Normal Glomerular Filtration Rate Research Articles

Fundamental equations and hypotheses governing glomerular hemodynamics.

The glomerular filtration rate (GFR) is the outcome of glomerular hemodynamics, influenced by a series of parameters: renal plasma flow, resistances of afferent arterioles and efferent arterioles (EAs), hydrostatic pressures in the glomerular capillary and Bowman's capsule, and plasma colloid osmotic pressure in the glomerular capillary. Although mathematical models have been proposed to predict the GFR at both the single-nephron level and the two-kidney system level using these parameters, mathematical equations governing glomerular filtration have not been well-established because of two major problems. First, the two-kidney system-level models are simply extended from the equations at the single-nephron level, which is inappropriate in epistemology and methodology. Second, the role of EAs in maintaining the normal GFR is underappreciated. In this article, these two problems are concretely elaborated, which collectively shows the need for a shift in epistemology toward a more holistic and evolving way of thinking, as reflected in the concept of the complex adaptive system (CAS). Then, we illustrate eight fundamental mathematical equations and four hypotheses governing glomerular hemodynamics at both the single-nephron and two-kidney levels as the theoretical foundation of glomerular hemodynamics. This illustration takes two steps. The first step is to modify the existing equations in the literature and establish a new equation within the conventional paradigm of epistemology. The second step is to formulate four hypotheses through logical reasoning from the perspective of the CAS (beyond the conventional paradigm). Finally, we apply the new equation and hypotheses to comprehensively analyze glomerular hemodynamics under different conditions and predict the GFR. By doing so, some concrete issues are eliminated. Unresolved issues are discussed from the perspective of the CAS and a desinger's view. In summary, this article advances the theoretical study of glomerular dynamics by 1) clarifying the necessity of shifting to the CAS paradigm; 2) adding new knowledge/insights into the significant role of EAs in maintaining the normal GFR; 3) bridging the significant gap between research findings and physiology education; and 4) establishing a new and advanced foundation for physiology education.

Metabolic Bone Disease due to Renal Tubular Acidosis as a Primary Manifestation in a Patient with Sjogren’s Syndrome: A Case Report

Background: Renal tubular acidosis (RTA) is a group of diseases where metabolic acidosis develops due to inability of renal tubules to maintain acid base balance despite normal glomerular filtration rate. Uncorrected acidosis in RTA can cause excess osteoclastic bone resorption and result in severe metabolic bone disease like rickets, osteomalacia and pathological fracture. Sjogren’s syndrome can cause distal RTA (type 1). Here, we report a case of a 35 years old female who presented with metabolic bone disease secondary to RTA resulting from Sjogren’s syndrome.

Early diagnosis of solitary functioning kidney: comparing the prognosis of kidney agenesis and multicystic dysplastic kidney

BackgroundIndividuals with congenital solitary functioning kidney (SFK) are at an increased risk of kidney damage. According to some studies, the risk is higher in unilateral kidney agenesis (UKA) than in unilateral multicystic dysplastic kidney (UMCDK). We hypothesized that with early detection of children with UKA and UMCDK, there would be no difference in the presence of hypertension, proteinuria, and reduced glomerular filtration rate (GFR) between UKA and UMCDK.MethodsBased on a long-term follow-up protocol, we evaluated a cohort of 160 children followed from birth for SFK (84 with UKA and 76 with UMCDK) detected by prenatal or routine neonatal ultrasound screening. Hypertension, proteinuria, and reduced GFR were monitored as markers of kidney damage. We compared the characteristics and outcomes of the subgroups of children with UKA and UMCDK.ResultsGFR was reduced in 42 (26.2%) children, of whom 41 showed only mild reduction. Hypertension and proteinuria were found in 22 (13.8%) and 14 (8.8%) children, respectively. Combined kidney damage was present in 57 (35.6%) children. The UMCDK and UKA subgroups differed in GFR at final examination, with UMCDK patients being significantly more likely to have normal GFR compared to UKA patients (82% vs. 67%; p = 0.039).ConclusionsOne third of the children showed signs of SFK damage, albeit mild. Patients with UKA had reduced GFR significantly more often than those with UMCDK, but did not differ in the rates of hyperfiltration injury or congenital anomalies of the kidneys and urinary tract (CAKUT) in SFK.Graphical A higher resolution version of the Graphical abstract is available as Supplementary information

Parental recovered acute kidney injury causes prenatal renal dysfunction and fetal growth restriction with sexually dimorphic implications for adult offspring.

Introduction: Acute kidney injury (AKI) is rapidly increasing in global incidence and a healthcare burden. Prior maternal AKI diagnosis correlates with later pregnancy complications. As pregnancy influences developmental programming, we hypothesized that recovered parental AKI results in poor pregnancy outcomes, impaired fetal growth, and adult offspring disease. Methods: Using a well-characterized model of rhabdomyolysis-induced acute kidney injury (RIAKI), a form of AKI commonly observed in young people, we confirmed functional renal recovery by assessing glomerular filtration rate (GFR) 2weeks following RIAKI. We bred sham and recovered RIAKI sires and dams in timed, matched matings for gestational day (GD) 16.5 and offspring (birth-12weeks, 6months) study. Results: Despite a normal GFR pre-pregnancy, recovered RIAKI dams at GD16.5 had impaired renal function, resulting in reduced fetoplacental ratios and offspring survival. Pregnant RIAKI dams also had albuminuria and less renal megalin in the proximal tubule brush border than shams, with renal subcapsular fibrosis and higher diastolic blood pressure. Growth-restricted offspring had a reduced GFR as older adults, with evidence of metabolic inefficiency in male offspring; this correlated with reduced renal AngII levels in female offspring from recovered RIAKI pairings. However, the blood pressures of 6-month-old offspring were unaffected by parental RIAKI. Conclusions: Our mouse model demonstrated a causal relationship among RIAKI, gestational risk, and developmental programming of the adult-onset offspring GFR and metabolic dysregulation despite parental recovery.

Dental and Periodontal Findings in Hemodialysis Patients

Abstract Background: End-stage renal disease (ESRD) are more to infections due to their decrease in immune systems and general debilitated health, most of patients with renal failure showing oral symptoms. Objectives: The aim of this study is to assessment the kind and severity of oral symptoms in ESRD patients undergoing hemodialysis and compare these results with healthy, disease-free persons. Materials and Methods: The study involved 40 individuals, comprising 20 hemodialysis patients and 20 healthy control. The patient group was randomly chosen from ESRD patients, while the control group consisted of disease-free persons with normal glomerular filtration rates. The symptoms such as dry mouth, taste changes, halitosis, and mucosal pain, and were oral changes like tongue coating, pallor, ulceration, and enamel hypoplasia. Results: The ESRD patients established significantly more oral changes compared to the control group. These due to metabolic disorders caused by renal failure. Conclusion: there is significant impact of ESRD on the oral health of the patients, with correlation between oral health and ESRD.

Functional and metabolomic analysis of urinary extracellular vesicles from juvenile mice with renal compensatory hypertrophy

Unilateral nephrectomy, a procedure reducing kidney mass, triggers a compensatory response in the remaining kidney, increasing its size and function to maintain a normal glomerular filtration rate (GFR). Recent research has highlighted the role of extracellular vesicles (EVs) in renal physiology and disease, although their involvement in unilateral nephrectomy has been underexplored. In this study, unilateral nephrectomy was performed on young mice, and urinary extracellular vesicles (uEVs) characterization and cargo were analyzed. Kidney volume increased significantly post-nephrectomy, demonstrating compensatory hypertrophy. Serum creatinine, cystatin C, and urinary electrolytes concentrations were similar in both nephrectomized and control groups. Western blot analysis revealed upregulation of sodium-glucose cotransporter 2 (SGLT2) and sodium chloride cotransporter (NCC), and downregulation of sodium‑potassium-chloride co-transporter (NKCC2) and epithelial sodium channel (ENaC) in the nephrectomized group. Metabolomic analysis of uEVs showed an enrichment of certain metabolites, including citrate and stachydrine. Interestingly, uEVs from the nephrectomized group demonstrated a protective effect, downregulating signal transducer and activator of transcription 3 (STAT3) and reducing reactive oxygen species (ROS) in renal proximal cells, compared to uEVs from the control group. This study suggests that uEVs contain bioactive components capable of inducing protective, anti-inflammatory, anti-fibrinolytic, and antioxidative effects in renal cells. These findings contribute to our understanding of uEVs' role in renal compensatory mechanisms after unilateral nephrectomy and may hold promise for future therapeutic interventions in renal diseases.

Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.

In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups. This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV. Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all). This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.

A Single-Center Study on the Clinical Profiles and Ultrasonographic Assessments of Living Kidney Donors in the Marathwada Region of Maharashtra.

Living donor kidney transplantation plays a vital role in renal replacement therapy, particularly in India, where a substantial increase in kidney transplants has been observed. Thorough assessments of living kidney donors are crucial, focusing on parameters such as kidney size and glomerular filtration rate (GFR). Despite the importance of GFR in donor assessments, there is a noticeable lack of data on normal GFR ranges in the Indian population. This study aims to address the gap in knowledge by establishing a reference range for GFR in healthy kidney donors from the Marathwada region of Maharashtra. The research also explores the clinical profiles and ultrasonographic features of living kidney donors. A retrospective analysis was conducted at the Mahatma Gandhi Mission (MGM) Medical College and Hospital in Aurangabad, involving 134 living kidney donors. Inclusion criteria encompassed healthy donors with a BMI of less than 30 kg/m², while donors with uncontrolled hypertension, diabetes, microalbuminuria, or a measured GFR below 70 mL/min/1.73 m² were excluded. Comprehensive medical histories, demographic parameters, and ultrasonographic assessments were conducted, with GFR measured using 99M technetium diethylenetriamine pentaacetate scans. The study reveals that the majority of donors were females (80.6%), and the highest number fell within the 41-50 age group. Parents constituted the primary donor category (68.7%), reflecting a familial inclination toward organ donation. Ultrasonographic assessments indicated larger kidney sizes compared to other studies, suggesting regional or population-specific differences. The mean GFR for the right and left kidneys, as well as the total GFR, was within the expected range. The negative correlation between age and GFR emphasizes the need to consider age in donor assessments. The findings emphasize the unique features of this population, including a higher average age, female preponderance, and larger kidney sizes. The study contributes to the understanding of living kidney donors' profiles in the region and highlights the importance of individualized assessments in the donor selection process.

Albuminuria, Forgotten No More: Underlining the Emerging Role in CardioRenal Crosstalk

Kidneys have an amazing ability to adapt to adverse situations, both acute and chronic. In the presence of injury, the kidney is able to activate mechanisms such as autoregulation or glomerular hyperfiltration to maintain the glomerular filtration rate (GFR). While these adaptive mechanisms can occur in physiological situations such as pregnancy or high protein intake, they can also occur as an early manifestation of diseases such as diabetes mellitus or as an adaptive response to nephron loss. Although over-activation of these mechanisms can lead to intraglomerular hypertension and albuminuria, other associated mechanisms related to the activation of inflammasome pathways, including endothelial and tubular damage, and the hemodynamic effects of increased activity of the renin–angiotensin–aldosterone system, among others, are recognized pathways for the development of albuminuria. While the role of albuminuria in the progression of chronic kidney disease (CKD) is well known, there is increasing evidence of its negative association with cardiovascular events. For example, the presence of albuminuria is associated with an increased likelihood of developing heart failure (HF), even in patients with normal GFR, and the role of albuminuria in atherosclerosis has recently been described. Albuminuria is associated with adverse outcomes such as mortality and HF hospitalization. On the other hand, it is increasingly known that the systemic effects of congestion are mainly preceded by increased central venous pressure and transmitted retrogradely to organs such as the liver or kidney. With regard to the latter, a new entity called congestive nephropathy is emerging, in which increased renal venous pressure can lead to albuminuria. Fortunately, the presence of albuminuria is modifiable and new treatments are now available to reverse this common risk factor in the cardiorenal interaction.

A physiological approach to renal clearance: From premature neonates to adults.

We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Renal insufficiency in breast cancer patients; a review study

The latest statistics and estimations indicated that breast cancer occurs in one-fourth of women worldwide and is responsible for one in six cancer deaths among women. A bilateral relationship seems to exist between breast cancer pathophysiology and kidney failure. Consideration should be given to this relationship when selecting a treatment protocol. This paper reviews the association between these two factors in breast cancer patients. There are many aspects to consider in the association between breast cancer and renal insufficiency. A breast cancer patient with normal kidney function is at risk of developing kidney failure due to paraneoplastic syndromes, hypercalcemia, and in rare cases, tumor lysis syndrome (TLS). In defining the optimal treatment protocol for each breast cancer patient, clinicians should consider the patient’s basal glomerular filtration rate (GFR). Frequent renal clearance monitoring and taking immediate action at the time GFR begins to decrease will lower the rate of kidney failure in breast cancer patients. Lastly, patients with chronic kidney disease who are recently diagnosed with breast cancer may have higher morbidity and mortality compared to breast cancer patients with normal GFR. Further investigation is needed to lower morbidity and mortality in such patients.

Comparison of plasma clearance of [51Cr]CrEDTA based on three, two and single samples to measure the glomerular filtration rate in patients with solid tumors: a prospective cross-sectional analysis

Objectives[51Cr]CrEDTA is used to measure the Glomerular Filtration Rate (GFR) in different clinical conditions. However, there is no consensus on the ideal number of blood samples to be taken and at what time points to measure its clearance. This study aimed to compare Slope Intercept (SI) and Single-Sample (SS) methods for measuring GFR in patients with solid tumors, stratified by age, GFR, and Body Mass Index (BMI). Methods1,174 patients with cancer were enrolled in this prospective study. GFR was calculated by the SI method using blood samples drawn 2-, 4-, and 6-hours after [51Cr]CrEDTA injection (246-GFR). GFR was also measured using the SI method with samples at 2 and 4 hours (24-GFR) and at 4 and 6 hours (46-GFR), and SS methods according to Groth (4Gr-GFR) and Fleming (4Fl-GFR). Statistical analysis was performed to assess the accuracy, precision, and bias of the methods. ResultsMean 246-GFR was 79.2 ± 21.9 mL/min/1.73 m2. ANOVA indicated a significant difference between 4Gr-GFR and the reference 246-GFR. Bias was lower than 5 mL/min/1.73 m2 for all methods, except for SS methods in subgroups BMI > 40 kg/m2; GFR > 105 or < 45. Precision was adequate and accuracy of 30 % was above 98% for all methods, except for SS methods in subgroup GFR < 45. Conclusion46-GFR and 246-GFR have high agreement and may be used to evaluate kidney function in patients with solid tumors. Single-sample methods can be adopted in specific situations, for non-obese patients with expected normal GFR.

Renal Salt Wasting: Earliest Manifestation of Rhabdomyolysis, Supreet/Mehandru Syndrome

Acute kidney injury is a feared and common complication of rhabdomyolysis, occurring in 10-40% of hospitalized patients with mortality rate as high as 59% in critically ill patients. However, there is a lack of information in the literature on renal salt wasting in rhabdomyolysis. We report 3 cases of rhabdomyolysis who developed renal salt wasting in presence of normal glomerular filtration rate. To the best of our knowledge, this is the first case report in humans displaying this phenomenon. Authors noted that all the three patients had urine pH of over 7.0. Literature reveals, patients with rhabdomyolysis and urine pH&lt;6.5 develop acute kidney injury whereas urine pH&gt;7.0 experienced renal salt wasting in presence of normal glomerular filtration rate. All 3 cases, previously not known to have hypertension, were noted to have elevated blood pressure during acute phase of rhabdomyolysis. Animal studies have shown that increase in blood pressure causes increase in renal interstitial pressures that results in naturesis and diuresis. All 3 cases had increased levels of plasma renin activity and aldosterone. There is a direct proportionality between increased blood pressure and naturesis. Clinicians should be aware of salt wasting as an early renal manifestation in patients with rhabdomyolysis

Chronic kidney disease increases cost of care and readmission risk after shoulder arthroplasty

Chronic kidney disease (CKD) is associated with adverse outcomes and higher costs after lower extremity arthroplasty from higher rates of infection, aseptic loosening, and transfusion and longer hospital length of stay (LOS). The purpose of this study was to compare health care utilization and 90-day encounter charges after SA in patients with and without renal disease. A secondary aim was to define patient characteristics of patients with renal disease. We conducted a retrospective cohort study of all patients who underwent primary shoulder arthroplasty from January 2015 to December 2019 by a single surgeon at a single institution. Patients without a baseline glomerular filtration rate (GFR) were excluded. We evaluated results for patients with CKD (GFR ≤59) and without CKD (GFR ≥60). Univariate regression was performed to assess the influence of CKD on healthcare utilization, including length of stay (LOS), transfusion, and risk for ED revisit or readmission during the 90-day postoperative period. In addition, 90-day encounter charges, revisit charges, and ED charges for patients with CKD were compared with those for patients with normal renal function. Last, multivariable linear regression models were used to assess the effect of eGFR on total 90-day encounter charges. 514 patients met the study inclusion criteria. 125 had CKD, 389 had normal GFR. Patients with CKD were more likely to require transfusion [OR 16.2 (1.9, 139.7), p=0.011] despite similar intraoperative estimated blood loss (156.9±132.5mL versus 153.8±89.7mL, p=0.768). In addition, CKD patients had longer LOS (2.8±1.3 days versus 2.3±1.0 days, p<0.001), had higher 90-day readmission rates (p=0.001), were more likely to visit the ED within 90 days after shoulder arthroplasty (p=0.018), and had higher total 90-day encounter charges ($37,769±$6,901 versus $35,684±$5,312, p=0.001). Each unit increase in eGFR independently reduced total encounter charges by $67 (-$132, -$2, p=0.043); dialysis patients incurred higher total 90-day encounter charges compared to patients with less severe renal disease ($42,733 ± $8,985 v. $37,531± $6,749, p=0.002). Also, patients with CKD were older (73.2±8.9 versus 68.1±9.4 years, p<0.001); had lower preoperative Hg (12.4±1.5g/dL versus 13.4±1.5g/dL; p<0.001), higher ASA score (p<0.001), and more preoperative comorbidities (5.9±2.9 versus 5.0±3.1, p=<0.001); and were more likely to use opioids preoperatively (p=0.043). Patients with CKD have a higher risk for blood transfusion, ED visits, and readmission after shoulder arthroplasty, with higher total 90-day encounter charges. Identifying and optimizing this patient population before surgery can reduce costs and improve outcomes, which benefits patients, physicians, institutions, and payors.

Associations between Inflammation, Hemoglobin Levels, and Coronary Artery Disease in Non-Albuminuric Subjects with and without Type 2 Diabetes Mellitus.

In this cross-sectional study, we evaluated the associations of inflammation and hemoglobin with coronary artery disease (CAD) in subjects with type 2 diabetes mellitus (T2DM) and preserved kidney function. We recruited 638 participants-254 with T2DM-subjected to coronary angiography with no known cardiovascular disease, normal glomerular filtration rates, and without albuminuria. The hemoglobin and serum levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), were measured. Multivariable analyses showed that inflammatory markers were not related to the severity of the stenosis in the group of subjects with diabetes. Conversely, inflammatory cytokines and albuminuria were directly related to the percentage of stenosis in subjects without T2DM (R2 = 0.038, p < 0.001). Patients with diabetes presented lower hemoglobin levels, particularly in those who also had significant CAD (14.4 [13.6-15.1] vs. 13.6 [12.2-14.8] g/dL, p = 0.03). Similarly, hemoglobin levels and albuminuria were inversely related to the severity of stenosis exclusively in subjects with diabetes, even after adjusting for multiple confounding factors (R2 = 0.081, p < 0.001). We conclude that reductions in hemoglobin levels in subjects with T2DM and normoalbuminuria may constitute a more relevant risk factor for CAD than inflammation.

Association of Klotho with Coronary Artery Disease in Subjects with Type 2 Diabetes Mellitus and Preserved Kidney Function: A Case-Control Study.

Circulating Klotho levels are significantly reduced in subjects with type 2 diabetes mellitus (T2DM) and in kidney disease patients. In this work, the relationship between Klotho levels and the coronary artery disease (CAD) burden in subjects with T2DM and preserved kidney function was analyzed. For this, we performed a cross-sectional case-control study involving 133 subjects with T2DM and 200 age-, sex- and CAD-incidence-matched, non-diabetic patients undergoing non-emergency diagnostic coronary angiography. All of them were non-albuminuric and with normal glomerular filtration rates. The concentrations of serum Klotho, fibroblast growth factor 23, and inflammatory markers were also measured. As expected, the serum Klotho concentration was lower in the T2DM group (12.3% lower, p = 0.04). However, within the group of patients with T2DM, those subjects with CAD presented significantly higher Klotho levels than those without significant coronary stenosis (314.5 (6.15-562.81) vs. 458.97 (275.2-667.2) pg/mL; p = 0.02). Multiple regression analysis revealed that serum Klotho was positively related with stenosis values exclusively in subjects with T2DM (adjusted R2 = 0.153, p < 0.01). Moreover, logistic regression analysis showed that Klotho was positively associated with the presence of significant CAD in the group of T2DM patients (OR: 1.001; p = 0.041). Our data suggest that higher levels of circulating Klotho in subjects with T2DM and preserved kidney function are associated with the presence of significant CAD.

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans.

Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR.

Comparison of Spot Urinary Protein Creatinine Ratio and 24 hour Urinary Protein Excretion in Children presenting with Nephrotic Syndrome in Tertiary Care Hospital of Eastern Nepal

Introduction: Nephrotic syndrome is an important chronic disorder in children and it’s one of the important diagnostic criteria is presence of heavy proteinuria (&gt; 40 mg/m2/hour). As 24-hour urinary protein estimation is cumbersome, inconvenient, time consuming and expensive, a more convenient and accurate method of urinary protein estimation is needed. 24-hour urinary protein estimation and urine protein/creatinine in a child with nephrotic syndrome correlates well but there are very few studies done in Nepal to prove this correlation. Hence, this study is undertaken with objective of evaluating usefulness of urine protein/creatinine (UP/UC) in random sample of urine as a rapid and reliable test for quantification of proteinuria and to know their correlation with 24hour urinary protein excretion. Objectives: Primary Objective: To evaluate accuracy of urine protein creatinine ratio (UP/UC) in early morning sample in comparison with 24 hours urinary protein excretion in children of nephrotic syndrome having normal Glomerular Filtration Rate. Secondary Objective: To evaluate usefulness of urine protein / creatinine ratio (UP/UC) in random sample of urine as rapid and reliable test for quantification of proteinuria. To evaluate biochemical and other laboratory abnormalities in children with nephrotic syndrome. To study varied clinical presentation of Pediatric nephrotic syndrome Methodology: This is a descriptive cross-sectional study conducted in pediatric unit, Nobel Medical College Teaching Hospital, Biratnagar for 12 months. In this study, 50 patients of both sexes, ranging from one to fifteen years of age were studied. The modes of presentation, laboratory investigation reports which included urine routine microscopy, 24-hour urine protein estimation, urine protein / creatinine in random sample of urine were documented and data was analyzed by linear regression. Results: Linear regression revealed that as timed 24-hour urine protein in gm/24 hour increased, Random urine/protein creatinine ratio mg/mg also increased linearly with correlation coefficient of r = 0.56 which was highly significant (p &lt; 0.001). Conclusion: This study concludes that UP/UC ratio in a spot urine reflects the amount of protein in 24-hour urine collection. UP/UC ratio &gt; 2 in patients with normal renal function represents nephrotic range proteinuria.

Evaluation of Renoprotective Effect of Lipoic Acid and Bosentan Against Diclofenac-Induced Acute Renal Failure

Acute renal failure also known as acute kidney injury (AKI) is a complex health condition related to significant morbidity and mortality. In hospitalized patients, around 19-33 percent of AKI episodes are linked to drug induced nephrotoxicity. Although considered safe, NSAIDs such as diclofenac have gained special attention over the past few years due to the potential risk of renal injury. The direct effect of diclofenac-induced renal injury depends on targeting the mitochondria in kidney tissue, and formation of reactive oxygen species (ROS) resulting in oxidative stress. Secondly, diclofenac inhibit renal prostaglandin production, limiting renal afferent arteriole vasodilation, increasing afferent resistance; thus decreasing the glomerular capillary pressure below normal values and glomerular filtration rate will decrease resulting in AKI. Alpha-Lipoic acid (ALA) has beneficial effects in prevention or relief of symptoms of oxidative stress- related diseases, as it acts as antioxidant and anti-inflammatory micronutrient. Bosentan is a competitive antagonist with dual endothelin-1 receptors, as renal vascular ET-1 system is upregulated under many pathophysiological situations. In present study, we investigated the effect of lipoic acid and bosentan in diclofenac induced acute renal failure in male rats.&#x0D; We observed that diclofenac increased serum levels of urea, creatinine, malondialdehyde, KIM-1, TGFβ1 and fibronectin significantly (p&gt;0.05) in the induction group compared to control group. While, SOD significantly (p&gt;0.05) reduced in the induction group compared to control group. Both of lipoic acid and bosentan alone didn’t significantly protect against diclofenac induced AKI. However, the combination group showed a significant protection against AKI. Pearson correlation analysis showed a significant positive correlation between (urea and KIM-1) and between (creatinine and KIM-1) (r2=0.792 and r2=0.677 respectively). Furthermore, there was a significant positive correlation between fibronectin and urea (r2= 0.498, p&gt;0.01) and fibronectin and creatinine (r2=0.356, p&gt;0.05). Interestingly, KIM-1 showed a significant positive correlation with fibronectin (r2=0.536, p&gt;0.01).&#x0D; ROC curve test was performed for KIM-1 and fibronectin biomarkers. The AUC for KIM-1 was 0.986 and for fibronectin was 0.829. We concluded that combination therapy of lipoic acid and bosentan showed a significant protective effect against diclofenac-induced AKI. In addition, fibronectin could be a promising biomarker for detection and diagnosis of acute kidney injury.&#x0D; Key words: Diclofenac, oxidative stress, alpha- lipoic acid, endothelin-1, bosentan

The effects of complex therapy with the additional dapagliflozin intake on the copeptin level in the blood serum of patients with diabetic nephropathy

Objective — to determine the effects of drug therapy with inclusion of sodium‑glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on the blood levels of copeptin as a biomarker of renal and vascular lesions in patients with diabetic nephropathy (DN) at various disease stages.&#x0D; Materials and methods. Examinations involved 83 in‑hospital patients with DN, treated in the clinic of L. T. Mala National Institute of Therapy. Patients were divided into 2 groups depending on the therapy. 42 patients received a standard course of treatment, including antidiabetic drugs, renin‑angiotensin‑aldosterone system blockers and statins. In addition to standard therapy, the remaining 41 patients were administered SGLT2 inhibitor dapagliflozin in a dose of 10 mg per day. Patients were re‑examined after 6 months treatment. Determination of the copeptin level in blood serum was carried out by the enzyme immunoassay method using the set of reagents Human CPP Elisa Kit manufactured by FineTest, China.&#x0D; Results. The results of investigation of the effects of complex nephroprotective therapy on the lipid profile indicators in patients with type 2 diabetes mellitus (DM2) demonstrated significant decrease in the levels of total cholesterol by 11.78% (р &lt;0.05), triglycerides by 19.75% (р &lt;0.05) and non‑significant increase of high‑density lipoproteins by 5.10%. In patients with DM2 and with glomerular filtration rate (GFR) &gt;90 mL/(min · 1.73 m2) (I stage chronic kidney disease (CKD)) the level of copeptin after treatment decreased by 19.3% (p &lt;0.05); in patients with (DM2) and GFR of 60—89 mL/(min · 1.73 m2) (CKD II stage) — by 18.9% (p &lt;0.05), and with GFR of 45—59 mL/(min · 1.73 m2) (CKD III stage) — by 24.8% (p &lt;0.05). The significant decrease of copeptin levels was revealed in diabetic patients with both preserved and reduced GFR. In DM2 patients with normal GFR, the copeptin level after standard treatment decreased by 17.6% (p &lt;0.05), and in case of dapagliflozin administration by 20.6% (p &lt;0.05). In patients with reduced GFR, blood serum copeptin levels decreased by 18.9% (p &lt;0.05) after standard therapy, and by 22.1% (p &lt;0.05) under the influence of dapagliflozin.&#x0D; Conclusions. Complex therapy with the use of SGLT2 inhibitor dapagliflozin contributed to more significant reduction of copeptin levels in patients with DN compared to the standard treatment, regardless of the kidneys’ functional state. The decrease of copeptin levels against the background of the improved main clinical and laboratory parameters indicates not only an improvement in the kidneys’ functional state, but also reduction of cardiovascular risk in this group of patients.&#x0D;