While acute kidney injury (AKI) after hematopoietic cell transplant (HCT) has been well-described in pediatric patients, literature regarding the long term renal consequences of HCT-related AKI, the development of chronic kidney disease (CKD), and CKD care in pediatric patients post-HCT is limited. CKD affects almost 50% of patients after HCT with multifactorial etiology including infection, nephrotoxic medications, transplant-associated thrombotic microangiopathy, graft-versus-host disease, and sinusoidal obstruction syndrome. As renal function declines in CKD, eventually progressing to end stage kidney disease (ESKD), mortality increases and is more than 80% among patients requiring dialysis. Using society guidelines and current literature, this review summarizes definitions and etiologies of and management strategies among patients with AKI and CKD post-HCT with an emphasis on albuminuria, hypertension, nutrition, metabolic acidosis, anemia, and mineral bone disease. The goal of this review is to aid early identification and intervention in patients with renal dysfunction prior to development of ESKD, and to discuss ESKD and renal transplant in these patients post-HCT. According to the Center for International Blood and Marrow Transplant Research, between 2008 and 2014, there were over 4400 pediatric allo-HCTs across 119 centers in the United States . In a pr2Patients who undergo HCT have unique risk factors for AKI in addition to those of the general population. These can include nephrotoxic medication exposures such as antimicrobials, preconditioning chemotherapy, use of biologics or immunotherapies, radiation therapy possibly leading to radiation nephropathy, and use of calcineurin inhibitors (CNIs) as prophylaxis for graft-versus-host-disease (GVHD) . Mechani2.1Transplant-Associated Thrombotic Microangiopathy (TA-TMA) is characterized by endothelial dysfunction leading to microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and multiorgan dysfunction typically within the kidneys, lungs, gastrointestinal (GI) tract, and central nervous system . ClinicaTA-TMA can be renally limited, but this does not always correlate with a rise in serum creatinine level. Kidney biopsy may be required to confirm the underlying diagnosis, especially in cases that exclusively involve the kidneys . A majorRisk factors for TA-TMA include high dose conditioning regimen, high dose chemotherapy, total body irradiation, donor type , HLA mismatch, CNI use, acute GVHD grade 2 to 4, and viral or other infections  . Infecti2.2GVHD is classically known to affect major organs including the skin, liver, and GI tract, but the kidney can also be involved. GVHD can present in the kidney as AKI, nephrotic syndrome, glomerulonephritis, or TA-TMA . Typical2.3Sinusoidal Obstruction Syndrome (SOS), previously known as hepatic veno-occlusive disease, occurs after endothelial injury within hepatic sinusoids and hepatocytes in zone 3 of the hepatic acinus causes hepatocellular necrosis, fibrosis, and vascular occlusion. Left untreated, this can result in liver failure, hepatorenal syndrome, multiorgan failure, and eventually death . This reDiagnostic criteria for SOS in children by the European Society of Blood and Marrow Transplantation (EBMT) was first proposed in 2017 and includes 2 or more of the following: thrombocytopenia , unexplained weight gain for 3 consecutive days despite diuretics or weight gain >5% from baseline, hepatomegaly above baseline (best if confirmed on imaging), ascites above baseline (best if confirmed on imaging), and rising bilirubin above baseline on 3 consecutive days or bilirubin ≥ 2mg/dL within 72h . EBMT pe2.4Viral infections can cause a variety of renal conditions. BK virus or adenovirus are common causes of hemorrhagic cystitis (HC). HC presents with hematuria, dysuria, flank pain, and potentially AKI. Risk factors for BK virus HC (BKV-HC) include treatment with rabbit thymocyte globulin, high BK virus levels, cord-blood or peripheral blood stem cell transplant, presence of GVHD (grade 2 to 4), age greater than 7 years old, and concurrent infection with other viruses. BKV-HC among pediatric patients is reported between 9.9% to 21.3% of patients after HCT , 28. RudPlasma BK virus levels are more indicative of renal involvement than urine BK virus levels. A prospective pediatric study by Cesaro et al. found plasma BK is predictive with a viral load of 10,000 copies/mL significantly associated with BK-HC in multivariate analysis , and BKV-HC associated with significantly higher risk of mortality  . A retro3Kidney injury associated with HCT has a prevalence of 10-70% in adult literature with median time to onset of AKI 33 to 38 days after transplantation . In pedi3.1There are several criteria published in the literature to diagnose AKI. These include the risk, injury, failure, loss of kidney function, and end stage kidney disease (RIFLE) system, the acute kidney injury network (AKIN) criteria for kidney injury, and KDIGO criteria , 31. As While current KDIGO criteria relies on SCr and increasing duration of oliguria to detect AKI, SCr can be a suboptimal AKI biomarker. SCr indicates actual loss of kidney function from an injury that occurred 48-72 hours prior and overestimates GFR due to tubular secretion. SCr is also impacted by sex, age, height, protein intake, and muscle mass –33. The Alternative biomarkers have been studied for more accurate diagnosis, but many are not currently available for widespread use. These include tubular injury biomarkers like urinary Neutrophil gelatinase-associated lipocalin (NGAL), urinary N-acetyl-beta-D-glycosaminidase (NAG), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP-7). Data also exists for urine CXCL10 and CXCL9 in identifying AKI after HCT . Biomark3.2Prior to HCT, renal function should be evaluated with baseline SCr and CysC as well as imaging to evaluate for structural renal abnormalities with ultrasound. Having a pre-HCT baseline SCr and CysC allow for more accurate staging and recognition of AKI post-HCT. During initial HCT admission, we recommend routine application of KDIGO AKI criteria to identify patients during earlier stages of AKI when intervention may prevent requirement prolonged AKI, severe AKI, or requiring renal replacement.Those patients who are found to have an elevated creatinine post-HCT compared to their pre-HCT baseline should undergo further investigation to determine the cause, typically with a combination of urine studies , serum studies , haptoglobin, and drug levels of calcineurin inhibitors, if applicable), serum viral studies for BK virus and adenovirus DNA, renal ultrasound (to assess for kidney size and look for signs of obstructive uropathy), and, if diagnosis is still unclear, possibly kidney biopsy , 19. If 4KDIGO practice guidelines recommend management of AKI based on stage of AKI. For those patients at risk of AKI, nephrotoxic agents should be discontinued where clinically possible, effective circulating volume should be optimized to ensure adequate perfusion pressure, functional hemodynamic monitoring should be considered, serum creatinine and urine output should be monitored closely, hyperglycemia should be avoided due to risk of osmotic diuresis, and radiocontrast should be avoided when clinically possible. Diagnostic workup should be considered starting at stage 1 AKI with possible changes in drug dosing by stage 2-3 and consideration for ICU admission and/or renal replacement therapy (RRT) .4.1Among children with AKI after HCT, increased fluid overload is independently associated with worse clinical outcomes and increased mortality . Based o4.2Several adult, and combined adult and pediatric studies, have shown that the degree of renal failure is associated with mortality, and mortality can be as high as 84% , 50. A m4.3Targeted interventions focused on suspected etiology of AKI should also be performed. Nephrotoxic agents should be minimized or avoided as clinically able. For clinically necessary but potentially nephrotoxic medications, drug levels should be monitored closely with dosing adjusted based on estimated renal function. Glomerulonephritis due to GVHD can be treated with high dose prednisone and/or calcineurin inhibitors. Rituximab use has been described as well . For SOSFor TA-TMA, especially secondary or drug-induced, management should focus on withdrawal of the inciting agents such as calcineurin inhibitors, antimicrobial treatment for any active infection, and maintenance of metabolic balance by correcting fluid overload. There is limited evidence for the use of plasma exchange which has unclear benefit  while Eculizumab has been shown to improve outcomes in severe TA-TMA with 1 year survival and case reports supporting its use . However4.4Early nephrology involvement is recommended given even mild AKI can be associated with residual kidney damage. If etiology is unknown, biopsy should be considered if there is significant or persistent AKI after HCT. Biopsy could provide evidence of kidney involvement by GVHD, TA-TMA, or viral infections, allowing for more targeted treatment. Given most processes in the kidney leading to AKI are inflammatory, early identification and targeted treatment can help reduce duration of inflammation, reducing the progression to fibrosis and eventual irreversible kidney damage with loss of renal tubules and glomerular function . Recurre5It is important to identify those patients who have progressed from AKI to CKD due to the long term health implications and complications of CKD that require closer monitoring. Krist-van Holthe et al. found that high SCr within 3 months of HCT correlated with CKD at 1 year after HCT, so it is important to follow high risk patients long-term who have had prior AKI .5.12) or one or more markers of kidney damage  (2), we recommend a similar monitoring and management strategies for these patients as they are still at risk of progressive renal dysfunction.The National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) consensus guidelines from 2012 define CKD as at least 3 months of either decreased GFR (GFR < 60ml/min/1.73mntation) . It shou5.2CKD is common among pediatric patients post-HCT with an incidence of 48% between 6mo and 10yr following HCT and with typical etiologies being idiopathic, TA-TMA, nephrotic syndrome, AKI, and drug toxicity usually attributed to calcineurin inhibitors . CKD cau5.3As shown in 5.4Similar to AKI management, it is important to slow progression of CKD by minimizing nephrotoxic exposures and AKI episodes, dosing medications based on estimated GFR, measuring drug levels when available, ensuring adequate hydration, optimizing blood pressure, and minimizing proteinuria. If hypertension and proteinuria are identified, initiation of an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) is recommended as this has been shown to be renoprotective long term at slowing progression of CKD, especially among those patients with significant proteinuria . All pat5.5Albuminuria is associated with progression of CKD as well as decreased post-transplant survival . DevelopAlbuminuria after HCT can occur as early as 2mo post-transplant, but typically occurs 6-12mo post-transplant which is temporally associated with discontinuation of immunosuppressive GVHD prophylaxis. Typical presentations include glomerulonephritis or nephrotic syndrome (NS). NS presents as proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. NS in a patient who has undergone HCT should be evaluated with a renal biopsy as 60-80% of cases are due to membranous nephropathy, followed by 22% with minimal change disease . NS usuaIf macroalbuminuria  is detected, then the patient should be started on an ACE-I or ARB, and albuminuria should be monitored every 3-6 months. Macroalbuminuria can be a marker of renal GVHD, so it may be useful to continue immunosuppression after 100 days after transplantation even if there is no other evidence of GVHD in other organ systems . Macroal5.6th percentile for sex, age, and height as measured on at least 3 occasions. HTN incidence has been reported as high as 80% in the first 2 years post-HCT in pediatric patients, typically occurring 1 month after HCT , and infter HCT . A long fter HCT .BP should be checked using validated pediatric equipment with correct cuff size and position on upper extremity, as able. Ideally, patients should be seated with their feet on the floor and with arms and back supported. Patients should be relaxed and not talking or moving for at least 5 minutes prior to BP being measured . For youth percentile for age, sex, and height. First line chronic antihypertensives in CKD are typically renin-angiotensin-aldosterone system antagonists (e.g. ACE-I and ARBs), and calcium channel blockers are also commonly used. Patients should be provided medical grade BP monitor for home and instructed to track daily BP log with notification parameters for high or low BP values. After BP monitor is obtained, it should be brought to clinic to confirm correlation with in-office BP monitor. If patient does not have electrolyte derangements requiring sodium supplementation, sodium restriction to <2g/day or adjusted for body size based on dietitian evaluation is also recommended  or to standard BP control (24 hour MAP 50th-99th percentile) using ramipril. The primary composite endpoint of 50% GFR decline and ESKD favored the intensive BP arm   .Children with systemic HTN have a narrower range of autoregulation in cerebral blood flow and an increased risk of cerebrovascular dysfunction, making them more susceptible to posterior reversible encephalopathy syndrome (PRES) . PRES pr5.7Patients with CKD are at increased risk of protein energy malnutrition which can significantly impact linear growth, neurocognitive development, and sexual development . For patGrowth parameters should be evaluated at least twice per year with greater frequency among patients with acute medical issues, polyuria, concern for growth delay, declining or low BMI, or decreased nutritional intake . InfantsPersistent metabolic acidosis can contribute to short stature and decreased linear growth potential, so patients with CKD stage 2-5 should have serum bicarbonate corrected to at least 22 mm/L , often times requiring bicarbonate supplementation to achieve these goals. Typically in conjunction with endocrinology, initiation of recombinant human growth hormone (rhGH) therapy can be considered in patients with short stature (height SDS < 1.88 or height for age <3%ile) or linear growth failure (height velocity for age SDS < -1.88 or height velocity for age <3%ile) persisting for at least 3 months despite correction of metabolic derangements and nutritional deficiency. Contraindications to rhGH include pre-existing intracranial hypertension that could be worsened by rhGH, closed epiphyses, severe secondary hyperparathyroidism (PTH > 500pg/mL), proliferative or non-proliferative diabetic retinopathy, active malignancy, acute critical illness, within 1 year after renal transplantation, or known hypersensitivity to any component of rhGH medication .5.8As renal function declines, the kidneys are unable to synthesize adequate levels of erythropoietin which can lead to a progressively more severe anemia. Anemia is associated with increased mortality and hospitalization frequency in both adults and children. Left untreated, anemia can lead to cardiovascular dysfunction, decreased quality of life, impaired cognition, and reduced exercise capacity . HemogloThe diagnosis of anemia in children with CKD varies depending on age. Regardless of age or CKD stage, the evaluation for anemia should include: complete blood count , absolute reticulocyte count, serum ferritin level, serum transferrin saturation (TSAT), serum vitamin B12 and folate levels . After iLimited pediatric randomized control trials (RCTs) show improved hemoglobin level, decreased transfusion need, and a positive correlation between hemoglobin changes and health related quality of life changes among those who received ESAs, but these RCTs had short treatment and follow-up periods , increased risk of thromboembolic complications , suggestive but not robust evidence of increased risk of hypertension , but insufficient evidence about ESA effect on tumor response  . A large5.9Based on the National Kidney Foundation KDIGO work group, patients with CKD, especially stage G3a-G5D, have significantly higher fracture rates than the general population, and infants and children with CKD suffer growth retardation and severe short stature , 74. PatMany studies have also shown an increased risk of all-cause mortality in patients with increased levels of serum phosphate. Due to this, regular and comprehensive evaluation for CKD-MBD should include serum calcium (Ca), serum phosphate (Phos), serum parathyroid hormone (PTH), serum alkaline phosphatase activity (AlkPhos), and serum 25-hydroxyvitamin D levels (25(OH)D). Patients with CKD stage 5 should also be evaluated for fracture risk, sometimes including bone mineral density testing assessing for osteoporosis. Routine evaluation for CKD-MBD should begin at CKD stage 2. For patients with CKD stage 3-5, frequency of evaluation should be based on rate of progression of CKD, magnitude of abnormality, and baseline levels. More frequent monitoring may be required to assess treatment efficacy and side effects. Serum 25(OH)D < 30 ng/mL should be supplemented with ergocalciferol (Vitamin D2) or cholecalciferol (Vitamin D3).6The prevalence of ESKD in adult HCT patients is as high as 4% of patients with CKD . PediatrPrior to renal transplantation, evaluation for pre-existing immune system impairment should take place when deciding on immunosuppressive agents following renal transplantation. The source of HCT  and renal transplant  can be thought of as biologically distinct groups, especially considering the differences in conditioning regimen . Given tAdult data suggests favorable outcomes after renal transplantation in patients who have undergone HCT , 88, 89.Pediatric literature is limited, but Thomas et al. discusses their single center experience with 3 pediatric patients and Bunin et al. describe 2 pediatric patients Table 4 7Patients undergoing hematopoietic stem cell transplant have unique risk factors for AKI including frequent nephrotoxic exposure, sinusoidal obstruction syndrome, graft-versus-host-disease, and transplant-associated thrombotic microangiopathy, and viral infections such as BK viremia. These patients are at risk for progression to CKD and ESKD. Renal transplantation after HCT has had favorable outcomes in adults with limited pediatric data.8Pediatric patients post-HCT are a growing group of high-risk patients who may progress to CKD, ESKD, and potentially renal transplantation in their lifetime. Future studies should focus on better characterizing renoprotective strategies and timely interventions within this population that are distinct from patients with CKD who have not undergone HCT.The corresponding author is responsible for ensuring that the descriptions are accurate and agreed upon by all authors. The authors have contributed in multiple roles. KV is responsible for writing the original draft and literature search. JA and CJ are responsible for literature search and editing for the original draft. All authors contributed to the article and approved the submitted version.


Patients with heart failure (HF) are generally at higher risk of developing type 2 diabetes and having uncontrolled blood glucose. Furthermore, the prevalence of uncontrolled blood glucose in patients with HF is largely unknown. Identifying the factors associated with poor blood glucose control is a preliminary step in the development of effective intervention programs. The current cross-sectional study was conducted at two major hospitals to explore the factors associated with blood glucose control among patients with heart failure and type 2 diabetes. In addition to sociodemographic, medical records were used to collect medical information and a validated questionnaire was used to evaluate medication adherence. Regression analysis showed that poor medication adherence  and increased white blood cells count  were associated with poor glycemic control. For enhancing blood glucose control among patients with HF and diabetes, future intervention programs should specifically target patients who have high WBC counts and poor medication. Heart Failure (HF) is a cardiovascular disease (CVD) that results from cardiac abnormalities that lead to reduced cardiac output and/or elevated cardiac pressures at rest or during physical stress , therefoDiabetes mellitus is a global public health concern and the seventh leading cause of death worldwide , 12. It Several factors have been identified to be associated with poor glycemic control in patients with diabetes in the literature. A study conducted in Ethiopia found that poor glycemic control was associated with illiteracy, and longer duration of diabetes . AnotherThe current cross-sectional study was conducted at the outpatient cardiology clinics in King Abdullah University Hospital and Al Bashir Hospital in the period from August 2021 through April 2022. The study timeline illustrates the research development and implementation steps throughout the study period .Consecutive sampling technique was utilized in the present study. Patients who had HF and type 2 diabetes for at least 6 months, aged 18 years or older, had a cardiologist’s assignment of NYHA classification, were taking at least one HF medication, and agreed to participate in the study were invited to participate in the study. Patients with acute decompensation of HF or an active listing for heart transplantation and patients with cognitive impairment were excluded from the study. Eligible patients were informed that participation is voluntary, they have the right to withdraw at any time, and their medical care and treatment will not be affected whether they participate or not. They were also informed that the collected data would only be used for research purposes and would be saved at the Principal Investigator’s office to ensure confidentiality. Each interview took approximately 10–15 minutes to be completed. An informed consent form was obtained from each patient agreed to participate in the study.The ethical approval was obtained from the Institutional Review Board (IRB) of KAUH at Jordan University of Science and Technology (Ref. # 32/141/2021).The trained researcher HH used a custom-designed questionnaire and utilized the medical records to collect information about participants’ age, gender, body mass index (BMI), marital status, place of residency, living arrangements, education, occupation status, monthly income, smoking status, physical activity at an average of 30–45 minutes of walking per day on most days of the week, and family history of cardiovascular diseases.The collected information also included NYHA heart failure classification, duration of HF, the presence and number of other comorbidities such as hypertension, diabetes, ischemic heart disease, chronic kidney disease, dyslipidemias and thyroid dysfunction. The researcher also collected information about the received medications, total number of medications, number of heart failure medications, frequency of taking medications, medications side effects, fears of medications side effects, medications satisfaction. The medical records were used to obtain biomedical data and laboratory tests including low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, total cholesterol, hemoglobin HbA1c, random blood glucose, systolic blood pressure, diastolic blood pressure, ejection fraction, serum creatinine, white blood cells, red blood cells and hemoglobin (Hb). Based on the American Diabetes Association guidelines of HbA1c target in patients with diabetes and coexisting chronic disease, the patients were considered to have controlled blood glucose if HbA1c was < 8%. We defined uncontrolled diabetes as an HbA1c ≥ 8.0% in accordance with recommendations from the American Diabetes Association and the AHA/HFSA , 30.This instrument was used to assess patients’ commitment to take their medications as prescribed; this simple, validated survey contains 4 questions, each question indicated a reason for medication omission such as forgetting, carelessness, or stopping when feeling better or worse . One scoUsing the Statistical Package for the Social Sciences (SPSS version 26 from IBM), descriptive and analytical statistics were conducted. Using the term of the mean (standard deviations), and frequencies (percentages) for descriptive analyses, continuous and categorical variables were described, respectively. The study sample’s differences according to glycemic control were tested using the independent sample t-test for normally distributed continuous variables and the Mann–Whitney U-test for non-normally distributed continuous variables. To figure out if there is an association between categorical variables and glycemic control, the Pearson Chi-square test was constructed, and the variables with a p-value < 0.2 were entered into the binary logistic regression to investigate the significant and independent predictors of glycemic control. Significance level was determined at P<0.05.Out of 428 patients who were diagnosed with HF and type 2 diabetes, a total of 242 patients agreed to participate in the present study. The mean age was 64±10. The majority of the participants were males (59.1%), married (95%), living with their families (94.6%), living in the city (69.8%), did not complete their education (74%), unemployed or retired (81%), had a monthly income less than 500 JD (70.2%), non-smokers (73.1%), and were not physically active (88%). As shown in Tables According to the 4-item Medication Adherence Scale, the majority of the patients showed moderate adherence to HF medications (83.9%), 10.7% showed low adherence, while only 5.4% had high medication adherence. Results showed that 118 patients (48.8%) were considered to have controlled blood glucose (HbA1c < 8.0%) and 124 patients (51.2%) were considered to have uncontrolled blood glucose (HbA1c ≥ 8.0%). The variables that were significantly associated with glycemic control in the univariate analysis were age (P<0.01), gender (P<0.05), and WBC count (P<0.05). Binary logistic regression was conducted to explore the variables that were significantly and independently associated with glycemic control. Variables with P<0.2 in the univariate analysis including age, gender, smoking status, NYHA classification, thyroid dysfunction, ACEIs/ARBs use, MMAS-4, TGs level, HDL level, WBC count, and EF were included in the multivariate analysis model. Results revealed that patients who were moderately adherent had lower odds to be in the uncontrolled type 2 diabetes group when compared to patients who were poorly adherent , and higher levels of WBC increased the odds to be in the uncontrolled type 2 diabetes group . Poor glycemic control has been associated with a negative impact on diabetic patients and the healthcare system, including increased healthcare costs, increased medication costs, and higher rates of hospitalization . Around The current study results found that nearly half of the patients who suffer from type 2 diabetes along with HF had poor glycemic control (48.8%), which was consistent with the findings reported in a US study that involved diabetic patients with a primary diagnosis of HF . AnotherOur study results revealed that poor medication adherence was significantly associated with poor glycemic control. Consistent results were reported in a cohort study of over eleven thousand patients with type 2 diabetes who were followed from 1994 to 2006 and were found to have poor glycemic control due to medication non-adherence . AnotherAnother significant predictor of poor glycemic control in the present study was the presence of a higher white blood cell count (WBC). Elevated WBC count may reflect chronic low-grade inflammation that involves the activation of the immune system and the release of inflammatory cytokines, which was thought to play a role in insulin resistance and type 2 diabetes pathogenesis , 46. An The current study has some limitations, since it is a cross-sectional study, cause-effect relationship cannot be established. Furthermore, due to social desirability bias, the self-report method used in the current survey may have affected the accuracy the data. Despite these limitations, this study provided unique insights into the predictors of poor glycemic control among Jordanian patients with HF and type 2 diabetes.Glycemic control in patients with type 2 diabetes and HF was inadequate in this study. Medication non-adherence and high WBC count were found to be associated with poor glycemic control. Future intervention programs should emphasize the importance of medication adherence in controlling blood sugar, particularly in patients with elevated WBCs count. Further prospective intervention studies need to address whether good glycemic control and reducing inflammation would have a positive impact on patients with HF and type 2 diabetes.


Microalbuminuria is an abnormal increase in albumin excretion rate with a specific range of 30-299 mg of albumin/g of creatinine or excretion of 20-200 mg/l of albumin in spot urine samples. Diabetic patients with microalbuminuria are at increased risk for cardiovascular death as compared with normoalbuminuria. The aim of this study was to find out the prevalence of microalbuminuria among patients visiting the Department of Nephrology in a tertiary care centre.This is a descriptive cross-sectional study conducted among diabetic patients visiting the Department of Nephrology in a tertiary care centre after obtaining ethical approval from the Institutional Review Committee (Reference number: 04072022/04). The study was conducted between 1 October 2022 to 30 November 2022 where patients providing written consent and had documented diabetes were included in the study whereas patients without documented diabetes, having comorbidities such as congestive heart failure, nephritic/nephrotic syndrome and those who refused to give consent were excluded from the study. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.Among 103 patients, microalbuminuria was found to be in 19 (18.45%) . Out of 19 patients, 8 (42.11%) were male and 11 (57.89%) were female. The mean HbA1c among participants with microalbuminuria was 7.67±0.67%.The prevalence of microalbuminuria among diabetic patients was similar to other studies done in similar settings. Adults with diabetes have a cardiovascular risk that is 2-4 times higher than that of adults without the disease.The aim of this study was to find out the prevalence of microalbuminuria among patients with diabetes mellitus visiting the Department of Nephrology in a tertiary care centre.This was a descriptive cross-sectional study conducted in the Department of Nephrology at Kathmandu Medical College and Teaching Hospital, Sinamangal, Kathmandu, Nepal from 1 October 2022 to 30 November 2022 after taking ethical approval from the Institutional Review Committee (Reference number: 04072022/04). Patients providing written consent and had documented diabetes were included in the study whereas patients without established diabetes, having comorbidities such as congestive heart failure, nephritic/nephrotic syndrome and those who refused to give consent were excluded from the study. Moreover, diabetic patients with comorbid conditions such as congestive heart failure, nephrotic syndrome and athletes participating in excessive exercise were also excluded from the study. Convenience sampling method was done. The sample size was calculated using the following formula:Where,n = minimum required sample sizeZ = 1.96 at 95% Confidence Interval (CI)4p = prevalence of microalbuminuria in diabetic patients taken from previous studies, 20.3%q = 1-pe = margin of error, 8%The minimum required sample size was 98. However, 103 samples were taken for the study.1 Patient demographics and laboratory findings were recorded.Patients who were diagnosed with diabetes mellitus and gave consent were worked-up for history and investigation to watch for possible microalbuminuria. After proper written consent, they were subsequently evaluated for the presence of urine microalbumin. Investigations and work-up were done to look for abnormalities of lipid profiles, serum urea, serum creatinine, complete blood count (CBC), arterial blood gas analysis (ABG) and echocardiography. A fundoscopic examination was done to look for diabetic retinopathy. The performed questionnaire was used for the study. Microalbuminuria was diagnosed with a urinary albumin concentration of 20-199 mg/L in a spot urine sample.Data were entered in Microsoft Excel and analysis was done using IBM SPSS Statistics version 24.0. Point estimate and 95% CI were calculated.Among 103 patients, microalbuminuria was found to be in 19 (18.45%) . Out of 19 patients, 8 (42.11%) were male .The mean age was 57.45±15.19 years and the mean duration of diabetes was 10.11 ±7.17 years. Mean HbA1c among participants with microalbuminuria was 7.67±0.67%. The mean serum urea concentration among participants with microalbuminuria was 41.58±28.64 mg/dl whereas the mean serum creatinine concentration was 1.38±0.38 mg/dl. Among 19, metformin was used by 7 (36.80%) .6 Furthermore, some studies conducted in India and Nepal reported a higher prevalence of microalbuminuria of 36.3% and 45.5% respectively.8Among 103 patients, microalbuminuria was found to be in 19 (18.45%). In a similar study, the prevalence of microalbuminuria was found to be 20.3% which was similar to our study. Several non-European populations worldwide have a high prevalence of microalbuminuria, this study confirms and extends previous observations.9 Other risk factors contributing to the progression to severely increased albuminuria include higher baseline levels of albuminuria, worse glycemic control as estimated from the HbA1c concentration, higher blood pressure, and cigarette smoking.12In the systematic review, patients with moderately increased albuminuria had a significantly higher risk than those with normoalbuminuria of progressing to severely increased albuminuria.13 This study showed that 57.9% of patients with high blood pressure had microalbuminuria.Blood pressure is one of the most important risk factors for microalbuminuria. High blood pressure may cause microalbuminuria by increasing glomerular filtration pressure and subsequent renal damage.15Excess salt intake produces an excess volume load and, thereby, causes an increase in intra-glomerular pressure and glomerular hyperfiltration, which results in the urinary excretion of albumin. An increase in blood pressure is also involved in the mechanism underlying salt-induced albuminuria. An elevated fasting plasma glucose level indicates the presence of insulin resistance that promotes sodium re-absorption and may increase the volume load. Alternatively, endothelial dysfunction may be involved in the mechanism underlying the observed relationship between urinary excretion of albumin and other factors.Although this study is conducted with a sufficient number of participants in a tertiary care centre, there are certain limitations of this study. Laboratory data are obtained from internationally approved laboratory facilities; however, there might be an error in reporting the findings. There might be multiple co-morbidities in a participant that is undiagnosed. This causes an overestimation of the prevalence of microalbuminuria.The prevalence of microalbuminuria in patients diagnosed with diabetes mellitus was found to be similar to other studies done in similar settings.


New physiologic findings related to sodium homeostasis and pathophysiologic associations require a new vision for sodium, fluid and blood pressure management in dialysis-dependent chronic kidney disease patients. The traditional dry weight probing approach that has prevailed for many years must be reviewed in light of these findings and enriched by availability of new tools for monitoring and handling sodium and water imbalances. A comprehensive and integrated approach is needed to improve further cardiac health in hemodialysis (HD) patients. Adequate management of sodium, water, volume and hemodynamic control of HD patients relies on a stepwise approach: the first entails assessment and monitoring of fluid status and relies on clinical judgement supported by specific tools that are online embedded in the HD machine or devices used offline; the second consists of acting on correcting fluid imbalance mainly through dialysis prescription  but also on guidance related to diet and thirst management; the third consist of fine tuning treatment prescription to patient responses and tolerance with the support of innovative tools such as artificial intelligence and remote pervasive health trackers. It is time to come back to sodium and water imbalance as the root cause of the problem and not to act primarily on their consequences  or organ damage . We know the problem and have the tools to assess and manage in a more precise way sodium and fluid in HD patients. We strongly call for a sodium first approach to reduce disease burden and improve cardiac health in dialysis-dependent chronic kidney disease patients. Despite recent improvements in dialysis patient outcomes –3, cardiFindings of recent studies may be taken as examples to highlight the burden of this problem. Fluid overload is quite common in hemodialysis patients. In a large cohort of incident hemodialysis patients >40.000), moderate fluid overload >2.5 l) assessed by multifrequency bioimpedance was noted in 46% of patients, while a more severe one (>6 l) was observed in about 10%  and losses  in which kidney function and neuroendocrine factors play a major role. Traditionally, total body sodium (TBS) distributed in the extracellular volume (ECV) and bone, was thought to remain relatively constant over time and adjusted to intake changes. This fine regulation of TBS depends on kidney function and blood pressure as described in a kidney-centric model elaborated by Guyton et al . Accordi factors –48. Phag factors . This meechanism . This inechanism , 51. In echanism . All theechanism .In anuric chronic kidney disease dialysis patients, sodium and water balance rely mainly on renal replacement treatment schedule, dietary intake and likely on skin, gut, lungs and oxidative process. Conventional, short and intermittent hemodialysis treatment schedules create cyclic fluctuation alternating between a slow loading phase  and a fast-unloading phase , making fluid and volume management quite challenging , 29. As Impairment of the sodium metabolism in patients with ESRD often results from longstanding pathologic processes that start early with kidney disease and aggravates steadily over time with progredient loss of kidney function. Sodium imbalance reflects the inability of the diseased kidney to handle daily sodium and water load.Sodium accumulation in the extracellular space is the most common and diagnosable consequence of sodium imbalance in CKD patients. This refers to sodium in the extracellular fluid volume, the so called osmotically active sodium, which tends to increase thirst with subsequent expansion of the extracellular volume in the circulation and the interstitial space. Edema, hypervolemia, hypertension and congestive heart failure are among the most common manifestations of sodium accumulation and fluid overload translating into consequent cardiac and vascular damages. This pathophysiological dynamic has rendered chronic fluid overload with or without hypertension to be recognized as one of the main causes of morbidity in CKD patients. However, as summarized in recent reviews, next to sequelae on fluid and hemodynamics, sodium imbalance also associates with multiple end organ damages including cardiac remodeling (left ventricular hypertrophy), proarrhythmic condition, white matter brain damage, atherosclerotic lesion, protein energy wasting, inflammation and lung disorder with pulmonary hypertension , 55.On the other hand, predialysis hyponatremia, reflecting hypotonicity and sodium-free water excess, is observed in 10 to 15% HD patients . HyponatSodium accumulation in tissue, as discussed in the previous paragraph, also associates with chronic kidney disease progression. As documented through functional Na MRI imThe unphysiological profile of intermittent HD is recognized as a leading cause of dialysis intolerance and multiorgan morbidity , 66. ThiThe HD cyclic phenomenon may refer to a tide phenomenon with two phases of loading  and unloading  as described in more details below , 35, 67.During the interdialytic period, anuric HD patients tend to accumulate sodium and fluid according to fluid and dietary intake, leading to chronic fluid overload. In this condition, fluid overload has two consequences: the first is marked by weight gain and progressive increase of systemic arterial pressure and pulmonary arterial pressure with cardiac stretching during the interdialytic phase; the second reflects fluid accumulation and translates into cardiac stretching and structural cardiac remodeling .During the intradialytic period, sodium and fluid are removed mainly through ultrafiltration  and negative dialysate-to-plasma sodium gradient. Volume depletion leads to hypovolemia that triggers adaptative hemodynamic response to preserve arterial pressure. To face hypovolemia and cardiac stroke reduction, hemodynamic stability (blood pressure and tissue perfusion) tends to be preserved by increasing vascular tone, mainly through vasoconstriction of alpha-adrenoceptor territories, and increase vascular refilling including venous return. Hemodynamic response and full adaptive response may be limited by critical hypovolemia  or cardiac impairment  or vascular refilling capacity . Recent functional dialytic imaging studies have shown that reductions in myocardial perfusion and contractility  are directly linked to ultrafiltration rate –72. In aWhatever the exact pathophysiologic consequences of this phenomenon, volemic changes (hyper- and hypo-volemia) provoke rapid alternating cycles of cardiac loading and unloading but still maintaining overtime an abnormal high pulmonary pressure level , 77. SucAdequate management of sodium, water, volume and hemodynamic control of hemodialysis patients relies on a stepwise approach , 67, 80:Sodium and fluid balance assessment and monitoring in HD patients is not an easy task . HoweverClinical management is currently summarized in the dry weight probing approach –84. The Non-invasive technology-based tools have been shown helpful to assess volemia, fluid status, or hemodynamic indicators .Inferior vena cava diameter (IVCD) and collapsibility index have been proposed to monitor intravascular volume and right atrial pressure or central venous pressure changes in dialysis patients with positive outcomes . HoweverRelative blood volume change (RBV) and refilling rate capacity during dialysis assessed by online blood volume sensor embedded in HD machines has been also proposed to guide fluid management , 95. In Bioimpedance has been proposed over the last few years as a more precise way to assess fluid status in dialysis patients , 102. SeEchocardiography is a reliable tool in expert hands to monitor cardiac impact of fluid depletion both on functional and morphological aspects –108. It Regional chest bioimpedance cardiographic device (NICaS), a non-invasive device, has been recently introduced to assess patient’s hemodynamic response to ultrafiltration . The devpost-hoc analysis for recurrent episodes of decompensated heart failure (HR 0.37) and cardiovascular events (HR 0.63) showed a significant risk reduction in the active arm. In hemodialysis patients with high cardiovascular risk, fluid management guided by lung ultrasound may help to reduce lung congestion more effectively than usual clinical care (Lung ultrasound has been proposed more recently to track silent fluid accumulation in the lung Interstitium (extravascular edema) reflecting both volume overload and cardiac dysfuntion , 112. Incal care .Cardiac biomarkers have been extensively explored in hemodialysis patients to disentangle fluid status and cardiac function or remodeling . Atrial via local or remote tissue organ damage. Consequences such as left ventricular hypertrophy and vascular stiffness positively associate with the amount of tissue sodium stored and may ultimately increase the risk of cardiac failure. In addition, sodium tissue accumulation contributes to metabolic and inflammatory disorders that enhance cardiovascular risk. In recent study assessing tissue sodium  by (Quantification of sodium accumulated in the tissue (skin and muscle) using sodium MRIs in dscle) by Na MRI inscle) by . A reducscle) by MRI remaiscle) by .New remote technology, so called ihealth trackers, offer convenient and interesting tools for monitoring in a fully automated and non-obstructive mode, HD patients during the interdialytic period . Long-teDry weight clinical management must be conceived as the overarching workflow aiming to ensure optimal fluid and hemodynamic management in dialysis patients , 129. ThReduce dietary salt intake is associated with clinical benefits, better cardiac outcomes in chronic kidney disease and hemodialysis patients. Adherence to a low-sodium diet is challenging but well established as crucial element for treatment success . Salt diReducing ultrafiltration rate is obviously the most logical approach to reduce cardiac morbidity in HD patients , 134. AgModulating a patient’s hemodynamic response through various tools embedded in HD machines is an appealing approach to maintain hemodynamic stability . MonitorAdjusting dialysis thermal balance to preserve peripheral vascular resistance and cardiac output is also a simple strategy to improve hemodynamic tolerance and reduce organ damage that has been proven clinically effective including systematic literature review , 146. InOptimizing sodium and water imbalance by means of hemodialysis is crucial to restore fluid and tonicity homeostasis , 149. ThBig data and artificial intelligence have already been successfully applied at the point of care to support physicians in the decision-making process. Availability of accurate, longitudinal, data set is a key factor for the development of reproducible predictive algorithms. In that setting, artificial intelligence relying on machine learning, neuronal network and deep learning, can be used to predict on an individualized, session-based, patient hemodynamic response  to dialysis-related prescriptions  on multiple relevant hemodynamic and dialysis adequacy parameters . Based oAdditional specific actions may be further required in cardiac compromised patients or to satisfy specific patient’s needs . It is nIn brief, indications of these medications and/or cardiac intervention should remain in the hand of cardiologists. At this stage, our point is to emphasize the fact that sodium, water and fluid imbalance should be the first line of action in HD patients. Medications and cardiac interventions are likely to be useful but should remain as second line of action and nevertheless used in combination with optimized sodium and water management.A comprehensive and integrated approach is needed to improve further cardiac outcome in HD patients. From clinical research, it is obvious that none of the tool described earlier used alone has the capacity to address issues raised by sodium, water and fluid imbalance. Future research should address this challenge by associating different levels of action as briefly schematized in As delineated in this comprehensive essay, new findings related to sodium homeostasis and pathophysiologic links require a new vision for sodium, fluid and pressure management in dialysis dependent chronic kidney disease patients. The traditional dry weight probing approach that has prevailed for many years must be reviewed in the light of these new findings and enriched by availability of new tools for monitoring and handling sodium and water imbalance. It is time to come back to sodium and water imbalance as cause root of the problem and not to act on their consequences  or organ damage . We know the problem and have the tools to assess and manage in a more precise way sodium and fluid disorders in hemodialysis patients. We strongly call for a sodium first approach to reduce disease burden and improve cardiac health in chronic kidney disease patients.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.Authors AM and BC were employed by company Fresenius Medical Care (FMC).The remaining 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.


Residual kidney function for patients with chronic kidney disease (CKD) is associated with better quality of life and outcome; thus, strategies should be implemented to preserve kidney function. Among the multiple causes that promote kidney damage, gut dysbiosis due to increased uremic toxin production and endotoxemia need attention. Several strategies have been proposed to modulate the gut microbiota in these patients, and diet has gained increasing attention in recent years since it is the primary driver of gut dysbiosis. In addition, medications and faecal transplantation may be valid strategies. Modifying gut microbiota composition may mitigate chronic kidney damage and preserve residual kidney function. Although various studies have shown the influential role of diet in modulating gut microbiota composition, the effects of this modulation on residual kidney function remain limited. This review discusses the role of gut microbiota metabolism on residual kidney function and vice versa and how we could preserve the residual kidney function by modulating the gut microbiota balance. Blautia, unidentified Ruminococcaceae and Parabacteroidies) with beneficial effects on health  are reduced because of limited SCFA-producing bacteria [Gut microbiota disturbances have been reported in patients with chronic kidney disease (CKD) in all disease stages. Although most studies have been conducted in haemodialysis patients, a few have been conducted in patients on peritoneal dialysis and patients not on dialysis . In genebacteria ,2. Deletbacteria ,4. Gut dbacteria .Gut dysbiosis in patients with CKD leads to complications, such as increased uremic toxins and reduced SCFA production, causing loss of residual kidney function. However, the link between gut dysbiosis and kidney function is bidirectional since uraemia can also lead to gut microbiota imbalance due to high urea secretion into the intestine lumen, which is hydrolysed by urease from bacteria, forming ammonia and other toxic products, like ammonium hydroxide that cause damage to the intestinal mucosa, pH and also disturb the commensal bacterial environment ,7,8. In milieu. As diet is the primary driver of altered gut microbiota, dietary changes are the best choice to modulate the microbiota. These include more dietary fibres and bioactive compounds and reduced animal protein intake (mainly red meat) by changing to a plant-based dietary pattern. Although some controversies exist, supplementation with probiotics, prebiotics and synbiotics is a valid option [Modulating gut microbiota composition is a promising therapeutic strategy to reduce complications in the toxic uremic d option . It is cd option . This naPreventing progression to kidney failure is an essential outcome for nondialysis CKD patients. Still, residual renal function is also crucial in preventing morbidity and mortality for patients undergoing dialysis. Patients with residual renal function have high clearance of uremic toxins, hydro-electrolytic balance, lower inflammation, improved anaemia control and a better quality of life .While blood pressure control and “disease-modifying” agents, such as renin–angiotensin–aldosterone system (RAAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors, reduce the risk of kidney failure, dietary strategies to prevent CKD progression are a current patient-prioritised area of research inquiry . The Kid2, there was a 12% reduction in risk for mortality. In terms of urine volume, for every 250 mL increase in urine volume, there was a 36% reduction in risk for mortality [Akkermansia has been positively correlated with overhydration [For haemodialysis (HD) patients, better residual kidney function is associated with better survival and quality of life outcomes. This is because of improved volume and electrolyte management, reduced inflammation and greater clearance of middle molecules . Unfortuortality . Preservortality . PD offeortality . Indeed,ortality . It shouortality , and hypGeneral strategies to preserve residual kidney function in the setting of CKD include avoidance of nephrotoxic exposures ; avoiding dehydration and repetitive episodes of acute kidney injury; blood pressure control with avoidance of intradialytic hypotension; and the use of incremental/individualised dialysis doses ,19. HighFirmicutes and Bacteroidetes are the most abundant [Clostridium, Lactobacillus, Bacillus, Ruminococcus, and Enterococcus are the most frequent genera inside the Firmicutes phylum [The human body is colonised by many microorganisms, including bacteria, archaea, viruses, and fungi  that coeabundant ,31. Mores phylum . The ints phylum .The gut microbiota plays essential functions in the host body, including nutritional status, energy metabolism, metabolic, protective structure, immunity, and others ,34. Beyolactobacilli and Bacteroides. The change was associated, at that time, with the low intestinal transit time and uremic immune dysfunction [Bifidobacterium species, B. catenulatum, B. longum, B. bifidum, L. plantarum, L. paracasei and K. pneumoniae compared to controls [Proteobacteria, Actinobacteria, and Firmicutes [Eggerthella lenta, Actinomyces Streptococcus, Clostridium III and Faecalicoccus from Actinobacteria, and Firmicutes phyla are related to inflammation [In 1978, it was first reported that patients with CKD had an altered gastrointestinal microbiota, with an increased abundance of streptococci, function . Subsequfunction . Wang etcontrols . Vaziri controls . More rermicutes . Gram-nermicutes . The genammation .Patients with CKD exhibit increased intestinal aerobes and reduced anaerobic bacteria with increased production of end-products of protein fermentation . Uremic Dysbiosis in CKD is commonly associated with inflammation and oxidative stress due to increased intestinal permeability, leading to endotoxin and uremic toxins translocation to the blood system ,53. LipoE. coli produces fMet-Leu-Phe (fMLF), and S. aureus produces fMet-Ile-Phe-Leu (fMIFL) that serve as agonists of formyl peptide receptor 1 (FPR1) in neutrophils, eosinophils, monocytes, mast cells, and macrophages, including in renal tubular epithelial cells [Gut dysbiosis provokes hypoxia, causing damage in the gut epithelium, since pathogenic bacteria do not contribute to SCFA production, leading to less activation of hypoxia-inducible factor-1 (HIF)—a factor essential to transcribing mucin-1 proteins that protect the integrity of the gut barrier . Pathogeal cells ,61. Thesal cells . A studyal cells .As discussed, uremic gut dysbiosis promotes an imbalance between proteolytic and saccharolytic bacteria. Increased urease activity by proteolytic communities leads to high syntheses of uremic toxins from amino acid fermentation. These toxic bacterial metabolites and bacteria are translocated into the circulation since there is a reduced integrity of the gut barrier, causing immune system activation. The Toll-like receptor-4 (TLR-4) can be activated in the immune cells in the kidneys by LPS and peptidoglycan, which binds the receptor, leading to stimulation of NF-κB and NLRP3 inflammasome, responsible for the synthesis of many inflammatory cytokines closely linked to the progression of kidney failure . AdditioIndoxyl sulfate produced by gut microbiota from tryptophan dietary fermentation activates the aryl hydrocarbon receptor (AhR) and NF-κB in podocytes and proximal tubules that lead to inflammation, glomerular injury, fibrosis and proteinuria ,69. IndoP-cresyl sulfate activates TWEAK-Fn14 and NF-kB in human proximal tubular epithelial cells . In endoVia fermentation of choline, L-carnitine and phosphatidylcholine, TMAO is produced, which is well known to accelerate kidney damage. Fang et al. (2021) reported that a streptozotocin-induced diabetes rat model that received TMAO in the drinking water not only presented inflammation via NLRP3 inflammasome activation and production of IL-1β and IL-18 but also developed kidney fibrosis .All of these uremic toxins are involved in mitochondrial dysfunction since it causes an alteration in proteins involved with mitofission, leading to reduced mitochondrial mass and biogenesis and high production of ROS due to a disturbance in electron transport involving NADPH oxidase. Activation of the renin–angiotensin–aldosterone system and inflammation provoked by high uremic toxin levels is also associated with mitochondrial dysfunction . As prevEscherichia coli harms kidney function in cardiac surgery-associated acute kidney injury since they can metabolise phenylalanine and tryptophan (aromatic amino acids) [Escherichia coli and Enterobacteriaceae, are increased in stage 5 CKD [Specific bacterial genera have been associated with immune system alteration and inflammation. o acids) . Indole ge 5 CKD .In summary, the gut microbiota interacts with kidney function; in turn, renal systems can cause alteration in the gut microbiota. Interventions to modulate the gut microbiota in CKD are beneficial since they reduce uremic toxicity, oxidative stress, mitochondrial dysfunction, and inflammation. Reduced uremic toxins and LPS production may reduce kidney failure and slow CKD progression . Figure Modulating the gut microbiota in CKD by blocking or reducing the production of uremic toxins may delay kidney disease progression. We present recent studies showing strategies that could slow the loss of kidney function and preserve residual kidney function. The modulation of gut microbiota composition may mitigate chronic kidney damage, and diet has gained increasing attention in recent years since it is the primary driver of the gut microbiota. Also, it is important noticing that modulation of gut microbiota can improve the metabolism in patients with diabetes mellitus, a significant cause of kidney damage progression .The fact that uremic toxins promote a progressive decline in renal function is well recognised . DietaryEbrahim et al. (2022) investigated the effect of ß-glucan supplement  on kidney function, uremic toxins plasma levels and gut microbiota in CKD 3–5 patients. IS, p-CS and p-cresyl glucuronide (pCG) plasma levels improved with the intervention without any change in kidney function over the 14-week study period. Furthermore, the supplementation beneficially affected the gut microbiome. It can be speculated that when the fibre supply is sufficient, gut microbiota uses less protein as an energy source, resulting in lower uremic toxin production .A meta-analysis of five randomised clinical trials and 179 HD patients showed that resistant starch (RS) improves residual kidney function. The hypothesis is that modulation of gut microbiota with RS increases the beneficial bacteria taxa and reduces the production of uremic toxins associated with less cytokine production, improving residual kidney function . StudiesLactobacillus plantarum A7 on kidney function were assessed by Miraghajani et al. (2019) in patients with diabetic nephropathy (stages 1–2). It was shown that eight weeks of intervention (200 mL/day probiotic soy milk) resulted in a significant reduction of kidney function biomarkers cystatin C and progranulin compared to the control group (soy milk) [Probiotics have emerged as a potential adjuvant intervention to restore the gut microbiome in CKD through bacteriocin production; increasing intestinal motility and, consequently, reducing the exposure time to toxic metabolites; attenuating increased intestinal permeability; modulating the host’s innate and adaptive immune systems; and modulating gut-derived uremic toxins and SCFA production. As a result, probiotics may contribute to mitigating inflammation, oxidative stress and, finally, the progression of CKD . Severaloy milk) . However10 UFC Streptococcus thermophilus KB19, Lactobacillus acidophilus KB27 and Bifidobacteria longum KB31) did not change eGFR or uremic toxins plasma levels in CKD 3–5 patients. Instead, the patients exhibited a significant increase in IL-6 levels [In contrast, we showed that three months of supplementation with a combination of three probiotic strains  was well tolerated and slowed the decline of kidney function measured by serum cystatin C [Recently, Zhu et al. (2021) showed that the statin C .Fermented foods, such as dairy, fruits and vegetable-based fermented food, contain bacteria with probable probiotic effects . Experimmilieu, the usefulness of probiotics in delaying the progression of kidney failure has yet to be confirmed [Although probiotics may have a salutary potential on the biochemical uremic onfirmed ,96. It ionfirmed ,97. As aonfirmed . In addionfirmed .Lactobacillus, Bifidobacteria and Streptococcus) resulted in a reduction in p-CS plasma levels. A change in the microbiota composition, with an increase in the Bifidobacterium and depletion of Ruminococcaceae was also observed [11 CFU/day  in a sachet. The synbiotic group presented an increase in the Bifidobacterium and Blautia spp. However, it was also found in the synbiotic group a decrease in eGRF, which was not expected and opposite from previous studies [In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) updated the synbiotic definition as “a mixture comprising live microorganisms and substrate(s) selectively utilised by host microorganisms that confers a health benefit on the host” . Thus, sobserved . In a fo studies .9 CFU and 60 mg of fructooligosaccharides—FOS) daily for 60 days. However, they reported significant improvement in constipation and better quality of life [Cosola et al. (2021) observed that patients in early CKD stages using a commercial synbiotic for two months reduced serum-free IS, small intestine permeability, abdominal pain and constipation syndromes . On the  of life . In addi of life . The inc2S). In a mouse model of CKD, high sulfur amino acid-containing diet resulted in post-translationally modified microbial tryptophanase activity. This reduced uremic toxin-producing activity and ameliorated the progression of CKD [Metabolic and hemodynamic effects of proteins are well known; thus, dietary protein restriction has long been used to slow the progression of CKD. Additionally, the quality of proteins plays a role in gut microbiota composition and function. Protein residues that escape the digestive process reaching the gut microbiota in the colon, can suffer proteolytic fermentation generating uremic toxins ,109,110.n of CKD . Moreoven of CKD . Based on of CKD . The proPolyphenols have anti-inflammatory and antioxidant properties that can be renoprotective and affect gut microbiota since they can act as a prebiotic . PolypheLactobacillales, Bifidobacterium, Clostridium cluster XVIII and Prevotella levels [Bifidobacterium spp., and Lactobacillus-Enterococcus spp., levels and SCFA production, improving both the immune system and intestinal barrier [Studies have shown that garlic may alter the gut microbiota, increasing the diversity of gut microbiota composition, which is beneficial to intestinal health. Garlic can restore a levels . Anthocy barrier . In a re barrier . Berry f barrier .3− to NO2− increasing nitric oxide (NO) synthesis. Components from beetroot increase alpha diversity and SCFA production [Cinnamon compounds such as cinnamaldehyde, trans-cinnamaldehyde, cinnamic acid and cinnamyl acetate also may improve the gut barrier integrity and modulate the gut microbiota, promoting the growth of salutogenic bacteria . Beetroooduction . Propolioduction ,124. In oduction . Turmerioduction .The metabolites produced by the gut microbiota from polyphenols promote several benefits to the gut barrier and the immune system, increase the body’s antioxidant capacity and interact with NF-kB-related inflammation . The phyClostridium difficile infection, with a 90% success rate. In other conditions, such as autoimmune, neurodegenerative, autism, diabetes, cancer and CKD, FMT studies have demonstrated substantial benefits [The faecal microbiota transplant (FMT) procedure is the transfer of the distal faecal microbiota from a healthy donor to the gastrointestinal tract of a dysbiotic recipient to re-establish the microbiota homeostasis, structure and diversity . FMT canbenefits .ob/ob mice, an increase in the abundance of the Odoribacteraceae bacteria family accompanied by a reduction of albuminuria and TNF-alpha. The authors declared that FMT is a safe treatment [Wang et al. (2020) transferred the FMT of patients with CKD and healthy individuals into germ-free CKD mice or antibiotic-treated CKD rats, and they observed that the animals that received that FMT from the CKD patients increased the production of uremic toxins, oxidative stress, and interstitial fibrosis . Anotherreatment .Few studies have been conducted in humans. In a case report, Zhou et al. (2021) reported that after two months of FMT, a patient with membranous nephropathy improved the nephrotic syndrome and kidney function . In anotA complex bidirectional interaction exists between medications and gut microbiota . AlthougLactobacillus, which is associated with tight junctions through the Toll-like receptor 2 pathway [Erysipelotrichaceae uncultured and Clostridium sensu stricto 1 (two genera related to the production of p-CS) [Clostridium_sensu_stricto_1, Ruminococcus_2, Eubacterium_nodatum and Phascolarctobacterium and decreased the abundance of the family Erysipelotrichaceae and the genus Coprococcus 3 (related to uremic toxins production) [The oral adsorbent AST-120 is a carbon particle in the intestine that absorbs uremic toxins and eliminates them by faeces . In a hy pathway . Anotherof p-CS) . Recentlduction) .Clostridiaceae and Enterobacteriaceae increased, uremic toxins levels did not alter. Moreover, A. muciniphila (from the phylum Verrucomicrobia), well known to have an anti-inflammatory effect, increased after the intervention [Another commonly used class of drugs in CKD are calcium and non-calcium-based phosphate binders). When Lau et al. (2018) administrated 4% of ferric citrate for six weeks in mice, they observed that whereas the α-diversity in rvention . In contrvention ,152,153.Gut dysbiosis in patients with CKD is involved with the loss of residual kidney function since the increased uremic toxin production, and endotoxemia are associated with complications, such as inflammation, oxidative stress, mitochondrial dysfunction, senescence and endothelial damage. Clinical studies must investigate if interventions that mitigate gut dysbiosis in CKD can slow progression and maintain residual renal function via inhibiting uremic toxins. Promising strategies include modulation of gut microbiota through increased intake of fibres, fermented food, plant-based polyphenols and faecal transplantation.


High protein intake may accelerate progression of chronic kidney disease (CKD). Estimation of dietary protein intake (DPI) is indispensable for management of CKD, but to achieve optimum DPI is quite challenging in routine clinical practice. We recently studied a beneficial effect of utilizing integrated care on the management of CKD at the rural community level. In that study, we created a short protein food-recall questionnaire (S-PFRQ) as a working tool to estimate DPI of the CKD patients during home visit by community health personnel. Herein, we reported the initial evaluation of the reliability of S-PFRQ from our previous study.  We compared the amount of DPI obtained from S-PFRQ with that obtained from protein-equivalent of total nitrogen appearance (PNA).  In the previous ESCORT-2 study, 914 patients with CKD stage 3 or 4, who were living in the rural area of Thailand, were prospectively followed while receiving integrated care for 36 consecutive months. During home visits by community nurses from subdistrict health centers, dietary food recall was made, recorded in S-PFRQ, and DPI was obtained. Among these, sixty patients were randomly selected, and 24-h urine was collected for urinary urea-N and estimation of PNA. A correlation was made between DPI obtained from S-PFRQ and PNA. P < 0.001). Interclass correlation between these 2 methods was 0.24, P = 0.007. The difference between the 2 methods remained constant across different amounts of DPI.  The DPIs derived from S-PFRQ and PNA were 28.8 ± 14.8 and 39.26 ± 17.79 g/day, respectively. The mean difference and 95% CI between the 2 methods was −10.43 (−7.1 to −13.8) g/day, respectively ( The DPI estimated from S-PFRQ significantly correlated to that from PNA. However, the S-PFRQ method yielded a DPI value which was about 10 g of protein or 25% less than the PNA method. Despite this amount of difference, this S-PFRQ is user-friendly and could be used during field work as an easy and simple tool for DPI estimation in resource-limiting condition. Chronic kidney disease (CKD) is a growing healthcare problem worldwide. It is estimated that about 800 million population on earth harbor CKD at any stage . CKD is At present, several alternative methods have been utilized as a tool for estimating DPI, namely, 3-day dietary recall, dietary food record, 24-h urine collection, and short food recall questionnaire , 14. TheIn our previous studies among patients with CKD stages 3-4 who were residing in rural communities of Thailand, we could demonstrate that our model of an integrated care for CKD conducted by healthcare personnel available in the rural healthcare setting  could be effective in delaying CKD progression , 17. In https://www.clinicaltrials.in.th (TCTR-20160614001). Details of the study had been described elsewhere , where UUN stood for 24-h urinary urea-N excretion] .t-test and ANOVA were performed for mean comparison between 2 categories and 3 categories variables, respectively. Pair t-test was used to compare the amount of DPI obtained from these 2 methods. Intraclass correlation coefficient [ICC] was used to compare reliability of DPI which was derived from these 2 methods. The Bland–Altman plot was made to analyze the agreement of these 2 methods. The calculation was made with SPSS software, version 23.Continuous variables were expressed as the mean ± standard deviation [SD]. Independent Among 914 patients enrolled in the ESCORT-2 study, 60 cases were eligible for the current study . Altoget2 body surface area. The BMI was 25.1 ± 2.83 kg/m2. The baseline serum albumin was 4.27 ± 0.41 g/dL. Fifty-eight percent of participants had positive proteinuria detected by urine dipstick. The 24-h urine volume was 1581 ± 612 ml  were −10.43 g protein/day (95% CI −7.1 to −13.8). The mean differences of DPI estimation from the 2 methods in patients with stage 3A, 3B, and 4 CKD were −18.35, −7.18, and −16.83 g protein/day, respectively . The meaP = 0.021) (P = 0.007).The Pearson correlation coefficient of DPIs estimated from these 2 methods was 0.126 (= 0.021) . The mea= 0.021) . OverallThe Bland–Altman plot was done to elucidate bias and limit of agreement of these 2 methods of DPI estimation as shown in CKD is now a significant health problem in both developed and developing countries. In the latter country group, limited access to kidney replacement therapy due to several factors signifies that delaying kidney disease progression is of prime importance. Among these disease-modifying factors, protein restriction is one of the key recommendations . The proEstimation of DPI with the S-PFRQ method could be lower than the PNA method due to several possible explanations including imperfect recall leading to underreporting of protein intake and consumption of protein from other foods not listed in the questionnaire. Food recall is a simple and convenient dietary intake assessment method. Yet, it relies on patient's memory which could be imperfect particularly in our study participants who are aging and undereducated population. A previous study conducted in non-CKD patients showed that daily protein intake estimation from 24-hour food recall was lower than urinary nitrogen excretion by 25.5% . A studyProteinuria is another factor that could affect estimation of protein intake by using the PNA method. In this study, we did not estimate proteinuria quantitatively. Thus, mean differences of DPI estimation from 2 methods could be higher than our findings. However, in this study, patients with heavy proteinuria were not eligible for participation . Thus, tThere are several limitations in our study. Due to 24-hour urine collection technical difficulties, we therefore randomly selected only 60 patients for initial evaluation of our food recall questionnaire performance. Secondly, proteinuria was assessed with the urine dipstick test. Proteinuria was therefore not quantified in the estimated daily protein intake from the PNA method. Lastly, our food recall questionnaire was designed for a 7-day period which might be too long period of time to recall. However, a 7-day period is intended to reduce selection bias and daily protein intake is supposed to be an average of 7-day period.Dietary protein modification would be effective for delaying CKD progression if it is implemented at an early stage of the disease when the patient is symptom-free. Having this simple questionnaire tool in hands, it will be convenient for primary health personnel, such as community nurses at subdistrict health office or the other, to give advice or instruct the patients to avoid consuming high amounts of dietary protein. Our S-PFRQ could be an example of a simple, but moderately efficient dietary assessment tool that could be adapted to use in other resource-limiting countries. It would create better healthcare professional-patient communication and promote adherence to low protein diet counseling , 27. NevWe hope that implementing this simple and friendly used tool in primary care settings would enable local health care personnel to be a meaningful driving force on delaying CKD progression at an early stage as expected.


Chronic kidney disease (CKD) in children is a major concern of medical care and public health as it is related to high morbidity and mortality due to progression to end-stage kidney disease (ESKD). It is essential to identify patients with a risk of developing CKD to implement therapeutic interventions. Unfortunately, conventional markers of CKD, such as serum creatinine, glomerular filtration rate (GFR) and proteinuria, have many limitations in serving as an early and specific diagnostic tool for this condition. Despite the above, they are still the most frequently utilized as we do not have better. Studies from the last decade identified multiple CKD blood and urine protein biomarkers but mostly assessed the adult population. This article outlines some recent achievements and new perspectives in finding a set of protein biomarkers that might improve our ability to prognose CKD progression in children, monitor the response to treatment, or even become a potential therapeutic target. CKD in children is a progressive condition leading to kidney failure with other dangerous consequences, including high cardiovascular risk, mineral and bone disorder, developmental delay, and growth retardation ,2. In thIt should be emphasized that the etiology of pediatric CKD differs significantly from the adult population, where it is mainly secondary to hypertension or diabetes. The pattern of causes of progressive kidney impairment in children in developed countries responsible for about two-thirds of all cases is congenital anomalies of the kidneys and the urinary tract (CAKUT), including obstructive uropathy, reflux nephropathy or hypo- and dysplastic kidneys, and glomerulopathies (steroid-resistant nephrotic syndrome and other chronic glomerulonephritides). Similarly, the reduction in the number of nephrons associated with low-birth weight and small-for-gestational-age infants, as well as the rising incidence of pediatric obesity, are very important predisposing factors of the development of CKD ,7,8.2 lasting for at least 3 months [According to the definition by KDOQI in 2002 and endorsed in 2012 by KDIGO, CKD in children is characterized by persistent kidney damage with normal eGFR (stage 1) or a drop in eGFR below 60 mL/min/1.73m3 months ,10. Diag3 months . It has 3 months . Each of3 months . Protein3 months . There a3 months ,17,18; hThe process of CKD begins with an initiating factor causing the chronic injury of affected cells ,20. RegaThere is a great need to establish a set of newer kidney biomarkers useful in the early detection and prognosis of the progression of CKD in children. We have to emphasize that CKD in children is not a homogeneous disorder, and proposed biomarkers may also reflect the condition responsible for the CKD.A biomarker should identify a normal or pathogenic process or a response to therapeutic intervention. Ideally, its measurement should be non-invasive, easy to perform, sensitive and specific, repeatable and low-cost ,22. The This paper aims to gather evidence from the literature, especially from the last 5 years, regarding the most common protein biomarkers of CKD in children and present them as a review.The analysis was performed with the guidelines of the updated PRISMA 2020 statement  . The revThe inclusion criteria were as follows: (1) human research; (2) study group <18 years old and >1 month old; (3) clinical diagnosis of CKD or condition leading to CKD; (4) “new” protein markers obtained in blood or urine  cohort and case-control investigations; (6) articles published in English in a peer-reviewed journal. The exclusion criteria were as follows: (1) animal research; (2) newborns or adults included; (3) no specific diagnosis of CKD; (4) presence of other severe diseases or treatment that might interfere with the results of obtained protein kidney markers; (5) no control group to compare samples or control group was not precisely chosen; (6) studies not in English; (7) full text not available.Three hundred and forty-eight records were found, but only thirty-five were under PRISMA’s guidelines. The excluded studies were duplications or did not meet inclusion criteria; for instance, there was no clear diagnosis of CKD or condition leading to kidney dysfunction; research was performed on animals; study groups were newborns or adults; markers were not proteins; were common, such as creatinine or proteinuria, not novel or obtained in material other than blood or urine. There were also 14 case reports excluded; 2 were not available as full-size text, and 1 was not in English .We designed a search protocol to include as much research on new potential kidney biomarkers as possible but only in the pediatric population with a clear CKD diagnosis or condition leading to the disease. The methodology of these studies may vary as the authors used different ways of assessing protein markers from the ELISA system when single proteins were involved to proteomics detecting whole panels of molecules. Moreover, examined populations were diverse both in terms of the causes of CKD and the number of participants included. Therefore, direct statistical analysis of these data was not conducted, and we only presented obtained values of the examined molecules and described associations between examined markers and other CKD features .The review of the existing literature on protein kidney biomarkers of CKD in children brought a broad spectrum of molecules detected in the urine and blood of affected subjects. The most studied are listed and discussed in the next section. Some molecules may detect the injury of kidney structures, while others predict the progression of the disease. Furthermore, few seem to combine these two roles. There are also markers that might even become a therapeutical target. As there is a wide diversity of these proteins, we decided to divide them according to the role they play in the process of progression of CKD and add commentary concerning their usefulness in the diagnosis of CKD.Summarized results of studies from the last five years on protein CKD markers in children are organized in NGAL, also known as lipocalin-2, is a 25 kDa protein produced by activated neutrophils as an innate antibacterial factor. However, NGAL seems to have more complex activities than the bacteriostatic effect. It can be found in the proximal and distant tubular cells of the kidney and, to some extent, is produced by epithelial cells of other organs, including the lungs, trachea, prostate or intestine . It is fUrinary IL-18 (uIL-18) is an inflammatory cytokine produced by macrophages and proximal tubular cells as an answer to ongoing injury and subsequent inflammatory reactions involving tubules . It takeKIM-1 is a transmembrane protein produced by proximal tubules and undetectable in a healthy kidney but is released and present in plasma and urine after renal injury . Moreove2) in 14 European countries. In this study, higher uEGF was independently related to decreased risk of progression of CKD [In humans, EGF is a protein expressed in the thick ascending limb of Henle’s loop and distal tubules . It inten of CKD . It seemα1-microglobulin is a small protein primarily produced by the liver as a free radicals scavenger, filtered by the glomerulus and reabsorbed by proximal tubular cells. It is present in urine after proximal tubular dysfunction . Increasp < 0.01 for both) [Tumor necrosis factor α (TNFα) is a multifunctional cytokine that plays a pivotal role in the process of inflammation. It regulates cell proliferation, differentiation and apoptotic death . TNFα inor both) . In the or both)   [UPAR is a membrane receptor protein expressed in podocytes, regulating their migration, adhesion and apoptosis. It is also found in endothelium and immature myeloid cells . Activat < 0 01) . In the  < 0 01) . Greenbe < 0 01)  (Table 1p < 0.01) [MCP-1 is a chemotactic factor for monocytes promoting their transformation into macrophages. It activates memory T lymphocytes, NK cells and basophils . It is f < 0.01) . Other rYKL-40 participates in tubular epithelium repair after ischemia-reperfusion injury . There aTGF-β1 is a pro-fibrotic growth factor produced by tubular epithelial cells, fibroblasts and different inflammatory cells in the condition of persistent inflammation with irreversible tissue damage. Few studies on CKD in adults confirm increasing urinary levels of TGF-β1 with the progress of CKD ,100. In BMP-7 is an antagonist of TGF-β1 and prevents inflammation and subsequent fibrosis. In the study by Musial et al., children with CKD had higher concentrations of BMP-7 when compared to healthy individuals . Some trMatrix metalloproteinase (proteases) family plays an important role in the degradation of the extracellular matrix. This effect is also crucial in the development and progression of CKD. MMP-2 and MMP-9 belong to gelatinases and are produced under normal conditions by the mesangial cells and tubular epithelial cells in the human kidney but at low levels . HoweverPIIINP, as a byproduct of collagen 3 deposition, is another marker of fibrosis. In a study on children with ureter obstruction, urinary PIIINP was related to worsening kidney blockage . It alsoSeveral studies in our research included markers that do not fit the preceding categories. Fibroblast growth factor 23 (FGF23) is somewhere between the “old-fashioned” kidney function indicators and newer markers. FGF23 is a phosphaturic factor as it inhibits both phosphate reabsorption in the kidney and vitamin D activation. It is crucial for the development of secondary parathyroidism in the course of CKD  and riseThe next protein that should be mentioned is retinol-binding protein (RBP), a transporter molecule for vitamins synthesized in the liver . RBP is A few other molecules were investigated as potential kidney biomarkers of CKD in children: clusterin, osteopontin, N-Acetyl-β-d-amino Glycosidase (NAG), symmetric and asymmetric dimethylarginine , or Trefoil Factor3 (TFF3) and results of recent studies were presented in 2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three of purine or pyrimidine metabolism , two amino acids , the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate and gulonate. Among those with baseline eGFR < 60 mL/min/1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with a lower risk of progression.In this review, we concentrated on protein markers that may serve as a diagnostic tool for CKD. Nevertheless, it is worth noticing that also metabolomic profiling may bring us the discovery of potential metabolite associations with CKD in children. In the study of Denburg et al. , the autIn this review, we provided insight into the most recent research on protein kidney markers with the potential for becoming a useful diagnostic indicator of CKD or even a target for future therapies. Despite there being so many studies in this field, we still do not have consistent conclusions about which molecules have the best utility as markers of CKD. One of the most promising seems to be NGAL; however, not when it is alone. Combination with EGF, which is highly specific for kidney tissue, might improve the identification of the risk of CKD progression. Nevertheless, “old type” markers such as creatinine, albuminuria or proteinuria, despite their limitations, are still used in the pediatric CKD population, and we cannot underestimate their importance in clinical practice . There i