UK Kidney association clinical practice guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease 2023 UPDATE

Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full “lay” summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals

Podocyte markers as an early diagnostic tool of diabetic nephropathy

Background: Diabetes mellitus (DM) is a chronic illness characterized by impairedmetabolism of carbohydrates, fat and protein secondary to a deficiency in secretionand/or action of insulin. Diabetic kidney disease (DKD) is a major complication of DM and many of these patients develop end-stage renal disease. Albuminuria has traditionallybeen used for the diagnosis and classification of DKD. Podocyte injury plays a crucial role in the pathogenesis and progression of DKD. Therefore, we investigated whether patients with DM and normoalbuminuria present podocyte markers in urine suggestive of early podocyte injury.Methods: We studied 80 patients with type 2 DM who were examined at the DiabetesClinic of the University Hospital of Heraklion, Crete, from January to June 2011.Exclusion criteria were (1) history of renal disease, (2) history of micro ormacroalbuminuria, (3) presence of urinary infection, (4) known duration of DM <1year and (5) use of nephrotoxic medication. We also studied 50 non-diabeticcontrols. All the subjects were categorized according to their urinary podocyte marker profile into 2 groups, those with only synaptopodin mRNA presence (synaptopodin only group) and those with nephrin and/or podocin mRNA presence in addition to synaptopodin in their urine (nephrin and/or podocin group).Results: Nine diabetic patients and 11 controls had increased urinary albumin excretion (UAE) on enrolment and, therefore, were not included in analysis. Among 71 normoalbuminuric patients with type 2 DM and 39 non-diabetic controls, synaptopodin mRNA was detected in the urine of all the diabetics and controls. The presence of nephrin and/or podocin mRNA in urine was more frequent among DM patients compared to controls (53.5 vs. 30.8%, respectively; p = 0.022). Binary logistic regression analysis revealed that the only significant predictor of the presence of nephrin and/or podocin mRNA in urine was the presence of DM (OR 2.59, 95% CI 1.14–5.91, p = 0.024, adjusted for all risk factors). A strong correlation between nephrin and podocin urinary mRNA levels was noted (r = +0.796, p < 0.001).Conclusion: Overall, this study demonstrated the presence of podocyte markers in the urine of normoalbuminuric diabetic patients. Nephrin and podocin mRNA is more prevalent in diabetic patients with normal UAE compared to controls, and this may reflect early podocyte injury. DM was the only significant determinant of their presence in urine of this population. Synaptopodin mRNA was uniformly detected in all the subjects independent of their DM status and, thus, synaptopodin is unsuitable for the diagnosis of podocyte injury. Therefore, it appears of particular importance to prospectively evaluate normoalbuminuric diabetic patients with urinary nephrin and/or podocin mRNA and identify a potential increased risk of DKD and if early treatment, for example, with angiotensin-converting enzyme inhibitors may retard the development of renal injury.Εισαγωγή: Ο σακχαρώδης διαβήτης είναι μια μεταβολική νόσος που χαρακτηρίζεται από χρόνια υπεργλυκαιμία και διαταραχή του μεταβολισμού υδατανθράκων, λίπους και πρωτεΐνης ως αποτέλεσμα ανεπαρκούς έκκρισης ή/και δράσης ινσουλίνης (1).Η διαβητική νεφρική νόσος (ΔΝΝ) είναι μια από τις σημαντικότερες επιπλοκές του ΣΔ. Ο ΣΔ είναι η κύρια αιτία της χρόνιας νεφρικής νόσου (ΧΝΝ) ενώ σημαντικό ποσοστό των ασθενών θα αναπτύξει τελικού σταδίου νεφρική νόσο. Η αυξημένη απέκκριση πρωτεΐνης και συγκεκριμένα λευκωματίνης στα ούρα (λευκωματινουρία) έχει αποτελέσει τον ακρογωνιαίο λίθο στη διάγνωση και παρακολούθηση της ΔΝΝ. Ωστόσο, η λευκωματινουρία έχει σοβαρούς περιορισμούς ως διαγνωστικός δείκτης της ΔΝΝ σε πρώιμο στάδιο όπου τυχόν θεραπευτικές παρεμβάσεις θα μπορούσαν να αναστρέψουν μέρος της νεφρικής βλάβης. Μέθοδοι:Μελετήσαμε 80 ασθενείς με ΣΔ τύπου 2 από το Μεταβολικό εξωτερικό ιατρείο του Πανεπιστημιακού Γενικού Νοσοκομείου Ηρακλείου. Κριτήρια αποκλεισμού αποτέλεσαν i) η παρουσία χρόνιας νεφρικής νόσου, ii) ιστορικό λευκωματινουρίας, iii) ενεργός λοίμωξη του ουροποιητικού, iv) λήψη νεφροτοξικών φαρμάκων και iv) η πρόσφατη έναρξη ΣΔ (<1 έτος). Η υπέρταση, η καρδιαγγειακή νόσος και υπερλιπιδαιμία δεν απετέλεσαν κριτήρια αποκλεισμού. Η ομάδα ελέγχου αποτελούνταν από 50 μη διαβητικά άτομα με αντίστοιχα κριτήρια αποκλεισμού. Πραγματοποιήθηκαν μετρήσεις ανθρωπομετρικές, βιοχημικές, ενώ ποσοτικοποιήθηκαν τα επίπεδα mRNA τριών ποδοκυτταρικών μορίων στα ούρα με real-time PCR. Αποτελέσματα:Εννέα διαβητικοί ασθενείς και 11 μάρτυρες φάνηκε είχαν αυξημένα επίπεδα λευκωματινουρίας και δε συμπεριλήφθηκαν στην τελική ανάλυση. mRNA συναπτοποδίνης ανιχνεύθηκε στα ούρα όλων των διαβητικών και μαρτύρωνΤα επίπεδα mRNA νεφρίνης ήταν υψηλότερα στα άτομα με ΣΔ από ότι στην ομάδα ελέγχου (p = 0.035). Το ίδιο ίσχυε και για την ποδοσίνη όμως η σχέση ήταν μόνο οριακά σημαντική (p = 0.058). Τα επίπεδα mRNA συναπτοποδίνης δε διέφεραν μεταξύ ασθενών και μαρτύρων. Η ανίχνευση mRNA νεφρίνης και/ή ποδοσίνης στα ούρα φάνηκε να είναι συχνότερη στην ομάδα των διαβητικών σε σχέση με την ομάδα ελέγχου (53.5 vs. 30.8%, αντίστοιχα, p = 0.022). Από τη δυαδική λογιστική ανάλυση παλινδρόμησης προέκυψε ότι η παρουσία του ΣΔ ήταν ο μόνος σημαντικός προβλεπτικός παράγοντας της παρουσίας νεφρίνης και / ή ποδοσίνης στα ούρα με τους διαβητικούς να έχουν 2.6 φορές μεγαλύτερη πιθανότητα να παρουσιάζουν mRNA νεφρίνης και/ή ποδοσίνης στα ούρα.Συμπεράσματα:Οι ασθενείς με ΣΔ και νορμολευκωματινουρία εμφανίζουν συχνότερα mRNA νεφρίνης και ποδοσίνης στα ούρα σε σχέση με τους μη διαβητικούς και πιθανά αυτό να οφείλεται σε πρώιμη ποδοκυτταρική βλάβη. Η παρουσία mRNA συναποτοποδίνης ήταν ομοιογενής στον πληθυσμό και δεν μπορεί να χρησιμοποιηθεί ως ειδικός δείκτης. Η προοπτική παρακολούθηση αυτών των ασθενών είναι σημαντική ώστε να προσδιοριστεί η προγνωστική σημασία των ευρημάτων ως προς την ανάπτυξη ΔΝΝ και ο ρόλος πρώιμων φαρμακευτικών παρεμβάσεων

The Impact of Antiplatelet Treatment on Endothelial Function

The vascular endothelium comprises a continuous single cell layer of endothelial cells which line the entire cardiovascular system. Impaired endothelial function underlies the pathogenesis and contributes to the progression of atherosclerosis. Oxidative stress, vasoconstriction, inflammation, proliferation and thrombosis occur in dysfunctional endothelium while the latter, is primarily mediated by platelet activation and adherence to vascular wall. Despite the primary action of antiplatelet agents including aspirin, P2Y12 ADP receptor antagonists and glycoprotein IIb/IIIa inhibitors, a growing body of literature suggests that an important mechanism of their action involves complex modulation of endothelial function via platelet-endothelial interactions, modification of the inflammatory cytokine cascade and nitric oxide mediated effects. These agents represent the mainstay in pharmacological treatment of all aspects of cardiovascular disease both in primary and secondary prevention. However beyond these properties, it is important to note that pharmacological modification of endothelial dysfunction has been postulated as a therapeutic target for reduction of cardiovascular events

Subclinical Organ Damage in White-Coat Hypertension: The Possible Role of Cystatin C

The authors investigated the relationship of white-coat hypertension (WCH) with subclinical organ damage and potential relevant mechanisms. A total of 386 untreated patients were enrolled and divided into 204 patients with WCH and 183 with normotension. Flow-mediated dilation (FMD), pulse wave velocity (PWV), intima-media thickness, left ventricular mass index (LVMI), and cystatin C levels were measured. All tests were two-sided, and a P value &lt;.05 was considered statistically significant. The WCH group exhibited higher LVMI and PWV values, decreased E/A ratio and FMD values, and increased prevalence for left ventricular hypertrophy compared with controls (P&lt;.001 for all). Cystatin C was significantly higher in the WCH group compared with controls (P=.035) and was positively associated with LVMI (P&lt;.05 for both). The presence of WCH is associated with more pronounced subclinical organ damage compared with normotension. Cystatin C may play a significant role and therefore warrants further investigation

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical manifestations in a Large Kindred

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Cardiorenal Syndrome: Challenges in Everyday Clinical Practice and Key Points towards a Better Management

Under the term cardiorenal syndrome (CRS) falls an increasing number of patients who present with combined heart and kidney dysfunction. Despite the increasing knowledge concerning CRS pathophysiology, diagnosis, and treatment, many of the aforementioned aspects remain obscure in everyday clinical practice. Some of the challenges that clinicians face when they treat CRS nowadays is the need for a patient-centered management with early diagnosis, early intervention, the distinction of true kidney injury from permissive renal function deterioration during decongestion therapy, and the development of therapeutic algorithms to guide therapy

Hsf-1 affects podocyte markers NPHS1, NPHS2 and WT1 in a transgenic mouse model of TTRVal30Met-related amyloidosis

Introduction: Familial amyloid polyneuropathy is characterized by transthyretin (TTR) deposition in various tissues, including the kidneys. While deposition induces organ dysfunction, renal involvement in TTR-related amyloidosis could manifest from proteinuria to end-stage kidney failure. As proteinuria is considered result of glomerular filtration barrier injury we investigated whether TTR deposition affects either glomerular basement membrane (GBM) or podocytes. Materials and methods: Immunohistochemistry, immunoblot and gene expression studies for nephrin, podocin and WT1 were run on renal tissue from human-TTRV30M transgenic mice hemizygous or homozygous for heat shock factor one (Hsf-1). Transmission electron microscopy was used for evaluation of podocyte foot process width (PFW) and GBM thickness in Hsf-1 hemizygous mice with or without TTRV30M or amyloid deposition. Results: Glomeruli of hsf-1 hemizygous transgenic mice showed lower nephrin and podocin protein levels but an increased podocyte number when compared to Hsf-1 homozygous transgenic mice. Nephrin, podocin and WT1 gene expression levels were unaffected by the Hsf-1 carrier status. TTRV30M deposition was associated with increased PFW and GBM thickness. Conclusions: Under the effect of Hsf-1 hemizygosity, TTRV30M deposition has deleterious effects on GBM thickness, PFW and slit diaphragm composition, without affecting nephrin and podocin gene expression

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred

Rationale & Objective: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. Study Design: Prospective observational study. Setting & Participants: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. Predictors: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. Outcomes: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. Analytical Approach: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. Results: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and “foam-cell” infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m 2 . The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. Limitations: The presence of cardiovascular disease was mainly based on medical history. Conclusions: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis

COVID-19-related acute kidney injury; incidence, risk factors and outcomes in a large UK cohort

Abstract Background Acute kidney injury (AKI) is common among patients hospitalised with COVID-19 and associated with worse prognosis. The aim of this study was to investigate the epidemiology, risk factors and outcomes of AKI in patients with COVID-19 in a large UK tertiary centre. Methods We analysed data of consecutive adults admitted with a laboratory-confirmed diagnosis of COVID-19 across two sites of a hospital in London, UK, from 1st January to 13th May 2020. Results Of the 1248 inpatients included, 487 (39%) experienced AKI (51% stage 1, 13% stage 2, and 36% stage 3). The weekly AKI incidence rate gradually increased to peak at week 5 (3.12 cases/100 patient-days), before reducing to its nadir (0.83 cases/100 patient-days) at the end the study period (week 10). Among AKI survivors, 84.0% had recovered renal function to pre-admission levels before discharge and none required on-going renal replacement therapy (RRT). Pre-existing renal impairment [odds ratio (OR) 3.05, 95%CI 2.24–4,18; p <  0.0001], and inpatient diuretic use (OR 1.79, 95%CI 1.27–2.53; p <  0.005) were independently associated with a higher risk for AKI. AKI was a strong predictor of 30-day mortality with an increasing risk across AKI stages [adjusted hazard ratio (HR) 1.59 (95%CI 1.19–2.13) for stage 1; p < 0.005, 2.71(95%CI 1.82–4.05); p < 0.001for stage 2 and 2.99 (95%CI 2.17–4.11); p < 0.001for stage 3]. One third of AKI3 survivors (30.7%), had newly established renal impairment at 3 to 6 months. Conclusions This large UK cohort demonstrated a high AKI incidence and was associated with increased mortality even at stage 1. Inpatient diuretic use was linked to a higher AKI risk. One third of survivors with AKI3 exhibited newly established renal impairment already at 3–6 months