Urologic complications (UCs) and urinary tract infections (UTIs) are common after kidney transplantation. Intraoperative stent placement at the vesicoureteric anastomosis reduces UC risk, but increases UTI risk.In 2014 our stenting protocol changed from external ureteric stent (ES) to internal double J stent (DJ). We retrospectively studied the occurrence of UCs and UTIs in relation to ES or DJ in 697 kidney recipients.An ES was used in 403 patients (57.8%), in 294 (42.2%) a DJ. ES was removed 7-12 days and DJ 3-4 weeks post-operative. Induction immunosuppression was the same in both groups. Primary outcomes at 6 months follow-up were UC (urinary leakage/ureter stenosis) and UTI; they were related to stenting procedure and clinical and transplant characteristics. The incidence of UCs was similar for ES (8.4%) and DJ (6.8%), p=0.389. ES use was a significant risk factor for UTI (OR 1.69 (1.15-2.50), p=0.008). Post-transplant hospitalization was significantly shorter in the DJ group. Despite more acute rejection episodes with ES , no clinical relevant differences in graft outcomes existed.A DJ is, compared to ES, associated with a lower incidence of UTIs and comparable occurrence of UCs and is therefore the preferred technique for stenting the vesicoureteric anastomosis. For patients with end stage renal disease, kidney transplantation is the preferred treatment option . Importavia cystoscopy, usually in the outpatient setting. There is a large variation in DJ stent duration, usually weeks longer than with ES , which is a flexible catheter that drains externally, percutaneously, from the donor kidney pyelum through the suprapubic bladder region, and the completely internal double J stent (DJ). The use of an ES has several advantages, such as removal without cystoscopy, selective monitoring of the urine output from the kidney graft, and generally a shorter period of a foreign body in situ. However, besides an extra external connection of the urinary tract, hospitalization is generally longer (1-2 weeks post-operative) with ES due to the in-hospital removal of the stent  and the indwelling catheter. There is no consensus and very little literature concerning the optimal stent duration for ES usage . In cont with ES . Overall with ES . However with ES , 11.Only a few studies comparing the use of a DJ versus (vs.) an ES in kidney transplantation have been performed, using a variety of definitions and presenting varying results regarding incidence of UC and UTI –19. In SWe performed a retrospective analysis of all consecutive adult kidney transplant recipients between September 2012 and December 2016 at the University Medical Center Groningen, the Netherlands. Data were obtained using a local registry of all kidney transplant recipients providing the baseline characteristics and kidney transplant outcomes. The data obtained from the patient medical records, contained the type of ureteric stents, indwelling catheter, UCs and UTIs. At admission for kidney transplantation, patients had given consent for using their data for future research and our local Medical Ethical Board waived the need for further consent. All data were anonymized and filed for analyses.via an extra-peritoneal approach. The vesicoureteric anastomosis was performed using a modified extravesical Lich-Gregoir technique or a full thickness technique. From September 2012 until September 2014 all kidney transplant recipients received an ES peri-operative. An 8-French, 125 cm enteral feeding tube used as splint, was placed in the graft pyelum and drained externally suprapubic through the bladder wall, hereby stenting the vesicoureteric anastomosis. The ES was removed by gently pulling between 7-12 days post-operative (depending on tightness of the ES and transplant function), without antibiotic prophylaxis. The peri-operatively placed indwelling catheter was usually removed 1-2 days after ES removal and patients were regularly checked for adequate bladder evacuation afterwards. Unto successful indwelling catheter removal, patients stayed in the hospital.All kidney transplantations were performed by a team of experienced transplant surgeons. The kidney allograft was placed in the right or left iliac fossa via cystoscopy. Around cystoscopic DJ stent removal, patients received antibiotic prophylaxis with ciprofloxacin 500mg twice daily, starting 12 hours before unto 24 hours after removal.From September 2014 onwards the stenting protocol changed with a transition period of 3 months. In the new protocol a 7-French, 16 cm, internal double J stent was placed peri-operatively, draining from the graft pyelum to the bladder. Based on patient characteristics, like medical history and presence of diuresis, and surgical conditions a ES could still be used. The indwelling catheter was removed on day 5 post-operative and patients were regularly checked for adequate bladder evacuation afterwards. Patients stayed in hospital until successful indwelling catheter removal. The DJ stent was removed 3-4 weeks post-operative at the outpatient clinic Pneumocystis jiroveci with co-trimoxazole 400/80 mg once daily.The standard immunosuppressive regimen consisted of prednisolone, mycophenolate mofetil and tacrolimus or ciclosporin. All patients received induction immunosuppressive therapy with the IL-2 receptor blocker Basiliximab and perioperative antibiotic prophylaxis with a single dose of cefazoline 2000mg. During the first 6 months after transplantation patients received prophylaxis against 5 CFU/ml) and requiring antibiotic treatment, excluding asymptomatic bacteriuria (ASB). A non-invasive UTI was defined as a UTI without signs or symptoms of tissue invasion and/or bacteremia.Primary outcomes were the occurrence of UCs and/or UTIs during the first six months after kidney transplantation. UCs were defined as urinary leakage or ureter stenosis requiring an intervention . Bladder retention, defined as failure of adequate bladder evacuation requiring indwelling catheter placement or intermittent self-catheterization, was not defined as UC because it is not considered a complication related to stenting of the vesicoureteric anastomosis. A UTI was defined as the clinical suspicion of UTI with leukocyturia and/or a positive urinary culture (≥10Secondary outcomes were graft function after 6 months [defined as creatinine clearance (ml/min) and proteinuria (g/24h)], and delayed graft function .Categorical data are presented as number and percentages, continuous data as median and interquartile range (IQR) or mean and standard deviation (depending on data distribution). To compare continuous variables, unpaired t-test or Mann-Whitney U test were used when appropriate. The Chi-square test, Fisher’s exact test or Fisher-Freeman-Halton test were used to compare proportions. Time to occurrence of UTI and UC were analyzed with Kaplan-Meier curves and Log Rank test was used to calculate the Hazard ratio (HR) and the 95% confidence interval (CI) to compare ES and DJ. Univariate analyses were performed to compare groups with and without UTI and UC. Multivariate binary backward and forward LR logistic regression was performed with the use of ES or DJ and additional variables with a p-value ≤0.1 by univariate analysis. Thereafter the binary logistic regression was repeated with method enter with the remaining significant variables and the use of ES or DJ to identify the possible influence of the used type of stent on the occurrence of UTI and UC. Multiple imputation (5 times) was performed for missing values and binary logistic regression was repeated with the imputed data to verify that the missing values did not influence the outcome. All reported p-values are two tailed and a p-value <0.05 was considered statistically significant. Analyses were conducted with SPSS version 23  and GraphPad Prism version 9 .During the inclusion period, 711 consecutive kidney transplants were performed of which 14 were excluded due to graft loss ≤1 week after transplantation. Of the remaining 697 kidney transplants, 13 were lost to follow-up for UC as outcome  and 10 were lost to follow-up for UTI as outcome . In 403 (57.8%) patients an ES was placed during the transplant procedure and in 294 (42.2%) patients a DJ. After December 2014, in 107 cases a ES was used due to patient and/or surgical characteristics. The mean recipient age at transplantation was 53 years for both groups and 40% were women. Patient characteristics of the ES and DJ group were mostly similar Table 1.A reduction in hospital stay after kidney transplantation was seen after the change in protocol, median of 7 (IQR 9-14) days after DJ placement and a median of 15 (IQR 13-17) days after ES placement (p<0.001). As expected, duration of stent placement was longer in the DJ group compared to the ES group . With respect to clinical outcome (6 months follow-up), no clear differences were found in the occurrence of bladder retention  and serum creatinine Table 2.The occurrence of an UC requiring intervention within 6 months after transplantation was similar between the ES group and DJ group; 34 (8.4%) vs. 20 (6.8%) patients, p=0.389, HR 1.27 (95% CI 0.74-2.18) Figure 1In univariate analysis, multiple risk factors for developing an UC within 6 months after kidney transplantation were identified Table 4.In the ES group more patients experienced at least one UTI within the first 6 months after kidney transplantation compared to the DJ group: 114 (28.3%) vs. 61 (20.7%) patients, p=0.023, HR 1.43 (95% CI 1.06-1.93) Figure 2In univariate analysis, multiple factors associated with the development of a UTI within 6 months after kidney transplantation were identified Table 6.Prophylactic stenting of the vesicoureteric anastomosis in kidney transplantation is nowadays standard practice in most kidney transplant centers. There is no consensus on the optimal stenting type and duration , 16–19. Our reported UC rates are 8.5% in the ES group vs. 6.8% in the DJ group. Previous research has shown comparable incidences ranging from 0.3-25.0% for ES vs. 0.0-5.4% for DJ –19. For The ES group showed significant more UCs in the first month after transplantation compared to the DJ group. After the first month, there is a comparable incidence of UC over the follow-up time. Earlier research also showed that the majority of the UCs occur in the first 4 weeks after transplantation . Shorterin situ is a risk factor for the development of bacteriuria, especially starting 1-2 weeks after placement , which is longer compared to earlier studies . The lonAlthough patients with an ES experienced (slightly) more UCs and UTIs, there were no clinical relevant differences in graft outcome 6 months after kidney transplantation. Creatinine clearance was slightly, but significantly, lower in the ES group and in these patients proteinuria was more often present. The higher rates of UCs and UTIs in the ES group could have led to these small, but clinically irrelevant differences , 26. IntThis study has a few strengths and limitations that need to be addressed. A major strength is the comparable circumstances and baseline characteristics between the two groups. Second, we described two large, representative groups with a longer follow-up compared to previous published cohorts. A limitation of our study is the retrospective design. Although we reviewed all the patients charts and used our local kidney transplantation database, it could be that the UCs and UTIs are not registered correctly. In contrast to other studies, we excluded patients with ASB as having a UTI since there is no need for treatment. This could have led to better results on UTI occurrence, but should not have influenced patient- and graft outcomes. A recent systematic review showed that after kidney transplantation untreated ASB vs. treated ASB have the same outcomes regarding graft function and risk of getting a symptomatic UTI . Lastly,Overall, using a DJ, compared to an ES, for stenting the vesicoureteric anastomosis after kidney transplantation, leads to significantly less urinary tract infections and a shorter hospitalization period post-transplantation which reduces healthcare related costs. Incidence of urological complications was comparable for both groups. There is no indication that a DJ performs worse compared to an ES with regards to graft outcomes. Our data suggests that use of a DJ is the preferred technique for stenting the vesicoureteric anastomosis during kidney transplantation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.IH participated in data collection, database editing, data analysis and manuscript writing. SM participated in research design, performance of research, data collection, database editing, data analysis, and manuscript writing. AJ, RP, and J-SS participated in research design and manuscript editing. JR participated in data collection and manuscript editing. BD participated in manuscript editing. CS participated in research design, data collection, database editing, data analysis and manuscript editing. IH and SM contributed equally as first author. All authors contributed to the article and approved the submitted version.


This narrative review aims to assess the pathophysiology, diagnosis, and treatment of resistant hypertension (RH) in end-stage kidney disease (ESKD) patients on dialysis, with a specific focus on the effect of renal denervation (RDN) on short-term and long-term blood pressure (BP) control. Additionally, we share our experience with the use of RDN in an amyloidotic patient undergoing hemodialysis with RH.High BP, an important modifiable cardiovascular risk factor, is often observed in patients in ESKD, despite the administration of multiple antihypertensive medications. However, in clinical practice, it remains challenging to identify RH patients on dialysis treatment because of the absence of specific definition for RH in this context. Moreover, the use of invasive approaches, such as RDN, to treat RH is limited by the exclusion of patients with reduced renal function (eGFR < 45 mL/min/1.73 m3) in the clinical trials. Nevertheless, recent studies have reported encouraging results regarding the effectiveness of RDN in stage 3 and 4 chronic kidney disease (CKD) and ESKD patients on dialysis, with reductions in BP of nearly up to 10 mmhg.Although multiple underlying pathophysiological mechanisms contribute to RH, the overactivation of the sympathetic nervous system in ESKD patients on dialysis plays a crucial role. The diagnosis of RH requires both confirmation of adherence to antihypertensive therapy and the presence of uncontrolled BP values by ambulatory BP monitoring or home BP monitoring. Treatment involves a combination of nonpharmacological approaches  and pharmacological treatments. A promising approach for managing of RH is based on catheter-based RDN, through radiofrequency, ultrasound, or alcohol infusion, directly targeting on sympathetic overactivity. Resistant hypertension (RH) is frequently observed in patients with chronic kidney disease (CKD). Despite anti-hypertensive treatment, it can lead to the progression of kidney function decline due to the sustained elevation in blood pressure (BP) level .Severe RH in patients undergoing dialysis (HD) has traditionally been an indication for bilateral nephrectomy . HoweverIn recent years, observations on bilateral native nephrectomy as antihypertensive treatment have provided the rationale for catheter-based renal denervation in CKD patients with true RH. Indeed, surgical ablation ameliorates sympathetic overactivity and prevents both hypertension (HT) and the progression of renal disease in experimental models. In this scenario, a percutaneous approach with bilateral renal sympathetic denervation using a radiofrequency ablation procedure has shown promising results as a new available therapeutic strategy in this condition .With this background in mind, our aim is to provide a comprehensive review of the pathophysiology, diagnosis, and treatment of RH in patients with end-stage kidney disease (ESKD) undergoing dialysis. Specifically, we focus on examining the impact of renal denervation (RDN) on short-term and long-term BP control. Furthermore, we present our experience with the use of RDN in an amyloidotic patient receiving maintenance hemodialysis with RH.We conducted a comprehensive search of the PubMed, Scopus, Google Scholar, and Web of Science databases for articles published from their inception up to April 30, 2023. We used the following search terms: “resistant hypertension,” “renal denervation,” “end-stage kidney disease,” “end-stage renal disease,” “kidney failure,” “renal replacement therapy,” “dialysis,” and “hemodialysis.” We primarily included articles published from January 1, 2013, to April 30, 2023, in the English language. However, we did not exclude relevant and highly referenced older publications.According to the 2017 American Heart Association and American College of Cardiology (AHA/ACC) hypertension guidelines , the 201True RH can be distinguished from pseudo-resistance if BP levels are above goal when measured in the dialysis using proper technique and confirmed with out-of-dialysis measurements, such as 24-h ambulatory BP monitoring (ABPM-24 h) or home BP monitoring, while excluding non-adherence to antihypertensive therapy .However, the diagnostic accuracy of BP measurements, typically taken pre or post dialysis, is limited by several technical and patient-related factors such as incorrect BP evaluation and reading, volume fluctuations, anxious state, and the white-coat effect , 14. AltThe primary cause of hypertension in dialysis patients is the sodium retention and volume expansion , 19. WheOther factors, such as endothelial dysfunction, activation of renin–angiotensin–aldosterone axis, and overactivity of sympathetic neural system, may also contribute to RH in dialysis patients . Over thESKD is characterized by significant modifications in the autonomic control of the cardiovascular system. These changes includes (1) heightened activity in the sympathetic nervous system that affects the cardiovascular system, (2) early onset of adrenergic abnormalities that are directly proportional to the severity of the renal dysfunction, (3) a decrease in the inhibitor influence of vagal nerve on sinus node, resulting in increased resting heart rates, (4) impaired modulation of both vagal and sympathetic cardiovascular effects by the arterial baroreceptors, (5) impaired control of sympathetic vasoconstrictor tone and renin release from the juxtaglomerular cells by cardiopulmonary receptor, (6) activation of chemoreflex, and (7) diminished sensitivity of the alpha adrenergic vascular receptors .The extent to which hemodialysis can reverse and possibly normalize the altered autonomic profile of HD patients remains a matter of controversy. While few studies documented improvements in the parasympathetic tone of the heart rate after a single hemodialysis session , no signMoreover, these discrepancies among studies can also be attributed to the different dialytic modalities adopted. For example, nocturnal hemodialysis and short daily hemodialysis can trigger positive autonomic effects, enhancing arterial baroreflex sensitivity and reducing the sympathetic activity. On the other hand, peritoneal dialysis does not have a significant effect on autonomic dysfunction , 33.Finally, volume overload may be another possible explanation of varying outcomes observed across different studies since central blood volume plays a crucial role in determining reflex responses .Despite the indication of antihypertensive drugs to achieve BP control, the benefits of non-pharmacological interventions for HD patients with RH should be considered.Indeed, the effectiveness of anti-hypertensive therapy in hemodialysis patients relies on maintaining euvolemia , 36. WhiAmong various non-pharmacological treatments for controlling the volume overload, salt restriction and dialysate sodium reduction are the most commonly used . The avaSimilarly, high concentrations of sodium in dialysate are often used to reduce the risk of intradialytic hypotension, but on the other hand, they increase the sodium load and balance, interdialytic weight, thirst, and BP. An individualized strategy to optimize the dose of dialysate sodium should be assessed in clinical trials in HD patients with RH .Furthermore, other studies, investigating the correlation of weight loss, assessed by BMI, with BP among HD patients, produced conflicting results. Although a link between higher BMI and higher BP has been demonstrated, a phenomenon referred to as the “paradoxical effect,” where an increase in BMI is inversely associated with BP levels, has been revealed .Finally, another simple and efficient non-pharmacologic approach could be to prescribe intradialytic or interdialytic exercise in HD patients  who ofteCombination drug therapy is necessary to reach BP targets in patients with RH, including those on hemodialysis. However, the potential risks of polypharmacy should be also considered, given the high pill burden of HD patients. There is currently insufficient evidence to suggest the superiority of any class of antihypertensive medication, either alone or in combination, for HD population, regardless of individual preferences. Nevertheless, although some antihypertensive drugs may offer additional cardio-protective benefits beyond their direct BP-lowering effects, their possible side effects should also be taken into account. Ultimately, the choice of an anti-hypertensive drug should aim to balance reducing cardiovascular risk with minimizing adverse effects. In clinical practice, other relevant characteristics, such as the drug’s dialyzability and timing of administration in relation to hemodialysis, can also inform drug selection , 50.Some drugs belonging to the anti-hypertensive class of beta-blockers, including carvedilol and atenolol, have been studied in HD patients , 52. TheRenin–angiotensin–aldosterone system (RAAS) blockade, achieved through use of ACE inhibitors and angiotensin-II receptor blockers (ARBs), can reduce systolic BP, comparable to that achieved by calcium-channel blockers (CCBs)  in HD paThe prescription of diuretics in HD patients with residual renal function for the treatment of the volume overload and improvement of left ventricular mass index and arterial stiffness remains a topic of debate with conflicting opinions. While loop diuretics have shown promising evidence in increasing urine output, no data support their efficacy in controlling BP in HD patients .However, if tolerated, loop diuretics should always be a part of combination drug therapy in cases of resistant hypertension, and high doses should be used due to the tubular mechanism of action that relies on glomerular filtration . In contAlthough both dihydropyridine and non-dihydropyridine CCBs are useful in managing resistant hypertension, amlodipine, a dihydropyridine CCBs, has been extensively studied in HD patients. Therefore, it could be considered a first-line association therapy for RH for its effects not only in controlling BP but also in reducing the cardiovascular risk . HoweverIn order to effectively control BP, the adherence to anti-hypertensive therapy is crucial in CKD patients, although CKD does not lead to a higher percentage of poor adherence to drugs compared to individuals without CKD .Reduced drug adherence, which can further worsen when CKD patients start dialysis, is one of the most frequent factors contributing to RH . HoweverStudies examining the reasons behind non-compliance with anti-hypertensive treatment in HD patients emphasize the significance of effective communication and the perceived benefit of the therapies, regardless of the antihypertensive class .In addition, other factors, including pill burden, drug interactions, and adverse effects, play a significant role in non-adherence to anti-hypertensive treatment , 66. TheThe two most extensively studied platforms for renal denervation (RDN) are radiofrequency RDN (rRDN) and ultrasound RDN (uRDN). In both procedures, the renal artery is accessed via the common femoral artery after selective renal angiography and placement of a 0.014″ guidewire in the renal arteries. It is worth highlighting that despite rRDN is designed to treat both the main and distal renal arteries while uRDN specifically the main renal arteries, the efficacy of both procedures is comparable •, 69.rRDN is currently performed using the Symplicity Spyral™ RDN system (Medtronic Inc.), which utilizes radiofrequency waves emitted from four radiopaque electrodes located on the helical shaped tip of the Spyral™ catheter .uRDN is performed using the Paradise Renal Denervation System , which incorporates a balloon at its distal tip surrounding an ultrasound emitting core. The Paradise catheter is an over-the-wire system connected to a console which inflates the balloon and continuously infuses sterile water to cool the arterial wall before, during, and after the treatment .In addition of the aforementioned technologies, ongoing clinical trials such as TARGET BP I  and TARGIn the first clinical trials investigating the efficacy and tolerability of percutaneous ablation of renal nerves in treatment of RH, renal dysfunction was listed as one of the exclusion criteria. Nevertheless, only a few studies have recently examined the effects of the RDN in patients with CKD stages III and IV, providing compelling evidence that RDN do not affect renal function .Furthermore, studies with long-term follow-up indicate RDN may even slow the progression of CKD and, in some cases, lead to improvement in albumin and protein urinary excretion , 74.However, it is still unclear to what extent the outcomes of renal denervation in CKD are related to direct effects of lowering sympathetic drive or indirect effects of BP reduction due to RDN .This uncertainly arises partly from limited data on the sympathetic effects of renal denervation in CKD. In a proof-of-concept study, conducted on nine ESKD patients undergoing hemodialysis, authors specifically evaluated the impact of endovascular RDN on muscle sympathetic nerve traffic . The resSymplicity HTN-1, symplicity HTN-2, and other smaller trials presented intriguing results concerning the potential role of RDN in treating RH within the hypertensive population. However, the symplicity HTN-3 trial yielded less encouraging outcomes. While it confirmed the safety of the RDN, it failed to prove its efficacy in comparison to a sham procedure for BP control , 78.2 and 1505 patients with eGFR ≥ 60 mL/min/1.73 m2 . T•. T80•].Subsequently, this initial data was confirmed by Schlaich et al.  which ilIn contrast, Ott et al. achieved noteworthy results in a 29-year-old HD woman who had RH with small native renal arteries (< 4 mm). Through catheter-based renal denervation performed on both native kidneys, notable systolic (38 mmHg) and diastolic BP (30 mmhg) reduction were obtained.p = 0.043) at 6 months following the procedure, both for daytime and nighttime values. Notably, it is intriguing to point out that even though three out of six patients had renal arteries with a diameter less than 4 mm, no procedural adverse events were recorded [The feasibility and safety of bilateral RDN in HD patients with small renal arteries were confirmed through a case series in which systolic and diastolic ABPM-24 h were significantly reduced an average of 20 ± 17 and 15 ± 12 mmHg  treated with intravascular renal denervation at a single center. Similarly, in this study, no procedure-related adverse events were observed. Remarkably, in the 50% of cases, antihypertensive therapy was discontinued, and one patient maintained normotension for an impressive 24-month duration. .The enduring efficacy of RDN in reducing the BP was further corroborated by Scalise et al., • in a stFurthermore, Hoye et al.  unveiledp < 0.05) and notable reductions in 24-h ambulatory systolic (p < 0.001) and diastolic (p = 0.001) BP over a span of at least 24 months.Collectively, to date, a unique meta-analysis has been conducted, focusing on impact of RDN in 238 RH patients with CKD. This analysis encompassed not only patients undergoing HD but also those with CKD stages 1–5, drawing data from 11 single-center studies, non-randomized, uncontrolled . The resA 47-year-old male, with a long history of HT and renal amyloidosis since 2009, has been following a dialysis program for the past 2 years, three times weekly. His antihypertensive therapy consisted of nifedipine 60 mg twice daily, ramipril 5 mg twice daily, furosemide 500 mg daily, doxazozine 4 mg three time daily, and valsartan 320 mg daily. In the last year, he was admitted to the emergency department three times in 2 months for hypertensive crisis (averaged BP of 250/140 mmHg) and acute encephalopathy with severe headache, vomiting, and blurred vision. Ocular fundus examination showed a grade III retinopathy. Brain CT showed no signs of bleeding, while electrocardiogram revealed sinus bradycardia with left ventricular hypertrophy, left anterior hemi-block, and left axial deviation, without alterations of the S/T segment. Echocardiography documented hypertensive heart disease with a LVMI of 165.3 g/m2; left ventricular ejection fraction (64%) and contractility function were normal. Laboratory tests showed hyperkalemia (5.34 mmol/L). The diagnosis of RH was confirmed by the 24-h ambulatory BP monitoring .The RDN procedure was completed without complications, and after 48 h, systolic BP decreased by up to 40 mmHg Fig. , panel BTo the best of our best knowledge, we report the first case report of RDN performed in amyloidotic patients on hemodialysis. In clinical practice, our case reveals that RDN could be technically feasible and potentially effective in ESKD patients’ dialysis dependent. While current evidence does not establish that RDN is superior to intensive  anti-hypertensive drug therapy in improving cardiac remodeling and function, our experience showed that RDN improved the quality of life of our patient and reduced the daily intake of anti-hypertensive medications from ten to four pills. Moreover, the significant improvements in office and ambulatory BP as well as LVMI values, observed in our patients, might carry significant clinical implications in reducing the very-high global cardiovascular risk faced by hypertensive patients on dialysis.Endovascular RDN can induce a sympatholytic effect, resulting in a significant reduction in BP and left ventricular mass index values. This procedure should be considered in carefully selected cases, particularly in young adults with dialysis-dependent ESKD and true RH, in order to mitigate the risk of severe, life-threatening organ damage. However, further larger-scale, randomized and sham-controlled clinical trials should be planned and conducted specifically in ESKD patients on dialysis treatment with RH.


Acute kidney injury (AKI) is a common postoperative complication among patients in the neurological intensive care unit (NICU), often resulting in poor prognosis and high mortality. In this retrospective cohort study, we established a model for predicting AKI following brain surgery based on an ensemble machine learning algorithm using data from 582 postoperative patients admitted to the NICU at the Dongyang People's Hospital from March 1, 2017, to January 31, 2020. Demographic, clinical, and intraoperative data were collected. Four machine learning algorithms  were used to develop the ensemble algorithm. The AKI incidence in critically ill patients after brain surgery was 20.8%. Intraoperative blood pressure; postoperative oxygenation index; oxygen saturation; and creatinine, albumin, urea, and calcium levels were associated with the postoperative AKI occurrence. The area under the curve value for the ensembled model was 0.85. The accuracy, precision, specificity, recall, and balanced accuracy values were 0.81, 0.86, 0.44, 0.91, and 0.68, respectively, indicating good predictive ability. Ultimately, the models using perioperative variables exhibited good discriminatory ability for early prediction of postoperative AKI risk in patients admitted to the NICU. Thus, the ensemble machine learning algorithm may be a valuable tool for forecasting AKI. Postoperative AKI is a major cause of poor outcomes after brain surgery. Many studies4 have confirmed that the occurrence of AKI is directly related to patient outcomes and results in a longer duration of postoperative mechanical ventilation, prolongation of the intensive care unit (ICU) and overall hospital stays, increased severity of disability, and significant increases in hospital mortality. The clinical diagnosis of AKI is largely dependent on serum creatinine (sCr) and urine output5. However, an increase in sCr usually indicates severely impaired renal function, and neurocritical patients often develop pituitary disorders, such as diabetes insipidus, leading to obvious abnormalities in urine output and consequently resulting in the inability to accurately diagnose AKI. Therefore, much research effort has been focused on the early and accurate identification of AKI in high-risk patients6.Acute kidney injury (AKI) is a common complication among neurocritical patients. According to the Kidney Disease: Improving Global Outcomes (KDIGO) study, the reported incidence of AKI is 11.6% in neurocritical patients, with approximately 3–12% of patients requiring hemodialysis7. Considerable research10 has focused on the application of ML methods in the prediction of postoperative mortality, recurrence, and adverse events in patients with brain tumors, neurovascular diseases, and traumatic brain injury. In recent years, ML has also been widely applied for the prediction of AKI in critically ill patients. For instance, He et al. extracted 76,957 encounters and relevant clinical variables from the electronic medical record system of a hospital to establish models for predicting AKI in general hospital populations using five ML methods11. Their results indicated that the constructed models provided good predictive performance. Although AI-based ML algorithms have shown promise for predicting AKI risk in several studies, the predictive performance of such models must be improved prior to widespread clinical application. Ensemble modeling, a relatively new approach that combines multiple ML models to enhance model accuracy, may be of value given recent evidence across medical specialties14.Artificial intelligence (AI) and machine learning (ML) are regarded as highly valuable tools that can assist in preoperative planning, intraoperative guidance, and outcome prediction for patients undergoing neurosurgeryCurrently, there are few universal models for predicting the risk of AKI after brain surgery, making it difficult to utilize the large amounts of data available in modern electronic health record systems. Therefore, this study aimed to establish an ensemble learning-based predictive model using a large number of preoperative, intraoperative, and postoperative ICU variables, including intraoperative vital signs, medication information, and intake and output data. Improved accuracy in postoperative AKI prediction may aid in early evaluation of the patient’s risk level, assist in clinical decision-making, and promote timely intervention.15  statementData were collected using a medical record information mining software program provided by Shanghai LeJiu Healthcare Technology Co., Ltd . The collected data included the following: (1) demographic data: age, sex, diagnosis, comorbidities; (2) surgical data: operative time, type of surgery, intraoperative intake and output, intraoperative urine output, intraoperative vital signs , intraoperative blood transfusion data, intraoperative medication data; (3) blood gas and biochemical indicators 24 h after ICU admission; (4) use of drugs: commonly used diuretics, including mannitol, furosemide, and torasemide, and contrast media; and (5) clinical outcomes, including hospital mortality, duration of mechanical ventilation, and length of ICU stay.This study was conducted in accordance with all related local guidelines and regulations, including those related to human genetics. This study was approved by the Ethics Committee of the Dongyang People’s Hospital (Dong Ren Yi 2021-YX-021), which waived the requirement for informed consent due to the retrospective and observational study design. The data were anonymized before analysis.16: increases in sCr ≥ 50% or an sCr increase of at least 26.5 mol/L within 2 days. Chronic kidney disease was defined as a baseline estimated glomerular filtration rate < 60 mL/min/1.73 m2. The diagnosis of AKI was based solely on the serum creatinine levels according to the KDIGO criteria. Because of the retrospective nature of the study, we did not have accurate data on urine output. Baseline sCr was defined as the lowest sCr level within 6 months before ICU admission17. For patients without previous sCr data, it was estimated using the following formula18: sCr = 0.74–0.2  + 0.08 (if black) + 0.0039 × age (in years).AKI was defined and staged in accordance with the 2012 KDIGO criteria19  to remove variables strongly correlated with other variables, after which 80 variables remained. Subsequently, the backward feature selection method, random forest sampling, and tenfold cross-validation were adopted. After variable performance  had been calculated and the variables had been ranked in order of importance, the 10 most important variables were ultimately retained.A total of 119 variables were preliminarily selected based on their potential to influence AKI as demonstrated in the literature and clinical practice. First, variables with missing data > 20% were eliminated, after which 93 variables remained. Data preprocessing was then performed using the caret package in R languageOutliers were detected using the interquartile range (IQR) . The outliers were excluded and treated as missing values. Variables with > 20% missing values were deleted. The missing values of the variables were replaced using multiple imputations.14 in R software. The resultant ensemble model was mainly trained using the following R packages: CARET, Ranger, arm, e1071, naivebayes, and gbm. The samples were randomly assigned to the training dataset for model training and test dataset for model validation in a 7:3 ratio. Supplementary Table Four different models were first constructed using the C5.0, support vector machine (SVM), Bayes, and extreme gradient boosting (XGBoost) ML algorithms. Hyperparameter tuning was performed using the grid search method . Then, the four models were ensembled using the caretEnsemble packageThe performance of each model was evaluated using the area under the receiver operating characteristic curve (AUC). The calibration performance of each model was evaluated using calibration curves. The confusion matrix was evaluated based on accuracy, precision, specificity, recall, and balanced accuracy using a cut-off of 0.5.20.Models were interpreted based on variable importance, which was sorted using the function “varImp” within the CARET package in R. A locally weighted regression technique was used to detect the cut-off values of the top four features that predicted AKI. Moreover, iBreakdown algorithms were used for individual interpretation21. Normally distributed measurement data were expressed as x ± s and compared between the groups using two-independent-samples t-tests. Meanwhile, non-normally distributed data were expressed as medians  and compared using the Mann–Whitney U tests. Enumeration data were expressed in terms of the rate and percentage and compared between groups using the χ2 test. All statistical analyses were performed using R software version 4.1.2. A P-value < 0.05 was considered significant.Descriptive statistical analyses were performed using the CBCgrps package in RThis study was approved by the Ethics Committee of Dongyang People’s Hospital (Dong Ren Yi 2021-YX-021).The requirement for informed consent was waived due to the retrospective and observational study design.A total of 582 postsurgical neurocritical patients were included in this study. Figure Among the 582 postsurgical patients included in this study, 517 (87.4%) underwent emergency surgery. Surgery was performed in the subdural space in 168 patients (28.9%), epidural space in 39 patients (6.7%), supratentorial lesions in 178 patients (30.6%), cranial base and posterior cranial fossa in 23 patients (3.9%), and other sites in 174 patients (29.9%). Table ML models were established using the C5.0, SVM, Bayes, and XGBoost ML algorithms and subsequently ensembled. Figure Supplementary Figure S4 shows the crude relationships between the top four features and AKI. Figure 22. Given the availability of considerable amounts of perioperative data, we adopted four commonly used ML methods to develop models for the early prediction of postoperative AKI. When the four models were ensembled, the resultant model exhibited better predictive ability, achieving an AUC of approximately 0.85, as well as satisfactory values for accuracy and recall.In the present study, approximately one in five patients admitted to the ICU following brain surgery developed AKI, which is consistent with previous resultsC5.0, SVM, Bayes, and XGBoost are the most common ML algorithms. The Bayes method provides the basis for probability learning methods, while the SVM is commonly used for classification. Both C5.0 and XGBoost are classic ML algorithms. These algorithms have good prediction effect for binary classification problems. However, the order of importance for variables differed for the five ML models. For example, the creatinine level on ICU admission played a major role in the C5.0 model. In the confusion matrix, the C5.0 model exhibited the best performance, with the highest accuracy, precision, specificity, and balanced accuracy values. However, the AUC value for the C5.0 model had poor performance and the worst calibration. The accuracy values for the SVM, Bayes, and ensemble models were similar, although the balanced accuracy and specificity values were higher for the ensemble model.23 utilized intraoperative physiologic data, laboratory indicators, and medication information from 2,911 adult surgical patients to develop a model for predicting postoperative AKI, which exhibited an AUC of 0.86. The authors also noted that incorporating intraoperative physiologic time series data enabled better identification of patients at risk for AKI. Lei et al.24 adopted ML algorithms for the prediction of postoperative AKI using data from 42,615 patients who underwent major non-cardiac surgery. Their results indicated that the inclusion of preoperative and intraoperative data increased the AUC of the gradient boosting machine from 0.712 to 0.804. Our results support the notion that ensemble models based on perioperative data can promote early and accurate prediction of post-brain surgery AKI.Similar to the present study, Adhikari et al.25. Arterial blood pressure is also closely related to AKI following high-risk surgery26. In a previous study, predictive models for postoperative AKI in the ICU were established using preoperative variables and intraoperative blood pressure27, yielding good predictive effects. Other studies have reported a close relationship between serum albumin level and the occurrence of postoperative AKI29. For instance, one retrospective cohort study reported that a low serum albumin level immediately after major abdominal surgery increased the risk of postoperative AKI30. Therefore, monitoring and control of intraoperative blood pressure, postoperative oxygenation index, and serum albumin level may aid in preventing AKI and provide guidance for effective clinical treatment.In the present study, the following variables were ranked highest in importance among the five ML models: initial creatinine level, urea level on ICU admission, intraoperative blood pressure, postoperative oxygenation index, and serum albumin level. Although the cause–effect relationships between each of these factors and postoperative AKI cannot be elucidated owing to the black-box nature of ML algorithms, the presence of significant correlations is certain. Therefore, we used a locally weighted scatterplot smoothing technique to assess the crude relationships between the top four features and AKI. The postoperative oxygenation index was negatively associated with AKI, with lower oxygenation values corresponding to higher AKI risk. The analysis indicated that the risk of AKI was lowest at a creatinine level of 40 μmoI/L, an albumin level of 39 mmol/l, and an average systolic pressure of 116 mmHg. Common causes of AKI include infection, hypovolemia, and hypoperfusion, which tend to cause hypoxia. Therefore, hypoxia is regarded as a frequent pathophysiological manifestation of AKIThe present study has certain limitations. First, this was a single-center retrospective study, in which samples were randomly divided into the training and test datasets in a 7:3 ratio. The lack of validation using external data therefore limits the applicability of the model results. Second, the ML algorithms used in this study may exhibit poor interpretability. To address this issue, the variables included in the models were ranked in the order of importance, and the iBreakdown algorithm was used for direct interpretations in individual patients. Third, given that the ratio between patients with and without AKI was 1:4, the dataset used for the present study was imbalance. However, we attempted to account for this using accuracy, precision, specificity, recall, and balanced accuracy values in addition to the common ROC model. Finally, the models constructed in the present study are applicable only for predicting the risk of AKI occurrence during the ICU stay. In future studies, the possibility of AKI occurring 24 or 48 h postoperatively should be investigated using preoperative and intraoperative variables to enhance the predictability and temporal validity of the models.In conclusion, our study showed that AKI is a prevalent condition affecting neurocritical patients. Through utilizing a comprehensive suite of perioperative variables, we have successfully developed an ensemble machine learning model that exhibits excellent predictive ability in forecasting AKI following brain surgery. However, future prospective studies will be necessary to validate the results of this study.Supplementary Information.


Prophylactic high-flow nasal cannula (HFNC) oxygen therapy can decrease the risk of extubation failure. It is frequently used in the postextubation phase alone or in combination with noninvasive ventilation. However, its physiological effects in this setting have not been thoroughly investigated. The aim of this study was to determine comprehensively the effects of HFNC applied after extubation on respiratory effort, diaphragm activity, gas exchange, ventilation distribution, and cardiovascular biomarkers.This was a prospective randomized crossover physiological study in critically ill patients comparing 1 h of HFNC versus 1 h of standard oxygen after extubation. The main inclusion criteria were mechanical ventilation for at least 48 h due to acute respiratory failure, and extubation after a successful spontaneous breathing trial (SBT). We measured respiratory effort through esophageal/transdiaphragmatic pressures, and diaphragm electrical activity (ΔEAdi). Lung volumes and ventilation distribution were estimated by electrical impedance tomography. Arterial and central venous blood gases were analyzed, as well as cardiac stress biomarkers.2O; p < 0.001), pressure–time product  and ΔEAdi . In addition, HFNC induced increases in end-expiratory lung volume and PaO2/FiO2 ratio, decreases in respiratory rate and ventilatory ratio, while no changes were observed in systemic hemodynamics, Troponin T, or in amino-terminal pro-B-type natriuretic peptide.We enrolled 22 patients  who had been intubated for 8 ± 6 days before extubation. Respiratory effort was significantly lower with HFNC than with standard oxygen therapy, as evidenced by esophageal pressure swings (5.3 [4.2–7.1] vs. 7.2 [5.6–10.3] cmHProphylactic application of HFNC after extubation provides substantial respiratory support and unloads respiratory muscles.Trial registration January 15, 2021. NCT04711759.The online version contains supplementary material available at 10.1186/s13613-023-01203-z. Postextubation respiratory failure and reintubation are frequent complications during weaning of mechanical ventilation in intensive care units (ICUs) , 2. ReinSeveral large clinical trials have evaluated the efficacy of postextubation HFNC on weaning outcomes –11. CompThe aim of the study was to compare comprehensively the effects of HFNC versus standard oxygen on respiratory effort, diaphragm activity, gas exchange, ventilation distribution, and cardiovascular biomarkers after extubation. Some of the results of this study have been previously presented in the form of an abstract .We conducted a prospective, randomized crossover physiological study between January 2021 and December 2022 in the ICU of the Hospital Clínico UC-CHRISTUS, Santiago, Chile. The study was approved by the ethical committee of the Pontificia Universidad Católica de Chile , and it was registered in clinicalTrials.gov (NCT04711759).2O and pressure support of 8 cmH2O. Inclusion in the study was confirmed and randomization performed only for patients who passed successfully the SBT, once they were extubated.All patients intubated for acute respiratory failure and mechanically ventilated for at least 48 h, in whom a spontaneous breathing trial (SBT) was planned by the attending physician, were screened for eligibility. Exclusion criteria were age < 18 years old, intubation for acute exacerbation of chronic obstructive pulmonary disease, contraindications to place an esophageal balloon catheter , or for the use of electrical impedance tomography (EIT) , tracheostomy, or do not reintubate order after extubation. If patients were eligible, informed consent was obtained from the next of kin, and before performing the SBT, the study monitoring was placed. All patients underwent a 30-min SBT with positive end expiratory pressure (PEEP) 0 cmHAfter extubation, patients were assigned to one of two sequences in a random order performed by a computer using the R Statistical software with blocks of 10. Patients allocated to the first sequence received standard oxygen therapy through a venturi mask for1 h , followed by 1 h of HFNC  with a gas flow of 50 L/min. Patients allocated to the second sequence received HFNC for 1 h, followed by 1 h of standard oxygen therapy through a venturi mask. Inspired O2 fraction was kept constant throughout the protocol. A washout period was not included as the effects of HFNC and standard oxygen were assumed to dissipate rapidly after stopping them, so it was considered unlikely that the effects of the first intervention would extend until the end of the second period. Other similar studies have used the same approach . At the ® Systems, Inc). The EAdi signal was collected from the RS232 port of SERVO-i ventilator at a sampling rate of 100 Hz  and recorded in a laptop.All patients were positioned at 45° and were ventilated with a Servo-i ventilator . A nasogastric catheter with electrodes to record the electric activity of the diaphragm (EAdi), and with esophageal and gastric balloons  was installed before the SBT. The placement of the catheter was guided by the EAdi signal and the correct position was confirmed by an occlusion test as previously described –22. The An electrical impedance tomography belt with 32 electrodes  was placed around the patient´s thorax at the fifth intercostal space. Before extubation, we connected the EIT flow sensor to the endotracheal tube and recorded 20 spontaneous breaths without positive pressure to calibrate the EIT signal (ΔZ) against measured tidal volumes, in order to estimate changes in lung volumes after extubation .Waveforms from EAdi, EIT, esophageal and gastric pressures were recorded during the last 5 min of each phase and synchronized offline : The average variation of esophageal pressure during inspiration, calculated as the difference between end-expiratory and end-inspiratory esophageal pressure.Pressure–time product per breath (PTP): The average of the area subtended by the Pes curve from the onset to the end of inspiratory effort by simplified calculation .Pressure–time product per minute (PTPmin): The average of the sum of PTP over one minute.Change in transdiaphragmatic pressure (ΔPdi): Transdiaphragmatic pressure (Pdi) was derived by subtracting Pes from Pga., while its change was calculated as the average variation of Pdi during inspiration .T): The tidal variation of impedance (ΔZ) was analyzed globally and divided into two regions of interest (dependent and non-dependent). Based on the previous calibration we estimated VT (VT-Glob) and subdivided it in a dependent and non-dependent VT .Global and regional tidal volume (VT-Glob.Minute ventilation: We estimated minute ventilation (Ventilatory ratio (VR): Index of impaired efficiency of ventilation calculated by the following Equation :\documenVariation of end-expiratory lung volume (ΔEELV): We calculated the difference in end-expiratory lung impedance (EELI) between standard oxygen and HFNC and, based on the previous calibration, we transformed this impedance difference into ΔEELV.Global inhomogeneity index (GI): Calculated as the sum of the impedance changes of each pixel concerning its median , divided by the sum of the impedance values of each pixel , 28.Anteroposterior ventilation ratio (A/P ratio): Calculated as the ratio between the sum of tidal impedance changes in the anterior and posterior halves of the functional image or the lung region of interest within it .Center of ventilation (COV): We determined it as a vertical coordinate that marks the point where the sum of the regional ventilation  divides the lung into two equal parts .Electrical activity of the diaphragm (ΔEAdi): Defined as the amplitude of EAdi during inspiration.Diaphragmatic neuromuscular coupling: Calculated as the ratio between ΔPdi and ΔEAdi (ΔPdi/ΔEadi) .T-Glob to ΔEAdi (VT-glob/ΔEAdi) [Neuroventilatory efficiency (NVE): Calculated as the ratio of Vb/ΔEAdi) .T-glob/ΔPes): Calculated as the ratio of VT-Glob to ΔPes (VT-Glob/ΔPes) [Dynamic compliance (Cdyn): (Vob/ΔPes) .Based on acquired signals from the esophageal/gastric pressure, EIT and EAdi monitoring, the following variables were calculated offline blinded to the sequence allocation:Based on an alpha value of 0.05, power set at 80%, and assuming a similar effect size to that previously reported in a study performed in acute hypoxemic respiratory failure patients , which fDemographic data for all subjects were summarized using descriptive statistics. The Shapiro–Wilk normality test was used to verify data distribution normality. Data are represented as mean ± standard deviation (SD) or median and interquartile range, as appropriate. We followed recommendations for crossover trials to compare the effects of oxygen mask versus HFNC .To analyze the effect of treatment, sequence, and carryover effect, we applied two-way repeated measures ANOVA. Linear regression was applied to analyze whether clinical variables could predict the magnitude of change in PTPmin induced by HFNC. GraphPad Prism v7  was used for calculations.n = 14, 63%), aspiration pneumonia , bacterial pneumonia , and other respiratory viruses . The main characteristics of patients are reported in Table Twenty-five patients were initially recruited in the study, but as 3 of them failed the SBT, only 22 were finally enrolled. Nine were women 41%), with a mean age of 59 ± 17 years old, a Charlson comorbidity index of 3 ± 2. APACHE II at ICU admission was 14 ± 8, and SOFA score the day of the study was 5 ± 3. Patients had been intubated for 8 ± 6 days before extubation. The main etiologies of acute respiratory failure were SARS-CoV-2  7–38%) in ΔPes, 35% IQR 15–41%) in PTP per breath, and 39% (IQR 22–45%) in PTPmin  compared to standard oxygen therapy. However, no differences were observed in diaphragmatic neuromuscular coupling or in neuroventilatory efficiency  when comparing HFNC with standard oxygen therapy. However, due to a lower respiratory rate , a median decrease of 16% (IQR 3–18%) in the estimated minute ventilation was observed with HFNC compared to standard oxygen therapy (Table p < 0.001). On the other hand, the distribution of ventilation was mainly dorsal without differences between HFNC and standard oxygen, evaluated either by A/P ratio or by COV . The change in PaO2/FiO2 ratio in response to HFNC was not associated to ΔEELV . No differences were observed in PaCO2  on pressure time product per minute. Figure S1. Offline synchronization of physiological waveforms in a representative patient during with standard oxygen and with high-flow nasal cannula oxygen therapy. Vertical dotted lines indicate the start of inspiration. Pes: Esophageal pressure; EAdi: Electrical activity of the diaphragm; Pdi: Transdiaphragmatic pressure; ΔZ: Global impedance variation. Figure S2. Pressure time product per minute during standard oxygen is correlated with the relative decrease in the same variable induced by high flow nasal cannula.


Hypertensive patients with atypical FMSF signals had less advantageous blood pressure profiles. Although the underlying factors causing these symptoms are unknown, the atypical FMSF pattern may reflect increased sympathetic stimulation and vascular resistance. The visual assessment of the FMSF curve may have important clinical implications that deserve further investigation.Flow-mediated skin fluorescence (FMSF) at 460 nm is a non-invasive method for assessing dynamic changes in the reduced form of nicotinamide adenine dinucleotide (NADH) and microcirculation in forearm skin under varying conditions of tissue perfusion. Typically, fluorescence increases during ischaemia, but atypical cases show a temporary signal decrease instead of a constant increase. This study aimed to explore the clinical implications of atypical FMSF patterns in patients with newly diagnosed untreated hypertension. NADH fluorescence and pulse wave analysis were performed on 65 patients. Differences in peripheral and arterial pulse pressure profiles were examined based on FMSF curve courses. Patients with atypical curve courses had significantly ( The reduced form of nicotinamide adenine dinucleotide (NADH) is a particle synthesised in the mitochondria (most of it) and in the cellular cytoplasm. Under aerobic conditions, it is converted to an ionic form by participating in many metabolic pathways. NADH is essential for the production of ATP. NADH accumulates in the cytoplasm during hypoxia/anoxia due to its inefficient oxidation to NAD+ by mitochondria ,2.Flow-mediated skin fluorescence (FMSF) at 460 nm is a non-invasive method for assessing dynamic changes in NADH and microcirculation in response to transient global ischaemia and subsequent reperfusion. FMSF measures the NADH fluorescence signal in the skin of the forearm in three phases: rest, ischaemia and post-ischaemic reperfusion  1,2].,2.1,2].First, FMSF detects the fluorescence signal at rest with normal tissue perfusion. Blood flow is always present during the resting phase. Therefore, skin fluorescence reflects the influence of both cellular metabolism and microcirculatory effects on NADH concentration in superficial keratinocytes.Next, skin fluorescence is measured during ischaemia with total, transient arterial occlusion and no blood flow. Transient total ischaemia is then induced by completely occluding the brachial artery with a blood pressure cuff inflated to 60 mmHg above systolic pressure . When blFinally, skin fluorescence is measured during reperfusion when the brachial cuff is deflated and blood flow to the skin is restored. During reperfusion, skin NADH levels are influenced by both cellular metabolism and the returning microcirculation. Initially, reperfusion is characterised by a sharp drop in the NADH signal. The supply of oxygen to the mitochondria allows them to immediately oxidise the previously accumulated reduced form to NAD+. The fluorescence signal then reaches its lowest value. After a rapid decrease, a slow return to the basal state is observed, with numerous oscillations of the signal related to the blood flow .The FMSF method has been used to investigate healthy people and athletes at rest and during various activities . It has Resting cellular NADH increases with age and in several cardiovascular diseases ,6, obstrTypically, 460 nm fluorescence increases during ischaemia. However, atypical responses are possible. Sometimes, there is no visible increase in the 460 nm skin fluorescence. The fluorescence signal decreases or fluctuates up and down during ischaemia.Such atypical patterns were initially thought to reflect the movement of the forearm when being tested . HoweverNo study has examined the clinical features of patients with HTN with typical and atypical FMSF . This st2), acute inflammation, pregnancy or lactation.Sixty-five patients with newly diagnosed primary HTN were enrolled in the study. Primary HTN was diagnosed based on 24 h ambulatory blood pressure monitoring (ABPM) according to the European Society of Hypertension 2018 guidelines . Two cliABPM was performed on all patients using the AND-TM 2430 monitor . ABPM was used for blood pressure assessment because of the accuracy of the measurement ,14. The Following the ESH 2018 guidelines, each ABPM device measured blood pressure every 15 min between 6 am and 10 pm and every 30 min between 10 pm and 6 am. Day and night times were determined individually according to the hours reported by the patient. ABPM values are on average lower than office BP values, and the diagnostic threshold for HTN is ≥130/80 mmHg over 24 h, ≥135/85 mmHg for the daytime average or ≥120/70 mmHg for the nighttime average. All these values are equivalent to office BP ≥140/90 mmHg.-Heart rate [beats/min] for daytime (DTHR) and nighttime (NTHR);-Systolic blood pressure [mmHg] for the day (DTSBP) and night (NTSBP);-Diastolic blood pressure [mmHg] for the day (DTDBP) and night (NTDBP).The parameters describing the ABPM, calculated as the average of the collected measurements, are listed below:The diagnostic threshold for HTN, based on the ABPM, was ≥130/80 mmHg over 24 h or ≥135/85 mmHg for the wake time average, or ≥120/70 for the sleep time.The skin emits 460 nm fluorescent light in response to excitation by 340 nm ultraviolet light. As the UV light does not penetrate deeper than 0.5 mm from the skin surface, the FMSF method provides information from the most superficial skin cells . However-Typical response—those with an expected increase and plateau in 460 nm skin fluorescence during ischaemia;-Atypical response—the remaining patients with a decrease, no increase, delayed and short-lived, or multimodal with brief increases and decreases in fluorescence.As described in previous studies on FMSF, skin fluorescence at 460 nm typically increases and reaches a plateau in response to ischaemia. During reperfusion, this fluorescence rapidly decreases to a minimum value, which is always below the baseline, and then gradually increases to pre-ischaemic values. As mentioned above and illustrated in Due to the unpredictable and non-uniform nature of atypical ischaemic patterns, no single mathematical parameter derived from linear regression analysis was able to distinguish atypical from typical patterns. Therefore, we decided to use the eyeballing approach, which seems to be the simplest and quickest method to differentiate between typical and atypical patterns.Radial pressure waveforms were recorded non-invasively using a piezoelectric tonometer . The recorded analogue signal was processed in real time using SphygmoCor software Mx,  for online reconstruction  of a pressure waveform characteristic of an ascending aorta. Pulse wave analysis was used to assess peripheral and central haemodynamics. Both pressure waveforms were averaged using the Sphygmocor software (Version 7.0) and the measured and derived parameters are shown in The reservoir–excess pressure model decomposes the arterial blood pressure waveform into three components: reservoir pressure, excess pressure and diastolic blood pressure (DBP). The reservoir pressure is the dominant component of the measured diastolic pressure, while the excess pressure is largely responsible for the early systolic pressure rise . The resThe time integral of the whole arterial pressure waveform is the total blood pressure time integral (TBTI) and has three separate components: the reservoir pressure time integral (RPTI), excess pressure time integral (EPTI) and diastolic pressure time integral (DBPTI) . The RPTThe following parameters were derived from the pulse wave analysis . For theThe study was designed and conducted following the tenets of the Declaration of Helsinki. The Bioethics Committee of the Medical University of Poznan approved the study . Written informed consent was obtained from all participants.p-value < 0.05 were considered statistically significant. All statistical analyses were performed with JMP Pro 17.Graphical analysis of data distribution (histograms and Q-Q plots) and the Shapiro–Wilk test showed that the distribution of continuous data was not normal; therefore, all data are summarised as median and 25th and 75th percentiles (Q1–Q3). The non-parametric Mann–Whitney test was used to compare patients with typical and atypical FMSF curves. Differences with a p = 0.32) and body mass index (27.7 (24.5–31.8) vs. 28.7 (25.3–34.1) kg/m2; p = 0.53) between these groups. The comparison of various features of blood pressure and radial and central pulse wave analysis are shown in Women accounted for 38% of all patients studied. Atypical ischaemic patterns were observed in 32.3% of patients. In the groups with typical and atypical FMSF curves, women accounted for 32% and 52%, respectively. No differences were found in the median age (38.5 (30.8–49.0) vs. 43 (37.0–48.5) years old; The groups did not differ in blood pressure as measured with the ABPM. However, there was a statistically significant difference in the mean nighttime heart rate and some parameters describing radial and central pulse wave analysis.Patients with an atypical skin fluorescence response to ischaemia had a faster resting heart rate and shorter diastolic duration, a reduced relative contribution of the diastole duration to the whole cycle length and reservoir pulse pressure integral of the central pulse wave. They also had significantly higher diastolic pressure, mean blood pressure, ratio of the time of arrival of the reflected wave to the ejection time in the peripheral artery and central parameters such as diastolic pressure, mean pressure during diastole, tension time index, diastolic time index and rate–pressure product.Patients with HTN and an atypical pattern of 460 nm skin fluorescence in response to transient ischaemia displayed significantly different pressure waveform characteristics compared to those with a typical FMSF shape. These patients had a faster resting and sleep heart rate, shorter absolute and relative diastolic duration, higher peripheral and central DBP, increased TTI and RPP and worse RPTI.FMSF records 460 nm skin fluorescence at rest, during ischaemia and reperfusion. During the resting and reperfusion phases, the level of NADH fluorescence is significantly influenced by blood flow, particularly in the skin vascular bed. In contrast, no blood flow occurs during the total brachial artery occlusion and induced forearm ischaemia. The results provide a unique opportunity to gain insights into the primary potential of 460 nm fluorescence and its linear dependence on the NADH content.Both mitochondria and cytoplasm contribute to NADH accumulation during ischaemia. Long hypoxia or anoxia reduces or ceases the oxidation of mitochondrial NADH, shifting anaerobic cytoplasmic glycolysis as a major source of cellular energy . HoweverThe cytoplasmic NAD/NADH ratio can be much higher than the mitochondrial NAD/NADH ratio in a typical eukaryotic cell. Therefore, cytoplasmic glycolysis may have a greater impact on NADH accumulation during ischaemia. However, this may not be true for all cell types, as some have a higher mitochondrial density and lower glycolytic capacity. In cardiomyocytes, the mitochondrial origin of NADH may be more important for its accumulation during ischaemia. However, NADH metabolism in the skin cells may be different from cardiomyocytes .Keratinocytes, the predominant cell type in the epidermis, have a low mitochondrial density and a distinct glycolytic phenotype compared to other cell types. NADH accumulation during skin ischaemia in the keratinocytes depends on the balance between glycolysis and mitochondrial respiration. Keratinocytes possess fewer mitochondria, exhibiting a discernible reduction in cristae abundance with limited oxidative phosphorylation potential . If glycWith ageing, numerous mtDNA mutations accumulate in the mitochondria of the skin, accompanied by a decrease in mitochondrial function, an increase in the production of reactive oxygen species, and an increased mitophagy and apoptosis . HyperteIn recent years, evidence of the role of mitochondria in HTN pathogenesis has increased. Chronically elevated blood pressure damages mitochondria, causing their dysfunction, increasing active oxygen species production and disturbing cellular homeostasis ,33. The Patients with HTN may have typical and atypical ischaemia-related NADH accumulation regardless of the potential mechanisms. Individuals with an atypical ischaemic phase of the FMSF curve have significantly higher DBP-related indices, rate pressure product and cTTI compared to other patients with HTN. They also present with faster pulse rates, shorter duration of the diastole and worse RPTI.The pulse rate and blood pressure elevation indirectly imply an increased sympathetic drive, afterload for the heart and myocardial oxygen consumption ,35,36. SThe skin is at the end of the blood supply, so any process that impedes the transfer of oxygen and nutrients in the long term may lead to adaptive changes in the skin. Hypertension-induced changes to arterial walls affect the blood flow and oxygen delivery to tissues, leading to local inflammation and oxidative stress, hypertrophy, hyperplasia, apoptosis or fibrosis of the arterial wall cells. Larger arteries become stiffer, thicker and narrower, while hypertrophy of smooth muscle in smaller arteries increases vascular resistance . VasculaEPTI is also influenced by vascular resistance, particularly in its early systolic pressure rise. Although indirect, vascular resistance contributes to RPTI as well. Reservoir pressure is determined by the compliance of the arterial system, which depends on the diameter and tone of the arteries. Both are modulated by vascular resistance. Further, a higher heart rate shortens the duration of diastole , reducescRPP is a product of heart rate and central systolic pressure that indirectly reflects myocardial oxygen consumption. A lower rate–pressure product is beneficial and occurs in physically active people . MyocardWe used a cross-sectional study design, which makes it impossible to assess causality. Only patients with untreated HTN were included. The FMSF measurement was performed only once for a given patient. The studied patients were adults aged between 19 and 66 years. Therefore, our results cannot be extrapolated to children and adults over 66 years of age. Only indirect parameters characterising arterial stiffness, afterload and vascular resistance were used. However, these parameters were measured non-invasively. In addition, this is a post hoc analysis of an already completed study that cannot be extended [The atypical pattern of the FMSF curve in patients with HTN may help to identify those with more advanced disease, longer duration or greater sensitivity to its clinical consequences. As such patients appear to have a more activated sympathetic nervous system, they may benefit from treatment with antiadrenergic drugs. Whether profiling of patients with HTN with FMSF as those with a typical and atypical ischaemic response could help to personalise antihypertensive therapy requires further study.It might be a good idea to develop an automated tool for analysing the FMSF signal, which would quantify the results and detect whether the ischaemic phase is typical or not. However, such a tool would require modelling with more training data and validation of the obtained models and parameters with an independent data set.Patients with HTN and atypical FMSF have a less favourable blood pressure profile. The atypical course of the NADH fluorescence curve in hypertensive patients indicates a different phenotype of the disease that may be secondary to increased sympathetic stimulation.


To evaluate the relationships between chronic kidney disease (CKD) with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness profiles of eyes in Asian and White populations.Cross-sectional analysis.A total of 5066 Asian participants  from the Singapore Epidemiology of Eye Diseases Study (SEED) were included, consisting of 9594 eyes for peripapillary RNFL analysis and 8661 eyes for GCIPL analysis. Additionally, 45 064 White participants (87 649 eyes) from the United Kingdom Biobank (UKBB) were included for both macular RNFL analysis and GCIPL analysis.2 in both data sets. To evaluate the associations between kidney function status with RNFL and GCIPL thickness profiles, multivariable linear regression with generalized estimating equation models were performed in SEED and UKBB data sets separately.Nonglaucoma participants aged ≥ 40 years with complete data for estimated glomerular filtration rate (eGFR) were included from both SEED and UKBB. In SEED, peripapillary RNFL and GCIPL thickness were measured by Cirrus HD-OCT 4000. In UKBB, macular RNFL and GCIPL were measured by Topcon 3D-OCT 1000 Mark II. Chronic kidney disease was defined as eGFR < 60 ml/min/1.73 mAverage peripapillary and macular RNFL thickness and macular GCIPL thickness.P = 0.015) and reduced eGFR  were associated with thinner average peripapillary RNFL. Presence of CKD  and reduced eGFR  were consistently associated with thinner GCIPL in SEED . In UKBB, after adjusting for the above-mentioned covariates (except ethnicity), reduced eGFR  was associated with thinner macular RNFL and CKD  was associated with thinner average GCIPL.In SEED, after adjusting for age, gender, ethnicity, systolic blood pressure, antihypertensive medication, diabetes, hyperlipidemia, body mass index, smoking status, and intraocular pressure, presence of CKD  have no proprietary or commercial interest in any materials discussed in this article. Previous studies have investigated the relationship of CKD with RNFL and GCIPL thickness profiles but presented inconsistent findings. This was partly because of small sample sizes and confinement to specific populations in these previous studies.13To better elucidate this aspect, a comprehensive evaluation on the associations between CKD with RNFL and GCIPL thickness in a larger sample size is warranted. Hence, this study aimed to evaluate the relationships between CKD and RNFL and GCIPL thickness profiles across Asian and White populations.We conducted a cross-sectional population-based study from study subjects enrolled in the 6-year follow-up visit from the Singapore Epidemiology Eye Disease study (SEED), comprised of 3 major Asian ethnic groups: Malays, Indians, and Chinese. Details of the SEED study’s methodology were reported previously.www.ukbibobank.ac.uk).The United Kingdom Biobank (UKBB) is a large, multisite, population-based study comprised of > 500 000 UK residents aged 40–69 years at baseline (2006–2010).Informed consent was obtained from all study participants for both SEED and UKBB. All study procedures for SEED and the UKBB were conducted in accordance with the Declaration of Helsinki. The SEED study was approved by the SingHealth Centralized Institutional Review Board, while the UKBB study was approved by the National Information Governance Board for Health and Social Care and National Health Service North West Multi-Centre Research Ethics Committee.Participants from SEED and the UKBB that underwent OCT imaging and had complete estimated glomerular filtration rate (eGFR) data were included. Additionally, participants aged ≥ 40 years with relevant systemic, ocular, and lifestyle-related data, including history of diabetes, hypertension, hyperlipidemia, smoking status, body mass index (BMI), and intraocular pressure (IOP) were included. Study eyes with poor OCT image quality were excluded from analysis. Additionally, confirmed glaucoma cases in SEED  and the UKBB  were also excluded.All participants underwent a standardized ocular examination at the Singapore Eye Research Institute. Before pupil dilation, IOP was measured using a Goldmann applanation tonometer (Haag-Streit). Additionally, gonioscopy and 24-2 SITA Fast Humphrey visual field  test were performed for glaucoma suspects and participants with known history of glaucoma before dilation. After dilation with tropicamide 1% and phenylephrine 2.5%, fundus examinations were performed.Intraocular pressure was measured using the Ocular Response Analyzer noncontact tonometer , and the Goldmann-correlated IOP values were used in this analysis.2. Retinal nerve fiber layer and GCIPL thickness parameters were determined by an automated algorithm incorporated in the Cirrus HD-OCT review software. Detailed descriptions of the measurement algorithms have been described previously.,2 elliptical annulus area centered on the fovea. Superior and inferior GCIPL hemisphere thicknesses were averaged from superior and inferior subfields, respectively. Poor scan quality was defined as poor OCT signal strength (< 6), misaligned scans, motion/blinking artifacts, segmentation errors, and retinal diseases diagnosed or observed from OCT scans known to impact GCIPL and RNFL thickness .After pupil dilation, images were acquired using a commercially available spectral-domain OCT (SD-OCT) . Optic disc cube (200 × 200) and macular cube (512 × 128) scans were acquired, covering a measurement area of 6 × 6mm2 area) in a dark room without pupil dilation.,A subset of the cohort (67 321 participants) had macular SD-OCT imaging collected. Certified UKBB ophthalmic technicians who were trained in collaboration with the Moorfields Eye Hospital Reading center captured SD-OCT images using the Topcon 3D OCT 1000 Mark II (Topcon).,A validated custom imaging segmentation software (version 1.6.1.1) by the Topcon Advanced Biomedical Imaging Laboratory was used to obtain automated segmentation of retinal boundaries and inner layers.Venous blood samples were collected in SEED and UKBB for biochemical testing. Body mass index was calculated as body weight (in kilograms) divided by body height (in meters) squared.Diabetes was defined by random glucose ≥ 11.1 mmol/L, glycosylated hemoglobin ≥ 6.5%, use of diabetic medication(s) and/or self-reported history in SEED. On the other hand, in UKBB, diabetes was defined based on the International Classification of Diseases code for diabetes or self-reported history of diabetes. In both data sets, hyperlipidemia was defined as total cholesterol ≥ 6.2 mmol/L, use of lipid lowering drugs, or self-reported history of hyperlipidemia. In both studies, hypertension was defined by systolic blood pressure (BP) ≥ 140 mmHg, diastolic BP ≥ 90 mmHg, use of hypertensive medication, and/or self-reported history of hypertension for both studies.Lastly, a detailed interviewer-administered questionnaire was used to obtain participant information regarding medication use, systemic and ocular history, sociodemographic information, and current smoking status for each respective study.Kidney function was indicated by the calculation of eGFR. Lower eGFR is indicative of poorer kidney function. Estimated glomerular filtration rate was calculated from the measurement of serum creatinine, using the Chronic Kidney Disease Epidemiology Collaboration equation as follows:2. We further stratified kidney function status into normal (eGFR > 90 ml/min/1.73 m2), mild (eGFR 60–89 ml/min/1.73 m2), moderate (eGFR 45–59 ml/min/1.73 m2), and severe decline (eGFR < 45 ml/min/1.73 m2).In both data sets, we defined CKD as eGFR < 60 ml/min/1.73 mAll statistical analyses were performed using R language . Age, systolic BP, BMI, IOP, and eGFR were analyzed as continuous variables, whereas gender, ethnicity, antihypertensive medication, diabetes, hyperlipidemia, smoking status, CKD, and stages of kidney function were analyzed as categorical variables.P value for significance was set at < 0.05.To investigate the associations between kidney function status with RNFL and GCIPL thickness profiles, we performed multivariable linear regression models with generalized estimating equations method (exchangeable correlation structures and a Gaussian link) in SEED and UKBB data sets separately. Additionally, the associations of CKD, decrease in eGFR, and stages of kidney function with RNFL and GCIPL were evaluated in separate multivariable models. In the models, we adjusted for potential confounders, including age, gender, ethnicity (except in UKBB), systolic BP, antihypertensive medication, diabetes, hyperlipidemia, BMI, smoking status, and IOP. The www.ophthalmologyscience.org). In UKBB, 84 876 participants had OCT data available. After the exclusion of poor-quality scans, non-White participants and retinal diseases that affect macular RNFL and GCIPL thickness measurements, 87 649 eyes were included for final macular RNFL and GCIPL analyses  in SEED, 1925 eyes were excluded due to unavailable OCT data. After the exclusion of poor-quality scans and retinal diseases that affect RNFL and GCIPL thickness, 9594 eyes were included for final peripapillary RNFL analysis, and 8661 eyes were included for GCIPL analysis . The meaanalyses . The meaanalyses .Figure 1P = 0.015) and inferior quadrant RNFL . Reduced eGFR (per 10 ml/min/1.73 m2) was significantly associated with thinner average RNFL , superior quadrant RNFL , and inferior quadrant RNFL . When categorized by CKD stages, severe kidney function decline (eGFR < 45 ml/min/1.73 m2) was significantly associated with thinner average RNFL , superior quadrant RNFL  and inferior quadrant RNFL . Additionally, when evaluating these associations by Asian ethnicity in SEED, we observed more prominent associations between kidney function and RNFL thinning in Malay and Indian eyes .The associations between kidney function and peripapillary RNFL in SEED are described in P < 0.001). Similarly, reduced eGFR (per 10 ml/min/1.73 m2) was associated with thinner average GCIPL , superior hemisphere GCIPL  and inferior hemisphere GCIPL  . When categorized by CKD stages, mild (eGFR 60–89 ml/min/1.73 m2), moderate (eGFR 45–59 ml/min/1.73 m2), and severe (eGFR < 45 ml/min/1.73 m2) kidney function decline were significantly associated with thinner average, superior hemisphere, and inferior hemisphere GCIPL . Additionally, when evaluating these associations by Asian ethnicity in SEED, more prominent associations were observed in Malay and Indian eyes. .2) was associated with average macular RNFL thinning . When categorized by CKD stages, mild (eGFR 60–89 ml/min/1.73 m2) kidney function decline was associated with average macular RNFL thinning . Broadly, increased severity of kidney disease was also associated with average macular RNFL thinning (P trend = 0.006). Furthermore, CKD was associated with average GCIPL thinning . In particular, severe kidney function decline (eGFR < 45 ml/min/1.73 m2) was associated with average GCIPL thinning .Using White data from the UKBB, we further evaluated the associations between kidney function with average macular RNFL and GCIPL thickness . After aWe investigated the associations of kidney function status with RNFL and GCIPL thickness in a multiethnic Asian population study. We also performed validation in UKBB’s White data set. Leveraging on approximately 9500 Asians patients' eyes and 87 000 White patients' eyes, this is one of the largest studies to date elucidating this association. In individuals with CKD and suboptimal kidney function, we observed significant RNFL and GCIPL thinning. This finding was largely consistent across Asian and White eyes. Our findings further support the notion that individuals with CKD may be more susceptible to RNFL and GCIPL thinning, which is an important marker for glaucoma development.In Asian patients' eyes, CKD and reduced eGFR were associated with thinner peripapillary RNFL. Similarly, in White patients' eyes, reduced eGFR was associated with thinner macular RNFL. Consistently, in Asian patients' eyes, we observed that CKD and reduced eGFR were associated with thinner GCIPL. Chronic kidney disease was also associated with GCIPL thinning in White patients' eyes. Across Asian and White patients' eyes, when evaluating the different stages of kidney disease, we observed a significant trend between declining kidney function with thinner RNFL and GCIPL. Taken together, these findings across Asian and White eyes further corroborate the overall relationship of kidney function with RNFL and GCIPL thickness.Previous studies have reported on the relationship of CKD with RNFL and GCIPL thickness. Similar to our study, Wu et al,,,,,,,,The association between kidney disease and neuroretinal thinning may be explained by shared structural and pathophysiologic mechanisms that affect both the kidney and retina.www.ophthalmologyscience.org). This observation could be partially explained by the inherent thinner RNFL and GCIPL profiles in Indians and Malay eyes,,Interestingly, when evaluating the associations between kidney function with RNFL and GCIPL thickness by ethnicity in Asian eyes, we observed that RNFL and GCIPL thinning were more prominently observed in Malay and Indian eyes (The strengths of this study include its large sample with validation of findings across Asians and Whites through the use of SEED and UKBB data sets. In addition, we performed a robust analysis which accounted for a wide range of potential confounders. Furthermore, a stringent quality check for OCT scans was performed, and scans with poor signal strength and/or segmentation errors were excluded from final analysis. However, our study has a few limitations. First, due to the cross-sectional nature of our study, we cannot definitively infer a causal relationship between CKD with RNFL and GCIPL thickness. Therefore, future longitudinal studies are still warranted. Second, peripapillary RNFL measurement was not available in the UKBB study; nevertheless, we used macular RNFL thickness as a proxy for peripapillary RNFL. However, because macular RNFL is inherently thinner than peripapillary RNFL, this aspect of our findings ought to be evaluated with caution. Lastly, despite following a standardized statistical analysis protocol across the SEED and UKBB studies, there are differences in study methodologies between the 2 studies. Hence, future multiethnic studies with a standardized examination protocol are still warranted to further elucidate the relationship between CKD and neuroretinal layers.In conclusion, we observed that CKD and compromised kidney function are associated with thinner RNFL and GCIPL in both Asian and White eyes. Hence, because RNFL and GCIPL are established markers of glaucoma, clinicians should closely monitor the pattern of RNFL and GCIPL loss to differentiate between neuroretinal damage caused by glaucoma and that associated with CKD.


BackgroundSeveral primary studies have looked at the burden of chronic kidney disease among diabetic patients, but their results have shown significant variance in India. In order to determine the combined prevalence of chronic kidney disease and associated risk factors among patients with diabetes, this study used a combination of methods.MethodsOver the course of two years, a cross-sectional observational study was undertaken in the Tertiary Care Teaching Hospital's Department of General Medicine including all chronic kidney disease patients of 18 years of age and above of either gender. People not suffering from the disease were chosen as controls. Kidney Injury Molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin-ELISA (NGAL-ELISA) sample analysis by the kit method was done. The study was carried out in accordance with Schedule Y, ICH GCP principles, and the Helsinki Declaration after receiving approval from the institutional ethics committee.Results2) was 69.83±7.91 and 108±3.7, respectively. The mean serum creatinine (mg/dL) was reported 3.79 in the CKDu group and 1.0 in the controls group.In our study, the urinary mean KIM-1 was 49.75±4.35 μg/g Cr in the Chronic Kidney Disease of Unknown etiology (CKDu) group and 1.43±0.15 μg/g Cr in the controls group. The mean NGAL levels of the CKDu Group and the controls group were 8.94±1.31 μg/g and 0.41±0.05 μg/g, respectively. In CKDu and the controls group, the mean eGFR (ml/min/1.73mConclusionDespite the urban centers previously being thought of as a non-endemic location, for the first time in the city, 60 CKDu patients are reported in this study. This is the first study to use the urinary biomarkers KIM-1 and NGAL to find suspected cases of CKDu and early kidney damage in local communities in the urban centers. It is a major health issue in global public health [A decreased glomerular filtration rate (GFR) of 60 ml/min/1.73 mc health .Studies indicate that a number of factors, including obesity, advanced age, hypertension, diabetes mellitus, male gender, dyslipidemia, HIV infection, usage of nephrotoxic drugs, heavy alcohol use, smoking, family history of kidney disease, electrolyte, and acid-base abnormalities, low-paying employment use of conventional nonallopathic medications, and low hemoglobin, are to blame for CKD, despite the fact that the exact cause of the condition is still unknown . Some ofThe proximal tubule apical membrane expresses kidney injury molecule-1 (KIM-1), a type 1 transmembrane protein, when there is kidney injury . KIM-1 wThe 25 kDa protein known as neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin superfamily. Although many other cells, such as renal tubular cells, can create NGAL in response to numerous stresses, it was initially discovered in active neutrophils. Additionally, it has been found to be involved in kidney development and damaged tubular regeneration. Later clinical studies found urine NGAL to be an early marker of acute kidney injury (AKI). In light of recent data, it may also serve as an investigation for a number of various renal and non-renal disorders .It is a prospective observational study done in the Department of General Medicine at Tertiary Care Teaching Hospital over a period of two years.Inclusion and exclusion criteriaThe inclusion and exclusion criteria are summarized in Table MethodologyThe constituents of the study that are most probable to produce reliable results are organized in a systematic manner by the research methodology. This study provides a concise overview of the materials and procedures used to assess the prevalence of CKD with an unknown etiology among hospitalized patients. Sixty different CKDu patients from the city of Southern Province were used in the case group. The groups were segregated using the random sampling technique and the two groups were based on relevant factors such as age, gender, medical history, and other relevant variables to ensure that the two groups were as similar as possible, except for the intervention being tested. KIM-1 and NGAL-ELISA sample analysis (kit method) was used.Statistical analysisThe gathered information was organized in a Microsoft Excel 2010  spreadsheet, and SPSS version 27.0  was used to analyze it. Frequency and percentage were used to represent the qualitative data. Additionally, it was displayed using typical images like bar diagrams and pie charts.2) in CKDu group and controls group were 69.83±7.91 and 108±3.7, respectively. The mean serum creatinine (mg/dL) in the CKDu group was 3.79 and in the controls group was 1.0.In our study, the subjects' demographics are presented in Table The present study helps to shed light on the function of innovative urine biomarkers (NGAL and KIM-1) in the earliest discovery of CKDu in Andhra Pradesh. Additionally, this is the first comparative study in India to examine chronic kidney disease with unknown etiology (CKDu) using a case definition based on WHO criteria.Males are more susceptible to CKDu in our study than females. In a similar study by Harambat et al. done in NCP, men are more likely to have CKDu (6%) than women (2.9%) . The preBased on the WHO's classification of CKDu as well as elevated levels of KIM-1 and NGAL, we present here a study report of 60 different CKDu patients from the city of Southern Province. Diabetes, hypertension, pyelonephritis, renal calculi, etc. are a few examples of co-morbid conditions that may affect urine KIM-1 and NGAL levels . In ordeDrastically increased levels of NGAL and KIM-1 in the urine were also used to confirm instances with CKDu. Both markers made it simple to identify the suspected instances. Farmers in emerging regions of urban centers with normal serum creatinine and eGFR as well as in apparent good health displayed higher levels of NGAL and KIM-1 in comparison to the two control groups, suggesting probable initial kidney injury. It might imply that excessive albumin filtration precedes tubular damage expressed by KIM-1. Similar cases with high urine NGAL, IL-18, and NAG levels have been reported among Nicaraguan sugarcane cutters , 20.However, only in CKDu with an eight-fold increase over the control group, did NGAL elevation become apparent. Similar findings were found by Bernardi et al., where NGAL levels in CKD sufferers were 26% higher . In anotLimitationsThe absence of established urine biomarker levels that suggest subclinical impairment in nephropathy in the local regions in which our study was carried out was a major study constraint. With the exception of a few recent studies, no prior research has been conducted in the region using comparable occupational cohorts. A follow-up study is necessary because it was also uncertain how each subject's short-term individual variance changed over time. Because only native male farmers in specific farming areas of our city were included in the current study, generalizing the results to the general population and other geographic places may be difficult.This is the first study to use the urine biomarkers KIM-1 and NGAL to identify suspected instances of CKDu and to detect early kidney impairment in our local populations using the mentioned markers. According to the findings of our cross-sectional study, high urinary ACR levels were substantially linked with the tubular damage indicated by urinary NGAL and KIM-1 markers. Urinary tubular indicators, found in farming communities in the city, confirm tubulointerstitial illness with tubular injury.