{"title":"Female sex hormones inversely regulate acute kidney disease susceptibility throughout life.","authors":"Yuichiro Kitai, Naoya Toriu, Takahisa Yoshikawa, Yoshiki Sahara, Sonoko Kinjo, Yoko Shimizu, Yuki Sato, Akiko Oguchi, Ryo Yamada, Makiko Kondo, Eiichiro Uchino, Keisuke Taniguchi, Hiroyuki Arai, Takayoshi Sasako, Hironori Haga, Shingo Fukuma, Naoto Kubota, Takashi Kadowaki, Minoru Takasato, Yasuhiro Murakawa, Motoko Yanagita","doi":"10.1016/j.kint.2024.08.034","DOIUrl":"10.1016/j.kint.2024.08.034","url":null,"abstract":"<p><p>While epidemiological and experimental studies have demonstrated kidney-protective effects of estrogen and female sex in adulthood, some epidemiological data showed deterioration of kidney function during puberty when estrogen production increases. However, molecular mechanisms explaining these conflicting phenomena remain unknown. Here, we showed that the pubertal sex hormone surge in female mice increases susceptibility to kidney ischemia reperfusion injury partly via downregulation of insulin-like growth factor 1 receptor (IGF-1R) expression in proximal tubules. Adult mice ovariectomized pre-pubertally (at postnatal day 21) showed strong tolerance to kidney ischemia, which was partly reversed by the administration of 17β-estradiol, while adult mice ovariectomized post-pubertally (at 8 weeks of age) were vulnerable to kidney ischemia. Kidney tubular IGF-1R protein expression decreased during postnatal growth but was highly expressed in adult mice ovariectomized pre-pubertally and in infant mice, which might be partly explained by different expression of an E3 ligase (MDM2) of IGF-1R. Mice deficient of Igf-1r in proximal tubules (iIGF-1RKO mice) during postnatal kidney growth showed increased susceptibility to ischemic injury. RNA-seq and western blotting analysis using proximal tubular cells from pre-pubertally ovariectomized iIGF-1RKO and control mice revealed altered expression of cell cycle-associated molecules such as cyclin D1. These results suggest that Igf-1r deletion during postnatal growth renders proximal tubular cells susceptible to ischemia possibly via altered cell cycle regulation. Thus, our findings provide evidence that exposure to pubertal sex hormones leads to increased susceptibility to kidney ischemia, which is partly mediated by modulation of IGF-1R signaling.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prenatal and preimplantation testing for monogenic kidney disorders.","authors":"Nine V A M Knoers","doi":"10.1016/j.kint.2024.06.031","DOIUrl":"10.1016/j.kint.2024.06.031","url":null,"abstract":"<p><p>In recent years, advances in genetic sequencing techniques and the analysis of sequencing data have significantly improved our ability to diagnose genetic kidney diseases. Identification of the disease-causing genetic variant(s) is crucial not only for prognostication and personalized management, but also for providing genetic counseling and guiding family planning decisions. It is particularly important that patients desiring children receive advice on their reproductive choices early, ideally before conception. This concise review focuses on the options available for prenatal and preimplantation genetic testing in the context of monogenic kidney diseases, including the latest progress and the legal and ethical issues associated with these reproductive technologies. Although these tests could be performed for all monogenic disorders where the disease-causing variant(s) has (have) been identified in the index patient, invasive prenatal testing is currently primarily performed for severe childhood-onset monogenic kidney disorders. Noninvasive prenatal diagnosis for monogenic disorders is a rapidly developing field that promises to provide an accurate and acceptable alternative to invasive procedures once several technical challenges have been addressed. Preimplantation genetic testing allows for the selection and implantation of embryos free from the disease-causing genetic variants, significantly lowering the risk of affected pregnancies. This option is becoming more popular among individuals with monogenic kidney diseases, particularly those with disorders that manifest later in life, such as autosomal dominant polycystic kidney disease. This review covers the procedure, its outcomes, and the technical, ethical and legal challenges of preimplantation genetic testing for monogenic kidney diseases.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":3.784,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dominique Vodovar, Cyril Mousseaux, Michel Daudon, Matthieu Jamme, Emmanuel Letavernier
{"title":"Amoxicillin crystalluria and amoxicillin-induced crystal nephropathy: a narrative review.","authors":"Dominique Vodovar, Cyril Mousseaux, Michel Daudon, Matthieu Jamme, Emmanuel Letavernier","doi":"10.1016/j.kint.2024.09.019","DOIUrl":"10.1016/j.kint.2024.09.019","url":null,"abstract":"<p><p>Amoxicillin crystalluria (AC) refers to the precipitation of amoxicillin in the urine as amoxicillin trihydrate crystals. Amoxicillin-induced crystal nephropathy (AICN) refers to the obstruction of kidney tubules by amoxicillin trihydrate crystals, resulting in acute kidney injury. Usually considered rare and not serious, AC and AICN would be more frequent in patients receiving high-dose i.v. amoxicillin (≥150 mg/kg per day) than previously reported. AC prevalence ranges from 24% to 41%. AICN prevalence remains unclear. AC is generally asymptomatic, but sudden macroscopic hematuria with cloudy urine suggests the diagnosis. AC is diagnosed by detecting amoxicillin trihydrate crystals in urine. AC is a risk factor for acute kidney injury. Diagnosing AICN is more challenging in the absence of noninvasive diagnostic tools. It is suspected in high-dose i.v. amoxicillin-treated patients who develop acute kidney injury and AC, and after excluding other causes of acute kidney injury (mainly sepsis and acute interstitial nephritis). When testing for AC is unavailable, the presence of demonstrated (high blood amoxicillin levels and low urinary pH) or suspected (rapid i.v. amoxicillin administration and hypovolemia) risk factors for AC suggests its diagnosis. AICN management includes discontinuation/reduction of amoxicillin doses and volume resuscitation to improve tubular flow and urine output and decrease amoxicillin supersaturation. Patients generally recover normal kidney function rapidly after stopping amoxicillin, but renal replacement therapy is required in 10%-40% of patients. No deaths have been directly attributed to AICN. Future studies are needed to assess the exact prevalence of AC/AICN and to define optimal therapeutic options.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":3.784,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sophie Caillard, Nicolas Meyer, Morgane Solis, Dominique Bertrand, Maite Jaureguy, Dany Anglicheau, Laure Ecotiere, Matthias Buchler, Nicolas Bouvier, Betoul Schvartz, Jean Philippe Rerolle, Anne Elisabeth Heng, Lionel Couzi, Agnes Duveau, Emmanuel Morelon, Yann LeMeur, Léonard Golbin, Eric Thervet, Ilies Benotmane, Samira Fafi-Kremer
{"title":"Insights from the BKEVER Trial comparing everolimus versus mycophenolate mofetil for BK Polyomavirus infection in kidney transplant recipients.","authors":"Sophie Caillard, Nicolas Meyer, Morgane Solis, Dominique Bertrand, Maite Jaureguy, Dany Anglicheau, Laure Ecotiere, Matthias Buchler, Nicolas Bouvier, Betoul Schvartz, Jean Philippe Rerolle, Anne Elisabeth Heng, Lionel Couzi, Agnes Duveau, Emmanuel Morelon, Yann LeMeur, Léonard Golbin, Eric Thervet, Ilies Benotmane, Samira Fafi-Kremer","doi":"10.1016/j.kint.2024.09.018","DOIUrl":"10.1016/j.kint.2024.09.018","url":null,"abstract":"<p><p>The MTOR inhibitors have demonstrated antiviral properties, and prior non-randomized studies have suggested they may have a suppressive effect on BKPyV replication. Here, in this randomized, multicenter, controlled trial (BKEVER study), we sought to evaluate the impact of everolimus (EVR) in facilitating the clearance of BKPyV compared to simply reducing immunosuppression among kidney transplant recipients (KTRs). All together, 130 KTRs presenting with BKPyV DNAemia were randomized 1:1 into two groups. The EVR group, in which mycophenolate mofetil (MMF) was replaced by EVR along with a decrease in calcineurin inhibitor trough levels and secondly the MMF group, in which the MMF dose was decreased by half along with a similar lowering of calcineurin inhibitor levels. The primary endpoint was the proportion of patients achieving viral clearance at six months. Secondary endpoints included the kinetics of BKPyV replication over time, the incidence of BKPyV-associated nephropathy, kidney graft function, the incidence of kidney graft rejection, and medication tolerability over two years. Significantly, BKPyV clearance was achieved in 55.7% of patients in the EVR group compared to 81.3% of patients in the MMF group at six months. The reduction in BKPyV DNA load was significantly more rapid in the MMF group. Calcineurin inhibitor trough levels were within expected target ranges and did not differ meaningfully between the two groups from randomization through month six. Two grafts were lost, and four patients died. Eleven patients in the EVR group and six patients in the MMF group developed biopsy-proven BKPyV nephropathy. Thus, in KTRs with BKPyV DNAemia, replacing MMF with EVR along with lowering calcineurin inhibitor levels did not lead to more frequent or faster clearance of BKPyV.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":3.784,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefanie Steiger, Li Li, Annette Bruchfeld, Kate I Stevens, Sarah M Moran, Jürgen Floege, Fernando Caravaca-Fontán, Safak Mirioglu, Onno Y K Teng, Eleni Frangou, Andreas Kronbichler
{"title":"Sex dimorphism in kidney health and disease: mechanistic insights and clinical implication.","authors":"Stefanie Steiger, Li Li, Annette Bruchfeld, Kate I Stevens, Sarah M Moran, Jürgen Floege, Fernando Caravaca-Fontán, Safak Mirioglu, Onno Y K Teng, Eleni Frangou, Andreas Kronbichler","doi":"10.1016/j.kint.2024.08.038","DOIUrl":"10.1016/j.kint.2024.08.038","url":null,"abstract":"<p><p>Sex is a key variable in the regulation of human physiology and pathology. Many diseases disproportionately affect one sex: autoimmune diseases, such as systemic lupus erythematosus, are more common in women but more severe in men, whereas the incidence of other disorders such as gouty arthritis and malignant cancers is higher in men. Besides the pathophysiology, sex may also influence the efficacy of therapeutics; participants in clinical trials are still predominately men, and the side effects of drugs are more common in women than in men. Sex dimorphism is a prominent feature of kidney physiology and function, and consequently affects the predisposition to many adult kidney diseases. These differences subsequently influence the response to immune stimuli, hormones, and therapies. It is highly likely that these responses differ between the sexes. Therefore, it becomes imperative to consider sex differences in translational science from basic science to preclinical research to clinical research and trials. Under-representation of one sex in preclinical animal studies or clinical trials remains an issue and key reported outcomes of such studies ought to be presented separately. Without this, it remains difficult to tailor the management of kidney disease appropriately and effectively. In this review, we provide mechanistic insights into sex differences in rodents and humans, both in kidney health and disease, highlight the importance of considering sex differences in the design of any preclinical animal or clinical study, and propose guidance on how to optimal design and conduct preclinical animal studies in future research.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":3.784,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T Alp Ikizler, Tilman B Drueke, Jürgen Floege, Germaine Wong
{"title":"Avoiding arrythmias by personalizing the dialysate concentration: a case for precision medicine in patients on dialysis.","authors":"T Alp Ikizler, Tilman B Drueke, Jürgen Floege, Germaine Wong","doi":"10.1016/j.kint.2024.10.009","DOIUrl":"10.1016/j.kint.2024.10.009","url":null,"abstract":"<p><p>Cardiac arrythmias are common in patients undergoing maintenance hemodialysis. In this issue, Charytan et al. showed that in patients with hyperkalemia (serum potassium concentration 5.1-6.5 mEq/l) on hemodialysis, a dialysate concentration of 3 mEq/l combined with sodium zirconium cyclosilicate on dialysis-free days is associated with a low frequency of atrial fibrillation compared with a dialysate concentration of 2 mEq/l over 8 weeks. Despite the obvious limitations such as small sample size, short treatment period, and absence of information on longer-term impact regarding patient important outcomes such as sudden death, this well-conceived pilot study provided impetus for larger prospective trials to test whether this personalized approach reduces major cardiovascular events and mortality.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David M Charytan, Wolfgang C Winkelmayer, Christopher B Granger, John P Middleton, Charles A Herzog, Glenn M Chertow, James M Eudicone, Jeremy D Whitson, James A Tumlin
{"title":"Effects of dialysate potassium concentration of 3.0mEq/l with sodium zirconium cyclosilicate on dialysis-free days versus dialysate potassium concentration of 2.0mEq/l alone on rates of cardiac arrhythmias in hemodialysis patients with hyperkalemia.","authors":"David M Charytan, Wolfgang C Winkelmayer, Christopher B Granger, John P Middleton, Charles A Herzog, Glenn M Chertow, James M Eudicone, Jeremy D Whitson, James A Tumlin","doi":"10.1016/j.kint.2024.10.010","DOIUrl":"10.1016/j.kint.2024.10.010","url":null,"abstract":"<p><p>The optimal approach towards managing serum potassium and hemodialysate potassium concentrations is uncertain. To study this, adults receiving hemodialysis for three months or more with hyperkalemia (pre-dialysis serum potassium (sK<sup>+</sup>) 5.1-6.5 mEq/l) had cardiac monitors implanted and were randomized to either eight weeks of 2.0 potassium/2.5 calcium mEq/l dialysate without sodium zirconium cyclosilicate (SZC) (2.0 potassium/noSZC) or 3.0 potassium/2.5 calcium mEq/l dialysate combined with SZC (3.0 potassium/SZC) on non-dialysis days to maintain pre-dialysis sK<sup>+</sup> 4.0-5.5 mEq/l, followed by treatment crossover for another eight weeks. The primary outcome was the rate of adjudicated atrial fibrillation (AF) episodes of 2 minutes or more duration. Secondary outcomes included clinically significant arrhythmias (bradycardia, ventricular tachycardia, and/or asystole) and the proportion of sK<sup>+</sup> measurements within an optimal window of 4.0-5.5 mEq/l. Among 88 participants (mean age: 57.1 years; 51% male; mean pre-dialysis sK<sup>+</sup>: 5.5 mmol/l) with 25.5 person-years of follow-up, 296 AF episodes were detected in nine patients. The unadjusted AF rate was lower with 3.0 potassium/SZC versus 2.0 potassium/noSZC; 9.7 vs. 13.4/person-year (modeled rate ratio 0.52; 95% confidence interval: 0.41; 0.65). Clinically significant arrhythmias were reduced with 3.0 potassium/SZC vs. 2.0 potassium/noSZC 6.8 vs. 10.2/person-year modeled rate ratio 0.47: 0.38;0.58). Fewer sK<sup>+</sup> measurements outside the optimal window occurred with 3.0 potassium/SZC (modeled odds ratio: 0.27:0.12, 0.35). Hypokalemia was less frequent (33 vs. 58 patients) with 3.0 potassium/SZC compared with 2.0 potassium/noSZC. Thus, in patients with hyperkalemia on maintenance hemodialysis, a combination of potassium 3.0 mEq/l and SZC on non-hemodialysis days reduced the rates of AF, other clinically significant arrhythmias, and post-dialysis hypokalemia compared with potassium 2.0/noSZC.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Higher intraoperative blood pressure does not reduce acute kidney injury in noncardiac surgery: what do the results of the POISE-3 trial tell us?","authors":"Nicholas M Selby, Lui G Forni","doi":"10.1016/j.kint.2024.10.011","DOIUrl":"10.1016/j.kint.2024.10.011","url":null,"abstract":"<p><p>Hypotension is a common cause of acute kidney injury (AKI), with strong associations between the duration and magnitude of hypotension seen across a range of situations including major surgery. However, it is less clear whether targeting higher intraoperative MAP results in lower rates of AKI. In a prespecified analysis of the Perioperative Ischemic Evaluation-3 (POISE-3) randomized controlled trial, this question is addressed for noncardiac major surgery. Despite an increase in cessation of antihypertensive medications and higher intraoperative mean arterial blood pressure in the intervention arm, no differences were seen in the rates of postoperative AKI. This commentary discusses the strengths and weaknesses of the trial, as well as providing some interpretation of results and their relevance to clinical practice.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A sub-study of the POISE-3 randomized trial examined effects of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of acute kidney injury.","authors":"","doi":"10.1016/j.kint.2024.10.007","DOIUrl":"10.1016/j.kint.2024.10.007","url":null,"abstract":"<p><p>In this pre-specified sub-study of the POISE-3 trial, we examined the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of postoperative acute kidney injury (AKI). Altogether, 7307 patients were included from 110 hospitals in 22 countries. Patients were 45 years and older, had or were at risk of atherosclerotic disease, took at least one antihypertensive medication, and were scheduled for noncardiac surgery. Hypotension-avoidance strategy: (i) target intraoperative mean arterial pressure (MAP) 80 mm Hg or over, (ii) on day of surgery and for two days after, hold renin-angiotensin-aldosterone system inhibitors and use other antihypertensives in stepwise fashion if systolic blood pressure (SBP) 130 mm Hg or more. Hypertension-avoidance strategy: (i) target intraoperative MAP 60 mm Hg or more, (ii) continue all antihypertensives before and after surgery. Primary outcome: postoperative AKI, an increase in serum creatinine concentration of either 26.5 μmol/L or more (0.3 mg/dL or more) within 48 hours of randomization or 50% or more within seven days of randomization. The hypotension-avoidance group (3654 patients) used fewer antihypertensive medications than the hypertension-avoidance group (3653 patients); specifically, 6% vs. 38% used an ACEI or ARB on the day of surgery, and 6% vs. 47% and 7% vs. 50% one and two days after surgery, respectively. Patients also spent about half as much intraoperative time with a MAP under 80 mm Hg (27 vs. 60 minutes, respectively), but had little difference in average BP before or after surgery. There was no significant difference in AKI risk (15.1% vs. 14.4%). Results were consistent with other definitions of AKI and in patients with preexisting chronic kidney disease. Thus, a hypotension-avoidance strategy targeting a MAP greater than 80 mm Hg in the operating room and discontinued blood pressure medication during the perioperative period did not confer a lower risk of AKI compared to a hypertension avoidance strategy. Clinical trial registration number: NCT03505723.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}