Investigation of the Relationship of Nesfatin-1, Adropin Levels and Claudin-2, Renalase Immunoreactivity with Kidney Function in an Experimental Hypertension Model.

OBJECTIVE: Hypertension is one of the cardiovascular diseases that causes the most mortality, and 95% of the causes are unknown. The aim of the study was to examine the possible correlation of nesfatin-1 levels, adropin levels, claudin-2 immunoreactivity (claudin-2 expression in the renal proximal tubule), and renalase immunoreactivity (renalase expression in the renal proximal tubule) with arterial blood pressure, kidney function, and kidney damage. METHODS: Adult male Sprague Dawley rats were divided into control and hypertension groups (8 per group). Angiotensin II vehicle was given to the control group and angiotensin II (0.7 mg/kg/day) to the hypertension group, both via an osmotic mini pump for 7 days. The animals blood pressures were measured by tail cuff plethysmography on days 1, 3, 5, and 7. On day 7, 24-hour urine, blood, and tissues were collected from the rats. RESULTS: In the hypertension group compared with the control group, there was an increase in systolic blood pressure levels after day 1. While claudin-2 immunoreactivity was reduced in the kidneys, renalase immunoreactivity was increased. There was a decrease in creatinine clearance and an increase in fractional potassium excretion (P < .05). CONCLUSION: Our results showed that claudin-2 and renalase are associated with renal glomerular and tubular dysfunction and may play discrete roles in the pathogenesis of hypertension. We believe that these potential roles warrant further investigation.

Angiotensin II hypertension along the female rat tubule: predicted impact on coupled transport of Na+ and K.

Chronic infusion of subpressor level of angiotensin II (ANG II) increases the abundance of Na+ transporters along the distal nephron, balanced by suppression of Na+ transporters along the proximal tubule and medullary thick ascending limb (defined as "proximal nephron"), which impacts K+ handling along the entire renal tubule. The objective of this study was to quantitatively assess the impact of chronic ANG II on the renal handling of Na+ and K+ in female rats, using a computational model of the female rat renal tubule. Our results indicate that the downregulation of proximal nephron Na+ reabsorption (TNa), which occurs in response to ANG II-triggered hypertension, involves changes in both transporter abundance and trafficking. Our model suggests that substantial (∼30%) downregulation of active NHE3 in proximal tubule (PT) microvilli is needed to reestablish the Na+ balance at 2 wk of ANG II infusion. The 35% decrease in SGLT2, a known NHE3 regulator, may contribute to this downregulation. Both depression of proximal nephron TNa and stimulation of distal ENaC raise urinary K+ excretion in ANG II-treated females, while K+ loss is slightly mitigated by cortical NKCC2 and NCC upregulation. Our model predicts that K+ excretion may be more significantly limited during ANG II infusion by ROMK inhibition in the distal nephron and/or KCC3 upregulation in the PT, which remain open questions for experimental validation. In summary, our analysis indicates that ANG II hypertension triggers a series of events from distal TNa stimulation followed by compensatory reduction in proximal nephron TNa and accompanying adjustments to limit excessive K+ secretion.NEW & NOTEWORTHY We used a computational model of the renal tubule to assess the impact of 2-wk angiotensin II (ANG II) infusion on the handling of Na+ and K+ in female rats. ANG II strongly stimulates distal Na+ reabsorption and K+ secretion. Simulations indicate that substantial downregulation of proximal tubule NHE3 is needed to reestablish Na+ balance at 2 wk. Proximal adaptations challenge K+ homeostasis, and regulation of distal NCC and specific K+ channels likely limit urinary K+ losses.

Comparing different markers of tubular dysfunction in transfusion-dependent thalassemia patients.

BACKGROUND: Renal tubular dysfunction was reported in transfusion-dependent thalassemia (TDT) patients and ranges from mild to severe. The objectives of our study were identification of the best marker of early renal tubular dysfunction in TDT patients among the three most commonly used urinary biomarkers, named neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and N-acetyl-D-glucosaminidase (NAG) and correlation of these biomarkers with different patient variables. METHODOLOGY: Sixty-one TDT patients and another 62 healthy children were enrolled in a cross-sectional study. Morning urine samples were taken for measurement of calcium, phosphorus, creatinine, microalbumin and markers of tubular dysfunction (NGAL, NAG and RBP). Urine NGAL/creatinine (UrNGAL/Cr), urine NAG/creatinine (UrNAG/Cr) and urine RBP/creatinine (UrRBP/Cr) ratios were used for accuracy. Patients were classified into 2 groups: group A, with tubular dysfunction and group b, without tubular dysfunction. RESULTS: Group A showed statistically significant higher UrNGAL/Cr (p < 0.001), UrRBP/Cr (p < 0.001) and UrNAG/Cr (p <0.001) than group B. In group A, microalbuminuria was detected only in 7 patients (28%) while it was detected in 12 patients (33.3%) in group B. By using ROC curve analysis, the diagnostic cutoff values for UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr were 3713.38, 1614.85 and 56.56 ng/g, respectively. We found a statistically significant superiority of UrNGAL/Cr over UrRBP/Cr (p < 0.001) and UrRBP/Cr over UrNAG/Cr (p < 0.001). CONCLUSION: Evaluation of UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr could early discriminate tubular dysfunction TDT patients from those with normal tubular function. UrNGAL/Cr is more accurate in early detection of tubular dysfunction when compared with the other two biomarkers.

ß-Thalassemia minor & renal tubular dysfunction: is there any association?

OBJECTIVE: Beta(ß)-thalassemia is one of the most common hereditary hematologic disorders. Patients with thalassemia minor (TM) are often asymptomatic and the rate of renal dysfunction is unknown in these patients. Due to the high prevalence of renal dysfunction in Iran, the current study aimed to determine renal tubular dysfunction in patients with beta-TM. METHODS: In this case-control study, 40 patients with TM and 20 healthy subjects were enrolled and urinary and blood biochemical analysis was done on their samples. Renal tubular function indices were determined and compared in both groups. Data was analyzed by SPSS software, version 20.0. RESULTS: The fraction excretion (FE) of uric acid was 8.31 ± 3.98% in the case and 6.2 ± 34.71% in the control group (p = 0.048). Also, FE of potassium was significantly higher in patients with TM (3.22 ± 3.13 vs. 1.91 ± 0.81; p = 0.036). The mean Plasma NGAL level was 133.78 ± 120.28 ng/mL in patients with thalassemia and 84.55 ± 45.50 ng/mL in the control group (p = 0.083). At least one parameter of tubular dysfunction was found in 45% of patients with thalassemia. CONCLUSION: Based on the results of this study, the prevalence of tubular dysfunction in beta-thalassemia minor patients is high. Due to the lack of knowledge of patients about this disorder, periodic evaluation of renal function in TM patients can prevent renal failure by early diagnosis.

Differential biomolecular recognition by synthetic vs. biologically-derived components in the stone-forming process using 3D microfluidics.

Calcium phosphate (CaP) biomineralization is the hallmark of extra-skeletal tissue calcification and renal calcium stones. Although such a multistep process starts with CaP crystal formation, the mechanism is still poorly understood due to the complexity of the in vivo system and the lack of a suitable approach to simulate a truly in vivo-like environment. Although endogenous proteins and lipids are engaged with CaP crystals in such a biological process of stone formation, most in vitro studies use synthetic materials that can display differential bioreactivity and molecular recognition by the cellular component. Here, we used our in vitro microfluidic (MF) tubular structure, which is the first completely cylindrical platform, with renal tubular cellular microenvironments closest to the functional human kidney tubule, to understand the precise role of biological components in this process. We systematically evaluated the contribution of synthetic and biological components in the stone-forming process in the presence of dynamic microenvironmental cues that originated due to cellular pathophysiology, which are critical for the nucleation, aggregation, and growth of CaP crystals. Our results show that crystal aggregation and growth were enhanced by immunoglobulin G (IgG), which was further inhibited by etidronic acid due to the chelation of extracellular Ca2+. Interestingly, biogenic CaP crystals from mice urine, when applied with cell debris and non-specific protein (bovine serum albumin), exhibited a more discrete crystal growth pattern, compared to exposure to synthetic CaP crystals under similar conditions. Furthermore, proteins found on those calcium crystals from mice urine produced discriminatory effects on crystal-protein attachment. Specifically, such biogenic crystals exhibited enhanced affinity to the proteins inherent to those crystals. More importantly, a physiological comparison of crystal induction in renal tubular cells revealed that biogenic crystals are less effective at producing a sustained rise in cytosolic Ca2+ compared to synthetic crystals, suggesting a milder detrimental effect to downstream signaling. Finally, synthetic crystal-internalized cells induced more oxidative stress, inflammation, and cellular damage compared to the biogenic crystal-internalized cells. Together, these results suggest that the intrinsic nature of biogenically derived components are appropriate to generate the molecular recognition needed for spatiotemporal effects and are critical towards understanding the process of kidney stone formation.

Renal cell markers: lighthouses for managing renal diseases.

Kidneys, one of the vital organs in our body, are responsible for maintaining whole body homeostasis. The complexity of renal function (e.g., filtration, reabsorption, fluid and electrolyte regulation, and urine production) demands diversity not only at the level of cell types but also in their overall distribution and structural framework within the kidney. To gain an in depth molecular-level understanding of the renal system, it is imperative to discern the components of kidney and the types of cells residing in each of the subregions. Recent developments in labeling, tracing, and imaging techniques have enabled us to mark, monitor, and identify these cells in vivo with high efficiency in a minimally invasive manner. In this review, we summarize different cell types, specific markers that are uniquely associated with those cell types, and their distribution in the kidney, which altogether make kidneys so special and different. Cellular sorting based on the presence of certain proteins on the cell surface allowed for the assignment of multiple markers for each cell type. However, different studies using different techniques have found contradictions in cell type-specific markers. Thus, the term "cell marker" might be imprecise and suboptimal, leading to uncertainty when interpreting the data. Therefore, we strongly believe that there is an unmet need to define the best cell markers for a cell type. Although the compendium of renal-selective marker proteins presented in this review is a resource that may be useful to researchers, we acknowledge that the list may not be necessarily exhaustive.

TDAG51 induces renal interstitial fibrosis through modulation of TGF-ß receptor 1 in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-ß induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-ß receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-ß receptor 1, thus, preventing TGF-ß-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-ß-IRE1-XBP1 pathway.

Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy.

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.

Tubular injury in diabetic ketoacidosis: Results from the diabetic kidney alarm study.

OBJECTIVE: Glomerular injury is a recognized complication of diabetic ketoacidosis (DKA), yet the tubular lesions are poorly understood. The aim of this prospective study was to evaluate the presence and reversibility of tubular injury during DKA in children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Blood and urine samples were collected from 40 children with DKA (52% boys, mean age 11 ± 4 years, venous pH 7.2 ± 0.1, glucose 451 ± 163 mg/dL) at three timepoints: 0-8 and 12-24 h after starting insulin, and 3 months after discharge. Mixed-effects models evaluated the changes in tubular injury markers over time (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], and interleukin 18 [IL-18]). We also evaluated the relationships among the tubular injury biomarkers, copeptin, a vasopressin surrogate, and serum uric acid (SUA). RESULTS: Serum NGAL, KIM-1, and IL-18 were highest at 0-8 h (306.5 ± 45.9 ng/mL, 128.9 ± 10.1 pg/mL, and 564.3 ± 39.2 pg/mL, respectively) and significantly decreased over 3 months (p = 0.03, p = 0.01, and p < 0.001, respectively). There were strong relationships among increases in copeptin and SUA and rises in tubular injury biomarkers. At 0-8 h, participants with acute kidney injury (AKI) [17%] showed significantly higher concentrations of tubular injury markers, copeptin, and SUA. CONCLUSIONS: DKA was characterized by tubular injury, and the degree of injury associated with elevated copeptin and SUA. Tubular injury biomarkers, copeptin and SUA may be able to predict AKI in DKA.

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease.

Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.

Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress.

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), ß 2-microglobulin (ß 2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine ß 2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model.

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging.

BACKGROUND: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. METHODS: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. RESULTS: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. CONCLUSION: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance.

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-ß-D-glucosaminidase concentrations ([Cd]u and [NAG]u) to the urine creatinine concentration ([cr]u). In theory, the sources of these errors are nullified by normalization of excretion rates (ECd and ENAG) to creatinine clearance (Ccr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, Ex/Ecr and Ex/Ccr were calculated as [x]u/[cr]u and [x]u[cr]p/[cr]u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m2. In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(ECd/Ccr) and log(ENAG/Ccr) than for log(ECd/Ecr) and log(ENAG/Ecr). Doubling of ECd/Ccr and ENAG/Ccr increased POR by 132% and 168%; doubling of ECd/Ecr and ENAG/Ecr increased POR by 64% and 54%. As log(ECd/Ccr) rose, associations of eGFR with log(ECd/Ccr) and log(ENAG/Ccr) became stronger, while associations of eGFR with log(ECd/Ecr) and log(ENAG/Ecr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R2 was consistently higher with normalization to Ccr. Our tabular and graphic analyses uniformly indicate that normalization to Ccr clarified relationships of ECd and ENAG to eGFR.

Acute Kidney Injury and Renal Tubular Damage in Children With Type 1 Diabetes Mellitus Onset.

CONTEXT: Acute kidney injury (AKI) and renal tubular damage (RTD), especially if complicated by acute tubular necrosis (ATN), could increase the risk of later chronic kidney disease. No prospective studies on AKI and RTD in children with type1diabetes mellitus (T1DM) onset are available. OBJECTIVES: To evaluate the AKI and RTD prevalence and their rate and timing of recovery in children with T1DM onset. DESIGN: Prospective study. SETTINGS AND PATIENTS: 185 children were followed up after 14 days from T1DM onset. The patients who did not recover from AKI/RTD were followed-up 30 and 60 days later. MAIN OUTCOME MEASURES: AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin and/or tubular reabsorption of phosphate < 85% and/or fractional excretion of Na (FENa) > 2%. ATN was defined by RTD+AKI, prerenal (P)-AKI by AKI+FENa < 1%, and acute tubular damage (ATD) by RTD without AKI. RESULTS: Prevalence of diabetic ketoacidosis (DKA) and AKI were 51.4% and 43.8%, respectively. Prevalence of AKI in T1DM patients with and without DKA was 65.2% and 21.1%, respectively; 33.3% reached AKI stage 2, and 66.7% of patients reached AKI stage 1. RTD was evident in 136/185 (73.5%) patients (32.4% showed ATN; 11.4%, P-AKI; 29.7%, ATD). All patients with DKA or AKI presented with RTD. The physiological and biochemical parameters of AKI and RTD were normal again in all patients. The former within 14 days and the latter within 2months. CONCLUSIONS: Most patients with T1DM onset may develop AKI and/or RTD, especially if presenting with DKA. Over time the physiological and biochemical parameters of AKI/RTD normalize in all patients.

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products.

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

GPR120 Ameliorates Apoptosis and Inhibits the Production of Inflammatory Cytokines in Renal Tubular Epithelial Cells.

Acute kidney injury (AKI) is the most common complication of sepsis with a high mortality rate. In this study, we focus on the renal injury caused by the immune response of renal tubular epithelial cells and inflammation-induced renal tubular epithelial cell apoptosis. We studied the role of GRP120 in the inflammation and apoptosis of human renal cell line HK-2 and mouse primary renal tubular epithelial cells. GPR120 agonist GW9508 activated the GPR120 pathway. Inflammatory factors were detected using quantitative real-time PCR and enzyme-linked immunosorbent assay. Cell apoptosis experiments included the annexin V and PI double-staining method combined with flow cytometry, TUNEL method, and Western blot. The level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS was significantly decreased (P < 0.05) in HK-2 and TECs after the activation of the GPR120 pathway. Besides, the cell apoptosis of both cells increased. Overexpressed GPR120 and shGPR120 were established. Treatment with lipopolysaccharide (LPS) increased the level of cytokines including TNF-α, IL-6, IL-1ß, and iNOS in HK-2 cell and TECs. Compared with control-LPS and negative control (NC)-LPS, the overexpression of GPR120 and shGPR120 could decrease and increase the level of secreted cytokines significantly (P < 0.05), respectively, after LPS-induced apoptosis. After H2O2- and LPS-induced apoptosis, respectively, compared with the control and NC groups, overexpressed GPR120 and shGPR120 could reduce and increase the expression of caspase-3, respectively. GPR120 could suppress the cellular immune response and apoptosis in renal tubular epithelial cells, thereby possibly protecting the kidney and relieving sepsis-induced AKI.

Association of Renal Glomerular and Tubular Function With Renal Outcome in Patients With Posterior Urethral Valves.

OBJECTIVE: To analyze renal glomerular and tubular function and their association in patients operated for posterior urethral valves and to prognosticate the risk for end-stage kidney disease (ESKD) METHODS: Sixty-three previously treated patients were evaluated for renal function during 1987-1991. The patients' age at evaluation was 11 years (range 2-24). Glomerular function was assessed by measuring glomerular filtration rate (GFR) and urine albumin excretion. Tubular function was determined by measuring urine concentration capacity and excretion of electrolytes (Na, K, Cl, Ca, P, Mg) and ß-2-microglobulin. Additionally, the prevalence of hypertension and serum parathyroid hormone and aldosterone values were registered. Tubular function was compared with GFR and the risk of developing ESKD before November 2018. RESULTS: Twenty of the study patients (32%) had decreased GFR. In addition, 19% had proteinuria and 56% were hypertensive. Those without proteinuria or hypertension had better GFR values (P < .01 for both). There was a significant correlation between GFR and all the tubular function (P < .05) variables (except excretion of chloride) measured. Compared to the patients with favorable renal outcome, the patients (n = 10) who later developed ESKD had significantly (P < .01) lower GFR and reduced urinary excretion of all measured electrolytes except calcium. Consistently, urine ß-2 microglobulin and serum parathyroid hormone and aldosterone values were significantly higher in the patients who developed ESKD (P ≤ .01). CONCLUSION: Both glomerular and tubular function decline was common and several parameters were likely to predict ESKD in posterior urethral valves patients.