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Penetrating head trauma (PHT) includes any traumatic injury where an object pierces the skull and breaches the dural membrane surrounding the brain. PHTs are less prevalent than blunt head injuries. However, they often have more complex damage, worse prognosis, and higher rates of morbidity and mortality. An 83-year-old man fell at his home and hit his head on the right side toward a shoji (a Japanese-style paper sliding door). He reported to the emergency room the following day with his family. He had a small wound before the right ear, which was sutured in the emergency room. A CT scan demonstrated tiny pieces of bone fragments inside the brain, as well as right temporal subcortical hemorrhage and pneumocephalus. He was admitted to the hospital and received intensive prophylaxis with antibiotics. He developed life-threatening skin disease and subsequent acute kidney disease requiring hemodialysis. He fully recovered from his life-threatening condition. Here, we report an unprecedented case of a penetrating head injury of an older adult caused by a shoji.

TEST FOR ADULTS WITH CHRONIC KIDNEY DISEASE Katherine Baczewski Mary Julius and Elizabeth Kern, Louis Stokes Cleveland Veteran Affairs Medical Center, Cleveland, Ohio High plasma potassium levels are common in patients with chronic kidney disease (CKD) and cause life threatening cardiac dysrhythmia. Self management by dietary restriction of potassium is critical. Currently, there is no valid instrument to quickly assess patient’s knowledge of dietary potassium. The purpose of this observational study was to develop and validate a novel paperbased test of knowledge of foods containing high versus low potassium (test), designed for clinical use in adult patients with CKD who need to restrict dietary potassium intake. The 21 item test allows individuals to choose from two food items, asking them to select the item lower in dietary potassium. Two forms (A) and (B) of the test were designed as parallel forms. Statistical analysis was determined using SAS, version 9.1. 34 participants with high knowledge and 34 participants with low knowledge of dietary potassium and 10 renal dietitians participated in the research by taking the potassium test. 10 renal dietitians also rated each item as essential/non-essential for patient knowledge.

Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.BackgroundBone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD).MethodsDiabetes was induced in 200g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 μg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured.ResultsDiabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34±0.02 mL/min/100 g body weight vs. 0.55±0.02 in normal). In the diabetic BMP-7 high-dose–treated rats, GFR was preserved (0.70±0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58±0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels.ConclusionBMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

PURPOSE: Though case management has been recommended to improve the outcomes of patients with costly or morbid conditions, it has seldom been studied in controlled trials. We performed a randomized, controlled clinical trial of an intensive, multidisciplinary case management program for patients with chronic renal insufficiency and followed patients for 5 years. PATIENTS AND METHODS: We enrolled 437 primary-care patients (73% of those eligible) with chronic renal insufficiency (estimated creatinine clearance consistently 1.4 mg/dL) who were attending an urban academic general internal medicine practice. The intensive case management, administered during the first 2 years after enrollment, consisted of mandatory repeated consultations in a nephrology case management clinic staffed by two nephrologists, a renal nurse, a renal dietitian, and a social worker. Control patients received usual care. Primary outcome measurements included serum creatinine level, estimated creatinine clearance, health services use, and mortality in the 5 years after enrollment. Secondary measures included use of renal sparing and potentially nephrotoxic drugs. RESULTS: There were no differences in renal function, health services use, or mortality in the first, second, or third through fifth years after enrollment. There were significantly more outpatient visits among intervention patients, mainly because of the added visits to the nephrology case management clinic. There were also no significant differences in the use of renal sparing or selected potentially nephrotoxic drugs. The annual direct costs of the intervention were $89,355 ($484 per intervention patient). CONCLUSION: This intensive, multidisciplinary case-management intervention had no effect on the outcomes of care among primary-care patients with established chronic renal insufficiency. Such expensive and intrusive interventions, despite representing state-of-the-art care, should be tested prospectively before being widely introduced into practice.

Purpose: To determine whether there is an independent association of acute renal failure requiring dialysis with operative mortality after cardiac surgery. Patients and Methods: The 42,773 patients who underwent coronary artery bypass or valvular heart surgery at 43 Department of Veterans Affairs Medical Centers between 1987 and 1994 were evaluated to determine the association between acute renal failure sufficient to require dialysis and operative mortality, with and without adjustment for comorbidity and postoperative complications. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were derived from logistic regression analysis. Results: Acute renal failure occurred in 460 (1.1%) patients. Overall operative mortality was 63.7% in these patients, compared with 4.3% in patients without this complication. The unadjusted OR for death was 39 (95% CI 32 to 48). After adjustment for comorbid factors related to the development of acute renal failure (surgery type, baseline renal function, preoperative intraaortic balloon pump, prior heart surgery, NYHA class IV status, peripheral vascular disease, pulmonary rales, left ventricular ejection fraction below 35%, chronic obstructive pulmonary disease, systolic blood pressure, and the cross-product of systolic blood pressure and surgery type), the OR was 27 (95% CI 22 to 34). Further adjustment was made for seven postoperative complications (low cardiac output, cardiac arrest, perioperative myocardial infarction, prolonged mechanical ventilation, reoperation for bleeding or repeat cardiopulmonary bypass, stroke or coma, and mediastinitis), that were independently associated with operative mortality. The OR adjusted for comorbidity and postoperative complications associated with acute renal failure was 7.9 (95% CI 6 to 10). Conclusions: Acute renal failure was independently associated with early mortality following cardiac surgery, even after adjustment for comorbidity and postoperative complications. Interventions to prevent or improve treatment of this condition are urgently needed.

This review of previous work provides credence that the fourth heart sound associated with electrocardiographic evidence of left atrial abnormality and hyperuricemia is an easily determined and cost-effective clinically determined functional surrogates of hypertensive heart and kidney involvement, respectively. These routinely obtained clinically measurable indexes are well established and are pathophysiologically related to the functional involvement of the heart and kidney from hypertensive cardiovascular disease. Moreover, these seemingly nonspecific findings provide strong clinical support for feasible means to determine the independent risk of hypertensive left ventricular hypertrophy and renal involvement in patients with hypertension. In these times of using routine clinical information for cost-effective outcomes, those measurements provide excellent surrogate pathophysiologic indices.

Despite tremendous advances in detection and treatment, including both non-pharmacologic and pharmacologic methods, hypertension continues to be a major health concern. In addition to efforts at reducing mortality, recent clinical and research attention has been focused on reducing morbidity from hypertension. Therefore, such efforts are focused on the effect of an elevated blood pressure on individual target organs and in particular on the heart, brain, and kidney. Although the role of blood pressure reduction alone in preserving target organ damage from hypertension is intensely debated, there is little debate that reducing blood pressure is important. The primary manner in which the blood pressure level is determined in the clinical setting continues to be the casual office measurement of blood pressure. However, the clinical use of ambulatory blood pressure determinations, including 24-hour automated blood pressure monitoring, is increasing. Recent data suggest that the determination of ambulatory blood pressures may be a better predictor not only of mortality but also of target organ damage from hypertension. This article will review recent key clinical studies addressing the role of ambulatory blood pressure on certain cardiac, cerebral, and renal manifestations of hypertension.

www.thelancet.com Vol 383 May 24, 2014 1791 On May 23, 2015, in collaboration with the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), The Lancet will publish a themed issue dedicated to renal care and research. Chronic kidney disease is often not considered a key non-communicable disease (NCD), but as specifi ed by WHO it acts as a risk multiplier for four major categories of NCD—cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes. Chronic kidney disease therefore needs to be embedded into the post-2015 health agenda. The aim of our themed issue will be to publish highquality original research on any aspect of kidney disease. Priority will be given to randomised trials that advance the evidence base relevant to treatment of disease, but any studies that have the potential to change clinical practice are welcome. Authors of accepted papers will be invited to present their research at The Lancet/ERAEDTA symposium during the Annual Scientifi c Sessions of the ERA-EDTA, which is being held in London, UK, on May 28–31, 2015. Articles should be submitted online with an accompanying covering letter referring to this call, the deadline for submissions being Nov 17, 2014. Reports of Late-Breaking clinical trials will be considered for fasttrack review, and the deadline is Feb 16, 2015 for these fast-track submissions. In these cases, we recommend that authors contact us as early as possible to discuss the trial and to allow possible coordination of timing of publication with presentation at The Lancet/ERAEDTA symposium. Authors should consult The Lancet’s Information for Authors for guidelines on manuscript preparation and submission. High-quality manuscripts submitted to The Lancet that are not of suffi ciently high priority for publication in The Lancet may be referred to another journal within The Lancet family. If also submitting your research to ERA-EDTA as an abstract for the annual meeting, please inform the conference organisers of your simultaneous submission to The Lancet so that publication can be scheduled appropriately.

The involvement of patients in nephrology clinical trials is limited despite their ability to prioritise research, help with study design, participation and implementation of results. The aim of this position paper is to review the need, challenges and assess the present situation of patient involvement; and describe the role of International Society of Nephrology in promoting patient involvement. Patient involvement across from priority setting through to implementation of the trial findings can ensure that the evidence generated aligns with their priorities, maximises recruitment and retention, as well as its impact on practice and policy. This has been demonstrated in UK, Australia, Canada and United States, however little is known about the involvement of patients in trials internationally. Barriers to patient involvement includes the patients’ lack of awareness of opportunities to participate, knowledge of clinical research, lack of time, ill health; and lack of initiative amongst researchers to provide opportunity. To assess patient involvement in clinical trials in kidney disease the International Society of Nephrology surveyed the members of the regional boards to which 177 members responded. The survey demonstrated the variability in patient involvement among different regions, highlighted the lack of nominated leads and formal mechanisms of patient involvement. Though members were keen to communicate with patient, social media was underutilised. The International Society of Nephrology will support patient involvement by developing tools and creating better awareness, to promote high quality clinical trials in Nephrology.

Highlights • We measured EEG spectral changes during hemodialysis. • We found slowing of the EEG background activity during hemodialysis. • These changes were correlated with risk factors of dialysis disequilibrium syndrome., Objective To investigate the EEG spectral changes induced during hemodialysis in patients with chronic kidney disease (CKD), and to identify the risk factors associated with changes in the Central Nervous System (CNS) during hemodialysis. Paradoxical neurological deterioration at the end of hemodialysis sessions, known as dialysis disequilibrium syndrome (DDS) has been described, but previous studies on EEG spectral changes during hemodialysis were controversial. Methods We performed quantitative EEG spectral analysis in 56 consecutive patients who underwent hemodialysis. We compared EEG at the start and at the end of the hemodialysis, and we correlated the spectral changes with the biochemical and clinical characteristics of the patients, using multivariate analysis. Results At the end of hemodialysis sessions, we found a significant increase in total EEG power, relative power in delta frequency band and the ratio of delta-theta/alpha–beta power. EEG spectral changes were associated with younger age, recent start of hemodialysis therapy, level of uremia and lower level of glycaemia. Conclusions Quantitative EEG spectral analysis showed that hemodialysis induced slowing of the EEG background activity. These changes were associated with risk factors of DDS. Significance EEG spectral changes are potential biomarkers for monitoring CNS function during hemodialysis.

Background Extracellular vesicles (EVs) harbor thousands of proteins that hold promise for biomarker development. Usually difficult to purify, EVs in urine are relatively easily obtained and have demonstrated efficacy for kidney disease prediction. Herein, we further characterize the proteome of urinary EVs to explore the potential for biomarkers unrelated to kidney dysfunction, focusing on Parkinson's disease (PD). Methods Using a quantitative mass spectrometry approach, we measured urinary EV proteins from a discovery cohort of 50 subjects. EVs in urine were classified into subgroups and EV proteins were ranked by abundance and variability over time. Enriched pathways and ontologies in stable EV proteins were identified and proteins that predict PD were further measured in a cohort of 108 subjects. Findings Hundreds of commonly expressed urinary EV proteins with stable expression over time were distinguished from proteins with high variability. Bioinformatic analyses reveal a striking enrichment of endolysosomal proteins linked to Parkinson's, Alzheimer's, and Huntington's disease. Tissue and biofluid enrichment analyses show broad representation of EVs from across the body without bias towards kidney or urine proteins. Among the proteins linked to neurological diseases, SNAP23 and calbindin were the most elevated in PD cases with 86% prediction success for disease diagnosis in the discovery cohort and 76% prediction success in the replication cohort. Interpretation Urinary EVs are an underutilized but highly accessible resource for biomarker discovery with particular promise for neurological diseases like PD.

Background There is limited literature on kidney disease in the Pacific Region, despite it being recognised as a leading cause of death in some Pacific Island nations. Kidney replacement therapy is only available in a handful of Pacific Islands. This paper reports the epidemiology of haemodialysis patients in Samoa. Methods Registry data from the National Kidney Foundation of Samoa was analysed to estimate the incidence and prevalence rates of kidney failure from the rates of haemodialysis in Samoa and to explore some of the demographic features related to kidney failure in Samoa Findings In total, 393 patients have received long-term haemodialysis in the National Kidney Foundation of Samoa since its inception in 2005 until August 2019. 43% of the haemodialysis population were women and the mean age of people dialysed was 54.9 years. The crude mean incidence rate of kidney failure in Samoa, based on treated kidney failure cases, is 224 patients per million population with a crude prevalence of 629 patients per million population. Diabetic nephropathy (69.4%) was the leading cause of kidney failure. Interpretation This is the first paper to report the epidemiology of haemodialysis patients in Samoa and reveals an urgent need for further studies on the extent of chronic kidney disease, and kidney failure, in Samoa to develop country specific prevention strategies to mitigate this growing burden and optimise care for kidney failure patients in Samoa. Funding : No funding was received for this study.

Background It is well established that single pill combination (SPC) therapies have the potential to improve patient adherence versus multi-pill regimens, thereby improving blood pressure control and clinical outcomes in populations with hypertension. Purpose To develop a microsimulation model, capturing different treatment pathways, to project the impact on clinical outcomes of using single pill combination therapies for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). Methods The model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices [CTP], single drug with dosage titration first then sequential addition of other agents [start low and go slow, SLGS], free choice combination with multiple pills [FCC] and combination therapy in the form of a single pill [SPC]. Model inputs were derived from Global Burden of Disease 2017 dataset, including demographics, health status/risk factors, transition probabilities and treatment attributes/healthcare utilization, and the model incorporated real-world challenges to healthcare delivery such as access to care, SBP measurement error, adherence and therapeutic inertia. Simulated outcomes of mortality, incidence of chronic kidney disease (CKD), stroke and ischemic heart disease (IHD), and disability-adjusted life years (DALYs) due to these conditions were estimated for population of 1,000,000 simulated patients for each treatment pathway and country. Results SPC therapy was projected to improve health outcomes over SLGS, FCC and CTP over 10 years in all five countries. SPC was forecast to reduce mortality by 5.4% (Italy), 4.9% (Russia), 4.5% (China), 2.3% (South Korea) and 3.6% (Mexico) versus CTP and showed greater projected reductions in mortality than SLGS and FCC. DALYs were projected to be reduced with SPC therapy by between 5.7% (Italy) and 2.2% (South Korea) compared with CTP and reductions in the incidence of clinical events were also projected with SPC therapy, with decreases in the range of 11.5% (Italy) to 4.9% (South Korea) versus CTP. Conclusions Ten-year projections of clinical outcomes associated with different anti-hypertensive treatment pathways in five countries indicated that both combination therapies (FCC and SPC) are likely to reduce the disease burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Gentilly, France

Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway., Graphical abstract fx1, Highlights • Chronic kidney disease (CKD) is a serious public health problem. • Redox signaling and wnt/β-catenin pathway were studied in CKD patients. • Clinical phenotypes and metabolites in CKD patients were studied by metabolomics. • Plasma and urine metabolites related to amino acid, purine and lipid metabolisms. • Four plasma and five urine metabolites were good correlated with GFR or creatinine.

Background Reducing the high patient and economic burden of early readmissions after hospitalisation for heart failure (HF) has become a health policy priority of recent years. Methods An observational study linking Hospital Episode Statistics to socioeconomic and death data in England (2002-2018). All first hospitalisations with a primary discharge code for HF were identified. Quasi-poisson models were used to investigate trends in 30-day readmissions by age, sex, socioeconomic status and ethnicity. Findings There were 698,983 HF admissions, median age 81 years [IQR 14]. In-hospital deaths reduced by 0.7% per annum (pa), whilst additional deaths at 30-days remained stable at 5%. Age adjusted 30-day readmissions (21% overall), increased by 1.4% pa (95% CI 1.3-1.5). Readmissions for HF (6%) and ‘other cardiovascular disease (CVD)’ (3%) remained stable, but readmissions for non-CVD causes (12%) increased at a rate of 2.6% (2.4-2.7) pa. Proportions were similar by sex but trends diverged by ethnicity. Black groups experienced an increase in readmissions for HF (1.8% pa, interaction-p 0.03) and South Asian groups had more rapidly increasing readmission rates for non-CVD causes (interaction-p 0.04). Non-CVD readmissions were also more prominent in the least (15%; 15-15) compared to the most affluent group (12%; 12-12). Strongest predictors for HF readmission were Black ethnicity and chronic kidney disease, whilst cardiac procedures were protective. For non-CVD readmissions, strongest predictors were non-CVD comorbidities, whilst cardiologist care was protective. Interpretation In HF, despite readmission reduction policies, 30-day readmissions have increased, impacting the least affluent and ethnic minority groups the most. Funding NIHR.

Highlights • Differences in risk factors for SBI between paroxysmal and persistent AF was studied. • NVAF patients (119 paroxysmal, 71 persistent) underwent brain MRI, TTE, and TEE. • DM and CKD, which represents microvascular disease, predicted SBI in paroxysmal AF. • There was no obvious therapeutic target for SBI after progression to persistent NVAF. • Intervention for DM and CKD from paroxysmal NVAF may prevent SBI and future stroke., Background Although silent brain infarction is an independent risk factor for subsequent symptomatic stroke and dementia in patients with nonvalvular atrial fibrillation, little is known regarding differences in risk factors for silent brain infarction between patients with paroxysmal and persistent nonvalvular atrial fibrillation. Methods This study population consisted of 190 neurologically asymptomatic patients (mean age, 64 ± 11 years) with nonvalvular atrial fibrillation (119 paroxysmal, 71 persistent) who were scheduled for catheter ablation. All patients underwent brain magnetic resonance imaging to screen for silent brain infarction prior to ablation. Transthoracic and transesophageal echocardiography was performed to screen for left atrial abnormalities (left atrial enlargement, spontaneous echo contrast, or left atrial appendage emptying velocity) and complex plaques in the aortic arch. Results Silent brain infarction was detected in 50 patients (26%) [26 patients (22%) in paroxysmal vs. 24 patients (34%) in persistent, p = 0.09]. Multiple logistic regression analysis indicated that age and diabetes mellitus or chronic kidney disease (estimated glomerular filtration rate

Background Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Methods We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study. Findings We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; p-value: 8.5e−4, Benjamini Hochberg [BH] adjusted p-value: 2.1e−3), after controlling for potential confounding factors. Interpretation This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin. Funding This work was supported by Nference, inc.

Background Diabetic nephropathy is the most common cause of end stage renal failure. We assessed the safety, tolerability, and explored therapeutic effects of adult allogeneic bone-marrow derived mesenchymal precursor cells (MPC) in patients with moderate to severe diabetic nephropathy. Methods Multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled trial assessing a single intravenous (IV) infusion of allogeneic MPC (United States adopted name: rexlemestrocel-L) 150 × 106 (n = 10), 300 × 106 (n = 10) or placebo (n = 10) in adults with diabetic nephropathy with an estimated glomerular filtration rate (eGFR) 20–50 ml/min/1.73 m2. Thirty patients at three Australian centers were enrolled between July 2013 and June 2014 and randomized 2:1, in two sequential dose cohorts, to receive rexlemestrocel-L or placebo. Study duration was 60 weeks. Primary endpoint was safety and tolerability. Primary exploratory efficacy endpoint was change from baseline in eGFR and directly measured GFR by 99Tc-DTPA plasma clearance (mGFR) at 12 weeks post-infusion. The trial was registered on ClinicalTrials.gov (NCT01843387). Findings All patients completed the study and were included in analyses applied to the intention to treat population. There were no acute adverse events (AEs) associated with infusion and no treatment-related AEs or serious AEs were deemed treatment-related by investigators. No patients developed persistent donor specific anti-HLA antibodies. Relative to placebo, a single IV rexlemestrocel-L infusion showed trends of stabilizing or improving eGFR and mGFR at week 12. The adjusted least squares mean (LSM ± SE) differences from placebo in changes from baseline at 12 weeks in the rexlemestrocel-L groups were 4.4 ± 2.16 and 1.6 ± 2.15 ml/min/1.73 m2 for eGFR and 4.1 ± 2.75 and 3.9 ± 2.75 for mGFR for the 150 × 106 and 300 × 106 cell groups, respectively. Interpretation This study demonstrates the safety of rexlemestrocel-L in diabetic nephropathy with suggestive effects on renal function to be confirmed in larger, appropriately powered trials., Highlights • We report the first clinical trial of adult, bone-marrow derived allogeneic mesenchymal precursor cells (MPCs) in diabetic nephropathy patients. • Our findings demonstrate the safety of a single infusion of MPCs in adults with type 2 diabetes and moderate to severe renal impairment. • Importantly, we observed no immunological evidence of sensitization to cell therapy following a single infusion. • Larger, longer duration studies are needed to confirm a signal of efficacy on renal function, as assessed by glomerular filtration rate. • These studies have implications for new treatment options for diabetic kidney disease. Current treatment of diabetic nephropathy reduces progression to renal failure by only 16-25%. Multiple preclinical studies have demonstrated intravenous mesenchymal lineage cells preserve or improve renal function and histology. We report the first trial of adult, allogeneic bone-marrow derived mesenchymal precursor cells (MPCs) in adult type 2 diabetic nephropathy patients. Our findings demonstrate the safety of a single infusion of MPCs. Importantly, there was no immunological evidence of sensitization to cell therapy following a single infusion. Larger, longer studies are needed to confirm a potential signal of efficacy on renal function. Further studies of this cell therapy have implications for a new treatment option in the preservation of renal function.

Highlights • Creatinine-based GFR estimates (eGFRcr) may contribute to misuse of metformin. • We examined the impact of cystatin C GFR estimates (eGFRcys) on metformin eligibility. • eGFRcys reclassified 20% of Veterans into different eGFR categories. • Old age and albuminuria were associated with more severe eGFRcys vs. eGFRcr., Aims Recommendations for metformin use are dependent on eGFR category: eGFR >45 ml/min/1.73 m2 – “first-line agent”; eGFR 30–44 – “use with caution”; eGFR60 ml/min/1.73 m2) differed with an absolute difference in eGFR of >5 ml/min/1.73 m2. We modeled predictors of metformin use and eGFR category discrepancy with multivariable relative risk regression and multinomial logistic regression. Results Subjects were 95% male, median age 68, and racially diverse (45% White, 22% Black, 11% Asian, 22% unknown). Metformin use decreased with severity of eGFRcr category, from 63% in eGFRcr >60 to 3% in eGFRcr 30 mg/g (aOR = 1.81, 1.20–2.73). Conclusions Metformin use is low among Veterans with CKD. eGFRcys may serve as a confirmatory estimate of kidney function to allow safe use of metformin among patients with CKD, particularly among older individuals and those with albuminuria.

Background Chronic kidney disease (CKD) has been shown to be associated with diabetic retinopathy (DR) and age-related macular degeneration (AMD), leading causes of blindness in elderly adults in previous studies. However, the association of CKD with visual impairment (VI) is not clear. We aimed to examine the association of CKD with VI and other age-related ocular diseases in a population-based sample of Asian adults. Methods We analyzed data from 10,033 adults aged 40–80 years who participated in the Singapore Epidemiology of Eye Diseases (SEED, 2004–11) Study. CKD was defined as an estimated glomerular filtration rate (eGFR), Highlights • Persons with CKD were 3 times more likely to suffer from visual impairment than persons without CKD. • CKD was associated with visual impairment, any ocular disease, cataract and retinopathy independent of potential risk factors. • In persons with diabetes, odds of visual impairment increased with increasing severity of CKD. • Our results suggest that screening for ocular disease and visual impairment is important in patients with CKD. This study reports the prevalence of visual impairment in persons with chronic kidney disease (CKD) and the associations of CKD with visual impairment and major ocular diseases, diagnosed based on comprehensive ophthalmological examination. There is a high burden of major eye diseases in persons with CKD, with nearly one in two suffering from visual impairment. Cataract and retinopathy, both independently associated with CKD, are potentially reversible causes of VI, especially if treated early. The evidence suggests a need for early eye screening in these high-risk individuals.

Highlights • Chronic kidney disease (CKD) patients may demonstrate elevated NGAL levels reflecting chronic impairment condition. • We evaluated plasma NGAL level for identification of AKI superimposed on CKD vs. “de novo” AKI among (STEMI) patients undergoing primary PCI. • NGAL is a useful tool for the identification of patients with CKD in high risk for AKI following primary PCI. However, Different cutoff values of plasma NGAL for “de novo” AKI and AKI superimposed on CKD may be necessary for Table 1, Table 2, Table 3 diagnosis., Introduction Elevated plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) is a marker of tubular damage and aid in the early identification of acute kidney injury (AKI). We evaluated NGAL levels for identification of AKI superimposed on chronic kidney disease (CKD) vs. “de novo” AKI among ST elevation myocardial infarction (STEMI) patients undergoing primary coronary intervention (PCI). Methods 217 STEMI patients treated with PCI were prospectively included, 34 (16%) had baseline CKD. Plasma NGAL levels were drawn 24 h following PCI. Receiver-operator characteristic (ROC) methods were used to identify optimal sensitivity and specificity for the observed NGAL range in AKI patients with and without CKD. Results Overall AKI incidence was 13%. NGAL levels were significantly higher for patients with AKI compared to no-AKI, irrespective of CKD. Different optimal cutoff value for NGAL to predict AKI were found for patients with CKD (133 ng/ml, sensitivity of 73% and specificity of 75%; AUC: 0.837, p

Highlights • Investigated renoprotective effect of SGLT2is in T2DM and CKD with normoalbuminuria. • More favorable effects of SGLT2is on renal function were observed. • Higher initial dip was possible marker of worsening renal function., Introduction We investigated the renoprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on renal function in patients with type 2 diabetes and chronic kidney disease (CKD) with normoalbuminuria. Methods A retrospective review of clinical records of Japanese participants with type 2 diabetes and CKD (estimated glomerular filtration rate [eGFR]

BackgroundThe COMBO stent is a biodegradable-polymer sirolimus-eluting stent with endothelial progenitor cell capture technology for faster endothelialization. ObjectiveWe analyzed COMBO stent outcomes in relation to bleeding risk using the PARIS bleeding score. MethodsMASCOT was an international registry of all-comers undergoing attempted COMBO stent implantation. We stratified patients as low bleeding-risk (LBR) for PARIS score≤3 and intermediate-to-high (IHBR) for score>3 based on baseline age, body mass index, anemia, current smoking, chronic kidney disease and need for triple therapy. Primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, myocardial infarction (MI) not clearly attributed to a non-target vessel or clinically-driven target lesion revascularization (TLR). Bleeding was adjudicated using the Bleeding Academic Research Consortium (BARC) definition. Dual antiplatelet therapy (DAPT) cessation was independently adjudicated. Results The study included 56% (n=1270) LBR and 44% (n=1009) IHBR patients. Incidence of 1-year TLF was higher in IHBR patients (4.1% vs. 2.6%, p=0.047) driven by cardiac death (1.7% vs. 0.7%, p=0.029) with similar rates of MI (1.8% vs. 1.1%, p=0.17), TLR (1.5% vs. 1.6%, p=0.89) and definite/ probable stent thrombosis (1.2% vs. 0.6%, p=0.16). Incidence of 1-year major BARC 3 or 5 bleeding was significantly higher in IHBR patients (2.3% vs. 0.9%, p=0.0094), as was the incidence of DAPT cessation (29.3% vs. 22.8%, p Conclusion Patients with intermediate-to-high PARIS bleeding risk in the MASCOT registry experienced greater incidence of 1-year TLF, major bleeding and DAPT cessation than LBR patients, without significant differences in stent thrombosis.

Both acute kidney injury (AKI) and chronic kidney disease (CKD) that lead to diminished kidney function are interdependent risk factors for increased mortality. If untreated over time, end stage renal disease (ESRD) is an inevitable outcome. Acute and chronic kidney diseases occur partly due to imbalance between the molecular mechanisms that govern oxidative stress, inflammation, autophagy and cell death. Oxidative stress refers to the cumulative effects of highly reactive oxidizing molecules that cause cellular damage. Autophagy removes damaged organelles, protein aggregates and pathogens by recruiting these substrates into double membrane vesicles called autophagosomes which subsequently fuse with lysosomes. Mounting evidence suggests that both oxidative stress and autophagy are significantly involved in kidney health and disease. However, very little is known about the signaling processes that link them. This review is focused on understanding the role of oxidative stress and autophagy in kidney diseases. In this review, we also discuss the potential relationships between oxidative stress and autophagy that may enable the development of better therapeutic intervention to halt the progression of kidney disease and promote its repair and resolution., Graphical abstract, Highlights • The molecular mechanisms underlying the regulation of oxidative stress responses and autophagy may exhibit considerable cross-talk. • The autophagy pathway may be regulated in the context of kidney diseases. Failure or disruption of the autophagy pathway may contribute to the pathogenesis of kidney diseases. • Targeting the autophagy pathway may show considerable therapeutic potential in the treatment and management of kidney disorders.

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H2O2.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH–dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2–mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease., Graphical abstract Image 1

Chronic kidney disease affects 40% of adults aged 65 and older. Anemia of CKD is present in 30% of patients with CKD and is associated with increased cardiovascular risk, decreased quality of life, and increased mortality. Hepcidin-25 (hepcidin), the key iron regulating hormone, prevents iron egress from macrophages and thus prevents normal recycling of the iron needed to support erythropoiesis. Hepcidin levels are increased in adults and children with CKD. Vitamin D insufficiency is highly prevalent in CKD and is associated with erythropoietin hyporesponsiveness. Recently, hepcidin levels were found to be inversely correlated with vitamin D status in CKD. The aim of this study was to investigate the role of vitamin D in the regulation of hepcidin expression in vitro and in vivo . This study reports that 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the hormonally active form of vitamin D, is associated with decreased hepcidin and increased ferroportin expression in lipopolysaccharide (LPS) stimulated THP-1 cells. 1,25(OH) 2 D 3 also resulted in a dose-dependent decrease in pro-hepcidin cytokines, IL-6 and IL-1β, release in vitro . Further, we show that high-dose vitamin D therapy impacts systemic hepcidin levels in subjects with early stage CKD. These data suggest that improvement in vitamin D status is associated with lower systemic concentrations of hepcidin in subjects with CKD. In conclusion, vitamin D regulates the hepcidin-ferroportin axis in macrophages which may facilitate iron egress. Improvement in vitamin D status in patients with CKD may reduce systemic hepcidin levels and may ameliorate anemia of CKD.

Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy in chronic kidney disease (CKD), the barriers associated with pathophysiological conditions limit therapeutic applicability to patients. We confirmed that level of cellular prion protein (PrPC) in serum was decreased and mitochondria function of CKD-derived hMSCs (CKD-hMSCs) was impaired in patients with CKD. We proved that treatment of CKD-hMSCs with tauroursodeoxycholic acid (TUDCA), a bile acid, enhanced the mitochondrial function of these cells through regulation of PINK1-PrPC-dependent pathway. In a murine hindlimb ischemia model with CKD, tail vein injection of TUDCA-treated CKD-hMSCs improved the functional recovery, including kidney recovery, limb salvage, blood perfusion ratio, and vessel formation along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients., Graphical abstract Image 1

Despite the increasing need to identify and quantify tissue oxygenation at the cellular level, relatively few methods have been available. In this study, we developed a new hypoxia-responsive reporter vector using a hypoxia-responsive element of the 5' vascular endothelial growth factor untranslated region and generated a novel hypoxia-sensing transgenic rat. We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney. With this model, we were able to identify diffuse cortical hypoxia in the puromycin aminonucleoside-induced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model. Expression of the hypoxia-responsive transgene increased throughout the observation period, reaching 2.2-fold at 2 weeks in the puromycin aminonucleoside model and 2.6-fold at 4 weeks in the remnant kidney model, whereas that of vascular endothelial growth factor showed a mild decrease, reflecting distinct behaviors of the two genes. The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models. Finally, we identified the localization of proliferating cell nuclear antigen-positive, ED-1-positive, and terminal dUTP nick-end labeled-positive cells in the hypoxic cortical area in the remnant kidney model. We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases.

Background The major gene mutated in autosomal dominant polycystic kidney disease was first identified over 20 years ago, yet its function remains poorly understood. We have used a systems-based approach to examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. Methods We performed transcriptional profiling of a large set of male and female kidneys, along with metabolomics and lipidomics analyses of a subset of male kidneys. We also assessed the effects of a modest diet change on cyst progression in young cystic mice. Fatty acid oxidation and glycolytic rates were measured in five control and mutant pairs of epithelial cells. Results We find that females have a significantly less severe kidney phenotype and correlate this protection with differences in lipid metabolism. We show that sex is a major determinant of the transcriptional profile of mouse kidneys and that some of this difference is due to genes involved in lipid metabolism. Pkd1 mutant mice have transcriptional profiles consistent with changes in lipid metabolism and distinct metabolite and complex lipid profiles in kidneys. We also show that cells lacking Pkd1 have an intrinsic fatty acid oxidation defect and that manipulation of lipid content of mouse chow modifies cystic disease. Interpretation Our results suggest PKD could be a disease of altered cellular metabolism., Highlights • Adult female mice have slower kidney disease progression than males in an orthologous Pkd1 model of ADPKD. • Omics and in vitro studies suggest Pkd1 deletion causes cell autonomous metabolic changes and fatty acid oxidation impairment. • Transcriptional sexual dimorphism in mouse kidneys is consistent with lipid metabolism modifying PKD progression in females. • Lower lipid content in diet correlates with slower PKD progression. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and characterized by the replacement of kidney parenchyma by cysts. Recent studies have identified metabolic differences and increased glycolysis in ADPKD. We now examine the effects of acquired loss of Pkd1 in adult mouse kidney as it transitions from normal to cystic state. We report females have less severe kidney disease and suggest metabolic differences could underlie this protection. Notably, we did not find altered glycolysis, but rather that Pkd1- cells have impaired fatty acid oxidation. We also showed that reducing the fat content in mouse diet correlated with less severe cystic kidney disease. Our results thus support the notion that abnormalities in lipid metabolism are an intrinsic component of ADPKD.

Introduction Chronic kidney disease (CKD) is a silent disease. Most CKD patients are unaware of their condition during the early stages of the disease which poses a challenge for healthcare professionals to institute treatment or start prevention. The trouble with the diagnosis of CKD is that in most parts of the world, it is still diagnosed based on measurements of serum creatinine and corresponding calculations of eGFR. There are controversies with the current staging system, especially in the methodology to diagnose and prognosticate CKD. Objective The aim of this review is to examine studies that focused on the different types of samples which may serve as a good and promising biomarker for early diagnosis of CKD or to detect rapidly declining renal function among CKD patient. Method The review of international literature was made on paper and electronic databases Nature, PubMed, Springer Link and Science Direct. The Scopus index was used to verify the scientific relevance of the papers. Publications were selected based on the inclusion and exclusion criteria. Result 63 publications were found to be compatible with the study objectives. Several biomarkers of interest with different sample types were taken for comparison. Conclusion Biomarkers from urine samples yield more significant outcome as compare to biomarkers from blood samples. But, validation and confirmation with a different type of study designed on a larger population is needed. More comparison studies on different types of samples are needed to further illuminate which biomarker is the better tool for the diagnosis and prognosis of CKD.

This paper aims to assist in the prevention of Chronic Kidney Disease (CKD) by utilizing machine learning techniques to diagnose CKD at an early stage. Kidney diseases are disorders that disrupt the normal function of the kidney. As the percentage of patients affected by CKD is significantly increasing, effective prediction procedures should be considered. In this paper, we focus on applying different machine learning classification algorithms to a dataset of 400 patients and 24 attributes related to diagnosis of chronic kidney disease. The classification techniques used in this study include Artificial Neural Network (ANN) and Support Vector Machine (SVM). To perform experiments, all missing values in the dataset were replaced by the mean of the corresponding attributes. Then, the optimized parameters for the Artificial Neural Network (ANN) and Support Vector Machine (SVM) techniques were determined by tuning the parameters and performing several experiments. The final models of the two proposed techniques were developed using the best-obtained parameters and features. The empirical results from the experiments indicated that ANN performed better than SVM, with accuracies of 99.75% and 97.75%, respectively, indicating that the outcome of this study is very promising.

Substantial progress has been made in the application of computer-driven methods to provide erythropoietic dosing information for patients with anemia resulting from chronic kidney disease. Initial solutions were simply computerized versions of traditional paper-based anemia management protocols. True personalization was achieved through the use of advanced modeling techniques such as artificial neural networks, physiologic models, and feedback control systems. The superiority of any one technique over another has not been determined, but all methods have shown an advantage in at least one area over the traditional paper expert system used by most dialysis facilities. Improvements in the percentage of hemoglobin measurements within target range, decreased within-subject hemoglobin variability, decreased erythropoiesis-stimulating agent dose, and decreased transfusion rates all have been shown.

This paper tests whether in utero conditions affect long-run developmental outcomes using the 1918 influenza pandemic in Taiwan as a natural experiment. Combining several historical and current datasets, we find that cohorts in utero during the pandemic are shorter as children/adolescents and less educated compared to other birth cohorts. We also find that they are more likely to have serious health problems including kidney disease, circulatory and respiratory problems, and diabetes in old age. Despite possible positive selection on health outcomes due to high infant mortality rates during this period (18%), our paper finds a strong negative impact of in utero exposure to influenza.

Chronic kidney disease (CKD), due to rising patients, the high probability of deterioration towards end-stage renal disease and inaccurate estimates of morbidity and mortality, constitutes a heavy burden on the sanitary infrastructure. The aim of this research is to build a model for machine-learning, which uses comorbidity and data on drugs and predicts population prevalence. Predictive health care prediction using machine learning is a daunting activity to help clinicians assess the precise therapies for life-saving. In this paper, the study applies machine learning method in combination with ensemble learning for estimation of chronic kidney disease with clinical evidence. They are based on chronic kidney disease datasets and the efficiency of these models is compared to choose the best classifier for chronic kidney disease prediction. The comparative analysis is estimated in terms of various metrics like classification accuracy, f-measure, percentage error, etc. The results of simulation shows that the proposed ensemble machine learning classifier namely Ensemble Support Vector Machine predicts well the chronic kidney disease from the datasets than other existing ensemble methods.

In the past 40 years, disordered mineral metabolism has been among the most intensely studied areas of nephrology. A June 2010 PubMed search for ‘secondary hyperparathyroidism and kidney disease’ yielded 5866 references. Among these are papers documenting the development and application of numerous therapeutic agents—including calcitriol, vitamin D analogs, phosphate binders, and cinacalcet—that remain in widespread use in the day-to-day management of dialysis patients worldwide. However, almost 6000 papers later, fundamental pathophysiological concepts remain unclear, particularly regarding the early pathogenesis of disordered mineral metabolism.

Insulin treatment in type 2 diabetes mellitus patients is still essential and its usage has increased during recent years. Despite this, the level of control continues to be very poor. Insulin treatment is initiated with control levels above the recommendations set by the Clinical Practice Guidelines (CPG) and patients are exposed to very high blood glucose levels during long periods of time. This paper reviews the role of insulin in the different CPG, the criteria for therapy initiation and intensification, the beginning of the intensification and the different types of insulin which are commercialized in our country. Moreover, we discuss insulinization in special situations such as corticosteroid treatment, fragile elderly patients, palliative care situations, chronic kidney disease or during Ramadan. Finally, the problem of therapeutic inertia in insulinization is also addressed.

The decline of the estimated glomerular filtration rate (eGFR) and the presence of albuminuria are the typical hallmarks of kidney disease arising as one of the most frequent diabetic complications over a long period of time, generally known as diabetic nephropathy or diabetes kidney disease (DKD). However, a decline in the renal function may occur in diabetic patients for other reasons unrelated to glycemic control, and this condition is known as non-diabetic kidney disease (NDKD). In this opinion paper we will review these conditions, and we outline the importance of other investigations, such as kidney biopsy and the measurement of novel biomarkers, in order to identify the disease progression early, and to allow a timely intervention. We will also focus on the actual limits of the quantitative measurements of albumin in urine, especially with regards to potential interferences due to the treatment of patients with statins.

Chronic kidney disease (CKD) not associated with known risk factors has been reported from parts of India and is presumed to be similar to CKD of unknown etiology (CKDu) that has been described from Central America. The reports from India have been fragmented without clear description of the disease phenotype or its determinants. This paper summarizes the current state of knowledge around CKDu in India based on a review of literature, multi-stakeholder consultation, and a survey of Indian nephrologists. We also contacted individual research groups to solicit data. Our findings suggest that that CKDu is reported from most regions in India; however, it is interpreted differently from the phenotype described from Central America and Sri Lanka. The differences include lack of a clear demographic or occupation group, older age of affected participants, and presence of mild hypertension and low-grade proteinuria. Well-designed prospective field studies with appropriate diagnostic workup are needed to establish the disease burden and identify etiologies, along with socioeconomic and health consequences, the intersection with the environment, and the public health response. Community-based research should phenotype the entire CKD population rather than be restricted to cases with presumed CKDu based on predefined criteria. Guidelines are needed for clinical evaluation, referral, management, and harmonization of clinical documentation and health records. More data are needed to support the existence of a unique CKDu phenotype in India.

To the Editor: Goraya et al.1 have, in their interesting paper, shown that short-term (30 days) dietary acid reduction due to fruit and vegetable (F+V) or sodium bicarbonate (NaHCO3) consumption attenuated kidney injury in hypertensive chronic kidney disease (CKD; stadium II) patients undergoing therapy with angiotensin-converting enzyme inhibitors. The F+V diet reduced systolic blood pressure and body weight, but NaHCO3 did not affect these parameters. In a comment on this paper, Uribarri and Oh2 stated that F+V diets rather than NaHCO3 supplementation might be the key to halting CKD progression. The truth seems to lie somewhere in between in that simultaneous use of F+V diets and NaHCO3 is required. In this study, NaHCO3 caused greater aldosterone reduction than the F+V diet. Because aldosterone is involved in kidney injury, long-term NaHCO3 supplementation can be more beneficial than the F+V diet alone. Furthermore, the F+V diet reduces urinary sodium concentration. An epidemiological study reported that lower sodium excretion in healthy patients is associated with higher cardiovascular disease mortality.3 Because the Na+ cation seems more likely to increase blood pressure when combined with the Cl− anion than with HCO3− (ref. 4), providing sodium through bicarbonate rather than kitchen salt seems reasonable. Low long-term dietary compliance is another issue with the F+V diet. Therefore, it seems that CKD patients should use NaHCO3 supplementation as well as F+V diets.

Peripheral vascular interventions (PVI) utilize iodinated contrast medium (ICM) to visualize intravascular lesions and guide therapy. The use of ICM carries a risk of postcontrast acute kidney injury (PC-AKI), which is increased in the elderly and in patients with chronic kidney disease (CKD). Furthermore, the risk of PC-AKI increases with the volume of ICM used. This paper reports a 94-year-old patient with CKD stage 4 who presented with chronic limb threatening ischemia. He underwent successful endovascular revascularization using a combination of CO2 and dilute ICM (total volume = 6.5 mL). The case demonstrates strategies to minimize ICM during PVIs.

Problem Parents of children with chronic kidney disease face tremendous burdens of care, having to adopt dual roles as parents and informal healthcare providers, delivering home-based clinical care, despite lacking proper qualification and training. Eligibility criteria A systematic review of qualitative studies was conducted to identify sources of distress among parents caring for children with chronic kidney disease undergoing dialysis, excluding children who have had renal transplants. Guided by PRISMA guidelines, six electronic databases (PubMed, Embase, PsycINFO, Scopus, Cochrane, Google Scholar) were searched for relevant articles published in English. A three-step inductive thematic synthesis method outlined by Thomas and Harden (2018) was used to form descriptive themes and the Critical Appraisal Skill Program (CASP) qualitative checklist was utilised to appraise the quality of included articles. Sample A total of 23,129 title and abstracts were reviewed; 161 full texts were reviewed. Thirteen papers, with the experiences of 183 parents, met the inclusion criteria. Most included studies were conducted in Western countries, which may limit the applicability of this review to other countries. Results Five themes emerged: disease-related distress, personal struggles, family structure, lack of resources and unrealistic social expectations. Conclusion Parents of children with chronic kidney disease undergoing dialysis experienced distress at multiple levels. Implication Healthcare professionals caring for children with chronic kidney disease could screen parents early for distress, and refer them to relevant psychosocial and community services.

The prevalence of chronic kidney disease (CKD) increases annually in the present scenario of research. One of the sources for further therapy is the CKD prediction where the Machine learning techniques become more important in medical diagnosis due to their high accuracy classification ability. In the recent past, the accuracy of classification algorithms depends on the proper use of algorithms for feature selection to reduce the data size. In this paper, Heterogeneous Modified Artifical Neural Network (HMANN) has been proposed for the early detection, segmentation, and diagnosis of chronic renal failure on the Internet of Medical Things (IoMT) platform. Furthermore, the proposed HMANN is classified as a Support Vector Machine and Multilayer Perceptron (MLP) with a Backpropagation (BP) algorithm. The proposed algorithm works based on an ultrasound image which is denoted as a preprocessing step and the region of kidney interest is segmented in the ultrasound image. In kidney segmentation, the proposed HMANN method achieves high accuracy and significantly reducing the time to delineate the contour.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.

Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of cross-specialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner. Resumen: Los pacientes con enfermedad renal crónica (ERC) que desarrollan insuficiencia cardíaca (IC) congestiva crónica presentan cifras inaceptablemente altas de síntomas, hospitalización y mortalidad. Actualmente, se echan en falta iniciativas institucionales dirigidas a identificar, prevenir y tratar la IC en los pacientes con ERC de manera multidisciplinar, prevaleciendo las actuaciones de las especialidades individuales. Los autores de este artículo de revisión respaldan la necesidad de crear equipos multidisciplinares cardiorrenales, en los que participen nefrólogos y enfermeras renales, que gestionen colaborativamente las intervenciones clínicas apropiadas en los entornos de pacientes con ERC e IC hospitalizados y ambulatorios. Es necesario y urgente que se elaboren guías y modelos de práctica clínica sobre la ERC con IC por parte de las sociedades profesionales de cardiología y nefrología, así como financiación para la investigación concertada entre ambas especialidades sobre la necesidad de futuros tratamientos para la IC en pacientes con ERC. La implementación de programas educativos cardiorrenales a todos los niveles en cardiología y nefrología ayudará a formar a los futuros especialistas y enfermeras para que tengan la capacidad de diagnosticar, tratar y prevenir la IC en pacientes con ERC de manera precisa, clínicamente efectiva y económicamente favorable.

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.

Sclerostin is sometimes presented as a promising biomarker in assessing bone health both in the general population and chronic kidney disease patients. However, it is still unclear whether it has any true added value compared to existing bone biomarkers in predicting bone turnover and/or bone density in chronic kidney disease patients. A wealth of papers has been published to evaluate the association between sclerostin and vascular calcifications development or even as prognostic biomarker for mortality, but often with conflicting results. Standardization and harmonization of analytical techniques is a prerequisite to advance clinical knowledge in sclerostin.

Background Fabry disease is an X-linked lysosomal storage disorder with a highly heterogeneous clinical presentation. This complex disease is caused by a deficient activity of the enzyme α-galactosidase A, which is involved in the catabolism of glycosphingolipids. The prevalence of Fabry disease is underestimated, due to the presence of atypical variants. High-risk screening protocols are particularly relevant for this disease due to the availability of treatments, such as enzyme replacement and chaperone therapies. As kidney manifestations are present in the majority of male and many female patients with Fabry disease, a high-risk screening protocol was performed for patients with chronic kidney disease of unknown etiology. Methods Recruitment of 397 participants took place in four centers across Canada from 2011 to 2017. Globotriaosylceramide (Gb3) was analyzed in dried urine spots by liquid chromatography/tandem mass spectrometry followed by globotriaosylsphingosine (lyso-Gb3) on the repeat analysis. Results The collection and shipment of urine specimens on filter paper resulted in easier handling/shipment and significant cost-saving. No Fabry patients were detected in this study. Conclusions Increased concentrations of urinary Gb3 were observed in 13.6% of patients with chronic kidney disease suggesting that chronic kidney disease or other comorbidities might be associated with increased urinary Gb3 concentrations.

Rationale & Objective Chronic kidney disease (CKD) can substantially affect patients' health-related quality of life. Electronic patient-reported outcome measures (ePROMs) may capture symptoms and health-related quality of life and assist in the management of CKD. This study explored patient and clinician views on the use of a renal ePROM system. Study Design Qualitative study. Setting & Participants 12 patients with stage 4 or 5 CKD (non–dialysis dependent); 22 clinicians (6 CKD community nurses, 1 clinical psychologist, 10 nephrologists, 3 specialist registrars, and 2 renal surgeons) in the United Kingdom. Analytical Approach Semi-structured interviews and focus group discussion during which patients received paper versions of the Kidney Disease Quality of Life-36 and the Integrated Patient Outcome Scale-Renal to exemplify the type of content that could be included in an ePROM. Thematic analysis of interview transcripts. Results 4 themes were identified: (1) general opinions of PROMs, (2) potential benefits and applications of an ePROM system, (3) practical considerations for the implementation of ePROMs, and (4) concerns, barriers, and facilitators. Patients were willing to complete ePROMs on a regular basis as part of their care despite clinician concerns about patient burden. Patients assessed the questionnaires favorably. Clinicians suggested that the extent of adoption of renal ePROM systems in routine clinical settings should be based on evidence of significant impact on patient outcomes. Clinicians were concerned that an ePROM system may raise patient expectations to unrealistic levels and expose clinicians to the risk for litigation. Patients and clinicians identified potential benefits and highlighted issues and concerns that need to be addressed to ensure the successful implementation of the renal ePROM system. Limitations Transferability of the findings may be limited because only English-speaking participants were recruited to the study. Conclusions A renal ePROM system may play a supportive role in the routine clinical management of patients with advanced CKD if the concerns of clinicians and patients can be sufficiently addressed.

Diet composition has long been known to influence acid–base balance by providing acid or base precursors. In general, foods rich in protein, such as meat, cheese, eggs, and others, increase the production of acid in the body, whereas fruit and vegetables increase alkalis. The capacity of acid or base production of any food is called potential renal acid load (PRAL). Diets high in PRAL induce a low-grade metabolic acidosis state, which is associated with the development of metabolic alterations such as insulin resistance, diabetes, hypertension, chronic kidney disease, bone disorders, low muscle mass and other complications. The aim of this paper is to review the available evidence which evaluates the association of the PRAL of the diet with the incidence of chronic diseases and metabolic disorders, as well as related mechanisms involved in their development. Resumen: En la actualidad se ha evidenciado el rol de la composición dietética en el equilibrio ácido-base, al proveer precursores ácidos y álcalis. De manera general, los alimentos altos en proteína, como la carne, los quesos, huevo, entre otros, incrementan la producción de ácidos en el organismo, mientras que las frutas y los vegetales incrementan los álcalis. La capacidad que tiene un alimento para producir precursores ácidos o bases se denomina carga ácida potencial renal (PRAL). Dietas con PRAL elevados ocasionan un estado de acidosis metabólica de bajo grado, el cual se ha asociado con el desarrollo de alteraciones metabólicas como resistencia a la insulina, diabetes, hipertensión, enfermedad renal crónica, alteraciones óseas y baja musculatura, entre otras complicaciones. El objetivo del presente trabajo es realizar una revisión de la evidencia disponible a la fecha que evalúa la asociación entre el PRAL de la dieta con la incidencia de enfermedades crónicas y alteraciones metabólicas, mencionando los mecanismos involucrados en su desarrollo. Keywords: Metabolic acidosis, Potential renal acid load, Net endogenous acid production, Proteins, Nutritional intervention, Palabras clave: Acidosis metabólica, Carga ácida potencial renal, Producción neta de ácido, Proteínas, Intervención nutricional