FF 81 Metformin Termination as explored by Target Trial Emulation

The FiltrateJoel Topf Bluesky: @kidneyboy.bsky.social‬Jordy Cohen Bluesky: @jordybc.bsky.social‬Swapnil Hiremath Bluesky: @hswapnil.medsky.social‬Special Guest Edouard “call me Ed” Fu Assistant Professor and Medical Student, and second author of his second paper covered on NephJC. LinkedIn | Leiden University Medical CenterEditing bySimon Topf and Sophia AmbrusoThe Kidney Connection written and performed by by Tim YauShow NotesEd’s first paper on NephJC: Timing of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study (NephJC | BMJ)Phenformin Wikipedia | Boca Raton NewsThe metformin black box (as part of the FDA Label)WARNING: LACTIC ACIDOSISPostmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metforminassociated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see PRECAUTIONS).Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and PRECAUTIONS).If metformin-associated lactic acidosis is suspected, immediately discontinue metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS).Target Trial Emulation A Framework for Causal Inference From Observational Data. Miguel A. Hernán, MD, DrPH; Wei Wang, PhD; David E. Leaf, MD JAMA 2022Stopping Versus Continuing Metformin in Patients With Advanced CKD: A Nationwide Scottish Target Trial Emulation Study (NephJC | PubMed)Toxicokinetics of Metformin During Hemodialysis (KI Reports)Metformin in People With Diabetes and Advanced CKD: Should We Dare? Editorial that ran in AJKD along side the Lambourg manuscript (AJKD)Immortal Time Bias in Cohort Studies of Kidney Transplant Recipients (Kim SJ Amer J Trans 2010)Ed’s Target trial review in JASN which Jordy mentioned and includes an explanation of the obesity paradox by depletion of the susceptibles. (Fu JASN 2023)Ed’s Grand Rounds at Ottawa on YouTube. Very good.Response by Cohen et al to Letter Regarding Article, “Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19” by Jordy and the crew Circ Res 2000Review article on the issue: Evaluating sources of bias in observational studies of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use during COVID-19: beyond confounding Jordy and a different crew J Hyperten 2021Figure S5: Weighted cumulative incidence curves for MACE, by treatment strategyThe S4 image that Swap lovedTubular SecretionsJordy Andor Season 2 on Disney+ (Wikipedia)Swapnil Murderbot on Apple TV+ (Wikipedia)Eduoard: New house and grant Grant Grant (Wikipedia)Joel Topf Three Body Problem Audio book (Audible)

One of NephJC signature moves has been to adapt new technologies and communication techniques to delivering state of the art nephrology education. Podcasts, Visual Abstracts, Tweetorials. NephJC has been on the front of these waves. Clearly one of the most exciting and controversial new technologies is artificial intelligence and it is unclear what role it may play in the NephJC educational package. Our blogs and tweets are written entirely by human minds but it is inevitable that as AI becomes the spellcheck of the 2020s, that it will leach into all of our writing. One AI tool that intrigues us is Google’s NotebookLM. This product can create podcasts from source documentation. We plan on publishing a podcast before each chat. We are fact checking them before publication, but some mistakes may slip through. Please send you feedback, we want to know what you think of this. As always, the email is [email protected] will supplement and not replace Freely Filtered. One possible future move is to separate out both podcasts to individual feeds, but for now they will piggyback on each other.

One of NephJC signature moves has been to adapt new technologies and communication techniques to delivering state of the art nephrology education. Podcasts, Visual Abstracts, Tweetorials. NephJC has been on the front of these waves. Clearly one of the most exciting and controversial new technologies is artificial intelligence and it is unclear what role it may play in the NephJC educational package. Our blogs and tweets are written entirely by human minds but it is inevitable that as AI becomes the spellcheck of the 2020s, that it will leach into all of our writing. One AI tool that intrigues us is Google’s NotebookLM. This product can create podcasts from source documentation. We have done a couple of dry runs converting our blogs into novel, low-effort, podcasts with impressive results. So, at least for now, we plan on publishing a podcast before each chat. We are fact checking them before publication, but some mistakes may slip through. Please send you feedback, we want to know what you think of this. As always, the email is [email protected] will supplement and not replace Freely Filtered. One possible future move is to separate out both podcasts to individual feeds, but for now they will piggyback on each other.

The FiltrateJoel TopfAC GomezSophia AmbrusoNayan AroraSpecial Guest Charles Edelstein, MD, PhD Professor, Medicine-Renal Med Diseases/HypertensionExtra-Special GuestMichelle Rheault, MD Professor of Pediatrics, University of MinnesotaEditing bySimon and Joel TopfThe Kidney Connection written and performed by by Tim YauShow NotesKDIGO ADPKD Guidelines:WebsiteGuideline PDFExecutive Summary PDFNephJC coverageConsortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP)Hy’s Law (Wikipedia) has three components:ALT or AST by 3-fold or greater above the upper limit of normalAnd total serum bilirubin of greater than 2× the upper limit of normal, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2× the upper limit of normal)And no other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injuryMeeting this definition yields a very high risk of fulminant kidney failure (76% in one series)Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database (PubMed) Two of 957 patients on tolvaptan met Hy’s law criteria. None had fulminant kidney failure.Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial (PubMed) Patients had a baseline urine volume on tolvaptan of 6.9 L/24 h. Urine volume decreased to 5.1 L/24 h with hydrochlorothiazide and to 5.4 L/24 h on metformin.TEMPO 3:4 Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (NEJM)Reprise Trial Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease ( NEJM | NephJC )Unified ultrasonographic diagnostic criteria for polycystic kidney disease by Edelstein in JASN (PubMed)Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies (PubMed)Charles’ draft choice Recommendation 4.1.1.1: We recommend initiating tolvaptan treatment in adults with ADPKD with an estimated glomerular filtration rate (eGFR) ‡25 ml/min per 1.73 m2 who are at risk for rapidly progressive disease (1B).Sophia’s draft choice Recommendation 1.4.2.1: We recommend employing the Mayo Imaging Classi cation (MIC) to predict future decline in kidney function and the timing of kidney failure (1B).Progression to kidney failure in ADPKD: the PROPKD score underestimates the risk assessed by the Mayo imaging classification (Frontiers of Science)AC’s draft choice Recommendation 9.2.1: We recommend targeting BP to ≤ 50th percentile for age, sex, and height or ≤ 110/70 mm Hg in adolescents in the setting of ADPKD and high BP (1D).HALT-PKD Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease (NEJM)Nayan’s draft choice Recommendation 6.1.2: We recommend screening for ICA in people with ADPKD and a personal history of SAH or a positive family history of ICA, SAH, or unexplained sudden death in those eligible for treatment and who have a reasonable life expectancy (1D).Screening for Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease (CJASN)Surgical Clipping Versus Endovascular Coiling in the Management of Intracranial Aneurysms (PubMed) Clipping is associated with a higher rate of occlusion of the aneurysm and lower rates of residual and recurrent aneurysms, whereas coiling is associated with lower morbidity and mortality and a better postoperative course.Joel’s editorial pick Recommendation 6.1.1: We recommend informing adults with ADPKD about the increased risk for intracranial aneurysms (ICAs) and subarachnoid hemorrhage (1C).Joel’s first draft pick The bring out your dead pick:Recommendation 4.3.1: We recommend not using mammalian target of rapamycin (mTOR) inhibitors to slow kidney disease progression in people with ADPKD (1C).Recommendation 4.4.1: We suggest not using statins specfiically to slow kidney disease progression in people with ADPKD (2D).Recommendation 4.5.1: We recommend not using metformin specifically to slow the rate of disease progression in people with ADPKD who do not have diabetes (1B).Recommendation 4.6.1: We suggest that somatostatin analogues should not be prescribed for the sole purpose of decreasing eGFR decline in people with ADPKD (2B).Perfect match: mTOR inhibitors and tuberous sclerosis complex (Orphanet Journal of Rare Diseases)Navitor Pharmaceuticals Announces Janssen Has Acquired Anakuria Therapeutics, Inc. (BioSpace) This is press release about acquiring the mTor1 inhibitor.Joel’s second draft pick Recommendation 4.2.1.1: We suggest adapting water intake, spread throughout the day, to achieve at least 2–3 liters of water intake per day in people with ADPKD and an eGFR ≥ 30 ml/min per 1.73 m2 without contraindications to excreting a solute load (2D).Nayan’s bonus draft Practice Point 4.7.1: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) should not be used to slow eGFR decline in people with ADPKD.Open-Label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients With ADPKD Receiving Tolvaptan (KIReports)SMART Trial of GLP-1ra in non-diabetics: Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial (PubMed)Tubular SecretionsNayan: Landman on Paramount Plus (IMDB)Sophia: PassNayan: steps in with The Pitt on HBO (Wikipedia)Charles: The White Lotus, Yellowstone 1923, Poirot (IMDB)AC: The PittMichael Crichton’s Estate Sends The Pitt to the Courtroom (Vulture)Joel: I Must Betray you by Ruta Sepetys (Amazon)

The Filtered Fragments (OG Filtrate)Joel TopfJennie LinSwapnil HiremathSpecial Guest Brad Rovin GN God and second author from The Ohio StateKoyal Jain GN Specialist from UNCAlfred Kim Rheumatologist from Washington UniversityEditing bySimon Topf and Nayan AroraThe Kidney Connection written and performed by by Tim YauShow NotesJoel’s monologue One of the most surprising facts of nephrology is that despite conventional wisdom that lupus nephritis is an antibody mediated disease, that over a decade ago, the LUNAR investigtors were unable to find a significant benefit when rituximab was added to conventional therapy. And this was after the equally negative phase 2 trial of rituximab, EXPLORER.In fact, despite this finding rituximab has been able to burough its way into treatment of many nephrologists and rheumatologists as well as the KDIGO guidelines where it is suggested for patients with persistent disease activity or inadequate response to initial standard-of-care therapy.This long conflict is now coming to an end. Obinutuzumab, a newer, better monoclonal antibody targeting the same CD20 that we grew to love with rituximab, but it has a number of advantages.One. It is humanized antibody rather than a chimeric mouse-human antibodyTwo. It’s cytotoxicity is not complement dependent an particular advantage if you want to deploy it ina disease where hypocomplementemia is a disease characteristicThree, and most importantly, it causes stronger and deeper b-cell depletion than rituximab. Better B-cell depletion in the blood and tissue.And this brings us to tonight’s topic, we had already seen the phase two results of obinutuzumab which, unlike EXPLORER, were positive, we will look at the phase three  regency trial. This makes the third novel lupus nephritis drug in the last 4 years. We continue to remake glomerular nephritis.LUNAR: Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study PubmedEXPLORER: Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial PubmedREGENCY: Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis NEJM | NephJCNOBILITY: B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial Annals of Rheumatic DiseaseComparison of intravenous and subcutaneous exposure supporting dose selection of subcutaneous belimumab systemic lupus erythematosus Phase 3 program PubMed CentralClass 5 lupus nephritis is slow to respond Long-term Use of Voclosporin in Patients with Class V Lupus Nephritis: Results from the AURORA 2 Continuation Study ACR Meeting abstractTubular SecretionsSwap: Young Adult novel I Must Betray You by Ruta Sepetys (Amazon)Koyal: Taekwondo (Wikipedia)Jennie: these unprecedented times Trump NYT: Administration Freezes $1 Billion for Cornell and $790 Million for Northwestern, Officials SayAl: Acquired PodcastBrad: The Feather Thief by Kirk Wallace Johnson (Amazon)Joel: Paradise on Hulu (Wikipedia)

The FiltrateJoel TopfJordy CohenNayan AroraSpecial Guest Katie Kwon @katiekwonmd.bsky.socialMariana Murea @MarianaMureaEditing bySimon Topf and Joel TopfShow NotesNephMadness at AJKDblog.orgThe Hemodialysis RegionVote for your favorites

The FiltrateJoel TopfSwapnil HiremathAC GomezSopia AmbrusoNayan AroraSpecial Guests Michelle Rheault, Director, Division of Pediatric Nephrology, Professor of MedicineTiffany Caza, Nephropathologist, Scientist and self-described Freely Filtered fan girlEditing bySimon Topf and Sophia AmbrusoShow Notes10. Healthcare Cyberattacks9. ApoE in C3 glomerulonephropathy8. Workforce woes in Adult and Pediatric Nephrology7. Hyponatremia correction meta-analysis6. Microvascular inflammation increases risk of graft loss - in all of its forms5. Xenotransplantation4. KDIGO CKD Guidelines3. Hypertension control trials (ESPRIT, BPROAD)2. The Renaissance of IgAN: IgAN treatment trials1. FLOW: GLP-1 RAs in CKD

The FiltrateJoel TopfSwapnil HiremathAC GomezJordy CohenNayan AroraSpecial Guest Brendon NuenEditing bySimon Topf and Nayan AroraShow NotesFINEARTS-HF in NEJM FINEARTS Kidney outcomes in JACCFINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes in Nature Medicine discussion in NephJC BARACH-D: Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial (Nature Medicine)Live Freely Filtered at KidneyWkSwapnil comes out as a SpiroStan post to NephJC TOPCATTOPCAT primary publication TOPCAT North American results TOPCAT funny business explained AHA/ACC/HFSA Heart Failure Guidelines (PDF)SGLT2i are 2aMRA are a 2bARBs are a 2bARNI are a 2bClinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to SpironolactoneKansas city cardiomyopathy questionnaire in patients with CKD without a diagnosis of heart failure: https://pubmed.ncbi.nlm.nih.gov/21187260/GFR slope with steroidal MRAs in HF: https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2635Why Has it Been Challenging to Modify Kidney Disease Progression in Patients With Heart Failure? (JACC)Tubular SecretionsSwap: Disclaimer on Apple TVAC: Duo Lingo Plushy (Amazon)Nayan: The Puzzle BoxJordy: Project Hail MaryBrendon has a podcast, The Kidney Compass with Shikha Wadhwani. And he recommends singer-songwriter, Maggie Rogers (YouTube)Joel: The Singularity Is Nearer: When We Merge with AI by Ray KurzweilClosing music, Tim Yau with The Kidney Connection

The Filtrate:Joel TopfSwapnil HiremathWith Special Guest:Michelle Hladunewich, Nephrologist at the University of TorontoMir Melamed, Maternal-Fetal Medicine at the University of TorontoEditor Simon TopfShow NotesPriscilla Smith’s letter:Dear Joel and the Freely Filtered team,I am a long-time fan of your podcast and was looking forward to hearing your recently aired discussion of the Praecis study of sflt1:PlGF use in preeclampsia. Preeclampsia and renal disease in pregnancy are areas that many nephrologists report a lack of knowledge or confidence in discussing and managing. I am a nephrologist who has been co-leading a renal pregnancy clinic in London while writing a PhD on progression of renal disease in pregnancy. I have had the immense privilege of working with experts and key opinion leaders in preeclampsia research both in the UK and internationally. As you know, preeclampsia is a serious and significant condition contributing to global maternal mortality and is also associated with future CKD and CVD risk so is both relevant and important within our professional group.Sadly, I found myself disappointed by the episode and felt it was a missed opportunity. I appreciate that you had difficulties obtaining appropriate experts to join the discussion, but perhaps it would have been better to delay production. While you all valiantly proceeded to discuss this important study, the topic is complex and there appeared to be a lack of understanding of the surrounding literature and pathogenesis of preeclampsia. Sadly, the maternal medicine expert’s comments at the end of the podcast added little as she seemed determine to negate any benefit from the results despite declaring she had no experience or expertise in the use of these biomarkers.There are many people who understand the clinical aspects of preeclampsia as well as having direct experience of the use and utility of these biomarkers who would have been able to contribute much to your conversation. I look forward to future discussions of renal disease in pregnancy on your podcast and would be happy to suggest some expert panellists if you ever find yourself stuck.Kind regards,Priscilla Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia (JCI 2003)sFlt background: Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta (PubMed)PlGF background: Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps (PubMed)The PRAECIS trial (NephJC | NEJM Evidence)

We had a great NephJC get together. We recorded the whole event and packaged it into a podcast.Musical entertainmentTim Yau (@Maximal_Change)Too Sweet by HozierFairy Tale of New York by written Jem Finer and Shane MacGowan. Hear it performed by the Pogues.Interview of Tom MuellerTom Mueller author of How to Make a KillingJade Teakall@jmteakellGraham Abra@GrahamAbraInterview of Tom MuellerTom Mueller author of How to Make a KillingJade Teakall @jmteakellGraham Abra @GrahamAbraNephMadness logo revealNephJC KidneysNephJC blog postNephJC Manuscript of the Year: Flow accepted by Meg JardineManjula Kurella Tamura, winner of the 2015 NephMadness, oh and author of NEJM manuscripts and subject of a NYT article.NephJC Visual Abstract of the Year: Corina Teodusiu, creator of the Flozinator logoNephJC Social Justice Award: ISN petition to the WHO on Kidney HealthMost Engaged Scientist Award: Michelle RheaultRookie of the Year: Milagros FloresMVP: Christina PopaNephJC Founders Award: Joshua WaitzmanNathan Hellman Social Media Project of the Year: Edgar Lerma and the ASN Visual Abstract TeamMore Music with TimSaginaw, Michigan as performed by Johny CashBetty, written by Taylor SwiftThe Kidney ConnectionFreely Filtered Kidney Week DraftPrevious drafts2021 ASN Kidney Week Draft2022 ASN Kidney Week Draft2023 ASN Kidney Week DraftList of all the simultaneous publications from Kidney Week 2024Sophia: SMART Trial (Link goes to the new KidneyCompass podcast that interview lead author Hiddo HeerspinkJordy’s editorial in the European Heart Journal. LinkJosh: APPLAUSE Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy in the NEJMAPPLAUSE results announcement at The World Congress of Neophrology in Buenos AriesIptapocan is a factor B inhibitionJordy: POISE-3 with simultaneous publication in KIMentions she wanted to pick KAT-AKI because she worked with Perry Wilson.Per Nayan, Amit Garg is the Beyonce of NephrologyAccord Trial (NEJM)Joel: HSK21541 for PruritusCorrection link to source (graph)Nayan: FINEARTS-HF with simultaneous publication in JACCBARACH-D: Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial (Nature Medicine)Swapnil comes out as a SpiroStanTOPCAT funny businessPATHWAY-2 Trial (NephJC coverage)Swap: K Bath and cardiac arrhythmia with simultaneous publication in Kidney InternationalCAST: A study that rocked the cardiology world and became the poster child for evidence-based medicine (Link)Tubular SecretionsSwap: Late breaking and high impact sessionsNayan: Intro to…Joel: Student poster on blood pressure techniqueJordy: The Penguin. A couple of mentee postersSophie: Tracks her sessions on paper.Josh: Quiz and Questionaire session with JC Velez, Bea Concepcione, Anna Burgner, Roger Rodby.