Kidney Int Research Articles

Research Highlights.

Research Highlights.

Research Highlights.

Research Highlights.

Editing of APOL1 mRNA reduces APOL1 expression and activation of innate immunity

The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.

Nephrotic syndrome: delays in diagnosis and a cause of pulmonary embolism not to miss

British Journal of Hospital MedicineEarly view Case ReportNephrotic syndrome: delays in diagnosis and a cause of pulmonary embolism not to missFrancesca Wright, Mark GilchristFrancesca WrightCorrespondence to: Francesca Wright; E-mail Address: [email protected]Department of Nephrology, Torbay Hospital, Torbay and South Devon NHS Foundation Trust, Torquay, UKSearch for more papers by this author, Mark GilchristDepartment of Respiratory Medicine, Torbay Hospital, Torbay and South Devon NHS Foundation Trust, Torquay, UKUniversity of Exeter Medical School, Exeter, UKSearch for more papers by this authorFrancesca Wright; Mark GilchristPublished Online:22 May 2023https://doi.org/10.12968/hmed.2023.0011AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View article References Hull RP, Goldsmith DJA. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185–1189. https://doi.org/10.1136/bmj.39576.709711.80 Crossref, Medline, Google ScholarKerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012;7(3):513–520. https://doi.org/10.2215/CJN.10131011 Crossref, Medline, Google ScholarKidney Disease Improving Global Outcomes Guidelines. Clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4S):S1–S276. https://doi.org/10.1016/j.kint.2021.05.021 Medline, Google ScholarKodner C. Diagnosis and management of nephrotic syndrome in adults. Am Fam Physician. 2016;93(6):479–485 Medline, Google ScholarLeeaphorn N, Kue-A-Pai P, Thamcharoen N et al.. Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies. Am J Nephrol. 2014;40(1):29–35. https://doi.org/10.1159/000364782 Crossref, Medline, Google ScholarMahmoodi BK, ten Kate MK, Waanders F et al.. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome. Circulation. 2008;117(2):224–230. https://doi.org/10.1161/CIRCULATIONAHA.107.716951 Crossref, Medline, Google ScholarNational Institute for Health and Care Excellence. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. 2020. https://www.nice.org.uk/guidance/ng158 (accessed 24 April 2023) Google Scholar FiguresReferencesRelatedDetails Ahead of PrintISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 22 May 2023 Information© MA Healthcare LimitedPDF download

Egyptian pediatric clinical practice adapted guidelines: evidence-based [2] steroid-resistant nephrotic syndrome (SRNS) 2022

BackgroundNephrotic syndrome is one of the most common chronic kidney diseases in children. Steroid sensitive type (SSNS) constitutes about 85–90%, whereas steroid-resistant type (SRNS) only 15–20% (Mickinney et al. Pediatr Nephrol 16:1040-1044, 2001). While MCD is the most common histopathology in SS type, children with SRNS have MCD, mesangial proliferative glomerulonephritis, or focal and segmental glomerulosclerosis (FSGS) (International Study Kidney Disease in children, Kidney Int 20;765-771, 1981). SRNS is defined as those who do not show remission after 6 weeks and standard dose of oral steroids ± 3 IV MPD doses (Trautmann et al. Pediatr Nephrol 35:1529-1561, 2020).ObjectivesThese national adapted guidelines aim to frame evidence-based recommendations adopted or adapted from the IPNA 2020, KDIGO 2021, and Japanese 2014 de novo guidelines for diagnosis and management of nephrotic children to be presented in two manuscripts: (1) steroid sensitive (SSNS) and (2) steroid-resistant nephrotic syndrome (SRNS).MethodologyFormulation of key questions was followed with a review of literature guided by our appraised guidelines using AGREE plus appraisal tool. Virtual monthly meetings all through the year 2021 were activated for reviewing and validation of final adaptation evidence-based draft, considering all comments of external reviewers including KDIGO assigned reviewer.DiscussionRationale behind the selection of adopted statements and tailoring of others to suit our local facilities, expertise, and our local disease profile was discussed in the text with reasons.ConclusionThe provided guidelines aim to optimize patient care and outcome and suggest research areas lacking validated research recommendations.

Six pills less: no benefit for bicarbonate supplementation in renal allograft recipients

Metabolic acidosis (defined as serum bicarbonate <22 mmol/L) is frequent in patients with chronic kidney disease and is associated with disease progression. 1 Chapter 3: management of progression and complications of CKD. Kidney Int Suppl (2011). 2013; 3 (No authors listed): 73-90 Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar Several prospective trials and meta-analyses 2 Hultin S Hood C Campbell KL Toussaint ND Johnson DW Badve SV A systematic review and meta-analysis on effects of bicarbonate therapy on kidney outcomes. Kidney Int Rep. 2020; 6: 695-705 Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar , 3 Witham MD Band M Chong H et al. Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT. Health Technol Assess. 2020; 24: 1-90 Crossref PubMed Scopus (8) Google Scholar , 4 Di Iorio BR Bellasi A Raphael KL et al. Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI study. J Nephrol. 2019; 32: 989-1001 Crossref PubMed Scopus (70) Google Scholar , 5 Dubey AK Sahoo J Vairappan B Haridasan S Parameswaran S Priyamvada PS Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial. Nephrol Dial Transplant. 2020; 35: 121-129 PubMed Google Scholar , 6 Navaneethan SD Shao J Buysse J Bushinsky DA Effects of treatment of metabolic acidosis in CKD: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2019; 14: 1011-1020 Crossref PubMed Scopus (60) Google Scholar have suggested potential positive effects (of low certainty) of sodium bicarbonate treatment on chronic kidney disease progression, and bicarbonate supplementation is recommended in patients with chronic kidney disease with serum bicarbonate less than 22 mmol/L. 1 Chapter 3: management of progression and complications of CKD. Kidney Int Suppl (2011). 2013; 3 (No authors listed): 73-90 Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar However, protective mechanisms are not fully understood and it is difficult to determine whether acidosis is a cause or consequence of renal function decline. Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trialIn adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. Full-Text PDF

PS-B01-11: GENERATION OF TRANSGENIC MICE WITH PROXIMAL TUBULE-SPECIFIC OVEREXPRESSION OF ATRAP AND ANALYSIS OF PROXIMAL TUBULE ATRAP IN BLOOD PRESSURE REGULATION

Objective: Proximal tubule angiotensin II type 1 receptor (AT1R) is involved in blood pressure (BP) regulation (Li XC, et al. Hypertension, 77:1285-1298, 2021). AT1 receptor-associated protein (ATRAP) interacts with AT1R and promotes constitutive internalization of AT1R, to inhibit pathological activation of its downstream signaling (Tamura K, et al. Hypertens Res, 45:32–39, 2022). Endogenous ATRAP is abundantly expressed along kidney tubules in the kidney, and our previous investigations using systemic ATRAP knockout and distal tubule-dominant ATRAP transgenic mice revealed that ATRAP suppressed Ang II-induced hypertension mainly through a distal tubule-mediated mechanism (Wakui H, et al. Hypertension, 61:1203–10, 2013; Ohsawa M, et al. Kidney Int, 86:570–81, 2014). On the other hand, proximal tubule-specific ATRAP knockout mice exhibited similar baseline BP and pressor response to Ang II compared with wild-type mice (Kinguchi S, et al. J Am Heart Assoc, 8(8):e012395, 2019). The present study was performed to investigate the effects of enhancement of proximal tubule ATRAP on Ang II-mediated hypertension, using proximal tubule-specific ATRAP transgenic mice. Design and method: [Experiment 1] Using mouse ATRAP cDNA linked to the type II sodium-dependent phosphate cotransporters (NPT2) promoter, we generated transgenic mice (NPT2-Tg mice) with proximal tubule-specific overexpression of ATRAP. ATRAP mRNA expression in the proximal tubule was quantified by a laser capture microdissection and quantitative reverse transcription-polymerase chain reaction analysis. [Experiment 2] Male NPT2-Tg and wild-type littermate control (LC) mice were divided into Ang II (1000 ng/kg/min) and vehicle groups. BP was measured using a tail-cuff method before and 14 days after treatment, and then mice were sacrificed and their organs were collected. Results: [Experiment 1] 5 of 12 lines of ATRAP Tg mice exhibited kidney overexpression of the ATRAP-transgene in comparison with LC mice. Kidney ATRAP expression at the protein level revealed the highest expression level of ATRAP in lines 23, approximately 10-fold higher compared to LC mice. Therefore, we chose line 23 (NPT2-Tg23) for further analysis. ATRAP mRNA expression was increased approximately 9-fold in the proximal tubules of NPT2-Tg23 mice compared with LC mice. On the other hand, ATRAP mRNA expression in the distal tubules was comparable between NPT2-Tg23 and LC mice. [Experiment 2] We are currently conducting the experiments and will present our findings at this conference. Conclusions: We succeeded in generating transgenic mice with proximal tubule-specific overexpression of ATRAP. We plan to present the results of the impact of enhancement of proximal tubular ATRAP on Ang II-dependent hypertension at this conference.

PS-B08-10: COMBINATION OF SYSTEMIC ATRAP DEFICIENCY WITH ANGIOTENSIN II STIMULATION ACCELERATES THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN STREPTOZOTOCIN TREATED MICE

Objective: One of the obstacles toward understanding the pathophysiology of diabetic nephropathy (DN) has been the lack of reliable animal models that faithfully replicate features of human DN. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R from the cell surface into the cytoplasm, resulting in the suppression of AT1R signaling pathway. We have recently reported that systemic ATRAP deficiency exaggerates streptozotocin (STZ)-induced DN via an activation of renal renin-angiotensin system (RAS) (Haruhara K, et al. Kidney Int 2022). However, STZ-induced diabetic ATRAP knockout mice still exhibited a modest increase in albuminuria with limited pathological changes just in glomerulus. To establish more robust DN models, we examined the effect of Ang II stimulation on the development of DN in STZ-treated ATRAP knockout mice. Design and method: Male eight weeks old C57BL/6 mice (Ctrl) and systemic ATRAP-knockout mice (KO) were divided into three groups: 1) Ctrl-STZ, 2) Ctrl-STZ-Ang II, and 3) KO-STZ-Ang II. Hyperglycemia was induced by intraperitoneal injection of 55 mg/kg STZ for consecutive 5 days. From 4 weeks after STZ administration, Ang II (1000 ng/kg/min) was continuously administered by osmotic mini-pumps for 6 weeks. During the experimental period, body weights and levels of blood glucose were measured every 2 weeks. At 6 and 10 weeks after STZ administration, 24-hour urine samples were collected in metabolic cages, and urinary albumin excretion (UAE) was evaluated by ELISA. At the end of experimental period, mice were euthanized to evaluate renal pathological changes. Results: During the experimental period, body weight gain and levels of blood glucose were not significantly different between the three groups. Nonetheless, although levels of UAE at 6 weeks after STZ administration were still modest and comparable between the three groups, levels of UAE only in the KO-STZ-Ang II group were remarkably increased compared to those in the Ctrl-STZ and Ctrl-STZ-Ang II groups at 10 weeks after STZ administration (679.1 ± 583.7 vs 69.9 ± 10.0 vs 61.3 ± 8.2 μg/day, respectively). Furthermore, in the KO-STZ-Ang II group, exacerbation of mesangial expansion and interstitial fibrosis was observed. Conclusions: In STZ-induced diabetic mice, combination of systemic ATRAP deficiency with Ang II stimulation accelerated the development of DN, suggesting a potential to become a promising mouse model replicating key features of human DN.

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

De novo posttransplant membranous nephropathy following BNT162b2 mRNA COVID-19 vaccine in a kidney transplant recipient

To the Editor: Mass COVID-19 vaccination programs in kidney transplant patients (KTRs) have demonstrated an excellent safety profile, without increased rates of ensuing alloimmune events. However, autoimmune diseases may seldom occur after vaccination. We report the case of a KTR who presented de novo posttransplant membranous nephropathy (MN) following administration of COVID-19 vaccine. A 66-year-old patient underwent first kidney transplantation for autosomal-dominant polycystic-kidney-disease-related end-stage kidney disease in June 2020. His medical history included hypertension and left nephrectomy in 2016. After basiliximab induction, the maintenance regimen consisted of tacrolimus, mycophenolic acid, and steroids. His baseline creatinine level was 100 μmol/L, and he remained free of proteinuria during the posttransplant course. A 3-month protocol graft biopsy was unremarkable. Immunohistochemistry (IHC) C4d staining was negative (Figure 1A,B). The patient received the second injection of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) in March 2021. Subsequent serology tests showed negative results, consistent with a blunted antibody response to the vaccine, as widely reported in KTRs. Eight weeks after the second vaccine dose, the patient underwent a 1-year protocol graft biopsy. Concurrent creatinine level and proteinuria were 120 μmol/L and negative, respectively. Light microscopy showed normal glomeruli and ruled out subclinical rejection(Figure 1D). However, C4d staining revealed the presence of granular staining along the glomerular basement membrane consistent with stage 1 MN (Figure 1E). Anti-phospholipase-A2-receptor (PLA2R) immunochemistry analysis showed strong positive staining on the glomerular capillary walls (Figure 1F). Circulating PLA2R antibodies were negative. Notably, IHC staining for PLA2R and C4d was retrospectively negative in the 3-month protocol graft biopsy (Figure 1E) and in the native kidney specimen (nephrectomy). The residual renal parenchyma on the native kidney contained non-sclerotic glomeruli. We retrospectively performed Jones staining which did not show irregularities of the glomerular basement membrane suggestive of membranous nephropathy. There was no available frozen sample on the renal parenchyma. Hence, the diagnosis of de novo posttransplant MN was firmly established. Screening for malignancy and infections remained negative, excluding secondary causes of MN. COVID-19 tests remained also negative (SARS-CoV-2 PCR was negative at MN diagnosis and 3 months after the diagnosis. Anti-Spike IgG were negative 1 and 2 months after the diagnosis). This is the first case of de novo posttransplant MN following mRNA COVID-19 vaccine. Interestingly, cases of de novo or relapsing MN after COVID-19 vaccine have recently been reported.1Aydin MF Yildiz A Oruc A et al.Relapse of primary membranous nephropathy after inactivated SARS-CoV-2 virus vaccination.Kidney Int. 2021; 100 (doi:10.1016/j.kint.2021.05.001): 464-465Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Da Y Goh GH Khatri P A case of membranous nephropathy following Pfizer-BioNTech mRNA vaccination against COVID-19.Kidney Int. 2021; 100 (doi:10.1016/j.kint.2021.07.016): 938-939Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 3Gueguen L Loheac C Saidani N Khatchatourian L Membranous nephropathy following anti-COVID-19 mRNA vaccination.Kidney Int. 2021; S0085-2538 (doi:10.1016/j.kint.2021.08.006): 00752-00757Google Scholar Additionally, rare cases of MN (including one PLA2R+ case) have been described after COVID-19 infection.4Nasr SH Alexander MP Cornell LD et al.Kidney biopsy findings in patients with COVID-19, kidney injury, and proteinuria.Am J Kidney Dis. 2021; 77 (doi:10.1053/j.ajkd.2020.11.002): 465-468Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The temporality between COVID-19 vaccination and PLA2R+ MN in a patient without history of MN and in whom the etiological workup has remained otherwise negative, supports a causal link. However, we must acknowledge that a coincidental association could not be ruled out. Given the lack of proteinuria, no specific treatment was introduced. The subclinical presentation of MN may be related to the mitigating effects of maintenance immunosuppressive therapy. In conclusion, auto-immune reactivity and MN may occur after mRNA COVID-19 vaccine. This report will raise awareness of nephrologists for the need to closely monitor patients with primary MN, following COVID-19 vaccination, including KTRs. If proteinuria occurs after vaccination, a graft biopsy should be promptly performed to firmly establish the diagnosis. We would like to thank Ms. Roberta Vellve for the English language review. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Additional supporting information can be found online in the Supporting Information section at the end of this article. 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Author Correction: Antihypertensive treatment with calcium channel blockers and renal protection: focus on lercanidipine and lercanidipine/enalapril.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (20): 7482-7492. DOI: 10.26355/eurrev_202210_30018-PMID: 36314318, published online on October 28, 2022. After publication, the authors applied some corrections to the text: - The section "Clinical Oharmacology of Lercanidipine" has been corrected into "Clinical Pharmacology of Lercanidipine" - The Legend of Figure 2 has been corrected as follows: Ca T-type channels vs. Ca L-type channels selectivity ratio. LAC, lacidipine, AML, amlodipine; MIB, mibefradil; LER, lercanidipine; *p<0.05, ** p<0.01 vs. LAC (low concentrations); †p<0.01 LAC vs. all other CCBs (high concentrations). Source: Modified from 25. - The reference 25 has been changed into: Hart P, Bakris GL. Calcium antagonists: Do they equally protect against kidney injury? Kidney Int 2008; 73: 795-796. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30018.

The Prognostic Value of Histopathological Classifications in ANCA-Associated Vasculitis

Renal involvement is a common and severe feature of ANCA-associated vasculitis, leading to end-stage kidney disease and death in a considerable number of patients. One of the challenges of ANCA-associated glomerulonephritis is to establish histological features of prognostic value, in order to identify patients who will benefit of immunosuppression. Although the prognostic value of the renal biopsy in ANCA-associated glomerulonephritis is widely recognized, there is no consensus regarding its pathologic classification. In 2010, Berden et al (J Am Soc Nephrol. 2010; 21: 1628-36) proposed a histopathologic classification based only on glomerular morphology, which is of prognostic value for short-term and long-term renal outcomes. However, over the last years, the results of several studies using multivariable approaches have suggested that the proposed histopathologic classes alone might not be sufficient to predict renal outcome. In order to refine the prognosis of patients with ANCA-associated vasculitis, in 2018, Brix et al (Kidney Int. 2018;94:1177-88) proposed the Renal Risk Score, based on clinical and pathological parameters. In this review, we discuss the prognostic value of the Histopathologic Classification and the Renal Risk Score and their role in routine clinical practice.

DCRM Multispecialty Recommendations in Patients With Heart Failure

Diabetes mellitus (DM), hypertension, obesity, and atherosclerotic cardiovascular disease (ASCVD) are associated with heart failure (HF). Comorbid metabolic conditions in patients with HF are associated with worse outcomes and may affect the management of HF by limiting treatment options and reducing adherence to therapy. 1 Bozkurt B Aguilar D Deswal A Dunbar SB Francis GS Horwich T et al. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the. American Heart Association. Circulation. 2016; 134: e535-e578 Google Scholar Practice guidelines for these diseases are drafted by the American Diabetes Association (ADA), the Kidney Disease Improving Global Outcomes (KDIGO) or the American College of Cardiology (ACC)/American Heart Association (AHA). These guidelines are drafted in silos, often without cross-collaboration with other cardiorenal/metabolic specialists. As a result, guidelines commonly differ in their recommendations. For example, the KDIGO guidelines and the ACC/AHA HF guidelines recommend different blood pressure goals for the management of hypertension. 2 Kidney disease: improving global outcomes blood pressure work g: KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021; 99: S1-87 Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar ,3 Heidenreich PA Bozkurt B Aguilar D Allen LA Byun JJ Colvin MM et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022; 145: e895-1032 PubMed Google Scholar Comanagement of DM, cardiorenal, and/or metabolic (DCRM) conditions is key to medical optimization. To introduce a more holistic approach to DCRM conditions, a volunteer task force created a multispecialty consensus for the management of complicated comorbid metabolic disease, the DCRM practice recommendations. 4 Handelsman Y Anderson JE Bakris GL Ballantyne CM Beckman JA Bhatt DL et al. DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complicat. 2022; 36108101 Crossref Scopus (4) Google Scholar Herein, we highlight the recommendations of these guidelines for the prevention and management of HF with concurrent DCRM comorbidities.

North American COVID-19 Myocardial Infarction (NACMI) Risk Score for Prediction of In-Hospital Mortality.

BackgroundIn-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is higher in those with COVID-19 than in those without COVID-19. The factors that predispose to this mortality rate and their relative contribution are poorly understood. This study developed a risk score inclusive of clinical variables to predict in-hospital mortality in patients with COVID-19 and STEMI.MethodsBaseline demographic, clinical, and procedural data from patients in the North American COVID-19 Myocardial Infarction registry were extracted. Univariable logistic regression was performed using candidate predictor variables, and multivariable logistic regression was performed using backward stepwise selection to identify independent predictors of in-hospital mortality. Independent predictors were assigned a weighted integer, with the sum of the integers yielding the total risk score for each patient.ResultsIn-hospital mortality occurred in 118 of 425 (28%) patients. Eight variables present at the time of STEMI diagnosis (respiratory rate of >35 breaths/min, cardiogenic shock, oxygen saturation of <93%, age of >55 ​years, infiltrates on chest x-ray, kidney disease, diabetes, and dyspnea) were assigned a weighted integer. In-hospital mortality increased exponentially with increasing integer risk score (Cochran-Armitage χ2, P ​< ​.001), and the model demonstrated good discriminative power (c-statistic ​= ​0.81) and calibration (Hosmer-Lemeshow, P ​= ​.40). The increasing risk score was strongly associated with in-hospital mortality (3.6%-60% mortality for low-risk and very high–risk score categories, respectively).ConclusionsThe risk of in-hospital mortality in patients with COVID-19 and STEMI can be accurately predicted and discriminated using readily available clinical information.

MO690: Overview of Peritoneal Dialysis Outcomes in Northern Cyprus: A Nation-Based Study

Abstract BACKGROUND AND AIMS Prevalence of patients with end stage renal disease (ESRD) undergoing renal replacement therapies (RRT) is increasing worldwide (Stel et al. Supplemented ERA-EDTA Registry data evaluated the frequency of dialysis, kidney transplantation, and comprehensive conservative management for patients with kidney failure in Europe. Kidney Int. 2021;100(1):182–95 and Bikbov et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020; 395(10 225): 709–33). Epidemiology of ESRD and treatment options for these patients should be considered in health system planning (Bikbov et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020; 395(10 225):709–33). By an enhanced national PD program, more patients may have chance to take advantage of this treatment option. In this study we aim to investigate whether PD is preferred as first dialysis treatment modality in Northern Cyprus and to evaluate PD duration, and outcomes in order to improve PD program. METHOD PD patients aged above 18 years who were followed between 2003 and 2021 in Northern Cyprus were screened retrospectively. Demographic data, primary kidney diseases, comorbidities and previous RRT modalities were investigated. Episodes of peritonitis, transfer to automated PD in the follow-up, total duration on PD treatment, transfer to renal transplantation or HD and mortality rate were evaluated. Reasons for shifting from PD to HD were analysed. Outcomes of elderly (aged 65 years and above) and diabetic patients who were dropped out from PD were found out. RESULTS A total of 123 patients (33 female/90 male) aged 18–83 years were included to the study. A total of 25 patients were actively doing PD, 2 moved to another country on PD therapy and 96 dropped out of PD. A total of 40% of 123 PD patients initiated RRT with PD (Fig. 1). Median time was found 1 month in the rest of patients to transfer PD from other modalities. Sixteen (16.8%) patients had renal transplantation during follow-up. Thirty-three patients (34.7%) transferred to HD. Insufficient dialysis (40.7%) and PD-related infections (29.6%) were the most common reasons for shifting from PD to HD (Fig. 2). Forty-six (48.4%) patients were died on PD therapy at the age of 67 ± 11. Cardiovascular events (50%) and various infections (35%) were the leading causes of mortality. A total of 48 (43.2%) PD patients had at least one episode of peritonitis. Automated PD was used by 58 (53.2%) patients. PD duration was 36 (1–150) months in patients who were dropped out of PD. Total duration on PD treatment was longer for males than females. Total duration on PD treatment, initiation RRT with PD, prevalence of hypertension, diabetes mellitus (DM), peritonitis and use of automated PD were not significantly different between elderly (patients aged ≥ 65 years, n = 34) and younger individuals (18–65 years). Comorbidity index was found significantly higher in elderly group (P &amp;lt; 0.001). PD duration was longer for males then females (P = 0.044) and the duration was similar in patients with or without DM, in the dropped-out patients (P = 0.205). CONCLUSION A significant amount of patients (60%) required HD before initiation of PD. Early admission of patients to nephrology department and timely initiation of education program may contribute to decrease need of HD before PD (Briggs et al. International variations in peritoneal dialysis utilization and implications for practice. Am J Kidney Dis. 2019; 74(1): 101–10). As elderly patients had similar results with younger ones, age should not be considered as a challenging barrier for PD initiation. Precautions to prevent development of peritonitis, ultrafiltration failure and dialysis insufficiency may contribute to extent total duration on PD treatment.

MO013: Relationship between Disease Awareness and Severity of Kidney Disease in Autosomal Dominant Polycystic Kidney Disease Patients

Abstract BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease with diffuse cysts in both kidneys and is responsible for 5–10% of end-stage renal disease Levy and Feingold (Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int. 2000;58(3):925). Recently, tolvaptan, which can improve kidney survival, was approved for the management of the disease (Drug Approval Package: Jynarque (tolvaptan) Otsuka Pharmaceutical Development &amp; Commercialization, Inc. application Number: 204 441, Approval Date: 04/23/2018). We examined the relationship between renal and extrarenal findings, disease severity and the level of consciousness of patients with ADPKD patients. METHOD About 516 patients who applied to nephrology clinics of seven different centers in Turkey were asked to answer the questionnaire about ADPKD that consisted of 38 questions. Disease severity was determined according to e-GFR, and disease awareness was assessed on a four-point scale by adapting the Disease Perception Scale to ADPKD. Awareness of patients was evaluated comparatively with chronic kidney disease stage, age, region and symptoms. RESULTS One out of five patients does not know that this disease is inherited. Mean awareness scores of the patients decreased significantly with increasing age. The average awareness score of the Central Anatolia region was significantly higher compared to other regions. Awareness scores were significantly higher in patients with flank pain and urinary tract stones. CONCLUSION To the best of our knowledge, this is the first study about ADPKD awareness. Although ADPKD is the most common hereditary kidney disease, the rate of patients’ knowledge on this subject is low. Awareness levels may vary according to age, regional differences or symptoms. Increased awareness might lead to better treatment and improved survival in those patients.

MO030: Familial clustering of a rare UMOD variant in undiagnosed hereditary nephropathy suggests the presence of a common ancestral founder mutation

Abstract BACKGROUND AND AIMS ADTKD–UMOD (Autosomal dominant tubulointerstitial kidney disease–UMOD) is a rare genetic disease due to a heterozygous mutation in the UMOD gene encoding uromodulin. It is classically characterized by minimal proteinuria, slowly progressive CKD, hyperuricemia and early-onset gout. With increasing awareness and testing, pathogenic variants in UMOD are being identified more frequently although the nonspecific nature of most symptoms makes clinical diagnosis difficult. We report the surprising finding of a rare UMOD variant in 11 seemingly unrelated families referred to Sheffield or Nottingham renal genetics services over a 15-year period with undiagnosed hereditary kidney disease. METHOD The probands identified were initially referred to renal genetics services based in Sheffield and Nottingham between 2006 and 2021, where they underwent genetic testing and a comprehensive renal workup. All had a family history of ESRD. A pathogenic variant of UMOD, c.278_289delinsCCGCCTCCT was identified in 11 probands by gene or panel-based sequencing. Family members of the affected probands were invited for genetic testing and clinical follow-up. A retrospective review of all patients screened or with ESRD at both renal genetic clinics was conducted. Molecular modeling of the variant was performed using in-silico tools. RESULTS Clinical data from 60 members (11 pedigrees) was obtained. All individuals were born in the United Kingdom and of White British ethnicity. A total of 37 tested positive for the variant, 3 were negative and 19 were not tested due to being deceased (n = 13) and for unknown reasons (n = 6). The median age of ESRD was 52 (range 32, 76) years. More females had ESRD comprising 67% (20/30). Of patients with available data, 68% (30/44) had hypertension, 7.3% (3/41) had proteinuria &amp;gt;30 mg/g and 18% (7/40) had mild hematuria. A total of 11% (6/57) had experienced ≥1 episode of gout with a median onset of 42.5 (range 29–61) years. Only one patient had asymptomatic renal calculi. All patients with CKD who carried the UMOD mutation (n = 22) had hypertension, apart from two who had unknown hypertensive status (n = 1) or reflux nephropathy causing kidney scarring (n = 1). Renal histology where available (8) showed glomerulosclerosis and tubulointerstitial fibrosis. Ultrasound kidney lengths were normal or reduced and renal cysts were only occasionally detected. Molecular modeling of the variant showed structural changes in the cysteine-rich (C6) with EGFII-like Ca2+ binding domain of UMOD, predicted to disrupt disulfide-bond formation (fifth cysteine C94–sixth cysteine C106) as well as by altering the loop (93–97) between two β-sheets of EGFII domain (AlphaFold), possibly altering calcium ion binding (DeepFRI). This variant was initially reported as a recurrent mutation in four apparently unrelated families [1] and has since been noted in a further 11 families [2], all of White British ethnicity. CONCLUSION We have identified a rare pathogenic UMOD variant shared by 11 apparently unrelated families with familial ESRD within a contiguous geographical region of England. The nonspecific symptoms associated with this variant (especially the rarity of gout) were atypical from those with more classical UMOD variants leading to a delay in diagnosis. Our findings and those of others suggest that this is likely to represent a common ancestral variant rather than a recurrent variant within the UK population. 1. Smith GD, Robinson C, Stewart AP et al. Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure. Clin J Am Soc Nephrol 2011; 6: 2766–2774. 2. Kidd K, Vylet'al P, Schaeffer C et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int Rep 2020; 5:1472–1485.

Sex Difference in Renal Artery Contractility in a Novel CRISPR/Cas9‐Generated P2X7 Knockout Rat

Purinergic signaling regulates numerous physiological processes, including renal hemodynamics. The P2X7 receptor (P2X7) is a non‐selective cation channel activated by extra‐cellular adenosine triphosphate (ATP) which plays an important role in immune cell response and inflammation. P2X7 is also expressed in endothelial cells. In the kidney, acute pharmacological blockade of P2X7 increases renal perfusion in healthy rats (Kidney Int. 88(5): 1079–1087, 2015). Here, we generated a novel P2X7 knockout (KO) rat and examined ex vivo contractility of the renal artery in male and female rats.A P2rx7 global KO rat was generated on a F344 IcoCrl background using CRISPR/Cas9 technology. KO was achieved via a two‐adenine insertion predicted to introduce a premature stop codon in exon 2. RNA and protein were extracted from KO and wild‐type (WT) kidneys to detect P2X7 by RTqPCR (n=4‐5/group) and western blotting (n=2/group). Bone marrow‐derived macrophages (BMDM) from KO and WT rats were used to assess P2X7 function by measuring interleukin (IL)‐1β release (ELISA) after stimulation with lipopolysaccharide (LPS) (1μg/mL, 4h) and ATP (3mM, 1h) (n=5‐6/group). RNA from BMDM was extracted after LPS to detect P2rx7, Il1b, Tnf and Il6 mRNA by RTqPCR (n=3/group), and Griess reaction was used to assess BMDM nitric oxide (NO) production (n=5‐6/group). One main renal artery from 2.5‐to‐4.5‐month‐old male and female KO and WT rats (n=8‐11/group) was mounted on a wire myograph to assess the response to 125 mM potassium physiological solution (KPSS) and to cumulative doses (1 nM‐30 μM) of phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP).The P2rx7 mutation in exon 2 was confirmed by genome sequencing (Sanger). P2rx7 mRNA abundance was decreased by ~60% in kidney and ~53% in BMDM from KO vs WT. P2X7 protein was detected in kidneys from WT but not from KO rats. P2X7 KO did not alter BMDM polarization after LPS stimulation. The induction of NO production was not different between genotypes (2.14±0.26 vs 2.31±0.43 μM, NS) and mRNA expression of M1 markers Il1b, Tnf and Il6 was similarly increased. In BMDM from male WT rats, ATP stimulation induced IL‐1β release; this response was markedly suppressed in KO BMDM (2577±70 vs 413±19 pg/mL, p&lt;0.0001). In the renal artery, the constriction induced by KPSS depolarization or by PE was not different between genotypes for either sex. In male rats, the maximum vasodilation induced by ACh was significantly decreased in KO compared to WT (IC50=0.25 vs 0.20 μM, NS; %Imax= 24±3 vs 10±2%, p=0.0015); this was not observed in females (IC50=0.11 vs 8.28 μM, NS; %Imax= 19±4 vs 12±4%, NS). The dilation induced by the direct NO donor, SNP was not affected by either genotype or sex.Global genetic deletion of P2X7 impaired endothelial‐dependent vasodilation in the renal artery of male rats that may reflect diminished NO production in response to ACh. Thus, the increased renal perfusion induced by P2X7 inhibitor may arise from off‐target effects. The potential sexual dimorphism in vascular expression and/or function of P2X7 requires further investigation.

Antibody responses to 2 doses of mRNA COVID-19 vaccine in pediatric patients with kidney diseases

Antibody responses to 2 doses of mRNA COVID-19 vaccine in pediatric patients with kidney diseases

Making 2022 the year of psychosocial care in the kidney care community

Journal of Kidney CareVol. 7, No. 1 EditorialMaking 2022 the year of psychosocial care in the kidney care communityPeter EllisPeter EllisEmail: E-mail Address: [email protected]Health and Social Care Consultant, Writer and EducatorSearch for more papers by this authorPeter EllisPublished Online:15 Feb 2022https://doi.org/10.12968/jokc.2022.7.1.4AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Ellis P. We live and we learn: saying goodbye to 2020. J Kidney Care. 2021; 6(1):4–5. https://doi.org/10.12968/jokc.2021.6.1.4 Link, Google ScholarEllis P. Empowering older patients choosing renal replacement therapy or conservative management. J Kidney Care. 2022; 7(1):XXX Google ScholarEllis P and Abbott J, Supervision, part four: group supervision. J Kidney Care. 2022; 7(1):XXX Google ScholarNewman E, Hynes M. Chronic kidney disease and coronary artery disease treatment. J Kidney Care. 2022; 7(1):XXX Google ScholarNicolai C, Holt A. Chronic kidney disease and coronary artery disease treatment. J Kidney Care. 2022; 7(1):XXX Google ScholarOzdemir S, Choong LHL, Gan SWS et al. Patient decision aid development for older adults with end-stage kidney disease in Singapore. Kidney Int Reports. 2021; 6: 2885–2896. https://doi.org/10.1016/j.ekir.2021.08.027. Google Scholar FiguresReferencesRelatedDetails 2 January 2022Volume 7Issue 1ISSN (print): 2397-9534ISSN (online): 2397-9542 Metrics History Published online 15 February 2022 Published in print 2 January 2022 Information© MA Healthcare LimitedPDF download