Aim
Activation of sodium reabsorption by urinary proteases has been implicated in sodium retention associated with nephrotic syndrome. The study was designed to test the hypothesis that nephrotic ...proteinuria in mice after conditional deletion of podocin leads to urokinase‐dependent, amiloride‐sensitive plasmin‐mediated sodium and water retention.
Methods
Ten days after podocin knockout, urine and faeces were collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity and ability to activate γENaC by patch clamp and western blot. Mice were treated with amiloride (2.5 mg kg−1 for 2 days and 10 mg kg−1 for 2 days) or an anti‐urokinase‐type plasminogen activator (uPA) targeting antibody (120 mg kg−1/24 h) and compared to controls.
Results
Twelve days after deletion, podocin‐deficient mice developed significant protein and albuminuria associated with increased body wt, ascites, sodium accumulation and suppressed plasma renin. This was associated with increased urinary excretion of plasmin and plasminogen that correlated with albumin excretion, urine protease activity co‐migrating with active plasmin, and the ability of urine to induce an amiloride‐sensitive inward current in M1 cells in vitro. Amiloride treatment in podocin‐deficient mice resulted in weight loss, increased sodium excretion, normalization of sodium balance and prevention of the activation of plasminogen to plasmin in urine in a reversible way. Administration of uPA targeting antibody abolished urine activation of plasminogen, attenuated sodium accumulation and prevented cleavage of γENaC.
Conclusions
Nephrotic range glomerular proteinuria leads to urokinase‐dependent intratubular plasminogen activation and γENaC cleavage which contribute to sodium accumulation.
IntroductionChronic kidney disease (CKD) is associated with significantly increased morbidity and mortality. No specific treatment of the underlying condition is available for the majority of ...patients, but ACE-inhibitors (ACE-I) and angiotensin II-receptor blockers (ARB) slows progression in albuminuric CKD. Adding a mineralocorticoid receptor-antagonist (MRA) like spironolactone has an additive effect. However, renin–angiotensin–aldosterone system (RAAS)-blockade increases the risk of hyperkalaemia which is exacerbated by the presence of CKD. Thus, hyperkalaemia may prevent optimal use of RAAS-blockade in some patients.This project hypothesises that adding a potassium binder (patiromer) allows for improved RAAS-blockade including the use of MRA, thereby reducing albuminuria in patients with albuminuric CKD where full treatment is limited by hyperkalaemia.If successful, the study may lead to improved treatment of this subgroup of patients with CKD. Furthermore, the study will examine the feasibility of potassium binders in patients with CKD.Methods and analysisAn open-label, randomised controlled trial including 140 patients with estimated glomerular filtration rate (eGFR) 25–60 mL/min/1.73 m2, a urinary albumin/creatinine ratio (UACR) >500 mg/g (or 200 mg/g if diabetes mellitus) and a current or two previous plasma-potassium >4.5 mmol/L. Patients who develop hyperkaliaemia >5.5 mmol/L during a run-in phase, in which RAAS-blockade is intesified with the possible addition of spironolactone, are randomised to 12-month treatment with maximal tolerated ACE-I/ARB and spironolactone with or without patiromer.The primary endpoint is the difference in UACR measured at randomisation and 12 months compared between the two groups. Secondary endpoints include CKD progression, episodes of hyperkalaemia, blood pressure, eGFR, markers of cardiovascular disease, diet and quality of life.Ethics and disseminationThis study is approved by The Central Denmark Region Committees on Health Research Ethics (REFNO 1-10-72-110-20) and is registered in the EudraCT database (REFNO 2020-001595-15). Results will be presented in peer-reviewed journals, at meetings and at international conferences.
Megalin in acute kidney injury: foe and friend Mahadevappa, Ravikiran; Nielsen, Rikke; Christensen, Erik Ilsø ...
American journal of physiology. Renal physiology,
01/2014, Letnik:
306, Številka:
2
Journal Article
Recenzirano
The kidney proximal tubule is a key target in many forms of acute kidney injury (AKI). The multiligand receptor megalin is responsible for the normal proximal tubule uptake of filtered molecules, ...including nephrotoxins, cytokines, and markers of AKI. By mediating the uptake of nephrotoxins, megalin plays an essential role in the development of some types of AKI. However, megalin also mediates the tubular uptake of molecules implicated in the protection against AKI, and changes in megalin expression have been demonstrated in AKI in animal models. Thus, modulation of megalin expression in response to AKI may be an important part of the tubule cell adaption to cellular protection and regeneration and should be further investigated as a potential target of intervention. This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of AKI as well as renal protection against AKI.
Cubilin is a large endocytic receptor serving such diverse functions as the intestinal absorption of the intrinsic factor-B(12) complex and the renal proximal tubule reabsorption of filtered proteins ...including albumin, transferrin, vitamin D-binding protein and other important plasma carriers. Cubilin is a structurally unique, peripheral membrane protein, which depends on the membrane protein amnionless (AMN) for correct apical translocation. In addition, AMN appears important for efficient internalization of intrinsic factor-B(12) in the intestine, whereas in the proximal tubule cubilin interacts with another endocytic receptor, megalin, for effective reabsorption. The importance of cubilin has been demonstrated in several animal models of cubilin deficiency as well as in a variety of human diseases. Recent demonstration of cubilin in podocytes from various species awaits further clarification with respect to the functional role as well as its role in pathology.
Screening for cardiovascular disease is currently recommended before kidney transplantation. The present study aimed to validate the proposed algorithm by the American Heart Association (AHA-2022) ...considering cardiovascular findings and outcomes in kidney transplant candidates, and to compare AHA-2022 with the previous recommendation (AHA-2012).
We applied the 2 screening algorithms to an observational cohort of kidney transplant candidates (n=529) who were already extensively screened for coronary heart disease by referral to cardiac computed tomography between 2014 and 2019. The cohort was divided into 3 groups as per the AHA-2022 algorithm, or into 2 groups as per AHA-2012. Outcomes were degree of coronary heart disease, revascularization rate following screening, major adverse cardiovascular events, and all-cause death. Using the AHA-2022 algorithm, 69 (13%) patients were recommended for cardiology referral, 315 (60%) for cardiac screening, and 145 (27%) no further screening. More patients were recommended cardiology referral or screening compared with the AHA-2012 (73% versus 53%;
<0.0001). Patients recommended cardiology referral or cardiac screening had a higher risk of major adverse cardiovascular events (hazard ratio HR, 5.5 95% CI, 2.8-10.8; and HR, 2.1 95% CI, 1.2-3.9) and all-cause death (HR, 12.0 95% CI, 4.6-31.4; and HR, 5.3 95% CI, 2.1-13.3) compared with patients recommended no further screening, and were more often revascularized following initial screening (20% versus 7% versus 0.7%;
<0.001).
The AHA-2022 algorithm allocates more patients for cardiac referral and screening compared with AHA-2012. Furthermore, the AHA-2022 algorithm effectively discriminates between kidney transplant candidates at high, intermediate, and low risk with respect to major adverse cardiovascular events and all-cause death.
Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and ...possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR.
Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation.
Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (p<0.001, r2adj. = 0.16; p<0.001, r2adj. = 0.25), as well as with mGFR at twelve months (p<0.001, r2adj. = 0.20; p<0.001, r2adj. = 0.16). However, plasma levels of free thiols at 30 minutes and 90 minutes, but not Day 1, were significantly higher among patients experiencing DGF.
Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors.
ClinicalTrials.gov Identifier: NCT01395719.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Systemically administered glucocorticoids constitute an essential part of the immunosuppressive regimen for transplant recipients, yet their known risks of causing hyperglycemia or posttransplant ...diabetes require close monitoring and minimisation of use, when possible, to prevent detrimental effects on patient morbidity and graft survival. Topical glucocorticoids, on the other hand, are rarely considered to affect glucose metabolism and therefore seldomly monitored, despite their wide and in some cases, long-term use. We report a case of a renal transplant recipient presenting with acute hyperosmolar hyperglycemia after treatment with topical glucocorticoids and present a mini review of the literature.
Acute interstitial nephritis (AIN) is an important and common cause of acute renal failure. There are no generally accepted guidelines for the treatment of AIN, due to the lack of prospective ...randomized trials. Since AIN is characterized by an enhanced immune response, immunosuppressive treatment could potentially improve prognosis by attenuating inflammation and subsequent fibrosis. Despite the limited evidence of effects of steroids and potential adverse effects, prednisolone is frequently used in the treatment of AIN and there is a strong need for clinical trials on the effects of immunosuppression, including steroids, in the treatment of AIN. We aimed to evaluate the effectiveness of prednisolone treatment in AIN, and hypothesized a positive effect of prednisolone treatment on renal function in AIN.
The study is a randomized, controlled, prospective, open label multicenter study, including incident adult patients with biopsy proven AIN. Patients will be randomized 1:1 to one of 2 treatment regimens: A. No prednisolone treatment (control group) and B. B) Oral prednisolone treatment staring with 60 mg daily tapered over 8 weeks. One hundred ten patients (55 in each group) are planned to be included and followed for 1 year. Primary outcome is renal function estimated by eGFR 3 months after inclusion. Secondary outcomes are renal function after 12 months and need for renal replacement therapy and quality of life after 3 and 12 months. In addition, with-in prednisolone group analysis are performed to estimate the importance of treatment delay. Exploratory analyses include analysis of biomarkers in urine and plasma and the evaluation of these biomarkers in relation to renal prognosis and re-evaluation of renal biopsies to identify possible renal prognostic factors.
Strengths and possible limitations in the design are evaluated. The study will provide important information on the effects of prednisolone treatment in AIN and as well as prognostic information relevant for future use of biomarkers and histology. Ultimately, this would lead to improved and evidence based clinical guidelines for the treatment of AIN.
ClinicalTrials.gov identifier NCT04376216 (Retrospectively registered on May 6, 2020).
While unilateral nephrectomy (UNx) is suggested to protect against ischemia-reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In ...this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia. MRI was performed 24 hours after reperfusion. Blood and renal tissue were harvested. RNA was isolated for microarray analysis and QPCR validation of gene expression results. The perfusion (T1 value) was significantly enhanced in the medulla of the post-ischemic kidney following UNx. UNx decreased the expression of fibrogenic genes, i.a. Col1a1, Fn1 and Tgfb1 in the post-ischemic kidney. This was associated with a marked decrease in markers of activated myofibroblasts (Acta2/α-Sma and Cdh11) and macrophages (Ccr2). This was most likely facilitated by down-regulation of Pdgfra, thus inhibiting pericyte-myofibroblast differentiation, chemokine production (Ccl2/Mcp1) and macrophage infiltration. UNx reduced ischemic histopathologic injury. UNx may exert renoprotective effects against IRI through increased perfusion in the renal medulla and alleviation of the acute pro-inflammatory and pro-fibrotic responses possibly through decreased myofibroblast activation. The identified pathways involved may serve as potential therapeutic targets and should be taken into account in experimental models of IRI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Survival after Wilms tumor has significantly increased and focus on late effects has become increasingly important. However, knowledge about long‐term renal function in survivors of Wilms ...tumor is missing. Our aim was to investigate evidence of kidney disease in 20‐ or more‐year survivors of Wilms tumor in a clinical setting, with siblings as comparisons.
Methods
In this cross‐sectional study, we established a cohort of Danish 20‐plus‐year survivors of Wilms tumor and siblings as controls. Participants answered a comprehensive health questionnaire supplemented by measurements of estimated glomerular filtration rate (eGFR), urine albumin‐to‐creatinine ratio, and blood pressure and were categorized according to the chronic kidney disease classification. Multiple linear regression analysis, taking family membership into account, was used to describe the differences in eGFR. Logistic regression analysis was performed to describe risk factors for the development of kidney disease.
Results
We included 99 survivors of Wilms tumor and 38 sibling controls with a median of 37 years of follow‐up. The eGFR of Wilms tumor survivors was 13 ml/min/1.73 m2 (95% CI –20; −5) lower when compared to sibling control. Evidence of kidney disease, with risk factors as hypertension and diabetes, was found in 19% of the Wilms tumor survivors and 2% developed end‐stage renal disease. Ninety‐two percent of the Wilms tumor survivors had an eGFR >60 ml/min/1.732.
Conclusion
Long‐term Wilms tumor survivors have on average a significantly decreased renal function along with the increased prevalence of kidney disease and end‐stage renal disease when compared to sibling controls. Still, most survivors had kidney function within the normal range.
Long‐term Wilms tumor survivors have on average a significantly decreased renal function along with increased prevalence of kidney disease and end stage renal disease when compared to sibling controls. Still, most survivors had kidney function within normal range.
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