Renal Resistance Research Articles

Early diagnosis and prevention of acute kidney injury in elderly patients after urgent abdominal surgery

Due to the rapidly aging of the population, the number of elderly patients is boosting. Elderly patients are a special cohort of patients due to their typical physiological and anatomical age-related changes, fragility, and comorbidity. One of the threatening perioperative complications is acute kidney injury (AKI), which is associated with a longer hospital stay, increased short-term and long-term mortality. Despite constant efforts to standardize the determination of AKI using serum creatinine, this method has several disadvantages, which makes the search for other diagnostic criteria for kidney damage urgent. Recently, the determination of biomarkers (lipocalin-2, interleukin-18, cystatin C), which can be useful in the early diagnosis of AKI, has become increasingly popular. Even though the filtration capacity of the kidneys is the only factor determining the serum cystatin C concentration, this marker is the most valuable. The use of ultrasound for the early diagnosis of AKI is also considered promising. Several studies show that the renal resistance index and semi-quantitative assessment of renal blood flow work are well for diagnosing persistent AKI. The high mortality rate and the lack of special treatment increase the need for AKI prevention in the elderly, the main one of which is careful clinical monitoring with timely correction of hypovolemia and hypotension. With invasive procedures, the risk of AKI can be reduced by maintaining mean arterial pressure > 80 mmHg and hematocrit > 30 %, as well as providing adequate oxygenation and volume restoration. Prescription of drugs should be individualized by adjusting doses based on the glomerular filtration rate and the patient’s age. However, the question of specific drug prevention of AKI remains open. Several studies have confirmed the renoprotective properties of dexmedetomidine in cardiac surgery, and some positive effects of pentoxifylline for the treatment of renal pathology are also described in the literature. This review explores the topic of AKI in elderly patients undergoing abdominal surgery and focuses on the early diagnosis and prevention of this syndrome.

Ultrasound examination as a method of early “bedside” diagnosis of acute kidney injury in geriatric patients after urgent abdominal surgery

Geriatric patients are particularly vulnerable to the development of postoperative complications, one of which is acute kidney injury (AKI). Early diagnosis of AKI is an important component of the effectiveness of its prevention and treatment. It is believed that ultrasound examination of renal blood flow may be a promising method for bedside diagnosis of AKI.
 The aim is to evaluate the predictive value of renal resistance index (RRI) and semiquantitative renal perfusion (SQP) as methods for early diagnosis of AKI in geriatric patients after urgent abdominal surgery.
 Materials and methods. A prospective single-center study included 40 patients (72.5 (65; 81.5) y. o.) who were assessed for the risk of development, the presence and stage of AKI, and additionally measured hemodynamic parameters, intra-abdominal pressure (IAP), and abdominal perfusion pressure (APP). Renal resistance index (RRI) and semi-quantitative renal perfusion score (SQP) were determined using Doppler ultrasound (ultrasound probe CH-6, SIEMENS, Acuson Antares). Statistical analysis was performed using the STATISTICA for Windows 13 program (StatSoftInc., No. JPZ804I382130ARCN10-J).
 Results. In the postoperative period, AKI developed in 26 patients (65%). Compared with patients without AKI, they had a 14% lower level of mean arterial pressure (MAP) (p=0.008), as well as an average of 4 mmHg higher IAP (p=0.005) and significantly lower APP (p=0.0348). Correlation analysis revealed a weak relationship between the values of MAP, IAP, APP and the development of AKI (r=0.34, r=0.41, r=0.392, respectively, p˂0.05).
 Patients with AKI had a 13.9% higher RRI than patients without AKI (0.75 (0.72; 0.81) r.u. vs 0.66 (0.61; 0.69) r.u., respectively, p=0.000001), however, the degree of SQP of the kidneys did not differ significantly between the groups (p=0.636). The correlation between the RRI and the development of AKI was of moderate strength (r=0.57, p˂0.05). MAP, IAP, and APP were significantly very weakly correlated with RRI (r=0.34; r=0.41, r=0.392, respectively, p˂0.05). ROC analysis showed that RRI>0.71 r.u. is the threshold level for AKI with 87.2% sensitivity and 73.5% specificity, and it has a high predictive value (area under the curve AUC 0.868 (p<0.0001)).
 Conclusions. High RRI values are associated with AKI in geriatric patients after urgent abdominal surgery. RRI may be a bedside diagnostic tool for AKI, in contrast to renal SQP, which has shown no predictive value.

Sir George Johnson FRCP (1818-96), high blood pressure and the continuing altercation about its origins.

What is the topic of this review? The review takes a historical approach to examining where in the body it might be possible to identify the most common cause, or causes, of long-term hypertension. It gathers evidence from histology, human and animal physiology, and computational modelling. The burden of decades of controversy is noted. What advances does it highlight? The review highlights the distinctive pathology of the afferent renal circulation and what its consequences are for the widespread view that essential hypertension is caused by elevated peripheral vascular resistance. The widely promulgated notion that long-term elevation in mean arterial blood pressure (MAP) can be caused by raised peripheral vascular resistance remains a subject of vigorous debate. According to the 1967 mathematical model of Guyton and Coleman, such a causal relationship is impossible, kidney function being the determining factor. We explore this altercation starting with Sir George Johnson's 19th-century renal vascular histological observations in patients with Bright's disease. We note the striking physiological measurements in hypertensives by Gómez and Bolomey in the 1950s, moving on to the mathematical modelling of the circulation from the 1960s up to the ∼100-parameter computer models of the present day. Confusion has been generated by the fact that peripheral resistance is raised in hypertension in close proportion to MAP whilst cardiac output often stays normal, an apparent autoregulation, the mechanism of which is poorly understood. All models allowing for the circulation to be an open system show that isolated changes in peripheral resistance cannot lead to long-term hypertension, but models fail so frequently to account for results from experiments such as salt loading that their credibility with regard to this key finding is compromised. Laboratory animal models of adrenergic renal actions resonate with a contemporary emphasis on the sympathetic nerve supply to the kidney as contributing to the characteristically markedly elevated renal afferent resistance that appears to be the most common cause of hypertension. Remarkably, there remains no account of the way in which the fixed structural changes in vessels observed by Johnson relate to this sympathetic overactivity, which can itself be modified by drugs in the medium term. In this account, we seek to locate the crime scene and identify a smoking gun.

Experience in the use of physical factors during the recovery of the renal parenchyma after percutaneous nephroscopy

The article reflects the results of the use of physical factors to restore the renal parenchyma in the early postoperative period after percutaneous nephroscopy in patients with urolithiasis. Material and methods: the study included 80patients with concretions of the renal pelvis after percutaneous nephroscopy (45men and 35women, average age — 46 years), who were divided into 2 comparable groups: groupI (main group) — 40 patients who underwent intravenous laser blood irradiation (ILBI) and ozone therapy — 6 procedures in the preoperative period, and polarized light and ILBI — 6 procedures in the early postoperative period; groupII (control group), which served as a background in the main group, were prescribed non-steroidal anti-inflammatory drugs after the surgery, taking into account bacterial urine culture. Inclusion criteria: patients with urolithiasis aged 28 to 62 years; indications for percutaneous nephroscopy. Exclusion criteria: concomitant diseases; compliance; pregnancy; acute inflammatory kidney diseases; abnormalities of the upper urinary tract. Results: The combined use of ILBI, ozone therapy and polarized light in the pre- and early postoperative period in patients with urolithiasis after percutaneous nephrolithotripsy allowed improving clinical, laboratory, subjective and objective indicators, as well as shortening the recovery period of the renal parenchyma, which was confirmed by the data of ultrasound studies in the dynamics in the form of a significant reduction in the recovery period of the index of renal vessels resistance and reduction of edema of the renal parenchyma. As a result of the application of the developed complex, the total bed-day of patients’ stay in the hospital decreased, and there was a rapid recovery of capacity to work. Conclusion: The developed method of the combined use of ILBI, ozone therapy and polarized light in the pre- and early postoperative period in patients with urolithiasis after percutaneous nephrolithiasis is pathogenetically justified and highly effective, which allows us to recommend it for wide use in urological practice.

Artificial Intelligence Pulse Coupled Neural Network Algorithm in the Diagnosis and Treatment of Severe Sepsis Complicated with Acute Kidney Injury under Ultrasound Image.

The objective of this study was to explore the diagnosis of severe sepsis complicated with acute kidney injury (AKI) by ultrasonic image information based on the artificial intelligence pulse coupled neural network (PCNN) algorithm. In this study, an algorithm of ultrasonic image information enhancement based on the artificial intelligence PCNN was constructed and compared with the histogram equalization algorithm and linear transformation algorithm. After that, it was applied to the ultrasonic image diagnosis of 20 cases of severe sepsis combined with AKI in hospital. The condition of each patient was diagnosed by ultrasound image performance, change of renal resistance index (RRI), ultrasound score, and receiver operator characteristic curve (ROC) analysis. It was found that the histogram distribution of this algorithm was relatively uniform, and the information of each gray level was obviously retained and enhanced, which had the best effect in this algorithm; there was a marked individual difference in the values of RRI. Overall, the values of RRI showed a slight upward trend after admission to the intensive care unit (ICU). The RRI was taken as the dependent variable, time as the fixed-effect model, and patients as the random effect; the parameter value of time was between 0.012 and 0.015, p=0.000 < 0.05. Besides, there was no huge difference in the ultrasonic score among different time measurements (t = 1.348 and p=0.128 > 0.05). The area under the ROC curve of the RRI for the diagnosis of AKI at the 2nd day, 4th day, and 6th day was 0.758, 0.841, and 0.856, respectively, which was all greater than 0.5 (p < 0.05). In conclusion, the proposed algorithm in this study could significantly enhance the amount of information in ultrasound images. In addition, the change of RRI values measured by ultrasound images based on the artificial intelligence PCNN was associated with AKI.

Backpropagation Neural Network Algorithm-Based Color Doppler Ultrasound Detection of Gestational Diabetes Mellitus and Perinatal Outcomes

In this work, the related risk factors and perinatal outcomes of pregnant women with gestational diabetes mellitus (GDM) were analyzed based on color Doppler ultrasound (CDU) diagnosis. Backpropagation (BP) algorithm-based CDU imaging algorithm (BPC) was constructed in this study and applied in CDU images of 80 pregnant women with GDM. Besides, amplitude and phase estimation (APES) and low-complexity adaptive beam (LCA) algorithms were introduced for comparison with BPC in turn. It was found that Dice similarity coefficient (96.44%), sensitivity (95.45%), and specificity (91.56%) of BPC were greater than those of APES (83.97%, 85.84%, 78.45%) and LCA (84.74%, 86.29%, 82.35%), while its running time (6.44 ± 1.39 s) was shorter than that of APES (11.87 ± 2.41 s) and LCA (13.76 ± 1.54 s) ( P &lt; 0.05 ). Pregnant women in the experimental group (group B) were older than those in the control group (group A) ( P &lt; 0.05 ). The pulsatility index (PI) and renal artery resistance index (RI) of fetuses in group B (0.95 ± 0.15) were higher than those of group A (0.57 ± 0.24) ( P &lt; 0.05 ). In addition, pregnancy age, family history of hypertension, and abortion history were positively correlated with GDM ( P &lt; 0.05 ). In conclusion, BPC could not only improve diagnosis accuracy in fetuses’ CDU images but also shorten calculation time. Pregnancy age, family history of hypertension, and abortion history were the related risk factors for GDM in pregnant women.

Is There a Relationship Between the Severity of Preeclampsia and Fetal Renal Doppler Indices?

Objectives: Preeclampsia is a high prevalence complication in pregnancy and is responsible for 36% of maternal mortality worldwide. The offspring of mothers with preeclampsia face many problems after birth and in their lifetime. The fetal renal is one of the most vulnerable organs following maternal preeclampsia. In this regard, the present study investigated the relationship between the severity of preeclampsia and fetal renal artery resistance and pulsatility. Materials and Methods: In general, 91 pregnant women were included and divided into control and preeclampsia groups. The control group included 43 women with normal pregnancy and the preeclampsia group consisted of 48 pregnant women who suffered from preeclampsia and were classified into patients in severe and non-severe preeclampsia groups each containing 24 cases. Renal artery Doppler ultrasound was performed, and then the systole/diastole ratio (S/D), pulsatility index (PI), and resistance index (RI) were measured as well. Results: The S/D ratio, RI, and PI significantly decreased in the preeclampsia group (P&lt;0.001) compared to the control group. The S/D ratio in severe preeclampsia was significantly lower in comparison with non-severe preeclampsia (P&lt;0.001). Finally, the amniotic fluid index was related to the PI (P&lt;0.05), and severe preeclampsia significantly increased the pregnancy termination before 34 weeks (P&lt;0.001). Conclusions: Preeclampsia deceased the resistance of renal arteries by altering the fetal renal blood flow. These changes can intensify in patients with severe preeclampsia compared to non-severe preeclampsia.

Systematic Scoring of Tubular Injury Patterns Reveals Interplay between Distinct Tubular and Glomerular Lesions in ANCA-Associated Glomerulonephritis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Acute tubular injury with the presence of tubulitis was previously reported to be of prognostic value in ANCA glomerulonephritis (GN). In particular, distinct tubular injury lesions were associated with the deterioration of kidney function at AAV disease onset, as well as renal resistance to treatment, and higher risk of progression to composite outcome in patients with AAV. To expand our knowledge regarding distinct tubular lesions in AAV, we aimed to describe acute tubular injury patterns in association with glomerular lesions in ANCA GN by systematic histological scoring. Methods: A total number of 48 renal biopsies with confirmed renal involvement of AAV admitted to the University Medical Center Göttingen from 2015 to 2020 were retrospectively examined. By systematic scoring of tubular injury lesions, the association between clinical parameters, laboratory markers, and histopathological findings was explored. Results: We have shown that cellular casts in renal biopsies were frequently observed in the majority of cases with ANCA GN. Furthermore, we showed that tubular epithelial simplification with dilatation correlated with MPA and MPO subtypes, C3c hypocomplementemia, severe renal involvement, and uACR. Red blood cell (RBC) casts were associated with increased levels of C-reactive protein (CRP), leukocyturia, and hematuria. Finally, we found that hyaline casts were associated with an increased fraction of glomeruli with global glomerular sclerosis. Conclusions: Acute tubular injury patterns were correlated with active ANCA GN, whereas tubular injury lesions reflecting the later stages of kidney disease correlated with chronic glomerular lesions. These results suggest an interplay between different renal compartments.

The role of the renal resistance index in patients with heart failure with reduced or preserved ejection fraction

BackgroundRenal impairment is a common phenomenon that portends a poor prognosis of heart failure (HF). The renal arterial resistance index (RRI) can be useful for defining renal function and predicting outcomes in patients with HF. This study aimed to investigate the determining factors of the RRI in HF patients with preserved ejection fraction (HFpEF) and with reduced EF (HFrEF). MethodsThis retrospective study included 330 patients with HF. We investigated the determining factors for the RRI and the association between the RRI and 1-year composite outcome, comprising all-cause mortality and re-hospitalization for HF. ResultsThe independent predictors of the RRI were tricuspid regurgitation peak gradient and estimated glomerular filtration rate in HFpEF, and pulse pressure and blood urea nitrogen in HFrEF. During the follow-up, 30 (9.1%) patients presented the composite outcome. Cox proportional hazard analysis revealed the association of the RRI with the composite outcome in both HFrEF (HR 1.08; 95% CI 1.03–1.14) and HFpEF (HR 1.07; 95% CI 1.03–1.12) without an interaction (p for interaction = 0.770). ConclusionsThe RRI was a consistent prognosticator in patients with HFpEF and those with HFrEF, while factors defining RRI were different between these groups.

MO329THE GENETIC DELETION OF THE DUAL SPECIFICITY PHOSPHATASE 3 (DUSP3) ATTENUATES KIDNEY DAMAGE FOLLOWING ISCHEMIA/REPERFUSION INJURY IN MOUSE

Abstract Background and Aims Dual Specificity Phosphatase 3 (DUSP3) is a positive regulator of the innate immune response in case of sepsis, but its role in the ischemic damage is unknown. Here, we study (i) whether and where DUSP3 is expressed in the renal parenchyma, and (ii) whether its genetic deletion in Dusp3 systemic knock-out (Dusp3-/-) mice attenuates the I/R-associated inflammation and injury. Method Experiment 1: Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal ischemia for 30 minutes followed by a reperfusion of 48 hours. Blood and kidneys were collected. Renal function was assessed upon I/R biomarkers, i.e. blood urea nitrogen (BUN) and creatinine (SCr). Expressions of inflammatory and immune markers were comparatively quantified at both mRNA (real-time qPCR) and protein (immuno-blotting and –staining) levels in ischemic vs. non-ischemic kidneys in Dusp3 WT vs. KO mice. Experiment 2: Ten C57BL/6 male WT and Dusp3-/- mice were anesthetized. Renal Doppler ultrasound was performed to assess the renal resistivity index (RRI). The expression of CD31 and VEGF vascular markers was quantified by the means of real-time qPCR and and immuno-staining (FiJi software). Results Experiment 1: An immuno-reactive signal for DUSP3 was detected in the glomeruli (in co-localization with nephrin) and in Meca-32-positive endothelial cells of both outer and inner medulla of mouse non-ischemic WT kidneys. No significant immunoreactivity for DUSP3 was detected in Dusp3-/- kidneys. Following renal I/R, the mRNA level of Dusp3 was increased 1.8-fold compared to baseline (p&amp;lt;0.001). Immunoblot quantifications showed a 77-fold increased expression of DUSP3 post renal I/R. Serum levels of I/R biomarkers were significantly lower in Dusp3-/- compared to WT mice following renal I/R (BUN: 78.4±33.7 vs. 258.9±162.9mg/dL; SCr: 0.1±0.07 vs. 0.8±0.9 mg/dL; p&amp;lt;0.01). At mRNA levels, Dusp3-/- ischemic kidneys showed a significantly decreased expression level of CD11b, TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b-positive cells were significantly reduced in Dusp3-/- vs WT renal parenchyma post I/R. Experiment 2: The RRI non-invasively measured by ultrasound was lower in Dusp3-/- group compared to controls (0.56± 0.03 vs. 0.66±0.02; p&amp;lt;0.001). The Dusp3-/- non-ischemic kidneys were characterized by a 1.8-fold increased surface of CD31-positive cells compared to WT kidneys (p&amp;lt;0.001). At mRNA levels, the Dusp3-/- kidneys showed significantly increased basal levels of CD31 and VEGF compared to controls. Conclusion The genetic deletion of DUSP3 is associated with (i) increased renal vascular density, (ii) decreased RRI and (iii) nephroprotection against renal I/R injury.

FC 004PHOSPHATE FACILITATES PHOSPHATURIA BY PIT-2-MEDIATED ACTIVATION OF ERK1/2 SIGNALLING INTERNALIZING NAPI-2A FROM THE APICAL BRUSH BORDER MEMBRANE INDEPENDENT OF FGF23

Abstract Background and Aims Increased phosphate load stimulates the secretion of fibroblast growth factor (FGF) 23 in the bone leading to decreased phosphate reabsorption in the kidney. FGF23 activates FGFR1/Klotho/ERK1/2 signalling in proximal tubule cells to suppress type II sodium phosphate transporters NaPi-2a and NaPi-2c in the apical brush border membrane (BBM) resulting in lower serum phosphate levels. The type III sodium-dependent phosphate transporters PiT-1 and PiT-2 are expressed in key organs of phosphate regulation and were shown to activate ERK1/2 in osseous cells in the presence of high extracellular phosphate. Furthermore, PiT-2 was shown to be responsible for the phosphate-dependent FGF23 secretion in bone cells. Whether phosphate itself can be sensed by kidney cells and stimulate its own excretion remains unknown. The aim of our study was to examine the molecular mechanism regulating renal phosphate transport in the setting of chronic oral phosphate loading in mice and to analyse phosphate sensing as well as phosphaturic actions of phosphate itself independent of FGF23. Method First, eight-week-old male C57BL/6 wildtype mice were fed a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD). Mice were sacrificed after six months and blood and urine were collected to determine parameters of phosphate homeostasis. Kidneys were isolated to evaluate the HPD-induced regulation of phosphate transporters by qPCR, immunoblot and histological analyses. Second, murine proximal tubule (mPT) cells were stimulated with either phosphate or FGF23 in the presence or absence of Foscarnet, as an inhibitor of phosphate transporters, to verify the molecular mechanism of phosphate sensing. Results Although, HPD caused significantly elevated circulating levels of intact FGF23 which resulted in hyperphosphaturia, serum phosphate levels were still enhanced compared to NPD-fed mice. Renal Klotho protein expression was significantly reduced in HPD mice and histological staining demonstrated lower Klotho accumulation in proximal and distal tubule cells, while FGFR1 was not altered. The FGF23/Klotho/FGFR1 downstream pathway revealed neither a clear activation of the ERK1/2 signalling pathway nor induction of the transcription factor Egr-1 due to HPD. Nevertheless, NaPi-2a mRNA expression was significantly reduced in HPD-fed mice compared to NPD group and NaPi-2c was unchanged. The amount of NaPi-2a protein in isolated BBM vesicles of HPD-fed mice was lower compared to NPD and immunofluorescent staining confirmed the internalisation of NaPi-2a from the apical BBM. Among the type III sodium-dependent phosphate cotransporters, renal PiT-1 mRNA expression was not altered in HPD-fed mice, but PiT-2 was significantly increased compared to NPD group and immunofluorescent staining revealed an enhanced localization of PiT-2 on the basolateral membrane of proximal tubule cells. Stimulation of mPTs with phosphate or FGF23 increased the expression of PiT-2, induced the phosphorylation of ERK1/2 and decreased NaPi-2a in vitro. The pre-treatment with Foscarnet blunted the phosphate-mediated activation of ERK1/2 signalling pathway, but not the FGF23-induced effects, suggesting a direct phosphate transporter-regulating mechanism of high phosphate in renal proximal tubule cells. Conclusion A chronic high dietary intake of phosphate results in downregulation of renal Klotho causing hyperphosphatemia, suggesting in part a renal resistance of FGF23/Klotho signalling pathway. However, HPD-induced internalization NaPi-2a from the apical BBM pointing to an FGF23-independent mechanism regulating phosphate reabsorption. Our data indicate that in the settings of high phosphate-mediated renal resistance of FGF23, phosphate itself may stimulate its urinary secretion via PiT-2-mediated activation of ERK1/2 signalling pathway which results in NaPi-2a downregulation and hyperphosphaturia independent of FGF23.

Fenoldopam and renal hemodynamics in shiga toxin-related hemolytic uremic syndrome.

Fenoldopam, a vasodilating agent, may represent a potential therapeutic opportunity to increase renal perfusion in those conditions where renal hemodynamics are severely impaired by vascular sub-occlusion, as, indeed, is the case in thrombotic microangiopathies. The renal resistance index (RRI) was measured, on and off fenoldopam, in 27 children with STEC-HUS. A 12% decrease in RRI was observed on fenoldopam compared to off treatment without changes in the systemic hemodynamics and with no side effects. If confirmed in larger series, fenoldopam may become an important addition to supportive care to reduce ischemic damage in STEC-HUS and improve long-term outcomes.

The bone is the major source of high circulating intact fibroblast growth factor-23 in acute murine polymicrobial sepsis induced by cecum ligation puncture.

Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.

Role of renal Duplex ultrasonography in evaluation of hepatorenal syndrome

BackgroundHepatorenal syndrome is a potentially fatal complication of advanced liver disease. Markers for early diagnosis and identification of high-risk patients are lacking. Our aim was to evaluate the role of renal Duplex ultrasonography in the diagnosis and early prediction of hepatorenal syndrome. This study included 50 patients. Clinical assessment, liver function tests, hepatitis C virus antibody, kidney function tests, and abdominal and renal color Duplex ultrasound were done to all subjects.ResultsUnivariate regression analysis for hepatorenal syndrome showed a statistically significant positive correlation with the Model For End-Stage Liver Disease score (p-value <0.0001) and renal artery hilum resistivity index (p-value = 0.0017). Logistic multivariable regression analysis proved that the renal artery hilum resistivity index was an independent predictor of hepatorenal syndrome. Renal artery hilum resistivity index can be used as a predictor of hepatorenal syndrome with 100% sensitivity and 66.7% specificity with a cut-off value > 0.77.ConclusionThe renal resistive index could be a good predictor of hepatorenal syndrome.

Renal Resistance Trend During Hypothermic Machine Perfusion Correlates With Preimplantation Biopsy Score in Transplantation of Kidneys From Extended Criteria Donors

Graft quality from extended criteria donors (ECDs) is extremely wide, and a reliable evaluation parameter is required. So far, biopsy is widely used to evaluate ECD organs and to decide whether double (DKT) or single (SKT) kidney transplantation should be performed. The aim of this study is to compare renal resistance (RR) trend during hypothermic machine perfusion (HMP) with a preimplantation biopsy score. From December 2014 to April 2020, HMP has been systematically applied to all organs from ECDs for at least 3 hours. All grafts underwent a preimplantation biopsy histologic assessment with Karpinski's score. SKTs or DKTs were performed accordingly. RR trend during the first 180 minutes of HMP was compared with the biopsy score. Eighty-three kidneys were used to perform 57 transplantations (31 SKTs and 26 DKTs). A biopsy confirmed suitability for transplantation in all cases, and the median score was 4 (range, 2-7). Kidneys with a score of 5 to 7 had significantly higher RR value than kidneys with a score of 0 to 4 at basal time (3.35 vs 2.71; P=.074), at 60 minutes (1.24 vs 0.94; P=.031), at 120 minutes (1.10 vs 0.81; P=.010), and at 180 minutes (1.00 vs 0.77; P=.022). A cutoff value of RR ≥0.88 at 120 minutes of perfusion had the best sensibility and specificity (0.71 and 0.75, respectively) to discriminate kidneys with a score of 5 to 7 from kidneys with a score of 0 to 4. No differences were found in postoperative outcomes between SKT and DKT recipients. RR trend during HMP correlates with the histologic score in ECD kidneys and can be used as a reliable parameter to evaluate graft quality.

Hypercalcemia in an Infant With Pseudohypoaldosteronism Type 1

Background: Pseudohypoaldosteronism type 1 (PHA1) is an aldosterone resistance syndrome due to insensitivity of target tissues to aldosterone action, with supraphysiologic aldosterone and renin levels. PHA1 presents usually in infancy and is divided into autosomal dominant (AD) and autosomal recessive (AR) form. A secondary form of PHA1 associated with UTI and/or renal malformations was described. In AD PHA1, salt loss is due to renal mineralocorticoid resistance while hyponatremia in AR PHA1 is caused by multi-organ salt loss. PHA1 has variable signs/symptoms associated with hyponatremia and hyperkalemia; thus, this clinical picture can be attributed to more common conditions such as dehydration, poor feeding, congenital adrenal hyperplasia. Clinical Case: A 5-month old male was admitted for airway evaluation. He was a 23-week gestation preemie, with chronic lung disease, failure to thrive. Patient was found to have hyponatremia, hyperkalemia, high FeNa of 1.3% (intrinsic renal disease) and elevated BUN/Cr (92/1.15). Renal US found echogenic kidneys with poor cortical medullary differentiation suggesting renal disease. Further evaluation noted high aldosterone (1700 ng/dL) and renin (400 ng/mL/hr) levels. He was placed on low protein formula to help optimize BUN level. Baby was diagnosed with secondary PHA1 due to renal disease and started on NaCl supplementation. This led to normalization of BUN, creatinine and improvement in electrolytes. Patient also had high serum calcium ranging from 11.1 to 12.0 mg/dL. Hyponatremia, hyperkalemia, hypercalcemia could be attributed to possible CAH, however state screen and ACTH stimulation test were normal. Further workup showed high 25-OH-vitamin D > 99 ng/mL, PTH 46.9 pg/mL, phosphorous 5.4 mg/dL and 1,25-OH-vitamin D 63.1 pg/mL. Urine Ca/cr ratio was 0.522. Vitamin D supplementation was stopped and daily total fluids increased. Subsequently, there was improvement in serum Ca at 10.9 mg/dL and 25-OH Vitamin D of 74 pg/mL. Next Generation Sequencing (NGS) was carried out, with a focus on the etiology of persisting hypercalcemia, including familial forms of hypercalcemia and Williams Syndrome. NGS revealed a likely pathogenic variant, c.2365 + 2T>C (p.?), in NR3C2, consistent with a diagnosis of AD PHA 1. Conclusion: This is a case of AD PHA1, marked by renal mineralocorticoid receptor resistance associated with persisting hypercalcemia. Initial hypercalcemia could be explained by hypervitaminosis D. It is important to note that electrolyte abnormalities, including persistent hypercalcemia, could be also secondary to the kidney disease found on renal US. There are only few reports of hypercalcemia in patients with PHA1 in the literature. In children with electrolyte abnormalities and failure to thrive, monitoring of serum and urine electrolytes would facilitate early accurate diagnosis and timely treatment.

Sporadic Pseudohypoparathyroidism 1B in Monozygotic Twins: Insights Into the Pathogenesis of Methylation Defects

Background: Pseudohypoparathyroidism (PHP) 1B is an imprinting disorder characterized by renal resistance to parathyroid hormone (PTH) without Albright Hereditary Osteodystrophy (AHO). PHP1B is associated with methylation defects at the GNAS differentially methylated regions (DMRs). In sporadic cases with PHP1B, the mechanistic basis of methylation defects remains to be solved, except in rare cases with uniparental disomy of chromosome 20. In addition, to date, monozygotic twin cases with sporadic PHP1B have not been reported. Clinical Case: The patients were 26-year-old Japanese female monozygotic twins. They had been born to nonconsanguineous parents after an uneventful pregnancy. Both twins had common biochemical features, including hypocalcemia, hyperphosphatemia, elevated PTH levels, and impaired urinary excretion of phosphorus and cAMP in response to teriparatide. They showed no signs of AHO. The serum calcium levels of their parents and brother were within the normal range, and family history was unremarkable. Based on these findings, the twins were diagnosed with PHP1B. Targeted bisulfite sequencing of the GNAS DMRs in all family members revealed almost complete gain-of-methylation at the NESP55 DMR, and loss-of-methylation at the AS, XL, and A/B DMRs in the twins, but not in other family members. Except for the GNAS locus, we did not find clear methylation defects in other imprinted genome loci in the twins. Methylation defects at the GNAS locus were further confirmed by methylation-sensitive restriction enzyme-qPCR. Whole-genome sequencing of the twins showed no pathogenic variants in the GNAS exons encoding the Gs alpha subunit. No large deletions or insertions were found at the STX16 locus or in the region from AS exon 5 to XL. Based on the SNP genotyping results, large paternal isodisomies in the GNAS DMRs were unlikely. Collectively, these results suggested that the twins had concordant methylation defects that are seen in the sporadic form of PHP1b. We speculate that an early developmental event before the twin splitting is responsible for the abnormal methylation of the GNAS DMRs. Conclusion: We report, for the first time, monozygotic twins with sporadic PHP1B who were phenotypically and epigenetically concordant. Our comprehensive molecular genetic analyses have thus far ruled out the previously described genetic defects underlying PHP1B. The current findings provide new insights into the mechanistic basis of the GNAS methylation defects in sporadic PHP1B.

Possible Protective Effect of Endothelin-1 Receptor Antagonist on Renal Impairment in Type 2 Diabetic Rats

Background: Diabetic nephropathy (DN) is characterized by persistent albuminuria and progressive decline in glomerular filtration rate (GFR). Bosentan is a non-peptide mixed antagonist of ET-1. Aim: To investigate the possible protective role of bosentan on renal impairment in T2DM rats and the mechanisms concerned. Materials: Fifty rats were randomly divided into five equal groups; Non-Diabetic (ND), Diabetic non-treated (DN), Diabetic Bosentan-treated (D-Bos.), Diabetic Metformin-treated (D-Met.), Diabetic combined Bosentan and Metformin-treated groups (D-Bos& Met.). T2DM was induced by Streptozotocin (STZ) (35mg/kg) and high fat diet (HFD) for 3 weeks. Both Bosentan and metformin were given orally for 4 weeks. At the end of the experiment, 24hrs urine samples were collected to measure urine (volume, albumin, NAG and creatinine), renal blood flow velocity (RBFV) and peripheral renal resistance (RVR) were measured using Doppler technique. Blood was collected directly from abdominal aorta to estimate fasting serum glucose, glycosylated hemoglobin (HBA1c), serum insulin, complete lipid profile, renal function tests and parameters of oxidative stress: malondialdehyde (MDA), total antioxidant capacity (TAC) and tumor necrosis factor-α (TNFα). Insulin resistance, serum LDL-cholesterol, urinary albumin creatinine ratio (UACR) and creatinine clearance (CC) were calculated. Results: Serum cysteine c, BUN, urinary albumin and UACR were significantly lowered in both D-Bos. & D-Met when compared to the corresponding values in DN while urinary volume, urinary creatinine, CC and RBFV were significantly elevated but serum creatinine, NAG & RVR were significantly lowered in D-Bos. only. Conclusion: Bosentan and metformin treatment both have a renoprotective effect. Combined treatment showed better results.

HIGH RENAL RESISTANCE INDICES AND HIGH PULSE PRESSURE MAY LIMIT NEPHROPROTECTIVE EFFICACY OF RENAL DENERVATION IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS

Objective: The combination of diabetes mellitus (DM) and resistant hypertension (RHTN) is associated with an increased risk of development and progression of chronic kidney disease (CKD). It has been shown that renal denervation have nephroprotective efficacy by slowing the decline in renal function in some patients. The aim of the study was to identify factors limiting the nephroprotective effect of renal denervation in patients with RHTN and DM. Design and method: Twenty seven patients with RHTN and type 2 DM were included in single-arm prospective interventional study (protocol number NCT01499810 on ClinicalTrial.gov) (mean age 61.6 ± 7.3 years, mean office (systolic/diastolic) blood pressure (BP) 171.8 ± 21.9/87.7 ± 17.7mmHg, mean eGFR 72.1 ± 19.9 ml/min/1.73 m2, HbA1c 6.3 ± 1.1%, 7 patients (26%) with stage 3 CKD, 8 men). All patients were underwent to ambulatory 24-hour BP, renal Doppler ultrasound and assessment of eGFR (CKD-EPI formula) at baseline and 3 years follow-up. The patients were advised not to change their medication regimen during the study. Nineteen patients completed 3 years of follow-up. The renal outcomes were 1) a decrease in eGFR = &gt; 30% from baseline; 2) decrease in eGFR &gt; 5 ml/min/1.73 m2/year; 3) their combination. Results: There was a significant decrease in mean 24-hour BP (SBP/DBP) (-14.3 ± 20.6 / -7.7 ± 10.6 mmHg, P = 0.02 /0.04). Six patients (32%) had renal outcomes at 3 years follow-up (5 pts (26%) with both outcomes, 5 patients (26%) had a decrease in eGFR = &gt; 30% from baseline and 5 patients had a decrease in eGFR &gt; 5 mL/min/1.73 m2/year). At baseline, patients with renal outcomes compared with patients without them had higher values of both 24-hour pulse BP (90.3 ± 7.1 vs 73.1 ± 12.5 mmHg, p = 0.007) and its variability (15.6 ± 2.6 versus 11.7 ± 3.0 mmHg, p = 0.01), as well as a higher mean value of renal resistive indices (RI) (RI in the trunk 0.79 ± 0.04 vs0.71 ± 0.06, p = 0.007; RI in segmental arteries 0.75 ± 0.08 vs 0.66 ± 0.08, p = 0.04). Conclusions: Our data indicate that a high value of pulse blood pressure and its variability, as well as high indices of renal resistance, can limit the nephroprotective efficacy of renal denervation, possibly due to chronic intrarenal barotrauma and irreversible changes in the kidneys.

Mesenchymal stromal cell treatment of donor kidneys during ex vivo normothermic machine perfusion: A porcine renal autotransplantation study.

Normothermic machine perfusion (NMP) of injured kidneys offers the opportunity for interventions to metabolically active organs prior to transplantation. Mesenchymal stromal cells (MSCs) can exert regenerative and anti-inflammatory effects in ischemia-reperfusion injury. The aims of this study were to evaluate the safety and feasibility of MSC treatment of kidneys during NMP using a porcine autotransplantation model, and examine potential MSC treatment-associated kidney improvements up to 14days posttransplant. After 75min of kidney warm ischemia, four experimental groups of n=7 underwent 14h of oxygenated hypothermic machine perfusion. In three groups this was followed by 240min of NMP with infusion of vehicle, 10million porcine, or 10million human adipose-derived MSCs. All kidneys were autotransplanted after contralateral nephrectomy. MSC treatment did not affect perfusion hemodynamics during NMP or cause adverse effects at reperfusion, with 100% animal survival. MSCs did not affect plasma creatinine, glomerular filtration rate, neutrophil gelatinase-associated lipocalin concentrations or kidney damage assessed by histology during the 14days, and MSCs retention was demonstrated in renal cortex. Infusing MSCs during ex vivo NMP of porcine kidneys was safe and feasible. Within the short posttransplant follow-up period, no beneficial effects of ex vivo MSC therapy could be demonstrated.