8–1.0, and > 1.0 g per kilogram of IBW between group 1 and group 2  and TG (≥ 1.7 mmol/L), a lack of regular physical activity, a history of hypertension, retinopathy, DKD and hyperuricemia. In the Beijing participants, a fat ratio of < 27% was associated with a lower risk of CKD, along with an OR of 0.43 , while in the Taiyuan participants, there were no additional relevant factors  was much higher than in Taiyuan 22.4%) and similar to that of Shanghai (38.6%) for hospitalised T2DM patients with similar diabetic duration and gender distinction % and sim and furtLike earlier reports , 23, 24,1c < 7.0%, BP < 130/80 mmHg, LDL-C < 2.6 mmol/L and TG < 1.7 mmol/L. The ABC control in the Hong Kong study was accomplished in 46.7% of patients with a BP of < 130/80 mmHg and in 61.7% of patients with an HbA1c of < 7.0% [The poor ABC control in Beijing and Taiyuan in this study was comparable to the findings in other Chinese studies , 6, suggf < 7.0% . These tf < 7.0%  studies.f < 7.0% .According to the nutritional evaluation, there was a significant difference in the dietary structure between Beijing and Taiyuan, not only among the overall study population, but among the CKD participants as well. Individual recommendations were made, taking into account nutritional balance, ABC control, and CKD protective needs. The actual carbohydrate, fat and protein in calorie ratios for Beijing were 49.6%:35.4%:14.4% and 61.5%:27.8%:10.8% for Taiyuan. The recommended adjustments were as follows: 53.0%:30.0%:17.0% for Beijing and 55.0%:27.0%:18.0% for Taiyuan. Although CKD patients were not found to have an excessive intake of fat or protein, a fat energy ratio of < 27 percent was associated with a lower risk of CKD in the Beijing participants—after allowing for potential variable factors such as smoking, alcohol consumption, educational level, diabetic duration and ABC control. A previous study identified a similar protective effect of a low-fat diet. When total red meat consumption was replaced with a low-fat diet, the positive association with CKD incidence was reversed [There are several limitations to this study. First, the testing equipment in each of the two hospitals was dissimilar, which would tend to impact the results in some ways. However, the research findings were still meaningful in terms of the sample size. Second, positive dietary effects on CKD prevalence may be due to a general increase in health awareness and individual compliance, and not exclusively due to a low-fat diet. The results do not allow the derivation of temporal relationships from a one-time assessment of eGFR, UACR, diet and the cross-sectional study design. Third, vinegar have been suggested ameliorating the hyperoxaluria-induced renal injury by improving the gut microbiota, insulin sensibibity and metabolomic profiles , 29. TaiIn summary, this study focused on the prevalence and management of CKD in hospitalised patients with T2DM within two districts—Beijing and Taiyuan. Variations in the frequency of albuminuria—as well as higher rate of ACEI/ARB, SGLT-2i and dyslipidaemia usage—may be among the reasons for the differences in the prevalence of CKD in Beijing and Taiyuan. A future management direction can be clearly seen here. To prevent the onset and progression of CKD in patients with T2DM, a timely screening, a comprehensive risk factor control and the early use of renal protective medications are essential.Additional file 1: Table S1. The prevalence of CKD in Beijing and Taiyuan. eGFR: estimated glomerular filtration rate; eGFR categories: G1, eGFR ≥ 90.0; G2, eGFR 60.0–89.9; G3a, eGFR 45.0–59.9; G3b, eGFR 30.0–44.9; UACR Categories: A1 < 30.0, A2:30.0–300.0, A3 > 300.0; UACR: urinary albumin-to-creatinine ratio. Table S2. Dietary assessment and recommendations in Beijing and Taiyuan. A: actual; R: recommended; A/R: actual/recommended; R-A: recommended minus actual; IBW: ideal body weight. CKD: chronic kidney disease; Beijing vs. Taiyuan,* P < 0.05, # P < 0.001. Categorical variables were expressed as numbers. Continuous variables were expressed as medianfor non-normally distributed variables.


Conclusion: Our results suggest that MLR and PLR are inexpensive and easily accessible biomarkers that predict a non-dipping pattern in hypertensive patients with stable CAD.Introduction. Chronic inflammation plays an essential role in the pathophysiology of both arterial hypertension (HTN) and coronary artery disease (CAD), and is more pronounced in individuals with a non-dipper circadian blood pressure (BP) pattern. A non-dipping BP pattern is in turn is associated with increased cardiovascular morbi-mortality, and a higher risk of atherosclerotic events. Neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR) and platelet to lymphocyte ratio (PLR) are readily available predictors of systemic inflammation and cardiovascular risk. The purpose of our study is to evaluate whether NLR, MLR and PLR can be used as cost-effective predictors of a non-dipping blood pressure pattern in hypertensive patients with stable CAD. Materials and Methods: We performed a cross-sectional retrospective analysis that included 80 patients with hypertension and stable CAD  referred to a cardiovascular rehabilitation center. All patients underwent clinical examination, 24 h ambulatory blood pressure monitoring (ABPM) and standard blood analysis. Results: Baseline demographic characteristics were similar in both groups. Patients with non-dipper pattern had significantly higher NLR ,  The global burden of hypertension (HTN) is increasing worldwide, partly due to the current obesity pandemic and to the increased prevalence of sedentarism and unhealthy lifestyle choices. Apart from it being a disease per se, HTN is also considered a major modifiable risk factor for cardiovascular morbidity and mortality . MedicalThe most recent European Society of Cardiology (ESC) guidelines have revised the standard HTN diagnostic protocol. Current standard is that the patient should undergo repeated office BP measurements, as well as home-based blood pressure monitoring (HBPM) or ambulatory blood pressure monitoring (ABPM). ABPM is a readily available, noninvasive instrument that assesses circadian BP variability and characterizes the individual dipping status. Current guidelines recommend an increased use of ambulatory devices, since ABPM is a more reliable tool for HTN diagnosis and control assessment, but also for BP profile characterization. This is useful in predicting HTN-mediated cardiovascular risk and target organs damage . BP valuSimilarly to the ESC guidelines, the most recent American College of Cardiology and American Heart Association (ACC/AHA) guidelines on hypertension also recommend an increased use of ambulatory blood pressure monitoring in order to accurately characterize circadian BP profile ,11,12.Current research supports the fact that HTN and coronary artery disease (CAD) both have inflammatory components ,14,15. PIn order to further investigate the inflammatory pathways in cardiovascular diseases, one of the most facile methods is the platelet to lymphocyte ratio (PLR). Though its initial use was that of a prognostic biomarker in oncological patients ,21, its Apart from PLR and MLR, the neutrophil to lymphocyte ratio (NLR) is a parameter with ease of determination and use in cardiovascular diseases ,39,40. TWe performed a retrospective cross-sectional study of all hypertensive patients with stable CAD referred for cardiac rehabilitation between January 2020 and June 2021 in the Cardiovascular Unit of the Clinical Rehabilitation Hospital , a nationally accredited clinic specialized in phase II-III cardiovascular rehabilitation . Our stuAll patients enrolled in the study were under optimal therapy, according to current European treatment guidelines ,45. HighAll patients underwent 24 h ambulatory BP monitoring using DMS-300 ABP . Automatic BP measurement were obtained every 30 min during daytime (07:00—23:00), and every 60 min during nighttime (23:00—07:00). Patients were instructed to remain silent and still during each automatic BP measurement. An ABPM recording was regarded valid and included in the analysis if it encompassed at least 70% successful BP recordings. Average 24 h, daytime and nighttime SBP and DBP were extracted from the ABPM report. BP dipping was computed by the following equation: (%) 100 × [ with 95% confidence intervals (CIs). Statistical analysis was performed in SPSS 20.0 .We analyzed the normality of distribution of continuous data using the Shapiro–Wilk test. Continuous variables with normal distribution are presented as mean ± standard deviation (SD). Non-normally distributed continuous variables are presented as median with interquartile range. Categorical variables are listed as number of cases (N) with percent frequency (%). An independent samples T-test was applied to compare continuous variables with normal distribution. A non-parametric Mann–Whitney’s U test was used to compare non-normally distributed continuous variables. A The study received approval from the Review Board/Ethics Committee of the Clinical Rehabilitation Hospital  (28567/21 December 2020) and of University of Medicine and Pharmacy “Gr. T. Popa” Iasi and complied with the Declaration of Helsinki. Informed consent was considered unnecessary, due to the retrospective design of this research .Our study included 80 patients  with a higher prevalence of grade 3 HTN (53%). p < 0.001, Our analysis included 36 patients with dipping pattern and 44 patients with non-dipping pattern. Among the hematological parameters, the PLR, NLR and MLR were significantly higher in the non-dipping subgroup compared to the dipping subgroup (p = 0.001). The prevalence of monotherapy and dual antihypertensive therapy was slightly increased in the non-dipper pattern subgroup, but the difference between groups did not reach statistical significance. Details are shown in All patients were under lipid-lowering and antiplatelet therapy. One third of patients (34%) were under nitrate treatment. All patients used previous prescribed antihypertensive medication during ABPM. Angiotensin-converting enzyme inhibitor (ACEi)/ angiotensin receptor blocker (ARB), beta-blockers and thiazide-like diuretics were most frequent and their use was balanced between the two subgroups. Only 12% of patients were treated with central alpha antagonists. Calcium antagonist use was significantly more frequent in patients with a dipper circadian profile, compared to non-dippers  possessObesity, diabetes and the related autonomic dysfunction are associated with a higher prevalence of non-dipping status. Furthermore, an impaired glucose metabolism also favors systemic inflammation, explaining why NLR and PLR were previously demonstrated to be useful predictors of prediabetes and diabetes mellitus ,76. HoweIn our study, both NLR, MLR and PLR values were found to be higher in patients with a non-dipper pattern. On the other hand, CRP did not significantly vary between subgroups. ACEi/ARBs were the most frequently prescribed antihypertensive classes, and had a similar distribution between our two subgroups. However, calcium antagonist use was significantly lower in the non-dipper HTN.To summarize, NLR, MLR and PLR are simple, readily available, inexpensive, and noninvasive parameters, which lately emerged as potent inflammatory and oxidative stress biomarkers. Because NLR, MLR and PLR are ratios, they are less prone to bias/variations with dehydration, over-hydration and blood specimen handling than other individual blood parameters taken separately ,55. AlthTo the best of our knowledge, our study is the first to analyze NLR, MLR and PLR levels in hypertensive patients with stable CAD. As inflammation plays a pivotal role in both hypertension and atherosclerosis, previous studies that analyzed the relationship between NLR, MLR, PLR and circadian BP variation excluded patients with CAD. Further studies should compare inflammatory biomarkers in hypertensive CAD patients with at least two different control groups: normotensive CAD patients and hypertensive patients without CAD. In our study MLR and PLR values, but not NLR values, were independent predictors for BP variability.The present study has some limitations. Principally, it is a single-center retrospective analysis that included a limited number of subjects and lacked the aforementioned control groups. Other important limitations included the use of a single determination of NLR, MLR and PLR and the lack of consideration for hsCRP, carotid intima–media thickness and other inflammatory biomarkers. Furthermore, some antihypertensive drugs possess anti-inflammatory properties and could therefore influence CRP, MLR and PLR. Although the use of different antihypertensive classes was generally balanced between subgroups, heterogeneity remained regarding the dose and the particular agent used in each patient, as well as regarding BP optimal control. For this reason, we chose not to include hemodynamic data in our study and to limit our statistical analysis to dipping versus non-dipping pattern. Although all patients tested negative for COVID-19 upon hospital admission, we did not perform COVID-19 antibody tests to accurately exclude any prior COVID-19 infection.Calcium antagonist use is associated with a higher likelihood of obtaining a physiological, dipper BP values pattern. PLR and MLR are significantly elevated in hypertensive stable CAD patients with a non-dipper BP pattern. These inexpensive and readily available laboratory parameters could prove valuable in the risk stratification of hypertensive CAD patients.


Screening processes to identify patients who have chronic kidney disease (CKD) early in the disease allow time to manage its comorbidities and complications effectively and aggressively. The Kidney Early Evaluation Program (KEEP), sponsored by the National Kidney Foundation (NKF), is a free screening program that targets people who have diabetes, hypertension, and parents, grandparents, or siblings with diabetes, hypertension, or CKD.To (1) introduce KEEP and its objectives and (2) review population data and progress with goals to date.The KEEP goals are to raise awareness of CKD, especially in high-risk patients, provide free testing, and encourage dialogue between patients and their physicians, leading to a treatment plan. Of the 55,000 patients who have been screened through KEEP, approximately 13,000 (29%), or nearly 1 in 3 patients, have been identified as having CKD. Once a patient has been diagnosed with CKD, clinicians must address risk factors such as diabetes, hypertension, and kidney-specific diseases  that contribute to the process of renal decline. The NKF through the Kidney Disease Outcomes Quality Initiative has assembled a series of guidelines addressing dialysis adequacy, vascular access, anemia, nutrition, CKD, bone and mineral metabolism, dyslipidemia, hypertension, cardiovascular disease, and diabetes.CKD is quite common but often unrecognized and undertreated, even though rigorous guidelines for diagnosis and care have been developed. Ten areas have been identified as important for optimal care of the CKD patient. Each of these areas should be addressed and closely monitored in this population: hypertension, anemia, glucose control, lipid control, smoking cessation, aspirin prophylaxis and use of a beta-blocker post-myocardial infarction, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, diet, exercise, and weight control.


Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), especially in end-stage renal disease (ESRD) patients and during the first year after transplantation. For these reasons, and due to the shortage of organs available for transplant, it is of utmost importance to identify patients with a good life expectancy after transplant and minimize the transplant peri-operative risk. Various conditions, such as severe pulmonary diseases, recent myocardial infarction or stroke, and severe aorto-iliac atherosclerosis, need to be ruled out before adding a patient to the transplant waiting list. The effectiveness of systematic coronary artery disease (CAD) treatment before kidney transplant is still debated, and there is no universal screening protocol, not to mention that a nontailored screening could lead to unnecessary invasive procedures and delay or exclude some patients from transplantation. Despite the different clinical guidelines on CAD screening in kidney transplant candidates that exist, up to today, there is no worldwide universal protocol. This review summarizes the key points of cardiovascular risk assessment in renal transplant candidates and faces the role of noninvasive cardiovascular imaging tools and the impact of coronary revascularization versus best medical therapy before kidney transplant on a patient’s cardiovascular outcome. Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), especially in end-stage renal disease (ESRD) . FurtherFinally, whether a systematic coronary artery disease (CAD) treatment before kidney transplant may improve short- and long-term cardiovascular outcomes is still under debate, not to mention that a nontailored screening could lead to unnecessary invasive procedures and delay or exclude some patients from transplantation unjustifiably .This review summarizes the key points of cardiovascular risk assessment and CAD management of renal transplant candidates, as suggested by the most representative scientific societies ,11,12,13ESRD patients have cardiovascular mortality twenty times higher than the general population . At leasAmong ACS, non-ST-elevation MI is more frequent than ST-elevation MI . Heart fSometimes these patients may complain of “atypical” symptoms or angina equivalents like dyspnea or fatigue . BesidesTraditional CVRF are highly prevalent in CKD patients. They contribute not only to the progression of the atherosclerotic process but also to kidney damage, generating a vicious cycle known as cardiorenal syndrome type 4 . Among a2 ..69].According to the recent European Society of Cardiology (ESC) Guidelines on “Cardiovascular Assessment and Management of Patients undergoing Non-Cardiac Surgery (NCS)” , the renIn conclusion, American and European scientific societies agree on a conservative screening approach for asymptomatic kidney transplant candidates with low cardiovascular risk. Stress tests and/or coronary angiography are not necessary if initial screening tests yield negative results ,13,69,70The ERBP Guideline recommends an echocardiography and an exercise tolerance test for all patients, while a stress imaging test (stress echocardiography (SE) or myocardial perfusion studies (MPS) is suggested only in cases of positive or inconclusive preliminary exams. Finally, coronary angiography is indicated if noninvasive stress imaging is positive . SE sensAccording to the 2022 Scientific Statement from the AHA , when a The ESC Guideline  considerCAD management in kidney transplant candidates is cumbersome. The main indication for revascularization is driven by the persistence of symptoms despite optimized medical therapy (OMT) and/or to improve prognosis.The management of CAD in CKD patients should be the same as in the general population ,72. NonpThe use of antiplatelets, statins, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-receptor blockers (ARB), and beta-blockers are currently recommended. The use of these drugs in waiting list patients, during the peri-operative period and late after kidney transplant guidelines is also recommended . HoweverThe Study of Heart and Renal Protection (SHARP) examined the effect of simvastatin versus simvastatin plus ezetimibe in patients with advanced chronic kidney disease without a previous coronary artery disease. The study demonstrated that lowering LDL cholesterol with simvastatin plus ezetimibe produces a 17% reduction in the primary endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization .Similarly, Sooho et al., in late-stage chronic kidney disease in a postend-stage renal disease transition population, showed that statin therapy reduces the all-cause of death and cardiovascular mortality at twelve months, as well as the hospitalization rate after initiating dialysis compared to the group of patients not treated by statins. Over 12 months of follow-up, patients who received statin therapy in the year before the transition to end-stage renal disease had a lower all-cause mortality rate , a 12% lower all-cause mortality risk in the unadjusted model , and (in adjusted models) a 17% lower risk of cardiovascular death  if compared with those who did not receive statin therapy .In recent years, sodium−glucose cotransporter 2 inhibitors (SGLT2i) have been shown to decrease both kidney and cardiovascular adverse outcomes in patients with kidney disease and heart failure ,81,82,83p = 0.00001] [p < 0.001)], and of the composite of death from cardiovascular causes or hospitalization for heart failure . Of note, the DAPA-CKD trial showed an all-cause mortality risk reduction   . Similar= 0.004] ,86.However, data about the safety and efficacy data on SGLT2i therapy in kidney transplant recipients are very limited because these studies focused predominantly on short-term outcomes, like glycemic control, body weight reduction, eGFR, and blood pressure (BP) changes. Long-term outcomes on chronic allograft function, cardiovascular morbidity and mortality, as well as graft and patient survival, remain to be explored in the future .Although a large number of previous randomized trials and meta-analyses, showed that myocardial revascularization of symptomatic patients with high-risk CAD had a better outcome compared with those treated by medical therapy only, these studies were not specifically designed for patients with end-stage renal failure on dialysis and/or waiting for renal transplantation ,90,91,92On the other hand, the KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation recommends excluding from the kidney transplant waiting list those asymptomatic patients with severe CAD unless their estimated survival meets the acceptable criteria outlined by national standards and in selected cases after successful revascularization  9]. Bey. Bey9]. Kumar et al. evaluated the role of coronary angiography in all potential transplant candidates over 50 years, and/or with diabetes, cardiovascular disease, symptoms or ECG signs of ischemia or previous myocardial infarction. Myocardial revascularization was performed in 28% of patients. At one and three-year follow-ups, the cardiac event-free survival was respectively 98.0% and 88.4% in those patients who underwent transplant after revascularization, and 94.0% and 90.0% in those on dialysis treatment and still on the waiting list .p = 0.01), stroke , and lower risk of repeated revascularization . Conversely, at four years follow-up, in the subgroup of patients on dialysis therapy, PCI had higher death , MI , and repeated revascularization  rates than CABG [Bangalore et al. compared a revascularization strategy by CABG or PCI in a cohort of 5920 patients with chronic renal failure. Compared with the CABG group, the PCI group had a lower short-term risk of death . Compared to optimized medical therapy, myocardial revascularization did not show any benefits. Finally, the recent ISCHEMIA-CKD trial  comparedHowever, the ISCHEMIA-CKD study was not specifically designed for kidney transplant candidates.p of interaction = 0.68). The authors concluded that an invasive strategy in kidney transplant candidates did not improve outcomes compared with conservative management [In a posthoc analysis of the ISCHEMIA-CKD study, Herzog et al. focused on the subgroup of patients included in the study who underwent cardiac stress testing prior to randomization as part of their assessment for kidney transplant listing. Among patients assigned to an invasive strategy versus conservative strategy, the adjusted hazard ratios for the primary outcome were 0.91  and 1.03 (95% CI: 0.78–1.37) for those listed and not listed, respectively  in renal transplant waiting list patients who underwent a second-generation drug-eluting stent (DES) implant or a bare-metal stent (BMS). According to DAPT duration, the DES group was divided into DES early interruption (three months after DES implantation) and DES late interruption (3–12 months after DES implantation); in the bare-metal stent group, DAPT duration was at least one month. No difference in myocardial infarction, death, and MACEs was found between DES-early and DES-late groups . For thiOne of the main questions still unanswered is if a systematic CAD screening among asymptomatic kidney wait-list patients can definitively improve patients’ outcomes. An ongoing randomized controlled trial named the CARSK study  will test the hypothesis that eliminating screening tests for unknown CAD is not inferior to regular screening for the prevention of MACEs of waiting list patients. By validating or refuting the use of screening tests during wait listing, CARSK will ensure judicious use of health resources and optimal patient outcomes .There is a growing use of noninvasive imaging assessment of the coronary anatomy, such as cardiac magnetic resonance (CMR) and positron emission tomography (PET), but more research is needed to precisely evaluate the sensitivity and specificity of these tests in patients in kidney transplant wait lists .Cardiovascular disease is the leading cause of morbidity and death in CKD patients. An accurate cardiovascular risk assessment of transplant candidates is mandatory to properly allocate the few available organs to those patients who have a low peri-operative transplant risk and a reasonable long-term life expectancy. However, in those more controversial cases, a multidisciplinary approach might be necessary to decide if a candidate must be maintained or excluded from the waiting list.


Coarctation of the aorta (CoA), is a congenital malformation, often combined with several cardiac abnormalities. At present, the operation effect is satisfactory, but postoperative restenosis is still a matter. Identification of risk factors for restenosis and prompt therapy adjustments may improve patient outcomes.A retrospective clinical study of patients under 12 who had CoA repair in 2012–2021, with a randomized cohort population of 475 patients.P = 0.009, HR = 0.68) and transverse aortic arch , arm-leg systolic pressure gradient ≥12.5 mmHg at discharge  were independent risk factors for reCoA.A total of 51 patients (M/F: 30/21) with a mean age of 5.33 (2.00–15.00) months and a median weight of 5.60 (4.20–10.00) kg. The mean follow-up was 8.93 (3.77–19.37) months. Patients were divided into 2 groups: no-restenosis (n-reCoA)  and restenosis (reCoA) . ReCoA was defined as a restenosis requiring interventional or surgery or a pressure gradient >20 mmHg at the repair site as reported by B-ultrasound with the presence of an upper and lower limb blood pressure gradient or growing dysplasia. The overall reCoA incidence was 25% (13/51). In multivariate COX regression, smaller preoperative z-score of the ascending aorta (The overall outcome of CoA surgery is successful. Smaller preoperative z-score of the ascending aorta and transverse aortic arch, and an arm-leg systolic pressure gradient ≥12.5 mmHg at discharge increase reCoA risk, and closer follow-up for such patients are required especially within 1 postoperative year. Coarctation of the aorta (CoA), a congenital abnormality, often occurs in the arterial catheter or arterial ligament region, which has an incidence rate of about 0.287‰ and accounts for 3.57% of all congenital cardiovascular malformations . It can P = 4V2. The Children's Hospital of Chongqing Medical University's Ethics Committee authorized the study, and all patients signed the informed consent form.This is a retrospective study of patients who underwent CoA surgical procedures at the Children's Hospital of Chongqing Medical University between 2012 and 2021. Patients were eligible if they met the following criteria: (1) age ≤12 years old, (2) had preoperative echocardiography and cardiac CT scan and three-dimensional reconstruction, (3) CoA is the main diagnosis, and (4) successful follow-up after discharge. Evaluate available data  to detect reCoA risk factors. A total cohort population of 51 people was enrolled randomly from 475 patients. Demographic data , perioperative data , and follow-up data were gathered. The surgical treatment was considered a success if patients did not die after the operation, the Doppler pressure gradient across the repair site <20 mmHg during the follow-up, and the blood pressure of the upper limb was lower than that of the lower limb, and no evidence of hypertension. The hypertension diagnostic criteria were based on the China Guidelines for Prevention and Treatment of Hypertension, the systolic blood pressure (mmHg) for boys over 100 + 2× age (years), and girls over 100 + 1.5× age (years), or taking antihypertensive agents. When the z-score of the transverse arch < −2, hypoplastic aortic arch (HAA) can be diagnosed. The pressure gradient obtained by echocardiography varies depending on the location of the constriction. Use echocardiography to determine the flow rate at the constriction, and the pressure was estimated using the simplified Bernoulli equation The suitable surgical technique was chosen based on the patient's clinical state, including combined intracardiac malformations, preoperative cuff blood pressure, medical imaging data such as ultrasonic cardiogram and CT scan, and requests of their parents. A median sternotomy method is chosen for patients with intracardiac abnormalities that require simultaneous repair and CPB. A lateral thoracotomy method is chosen for patients with intracardiac abnormalities that can be treated minimally invasively without CPB. EEEA, ESA, and PAP are the three main categories of surgical techniques. The anastomotic strain encountered throughout the procedure determines the use of certain surgical techniques. In general, patients with simple isthmus aortic coarctation are treated with EEEA, whereas those with hypoplastic aortic arch may be treated with ESA and PAP. It should be highlighted that SAR was chosen by two patients. After performing SAR on the two patients during the operation, the surgeon noticed that the invasive systolic blood pressure difference between the brachial artery and the femoral artery had returned to normal (upper limb < lower limb). The surgeon then immediately informed the patients' families of this finding and they decided to change the preoperatively decided surgical plan and adopt SAR.P < 0.2) with univariate COX regression were included in multivariable COX regression operated by stepwise regression. ROC curve was used to determine the best cutoff (Jordan index-based) with the maximum sensitivity and specificity for a critical continuous risk factor. AUC measured accuracy. ReCoA-free survival rate was conducted by Kaplan–Meier curve. The log-rank test compared patient subgroups' differences in freedom from event (reCoA vs. n-reCoA) rates. The statistically significant difference was defined as P < 0.05, and all statistical analyses were performed using SPSS26.0 software.Kolmogorov-Smirnov test examines the normality of continuous variables. Normal distribution variables were shown as mean ± standard deviation (SD), compared by Student's t-test or ANOVA. The skewed distribution variables were shown as medians , compared by the Wilcoxon signed-rank test. Chi-square test, corrected Chi-square test, or Fisher exact test compared rates or component ratios. Echocardiographic data and demographics were potential predictors. Only variables (P = 0.050). As for gender, 10 males and 3 females had reCoA (P = 0.125). And 6 of 26 VSD patients (23%) and 7 of 25 non-VSD patients (28%) had ReCoA (P = 0.687). Surgical age shows no significant difference in <1 month compared with the other two groups (P = 0.751). Variables including surgical weight and CPB time did not statistically differ (P > 0.05).The study cohort included 51 patients  with a 25% (13/51) incidence of reCoA. The median weight was 5.60 kg  and the mean age was 5.33 months . The mean follow-up was 8.93 months . Patients were divided into two groups: n-reCoA  and reCoA . P > 0.05) ( > 0.05) . We may  > 0.05) .P = 0.727). Although the mean gradient of G1 was almost identical to that of G2 one day after surgery , it was significantly higher in G2 than G1 three days after surgery  and at discharge . The gradient of G2 at discharge was about 9 times that of G1 and gradually increased during the period , while the gradient of G1 at discharge was lower than that during hospitalization (lization .P = 0.019) while almost similar preoperatively . Both groups had significantly lower velocity after the operation   .P = 0.009), which was almost comparable to G2 before surgery . Gradient made a significant reduction in both groups   .P = 0.539; Postoperative: G1: 0.60 ± 0.03, G2: 0.58 ± 0.03, P = 0.732). The diameter increased significantly in both groups at discharge   .Use ROC curve to determine which time point between pre-surgery and discharge most affected reCoA and was then included in COX regression. The arm-leg systolic blood pressure gradient, Doppler peak blood flow velocity, and pressure gradient across the repair site (at discharge) were all well affected .P < 0.2 in univariate COX regression (P < 0.05).The multivariate COX regression includes variables with gression . Among tThe Kaplan-Meier curve predicted freedom from reCoA was 70.9% after an average follow-up of 8.93 months  .The median time from discharge to reCoA was 3.77 months . All 13 patients had reCoA within one year, 1 had balloon angioplasty one year after discharge, and 1 is taking antihypertensive agents now, the other 11 patients are currently under close follow-up at the discretion of their parents.P < 0.001).The optimum cutoff for arm-leg systolic pressure gradient at discharge, based on the ROC curve and AUC area, was 12.5 mmHg, with a sensitivity of 76.9% (G2: 10/13) and specificity of 97.4% (G1: 1/38). Thus, patients with a gradient of 12.5 mmHg or higher at discharge had a significantly increased risk of reCoA during follow-up , the sixth most common CHD , may occP = 0.249), which consists of multiple studies . 11 females had reCoA (1 Turner's syndrome), which they considered difficult to explain. It has been reported that 7%–12% of Turner syndrome girls in childhood have COA   . Bacha s = 0.73) . It has P = 0.07)  . We did  = 0.07) , 19, 27.P = 0.04, HR = 5.57), while multivariate analyses did not   , and lon = 9.26) . EEEA ca = 9.26) . Meantim = 9.26) , 34 and  = 9.26) , so it m = 9.26) , 37. Res = 9.26) , 37, 38. = 9.26) , 17, 39, = 9.26) . One reCP = 0.075). Although fewer patients had SAR, we assumed that careful selection of operation according to ease patients may even prevent major surgery. Therefore, in the future, we may take more in-depth research on the morphology and hydrodynamics of the aortic arch during the perioperative period, and even pre-do the operation with Virtual Reality (VR), to allow surgeons to better determine the therapy for patients.Each strategy has pros and cons. EEEA or ESA may cause patients to suffer from large-scale surgery, which is psychologically and financially taxing. Nearly 60% of patients in this research had successful EEEA. Meantime, if we took EEEA, ESA, and PAP as radical surgery whereas SAR was considered a relative surgery. Neither was proven to be reCoA risk factor (z-score of the ascending aorta impacted reCoA (P = 0.009), which matched Kumar (P < 0.01). McElhinney agreed , but disagreed when body weight was the indicator  . Burch found that for every 1 mm increase in aortic arch transverse diameter, reCoA risk was reduced   . However = 0.57)  cannot r = 0.57) . We beliP < 0.001, log-rank = 49.06). Kumar examined blood pressure gradients at 24 h, 48 h, and 72 h following surgery and at discharge, finding that the gradient at discharge was significant compared with other points . Although we considered that in the early postoperative stage, blood pressure was unstable due to operation, anesthesia, and other factors, we think the conclusion is reliable. In the future, more precise pressure measurements can help further explore its relationship with reCoA.Arm-leg systolic blood pressure gradient ≥12.5 mmHg at discharge affected reCoA  developed reCoA within 6 postoperative months, and all within one year. Therefore, we suggested that closer follow-up is necessary for the first year postoperatively.This work is unusual because we evaluated the impacts of several parameters on reCoA and found the blood pressure cutoff and its specificity and sensitivity to better predict reCoA, which has great practical application. However, our study had several limitations. This is a retrospective study that has the inherent limitations of any retrospective study. Five congenital cardiac surgeons operated the surgical procedures and at least three different echocardiography specialists were included to take the measurements of aortic arch morphology preoperatively and postoperatively. Meanwhile, several issues need to be explored, including the best preoperative z-score cutoff of the ascending aorta and transverse aortic arch, which may be examined in a larger sample cohort. For reCoA, because the follow-up did not exactly follow the plan, the accurate reCoA time may be earlier, but all reCoA can be found within 1 year after the surgical procedure, so we think it does not affect the study results.z-score of the ascending aorta, the smaller preoperative z-score of the transverse aortic arch, or the discharge arm-leg systolic blood pressure gradient ≥12.5 mmHg make an increased risk of reCoA. We suggested more active follow-up for such patients, especially within 1 postoperative year, to detect reCoA timely.In conclusion, the smaller preoperative


Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death. In this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined.We observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range. Our results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy. MEJ Reinders was affiliated with Leiden University Medical Center at the time of the trial and is currently affiliated with Erasmus University Medical Center.Mesenchymal stromal cell (MSC) therapy has gained significant interest in kidney transplantation in recent years. MSC therapy has been investigated in several clinical research settings, either as induction therapy, treatment of acute rejection, or support of maintenance therapy allowing weaning of immunosuppressive drugs –5. In thMSCs are thought to promote immunological tolerance after transplantation and to have immune-modulatory and anti-inflammatory properties , 9, 10. de novo donor-specific antibody (DSA) development  has been identified as an interesting biomarker for rejection in solid organ transplantation . The preelopment . More reelopment . This stelopment .in vivo. Since we used third-party MSC, this study is the first to separate cfDNA for three genomes: the recipient, the kidney donor, and the MSC donor. Our results confirm the short life span of MSC in humans upon infusion.In the human setting, the fate and working mechanism of MSC remain unclear. In the current study, we measured patient, kidney donor, and MSC donor-specific cfDNA levels at several time points after MSC infusion as an indirect measure of allogeneic MSC cell death ®), and everolimus. Six months after kidney transplantation (weeks 25 and 26), patients received two doses of allogeneic MSC with a target of 1–2 × 106 cells/kg of body weight. These MSCs were specifically selected to have no repeated HLA mismatches with the kidney donor for HLA-A, HLA-B, HLA-DR, and HLA-DQ, to minimize the risk of antidonor immune response against the kidney graft. For the complete characteristics and study design, we refer to previous papers regarding the Neptune study . The final time points 5 and 6 were 1 and 8 weeks after the second infusion (Single-nucleotide polymorphism (SNP) typing to identify the three genomes was performed on genomic DNA. cfDNA was measured using the AlloSeq cfDNA assay (CareDx Inc.), which is a multiplexed polymerase chain reaction (PCR)-based method to prepare libraries for sequencing from cfDNA extracted from plasma. Following cfDNA extraction, the cfDNA was amplified using PCR primer pairs covering 202 SNP loci. Amplification was performed on a SimpliAmp (Thermo Fisher), followed by a short library preparation, consisting of a double bead purification and two ethanol washes. The resulting PCR products were sequenced on an Illumina MiniSeq instrument  with the high-output flow cell in batches of a maximum of 24 samples. The sequencing data were analyzed using CareDx AlloSeq cfDNA software, where the read counts of amplified sequences were used to measure the amount of donor-derived cfDNA relative to the total amount of cfDNA in the plasma sample.R2 of 0.91362 for clinical samples, 0.945799 for analytical samples near LoD/LoQ, and 0.999138 in linearity analysis (tested up to 70%)  and showed agreement with orthogonal results with an  to 70%) , 28.To validate the ability to accurately determine the relative levels of three sources of cfDNA, we first prepared several genomic DNA mixtures from donor/recipient couple 7 and the corresponding MSC product that was infused. Different percentages of genomic DNA derived from donor, recipient, and MSC products were tested, with donor and MSC product cfDNA as low as 0.5%. As shown in Next, we analyzed the plasma samples from all patients included in the Neptune trial.In 6 MSC/kg. The highest absolute number of MSC  was infused in recipient 10 during the second infusion, at week 26. The lowest number, 98.8 × 106 in total, was infused in patient No. 1 during the first infusion at week 25  to 93.3 kg (recipient No. 7). The mean of the number of infused MSC was 1.5 × 10in vivo. We first investigated the capacity and accuracy of the applied technique to separate three different genomes by cfDNA measurement. Until now, studies have described the separation of two different genomes, for example, derived from recipients and kidney allografts  and decline 1 week after infusion suggest that the MSC died within 7 days, which is in line with preclinical studies –12. HoweAnother important result from this study is that cfDNA derived from the kidney graft was consistently low over time, in line with the results from the DART trial (median cfDNA of 0.3% of the group without ABMR) . Only at6 cells/kg of body weight), so we assume that the variation in percentage MSC-derived cfDNA is due to patient factors rather than reflecting the absolute amount of degraded MSCs. In addition, as mentioned before, there is a possibility that not all MSCs have died and a subset survives. However, 7 days after infusion, no MSC-derived cfDNA was detectable in all patients. Future research with a combination of cfDNA measurement and cell labeling would probably help to address this point. Besides the fate of MSC, more insight into the actual working mechanism is interesting. Previously, it has been shown that apoptosis, dependent on IDO activity, seems to be an important factor for the immunomodulatory effect of MSC (The study has several limitations. The amount of MSC-derived cfDNA is expressed as a percentage of total cfDNA and not as an absolute amount. This means that we were not able to investigate the relative number of MSCs that died. However, the amount of MSCs infused was comparable in all patients (1.5 × 10t of MSC –34. ThisSince this is the first study to separate three genomes with cfDNA measurement, this sets the stage for further research in transplantation, especially in studies using third-party products. Furthermore, this study shows that in the setting of clinical kidney transplantation, MSCs perish shortly after infusion, suggesting that their mechanism of action is an indirect process. It is important to further investigate this process, as it may open the possibility of developing therapies specifically directed at the downstream processes. This may ultimately result in the development of cell-free treatments with the same results but without the risks associated with cellular therapies.The datasets presented in this article are not readily available due to storage restrictions of the original data from the Neptune study, following the rules of the CCMO. Requests to access the datasets should be directed to the principal investigator of the study.The studies involving humans were approved by the local ethics committee and by the Central Committee on Research involving Human Subjects. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.GD: analyzed the data and wrote the manuscript. JD: performed the experiments. JF, CK, MR, and SH: designed the study and co-wrote the manuscript. All authors contributed to the article and approved the submitted version.


Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics , we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.The mammalian target of rapamycin inhibitors  are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions . Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival  and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several  New-onset diabetes after transplantation (NODAT) refers to the occurrence of diabetes in previously non-diabetic clinically stable kidney transplant recipients who had been discharged from the hospital and tapered to their maintenance immunosuppressive therapy .It occurs in almost 4% to 27% of kidney transplant recipients  and it mTo diagnose NODAT, the International Consensus Guidelines published in 2003 recommended to use the same diagnostic criteria adopted by the American Diabetes Association and the World Health Organization (ADA/WHO) for type 2 diabetes in non-transplant patients: fasting glucose ≥126 mg/dL (7 mmol/L) on more than one occasion, random glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms, two-hour glucose after 75 g oral glucose tolerance test of ≥200 mg/dL (11.1 mmol/L), and hemoglobin A1C (HbA1c) ≥ 6.5%  (Risk factors for PTDM are similar to those for type 2 diabetes mellitus: increased age (>40 years), family history of type 2 diabetes, ethnicity , abnormal glucose tolerance (expressed by fasting blood sugar levels between 90 and 100 mg/dL), and specific genetic factors –12.Other risk factors for PTDM include the metabolic syndrome and the obesity, responsible for the insulin resistance and the glucose intolerance. Indeed, the adipose tissue from obese subjects increases the expression of Tumor Necrosis Factor-α (TNF-α) , which dAlso, viral infections may increase the risk of PTDM. Hepatitis C virus (HCV)  infectioHowever, in kidney transplant recipients, the administration of immunosuppressive drugs may further impact the incidence of PTDM. Corticosteroids (administered at high dosages as part of the induction therapy and/or for treating acute rejection and as main constituent of the maintenance immunosuppressive protocol) and calcineurin inhibitors  are the main responsible for this complication, while the diabetogenic effects of mammalian target of rapamycin inhibitors (mTOR-Is) are still debated .mTOR inhibitors  exert their pharmacological effects via inhibition of the serine/threonine kinase mammalian target of rapamycin (mTOR). mTOR integrates signals from growth factors, hormones, nutrients, and cellular energy levels to regulate protein translational and cell growth, proliferation, and survival . mTOR exmTORC1 also includes RAPTOR , 25, MLSThis complex is less sensitive to the acute treatment with mTOR-Is, while long-term administration of these medications inhibits mTORC2 activity by acting on complex integrity , 32.The use of mTOR-Is as immunosuppressants in solid organ transplantation is mostly based on their ability to block cell cycle progression from G1 to the S phase and cellular proliferation . AdditioBecause of their specific pharmacological characteristics, mTOR-Is are highly effective in renal transplantation, and owing to their relative lack of nephrotoxicity, these inhibitors are a valid alternative to CNIs for the maintenance of immunosuppression in renal transplant recipients with chronic allograft nephropathy .Although the clinical utility of this drug category is clear, as other immunosuppressive drugs, mTOR-Is may persuade the development of some adverse effects that need to be immediately recognized and treated to avoid severe illness in kidney transplant recipients.in vitro and in animal models, mTOR-Is may decrease beta-cell mass through an increment of the rate of apoptosis  activate mTORC1 through the IRS/PI3K/Akt pathway . The mTOPsammomys obesus) worsened the metabolic state of the diabetic animals: augmented insulin resistance, β-cell dysfunction, and death, thereby preventing β-cell adaptation to hyperglycemia -1alpha, cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 2 (CRTC2), and forkhead box O1 (FoxO1) .in vitro and in vivo studies have revealed the association between adipogenesis and the mTOR pathway  partially restored the detrimental effects on metabolism with enhanced insulin sensitivity, increased oxygen consumption, and improved serum lipid profile with a certain degree of glucose intolerance .Furthermore, in several maintenance immunosuppressive therapeutic protocols, mTOR-I are combined with CNIs.Numerous observations have reported that CNIs treatment may lead to PTDM by a multifactorial mechanism, which includes impaired insulin secretion, insulin resistance, altered glucokinase function, mitochondrial impairment, and pancreatic β-cell apoptosis –79.The mechanism in pancreatic insulin-secreting β cells seems to be mediated by the inhibition of two targets of calcineurin: nuclear factor of activated T-Lymphocytes (NFAT) and cAMP responsive element binding protein (CREB) . Both trAdditionally, pancreatic islets treated with CNIs showed significant morphological alterations in the form of cytoplasmic swelling and vacuolization, degranulation, and immunohistochemical and ultrastructural loss of secretory granules , 86.Tacrolimus (TAC) appears also to reduce insulin secretion through a downregulation of the production of ATP and glycolysis due to a reduced activity of glucokinase, a rate-limiting enzyme in glycolysis that represents an important glucose sensor in pancreatic β-cells .The diabetogenic effect of TAC can also be enhanced by mitochondrial dysfunction through a decrease in both mitochondrial respiration activity and mitochondrial mass .Most studies comparing the diabetogenic effects of the CNIs report higher rates of PTDM among patients receiving TAC compared to cyclosporine A (CsA) –90.During the last two decades, mTOR-Is (mainly Everolimus) have been widely used as part of the maintenance immunosuppressive therapy of kidney transplant recipients and clinical studies/trials have investigated their possible pathogenetic impact on PTDM .p = 0.07) (p = 0.69)  . Instead = 0.69) . This stde novo renal allograft recipients demonstrated higher incidence of PTDM in TAC recipients confirming a diabetogenic effect of TAC compared to SRL  also described no differences in the incidence of hyperglycemia and insulin-dependent PTDM in patients treated with SRL compared to CsA . The evad to SRL . These rAlso in the conversion trials, the switch from CNI to mTOR-I has not shown clear diabetogenic effects. However, some authors have reported an increased risk of PTDM in mTOR-I-treated patients due to a drug-related enhancement of peripheral insulin resistance and impairment of the compensatory beta-cell response .In both CONCEPT and ZEUS studies, the early conversion from CsA-based to SRL-based therapeutic regimen (3 or 4.5 months after transplantation) did not induce PTDM in a 12 months-period post-transplantation , 99.p = 1.000)  study, where the renal allograft recipients were randomly assigned (2:1) to undergo conversion from CsA- or TAC-based immunosuppression to SRL or to continue receiving CNI-based therapy for 2 years, the frequency of PTDM was similar between the two study regimens  .Holdaas et al., in the ASCERTAIN study, which included kidney transplant patients with allograft impairment (GFR 30–70 mL/min) who underwent the minimization of CNI or conversion to Everolimus (EVR), reported a percentage of patients with PTDM of 4.7% in the CNI withdrawal group, 4.9% in the minimization group and 3.3% in the control group .All these studies –101, altNevertheless, a recent systematic review and meta-analysis established that the conversion from CNIs to mTOR-Is did not significantly decrease the risk of PTDM .Instead, Veroux et al.  showed tUnfortunately, also the impact of the combined therapy of mTOR-Is plus CNIs on PTDM is still argued.de novo renal transplant recipients, reported a higher incidence of PTDM in patients receiving 3 mg/day EVR (12.6%) compared to those receiving a low dose of EVR (6.7%) and MMF (5.6%)  vs. MMF (2 g/day) along with CsA microemulsion  and corticosteroids in F (5.6%) .p = 0.005). However, the number of patients requiring insulin for PTDM was similar in the TAC/SRL 2 mg and TAC/MMF groups (p > 0.05)  with a TAC plus MMF immunosuppressive schema, authors found that a larger number of patients treated with TAC plus SRL at 2 mg developed PTDM ( > 0.05) .N = 318) or TAC with MMF (N = 316), 6 months’ creatinine clearance was comparable between the 2 immunosuppressive schemas. Biopsy-confirmed acute rejection was 15.1% (TAC/SRL) and 12.3% (TAC/MMF). In both groups, graft survival was 93% and patient survival was 99%. Premature withdrawal due to an adverse event was twice as high in the TAC/SRL group (15.1% vs. 6.3%). The incidence of any antidiabetic treatment for >30 consecutive days in previously nondiabetic patients was 17.8% in TAC/SRL, and 24.8% in TAC/MMF , while a slightly smaller percentage of PTDM was registered in the TAC/MMF group (19%) than TAC/SRL (32%) and CsA/SRL (31%) group. However, difference did not reach any statistical difference (p = 0.16)  to compare TAC/SRL, TAC/MMF, and CsA/SRL. In this report, the incidence of PTDM was not significantly different among the three groups ( = 0.16) . These r = 0.16) , 108.de novo renal-transplant recipients were randomized to EVR 1.5 or 3 mg/day  with reduced-exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard-exposure CsA. The overall incidence of PTDM and adverse events were comparable between the groups. Corticosteroids were used in more than 99% of patients in each group during the study, with more than 70% receiving corticosteroids without discontinuation throughout the 24-month study period  within 24 h of transplantation to receive EVR with reduced-exposure CNI (EVR + rCNI) or mycophenolate with standard-exposure CNI, the incidence of PTDM was similar in both the arms (19.6% vs. 18.6%) (In the recent TRANSFORM (Transplant efficacy and safety outcomes with an EVR-based regimen) study, a 24-month, prospective, open-label trial in 2037 . 18.6%) . Even if. 18.6%) . This stAfter reviewing the available literature on this topic area, we cannot draw any definite conclusions about the diabetogenic impact of the mTOR-Is. However, we can encourage clinicians to lower the dose of these immunosuppressive drugs in patients at high risk of PTDM. Moreover, our paper shows that the transplant scientific community should undertake more research programs to better study this important topic.SG, SM, DT, and GZ searched the literature and wrote the manuscript. GZ, GS, and LG revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.