Glomerular Function Research Articles

Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.

Impact of Vancomycin Loading Doses and Dose Escalation on Glomerular Function and Kidney Injury Biomarkers in a Translational Rat Model.

Vancomycin-induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in the glomerular filtration rate (GFR) and correlations with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague-Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had low GFRs and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2 compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high-dose folic acid. Rats in both the low- and high-dose vancomycin groups had higher GFRs on all dosing days than the positive-control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFRs on days 1, 2, and 4. Compared to low-dose vancomycin, the KIM-1 was elevated among rats in the high-dose group on dosing day 3. The GFR correlated most closely with the urinary injury biomarker KIM-1 on all experimental days. Vancomycin loading doses were associated with significant losses of kidney function and elevations of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker increases corresponded to the magnitude of the vancomycin dose (i.e., a higher dose resulted in worse outcomes).

Podocyte Geranylgeranyl Transferase Type-I Is Essential for Maintenance of the Glomerular Filtration Barrier.

A tightly regulated actin cytoskeleton attained through balanced activity of RhoGTPases is crucial to maintaining podocyte function. However, how RhoGTPases are regulated by geranylgeranylation, a post-translational modification, has been unexplored. The authors found that loss of the geranylgeranylation enzyme geranylgeranyl transferase type-I (GGTase-I) in podocytes led to progressive albuminuria and foot process effacement in podocyte-specific GGTase-I knockout mice. In cultured podocytes, the absence of geranylgeranylation resulted in altered activity of its downstream substrates Rac1, RhoA, Cdc42, and Rap1, leading to alterations of β1-integrins and actin cytoskeleton structural changes. These findings highlight the importance of geranylgeranylation in the dynamic management of RhoGTPases and Rap1 to control podocyte function, providing new knowledge about podocyte biology and glomerular filtration barrier function. Impairment of the glomerular filtration barrier is in part attributed to podocyte foot process effacement (FPE), entailing disruption of the actin cytoskeleton and the slit diaphragm. Maintenance of the actin cytoskeleton, which contains a complex signaling network through its connections to slit diaphragm and focal adhesion proteins, is thus considered crucial to preserving podocyte structure and function. A dynamic yet tightly regulated cytoskeleton is attained through balanced activity of RhoGTPases. Most RhoGTPases are post-translationally modified by the enzyme geranylgeranyl transferase type-I (GGTase-I). Although geranylgeranylation has been shown to regulate activities of RhoGTPases and RasGTPase Rap1, its significance in podocytes is unknown. We used immunofluorescence to localize GGTase-I, which was expressed mainly by podocytes in the glomeruli. To define geranylgeranylation's role in podocytes, we generated podocyte-specific GGTase-I knockout mice. We used transmission electron microscopy to evaluate FPE and measurements of urinary albumin excretion to analyze filtration barrier function. Geranylgeranylation's effects on RhoGTPases and Rap1 function were studied in vitro by knockdown or inhibition of GGTase-I. We used immunocytochemistry to study structural modifications of the actin cytoskeleton and β1 integrins. Depletion of GGTase-I in podocytes in vivo resulted in FPE and concomitant early-onset progressive albuminuria. A reduction of GGTase-I activity in cultured podocytes disrupted RhoGTPase balance by markedly increasing activity of RhoA, Rac1, and Cdc42 together with Rap1, resulting in dysregulation of the actin cytoskeleton and altered distribution of β1 integrins. These findings indicate that geranylgeranylation is of crucial importance for the maintenance of the delicate equilibrium of RhoGTPases and Rap1 in podocytes and consequently for the maintenance of glomerular integrity and function.

Static cutoffs or tables for the diagnosis of hypertension? Effect on identification of organ damage in youths with obesity

Background and aimRecently, the European Society of Cardiology task force released a Consensus document (ESC-CD) on pediatric hypertension (HTN) supporting the use of normative tables (age range 6–16 years) for the diagnosis of HTN, while the Hypertension Canada Guidelines (HTN-CGs) proposed static cutoffs. We aimed to assess the prevalence of HTN by ESC-CD or HTN-CGs and their association with glomerular function and left ventricular (LV) geometry in youths with overweight/obesity (OW/OB). Methods and resultsData of 3446 youths were analyzed. HTN by was defined using normative tables (ESC-CD) or static cutoffs of BP ≥ 120/80 in children (age <12 years) and ≥130/85 mmHg in adolescents (age ≥12 years) (HTN-CGs). Mildly reduced glomerular filtration rate was defined by GFR <90 ≥ 60 mL/min/1.73 m2. Concentric LV hypertrophy (cLVH) was assessed in 500 youths and defined by LVH and high relative wall thickness as proposed by ESC-CD. Prevalence of HTN was 27.9% by ESC-CD and 22.7% by HTN-CGs. The association with mildly reduced glomerular filtration rate was significant only in hypertensive adolescents classified by HTN-CGs [Odds Ratio (OR), 95%Cl] 2.16 (1.44–3.24), whereas the association with cLVH was significant using both criteria: children OR 2.18 (1.29–3.67) by ESC-CD and 2.27 (1.32–3.89) by HTN-CGs; adolescents OR 2.62 (1.17–5.84) by ESC-CD and 2.83 (1.14–7.02) by HTN-CGs. ConclusionAlthough static cutoffs may represent a simplification for HTN identification, tables by ESC-CD detect a higher number of hypertensive youths before a clear appearance of glomerular impairment, which offers advantages in terms of primary cardiovascular prevention.

The Good and the Bad of SHROOM3 in Kidney Development and Disease: A Narrative Review.

Multiple large-scale genome-wide association meta-analyses studies have reliably identified an association between genetic variants within the SHROOM3 gene and chronic kidney disease. This association extends to alterations in known markers of kidney disease including baseline estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and blood urea nitrogen. Yet, an understanding of the molecular mechanisms behind the association of SHROOM3 and kidney disease remains poorly communicated. We conducted a narrative review to summarize the current state of literature regarding the genetic and molecular relationships between SHROOM3 and kidney development and disease. PubMed, PubMed Central, SCOPUS, and Web of Science databases, as well as review of references from relevant studies and independent Google Scholar searches to fill gaps in knowledge. A comprehensive narrative review was conducted to explore the molecular mechanisms underlying SHROOM3 and kidney development, function, and disease. SHROOM3 is a unique protein, as it is the only member of the SHROOM group of proteins that regulates actin dynamics through apical constriction and apicobasal cell elongation. It holds a dichotomous role in the kidney, as subtle alterations in SHROOM3 expression and function can be both pathological and protective toward kidney disease. Genome-wide association studies have identified genetic variants near the transcription start site of the SHROOM3 gene associated with chronic kidney disease. SHROOM3 also appears to protect the glomerular structure and function in conditions such as focal segmental glomerulosclerosis. However, little is known about the exact mechanisms by which this protection occurs, which is why SHROOM3 binding partners remain an opportunity for further investigation. Our search was limited to English articles. No structured assessment of study quality was performed, and selection bias of included articles may have occurred. As we discuss future directions and opportunities, this narrative review reflects the academic views of the authors.

Changes of antioxidant enzymes in the kidney after cardiac arrest in the rat model.

Globally, cardiac arrest (CA) is a leading cause of death and disability. Asphyxial CA (ACA)-induced kidney damage is a crucial factor in reducing the survival rate. The purpose of this study was to investigate the role of antioxidant enzymes in histopathological renal damage in an ACA rat model at different time points. A total of 88 rats were divided into five groups and exposed to ACA except for the sham group. To evaluate glomerular function and oxidative stress, serum levels of blood urea nitrogen (BUN) and creatinine (Crtn) and malondialdehyde (MDA) levels in renal tissues were measured. To determine histopathological damage, hematoxylin and eosin staining, periodic acid-Schiff staining, and Masson's trichrome staining were performed. Expression levels of antioxidant enzymes including superoxide dismutase-1 (SOD-1), superoxide dismutase-2 (SOD-2), catalase (CAT), and glutathione peroxidase (GPx) were measured by immunohistochemistry (IHC). Survival rate of the experimental rats was reduced to 80% at 6 h, 55% at 12 h, 42.9% at 1 day, and 33% at 2 days after return of spontaneous circulation. Levels of BUN, Crtn, and MDA started to increase significantly in the early period of CA induction. Renal histopathological damage increased markedly from 6 h until two days post-CA. Additionally, expression levels of antioxidant enzymes were significantly decreased at 6 h, 12 h, 1 day, and 2 days after CA. CA-induced oxidative stress and decreased levels of antioxidant enzymes (SOD-1, SOD-2, CAT, GPx) from 6 h to two days could be possible mediators of severe renal tissue damage and increased mortality rate.

Editorial introductions.

Editorial introductions.

Proficient Novel Biomarkers Guide Early Detection of Acute Kidney Injury: A Review

The definition of acute kidney injury (AKI), despite improvements in criteria, continues to be based on the level of serum creatinine and urinary output that do not specifically indicate tubular function or injury, or glomerular function or injury that is not significant enough to warrant acute hospitalization of the patient. Finding novel biomarkers of AKI has become a major focus nowadays in nephrology to overcome the further complications of end stage renal disease (ESRD). Many compounds, such as KIM 1, IL 18, NGAL, uromodulin, calprotectin, vanin 1, galactin 3, platelet-derived growth factor (PDGF), urinary Na+/H+ exchanger isoform 3 (NHE3), retinol binding protein (RBP) and Cystatin C, are released from the renal tubules and thus any alterations in tubular function can be detected by measuring these parameters in urine. Additionally, glomerular injury can be detected by measuring immunoglobulin G, nephrin, podocalyxin, podocin, transferrin, netrin-1, pyruvate kinase M2, etc. in urine. These novel biomarkers will be useful for timing the initial insult and assessing the duration of AKI. According to available research, these biomarkers could be applied to assess the onset of AKI, distinguishing between kidney injury and dysfunction, directing the management of AKI, and enhancing disease diagnosis. Therefore, we intend to present recent developments in our understanding of significant biomarkers implicated in various aspects of renal damage. Numerous biomarkers are implicated in various pathophysiological processes that follow renal injury, and can improve prognosis and risk classification.

Spectrum of renal dysfunction after curative parathyroidectomy in symptomatic primary hyperparathyroidism

ObjectiveThe long-term renal consequences of curative parathyroidectomy (PTX) in symptomatic primary hyperparathyroidism (sPHPT) are not well characterized. We aimed to assess renal glomerular and tubular functions in an sPHPT cohort at ≥1 year's follow-up. DesignRetrospective-prospective study. MethodssPHPT patients with preoperative eGFR ≥60mL/min/1.73m2 and in remission (normocalcemic) for ≥1 year after PTX underwent clinical and biochemical assessment (calcium profile, renal parameters). Ammonium chloride and bicarbonate loading tests were performed in patients with renal tubular dysfunction (RTD). ResultsForty-eight patients (31 females) with median plasma PTH 1,029 (338–1604) pg/mL and mean eGFR 109.2±26.0mL/min/1.73m2 at diagnosis were evaluated at 5.62±3.66 years after curative PTX. At follow-up, eGFR was <60mL/min/m2 in 5 patients (10.4%). Patients with >10% drop in eGFR (n=31) had significantly higher pre-PTX plasma PTH (1,137 vs. 687pg/mL), and longer time to post-PTX evaluation (6.8 vs. 3.4 years). RTD was seen in 11 patients (22.9%): urinary low molecular weight proteinuria (14.6%), distal renal tubular acidosis (12.5%), hypophosphatemia (8.3%), and hypokalemia (8.3%); RTD was associated with significantly lower post-PTX eGFR (72.7 vs. 95.4mL/min/m2). Five of the 7 RTD patients undergoing loading test had impaired urinary acidification, whereas none had impaired bicarbonate resorption. ConclusionsReduction in eGFR and subclinical RTD were prevalent at long-term follow-up in the present Asian-Indian cohort with cured sPHPT. Further studies are warranted to understand the clinical implications of these various renal abnormalities.

ACTING EARLY TO PROTECT RENAL: BEYOND GLYCEMIC CONTROL OF SGLT2 INHIBITORS

Type 2 Diabetes Mellitus (T2DM) is the leading cause of chronic kidney disease (CKD), accounting for almost half of all cases of kidney failure that necessitate replacement therapy. Cardiovascular disease (CVD) is the leading cause of death in patients with T2DM and CKD. To lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule, sodium/glucose cotransporter 2 inhibitors (SGLT2-i) were developed. Consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death) were recognized in clinical trials designed to demonstrate the CVD safety of SGLT2i in type 2 diabetes mellitus (T2DM), as well as reductions in CVD events. The DECLARE-TIMI58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58, or DECLARE) trial in patients with T2DM, urinary albumin-creatinine ratio &gt;300 mg/g, and estimated glomerular filtration rate of 30 to 90 mL/min/1.73 m2 established the kidney and CVD benefits of dapagliflozin in patients with CKD. SGLT2i boost glomerular hemodynamic function and are figured to augment other local and systemic processes that contribute to the development of CKD and CVD. According to latest Indonesian Society of Endocrinologist’s guideline, patients with T2DM was recommended to use SGLT2i to reduce their risk of CKD and CVD, in accordance with the clinical trial entry criteria. To achieve widespread use of these life-saving medications, effective implementation strategies are required.

Insights into glomerular function and disease pathogenesis.

Insights into glomerular function and disease pathogenesis.

Expression of Wilms’ Tumor 1 Antigen, Vimentin, and Corticotropin-Releasing Factor in the Human Kidney with Focal Segmental Glomerulosclerosis and Effect of Oxidative Stress on These Markers in HEK 293 Cells

Introduction: Wilms’ tumor 1 antigen (WT1) expression in podocytes has the important role of maintaining their integrity and glomerular function. Vimentin also plays a role in preserving podocyte function and in morphological changes observed after injury. Corticotropin-releasing factor (CRF) is important in stress and in maintaining homeostasis. According to our previous studies, tyrosine (Tyr) isoforms (meta- and ortho-Tyr) may play a role in the development of many diseases. Methods: Our aim was to investigate the expression of WT1, vimentin, and CRF in the human kidney and in HEK 293 cell cultures. Histological and clinical features of 42 focal segmental glomerulosclerosis (FSGS) patients were evaluated and compared to those of patients with thin basement membrane as a control group. Cells were cultured in medium containing para-, meta-, and ortho-Tyr, and their expression of WT1, vimentin, and CRF were determined by immunocytochemistry. Podocyte foot process effacement was investigated by electron microscope. Results: The intensity of WT1 staining in glomeruli was the same in FSGS and control groups, but it was lower in the tubulointerstitium of FSGS patients. Vimentin was lower in glomeruli of FSGS patients (p = 0.009), and it was higher in the tubulointerstitium compared to the control group (p = 0.003). CRF intensity was lower in the glomeruli (p = 0.002). Podocyte foot process effacement determined by electron microscope showed correlation with vimentin and CRF in glomeruli. WT1 staining intensity was lower in meta- and ortho-Tyr group (p = 0.001; p = 0.009). Vimentin was lower in the meta-Tyr group (p = 0.001). Discussion: Our observations on kidney biopsy samples support that the reduction of WT1 and vimentin could be characteristic for FSGS. Our results on HEK cells suggest that meta- and ortho-Tyr may play a role in the development of FSGS.

Comprehensive Study of Cellulosic and Synthetic Membranes for Dialyzer

The kidney is the primary osmoregulatory organ in the mammalian body, removing harmful wastes such as ammonia and excess fluid from the blood and maintaining the ionic concentrations of the blood by retaining electrolytes, calcium, and phosphorus. In kidney failure, the kidneys are unable to filter the blood effectively. Dialysis is a survival treatment for patients with kidney failure. Dialysis involves the exchange of blood and dialysate across a semipermeable membrane. Concentration gradients drive diffusion, and hydrostatic pressure gradients drive convection. There are two different types of dialysis: peritoneal and hemodialysis. During hemodialysis, the blood is filtered by an external device called a dialyzer. Since the 1950s, dialyzers have been used commercially for hemodialysis; their removal capacity of uremic substances, biocompatibility, and combination of glomerular and renal tubular function have all been the subject of ongoing development. Despite the progress, mortality remains high. Investigating how dialysis membranes affect long-term morbidity and mortality in hemodialysis maintenance patients is essential. Dialyzer membranes play a vital role in dialysis treatment. Important characteristics of membrane material include permeability, hydrophilicity, and biocompatibility. Cellulosic and synthetic polymeric membranes are the two primary types of dialysis membranes. This article comprehensively analyzes the concept of dialysis and the characteristics of dialyzers and their types. This review focuses critically on the membranes of the dialyzer and their classification. We anticipate that this review will aid researchers in selecting the optimal dialyzer and membrane material to improve hemodialysis treatment outcomes for renal disease patients.

Brain-specific biomarkers in urine as a non-invasive approach to monitor neuronal and glial damage.

This study evaluates the quantitative measurability of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and total tau (t-tau) in urine of patients with acute cerebral damage. Serum and urine samples were prospectively collected from patients with an acute ischemic stroke or intracerebral hemorrhage (target group) and compared to healthy subjects (control group); samples were measured using ultrasensitive single-molecule arrays (Simoa®). Glomerular barrier function was assessed based on albumin-creatinine ratio (ACR); biomarker-creatinine ratios were calculated for correction of urine dilution. Ninety-three urine-serum pairs in the target group and 10 urine-serum pairs in the control group were measured. The mean absolute concentration ± standard deviation in urine of the target and control groups were 184.7± 362.4pg/ml and 27.3± 24.1pg/ml for GFAP (r= 0.3 [Wilcoxon effect size], p= 0.007), 17.5± 38.6pg/ml and 0.9± 0.3pg/ml for NfL (r= 0.4, p< 0.005), 320.2± 443.3pg/ml and 109.6± 116.8pg/ml for UCH-L1 (r= 0.26, p= 0.014), and 219.5± 255.8pg/ml and 21.1± 27.1pg/ml for t-tau (r= 0.37, p< 0.005), respectively, whereas biomarker-creatinine ratio was significantly different only for NfL (r= 0.29, p= 0.015) and t-tau (r= 0.32, p< 0.01). In patients with intact glomerular barrier (ACR<30 mg/g), only NfL in urine was significantly different between the target and control group and showed a significant correlation with the respective serum concentrations (r= 0.58 [Pearson's correlation-coefficient], p< 0.005). All four investigated biomarkers could be measured in urine, with NfL and t-tau showing the strongest effect size after correction for urine dilution. NfL revealed the most accurate relation between serum and urine concentrations in patients with intact kidney function.

Development and anatomo-physiological features of kidneys in premature newborns

A premature baby in need of resuscitation after birth is exposed to damaging factors that affect the entire body, including the kidneys. The review considers the stages of development and identifies the main anatomical and physiological features of the kidneys in premature babies. The main risk factor for the development of pathology associated with immaturity of the kidneys in preterm infants is imperfect glomerular and tubular functions of the kidneys, a large capillary surface of the kidneys, high renal blood flow, imperfect regulation of the acid-base balance, and the ability to concentrate, which become untenable under the influence of external loads. Any damaging factor in the antenatal period in premature infants, considering the anatomical and physiological characteristics and the imperfect compensatory response from the kidneys, can permanently change the structure of the kidneys, which will lead to the development of chronic kidney disease in the future. Proper management of premature newborns, considering the anatomical and physiological characteristics of the kidneys, will significantly reduce the risk of severe complications and mortality among premature newborns, and improve the long-term clinical prognosis in such children.

Cystatin C in addition to creatinine for better assessment of glomerular renal function decline in people with HIV receiving antiretroviral therapy.

To compare the estimated glomerular filtration rate (eGFR) using the creatinine equation (eGFRcreat) or the cystatin C equation (eGFRcys) in people with HIV (PWH) under antiretroviral drugs. We specifically included patients with an eGFRcreat around 60 ml/min per 1.73 m2 to evaluate agreement on stage 2 and 3 chronic kidney disease (CKD) classification. eGFRcreat, eGFRcys and resulting CKD staging were determined in 262 consecutive patients with HIV-1 (PWH) with a suppressed viral load (<200 copies/ml) under antiretroviral drugs and having impaired renal function (eGFRcreat between 45 and 80 ml/min per 1.73 m2). Antiretroviral drugs regimens were classified into eight groups: cobicistat (COBI)+elvitegravir (EVG), ritonavir (RTV)+protease inhibitor, dolutegravir (DTG), DTG+rilpivirine (RPV), RPV, raltegravir (RAL), bictegravir (BIC), and other antiretroviral drugs. Mean eGFRcys was higher than mean eGFRcreat (77.7 ± 0.5 vs. 67.9 ± 7.9 ml/min per 1.73 m2, P < 0.0001). The differences were significant in five treatment groups with COBI/EVG; DTG; DTG+RPV; RPV; RAL. CKD classification was modified for 51% of patients when using eGFRcys instead of eGFRcreat, with reclassification to less severe stages in 37% and worse stages in 14%. This study highlighted significant differences in eGFR depending on the renal marker used in PWH, having a significant impact on CKD classification. eGFRcys should be an additive tool for patients having eGFRcreat around 60 ml/min per 1.73 m2 for better identification of renal impairment.

A novel and robust approach to defining population-based reference ranges for a serum free light chain assay in a clinical laboratory

Abstract Serum protein electrophoresis and immunofixation are used to detect the presence of monoclonal heavy and light immunoglobulin chains for the diagnosis of plasma cell neoplasms (PCN). In conjunction, the Freelite® assay has been used to detect excess free kappa and lambda light chains produced by PCN, where the kappa:lambda free light chain ratio (KLR) serves as a surrogate marker of clonality and disease. The manufacturer-defined KLR reference range of 0.26-1.65 is used in internationally recognized criteria for PCN diagnosis and monitoring, and KLR results affect clinical decision making, disease categorization, and response assessment. Our laboratory has verified the manufacturer-defined Freelite® KLR reference range three times using healthy control sera since assay implementation in 2006. Despite this, high percentages of abnormal KLR have consistently been observed among immunofixation-defined monoclonal-negative specimens. We therefore retrospectively interrogated 48,012 serum free light chain clinical results reported at our institution between 2010-2020 by extracting results from our laboratory information system and analyzing population distributions using the R programming language. For all specimens, the distribution of KLR values was shifted towards the towards the upper limit of the manufacturer-defined reference range, indicating that it poorly describes both our monoclonal-negative and monoclonal-positive patient populations. Furthermore, &amp;gt;80% of monoclonal-negative specimens exhibited KLR above the median of the manufacturer-defined reference range (0.26-1.65), while 24% (1,226/5,057) unexpectedly exhibited KLR &amp;gt;1.65. We found that this phenomenon has been present consistently since 2010 and is not affected by patient sex or age, impaired renal function, lot-to-lot variation, or assay drift. We therefore sought to establish an institution-appropriate KLR reference range by defining a reference population from within our existing dataset. We leveraged International Classification of Diseases codes, estimated glomerular function data, and serum/urine immunofixation results to exclude specimens from individuals with PCN- or renal-related diagnoses, impaired renal function, and prior, current, or subsequent monoclonal components. The resultant 1,536 monoclonal-negative reference specimens were then classified according to the manufacturer-defined KLR reference range, where 13% remained abnormally elevated, consistent with the published false positive rate in healthy volunteers. Lastly, we determined a new KLR reference range of 0.66-2.21 using the central 95% of KLR values from these reference specimens. When applied to our dataset, this institution-specific KLR reference range improved the accurate classification of specimens containing monoclonal free light chains by immunofixation, while reducing the false-positive rate in monoclonal-negative specimens. Together, our findings support the use of historical KLR and immunofixation data from routine clinical testing to derive institution-appropriate KLR reference ranges, which can then be used for continuous quality improvement. Implementation of this more-accurate KLR reference range should improve subsequent test utilization by non-specialist providers, reduce concern for/over-diagnosis of kappa-involved disease, and improve the detection and monitoring of lambda-involved disease.

Role of insulin signaling and its associated signaling in glomerulus for diabetic kidney disease.

The number of patients with diabetic kidney disease (DKD) has been rising significantly over the last several decades and is one of the most frequent causes of chronic kidney disease (CKD) in the United States. Hyperglycemia accelerates development of DKD, a direct result of increased intracellular glucose availability. Two large clinical studies, the Diabetes Control and Complications Trial in type 1 diabetes and the United Kingdom Prospective Diabetes Study in type 2 diabetes showed that intensive glycemic control delayed the onset and the progression of DKD. On the other hand, it is reported that glycemic control alone is not sufficient to control DKD progression. Recent data support that insulin signaling and its associated signaling contribute significantly to preserve glomerular function. However, little is known about the key regulators of insulin signaling in glomerular component cells. In this review, we summarize the novel knowledge regarding the reno-protective effects of insulin signaling or its associated signaling in glomerular constituent cells on DKD.

Sparsentan Improves Glomerular Endothelial and Podocyte Functions and Augments Protective Tissue Repair in a Mouse Model of Focal Segmental Glomerulosclerosis (FSGS)

Sparsentan Improves Glomerular Endothelial and Podocyte Functions and Augments Protective Tissue Repair in a Mouse Model of Focal Segmental Glomerulosclerosis (FSGS)

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue.

Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues.