Freely Filtered, a NephJC Podcast

The Filtrate Joel Topf Bluesky: @kidneyboy.bsky.social‬ [https://bsky.app/profile/kidneyboy.bsky.social] Jordy Cohen Bluesky: @jordybc.bsky.social‬ [https://bsky.app/profile/jordybc.bsky.social] Swapnil Hiremath Bluesky: @hswapnil.medsky.social‬ [https://bsky.app/profile/hswapnil.medsky.social] Special Guest Edouard “call me Ed” Fu Assistant Professor and Medical Student, and second author of his second paper covered on NephJC. LinkedIn [https://www.linkedin.com/in/edouardfu/] | Leiden University Medical Center [https://www.lumc.nl/en/afdelingen/Clinical-Epidemiology/el-fu/] Editing by Simon Topf and Sophia Ambruso The Kidney Connection written and performed by by Tim Yau Show Notes Ed’s first paper on NephJC: Timing of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study (NephJC [https://www.nephjc.com/news/dialysis-timing] | BMJ [https://pubmed.ncbi.nlm.nih.gov/34844936/]) Phenformin Wikipedia [https://en.wikipedia.org/wiki/Phenformin] | Boca Raton News [https://news.google.com/newspapers?nid=1291&dat=19770726&id=mt4PAAAAIBAJ&pg=4457,3796314] The metformin black box (as part of the FDA Label [https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf]) WARNING: LACTIC ACIDOSIS Postmarketing 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 2022 [https://jamanetwork.com/journals/jama/fullarticle/2799678] Stopping Versus Continuing Metformin in Patients With Advanced CKD: A Nationwide Scottish Target Trial Emulation Study (NephJC [https://www.nephjc.com/news/metformin-tte] | PubMed [https://pubmed.ncbi.nlm.nih.gov/39521399/]) Toxicokinetics of Metformin During Hemodialysis (KI Reports [https://www.kireports.org/article/S2468-0249(17)30050-5/pdf]) Metformin in People With Diabetes and Advanced CKD: Should We Dare? Editorial that ran in AJKD along side the Lambourg manuscript (AJKD [https://www.ajkd.org/article/S0272-6386(24)01053-9/fulltext]) Immortal Time Bias in Cohort Studies of Kidney Transplant Recipients (Kim SJ Amer J Trans [https://www.amjtransplant.org/article/S1600-6135(22)19560-2/fulltext] 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 [https://journals.lww.com/jasn/fulltext/2023/08000/target_trial_emulation_to_improve_causal_inference.5.aspx] 2023) Ed’s Grand Rounds at Ottawa on YouTube [https://www.youtube.com/watch?v=6L3-0I1EEGM]. 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 [https://pmc.ncbi.nlm.nih.gov/articles/PMC7265880/] 2000 Review 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 [https://pubmed.ncbi.nlm.nih.gov/33186321/] 2021 Figure S5: Weighted cumulative incidence curves for MACE, by treatment strategy The S4 image that Swap loved Tubular Secretions Jordy Andor Season 2 on Disney+ (Wikipedia [https://en.wikipedia.org/wiki/Andor_(TV_series)]) Swapnil Murderbot on Apple TV+ (Wikipedia [https://en.wikipedia.org/wiki/Murderbot_(TV_series)]) Eduoard: New house and grant Grant Grant (Wikipedia [https://en.wikipedia.org/wiki/Koyaanisqatsi]) Joel Topf Three Body Problem Audio book (Audible [https://www.audible.com/pd/The-Three-Body-Problem-Audiobook/B0BVW67D5L?ds_rl=1261256&gad_campaignid=16881025087&gad_source=1&gclid=Cj0KCQjwj8jDBhD1ARIsACRV2TsaYXXLd95CQeptTDl2TICfVUdOlDu8jvQv5qYT_QLqECcYjJ7psUoaAlS-EALw_wcB&gclsrc=aw.ds&source_code=GPAGBSH0508140001&source_code=GO1PP30DTRIAL54703142491H0])

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 [https://notebooklm.google]. 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 Captopril@NephJC.com [Captopril@NephJC.com] This 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 [https://notebooklm.google]. 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 Captopril@NephJC.com [Captopril@NephJC.com] This 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 Filtrate Joel Topf AC Gomez Sophia Ambruso Nayan Arora Special Guest Charles Edelstein, MD, PhD Professor, Medicine-Renal Med Diseases/Hypertension Extra-Special Guest Michelle Rheault, MD Professor of Pediatrics, University of Minnesota Editing by Simon and Joel Topf The Kidney Connection written and performed by by Tim Yau Show Notes KDIGO ADPKD Guidelines: Website [https://kdigo.org/guidelines/autosomal-dominant-polycystic-kidney-disease-adpkd/] Guideline [https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline.pdf] PDF Executive Summary [https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf] PDF NephJC [/news/adpkd-kdigo2025] coverage Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP [https://repository.niddk.nih.gov/study/10]) Hy’s Law (Wikipedia [https://en.wikipedia.org/wiki/Hy%27s_law]) has three components: ALT or AST by 3-fold or greater above the upper limit of normal And 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 injury Meeting 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 [https://pmc.ncbi.nlm.nih.gov/articles/PMC4608984/]) 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 [https://pubmed.ncbi.nlm.nih.gov/35314480/]) 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 [https://www.nejm.org/doi/full/10.1056/NEJMoa1205511]) Reprise Trial Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease ( NEJM [https://www.nejm.org/doi/full/10.1056/NEJMoa1710030] | NephJC [/news/reprise] ) Unified ultrasonographic diagnostic criteria for polycystic kidney disease by Edelstein in JASN (PubMed [https://pubmed.ncbi.nlm.nih.gov/19073819/]) 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 [https://pmc.ncbi.nlm.nih.gov/articles/PMC10220412/#:~:text=Based%20on%20the%20present%20study,with%20evidence%20of%20rapid%20progression.]) 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 [https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1470309/full]) 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 [https://www.nejm.org/doi/full/10.1056/NEJMoa1402685]) 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 [https://pmc.ncbi.nlm.nih.gov/articles/PMC6682822/]) Surgical Clipping Versus Endovascular Coiling in the Management of Intracranial Aneurysms (PubMed [https://pmc.ncbi.nlm.nih.gov/articles/PMC8760002/]) 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 [https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02266-0]) Navitor Pharmaceuticals Announces Janssen Has Acquired Anakuria Therapeutics, Inc. (BioSpace [https://www.biospace.com/navitor-pharmaceuticals-announces-janssen-has-acquired-anakuria-therapeutics-inc#:~:text=AT%2D20494%20is%20an%20orally%20bioavailable%20small%20molecule,diseases%20including%20autosomal%20dominant%20polycystic%20kidney%20diseases.]) 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 [https://www.kireports.org/article/S2468-0249(25)00048-8/fulltext]) 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 [https://pubmed.ncbi.nlm.nih.gov/39455729/]) Tubular Secretions Nayan: Landman on Paramount Plus (IMDB [https://www.imdb.com/title/tt14186672/]) Sophia: Pass Nayan: steps in with The Pitt on HBO (Wikipedia [https://en.wikipedia.org/wiki/The_Pitt]) Charles: The White Lotus, Yellowstone 1923, Poirot (IMDB [https://www.imdb.com/title/tt0094525/]) AC: The Pitt Michael Crichton’s Estate Sends The Pitt to the Courtroom (Vulture [https://www.vulture.com/article/er-the-pitt-lawsuit-everything-we-know.html]) Joel: I Must Betray you by Ruta Sepetys (Amazon [https://www.amazon.com/Must-Betray-You-Ruta-Sepetys/dp/198483603X])

The Filtered Fragments (OG Filtrate) Joel Topf Jennie Lin Swapnil Hiremath Special Guest Brad Rovin [https://wexnermedical.osu.edu/find-a-doctor/brad-rovin-md-1348] GN God and second author from The Ohio State Koyal Jain [https://www.med.unc.edu/medicine/nephrology-hypertension/people/koyal-jain/] GN Specialist from UNC Alfred Kim [https://physicians.wustl.edu/people/alfred-kim-md-phd/] Rheumatologist from Washington University Editing by Simon Topf and Nayan Arora The Kidney Connection written and performed by by Tim Yau Show Notes Joel’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 antibody Two. It’s cytotoxicity is not complement dependent an particular advantage if you want to deploy it ina disease where hypocomplementemia is a disease characteristic Three, 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 Pubmed [https://pubmed.ncbi.nlm.nih.gov/22231479/] EXPLORER: 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 Pubmed [https://pubmed.ncbi.nlm.nih.gov/20039413/] REGENCY: Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis NEJM [https://www.nejm.org/doi/full/10.1056/NEJMoa2410965] | NephJC [https://www.nephjc.com/news/regency-obi-ln-prnn2] NOBILITY: B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial Annals of Rheumatic Disease [https://ard.bmj.com/content/81/1/100] Comparison of intravenous and subcutaneous exposure supporting dose selection of subcutaneous belimumab systemic lupus erythematosus Phase 3 program PubMed Central [https://pmc.ncbi.nlm.nih.gov/articles/PMC5054300/] Class 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 abstract [https://acrabstracts.org/abstract/long-term-use-of-voclosporin-in-patients-with-class-v-lupus-nephritis-results-from-the-aurora-2-continuation-study/#:~:text=Patients%20with%20Class%20V%20lupus%20nephritis%20may,reduce%20proteinuria%20in%20this%20population%20are%20needed.&text=Conclusion:%20Voclosporin%2Dtreated%20patients%20with%20pure%20and%20mixed,treated%20with%20MMF%20and%20low%2Ddose%20steroids%20alone.] Tubular Secretions Swap: Young Adult novel I Must Betray You by Ruta Sepetys (Amazon [https://www.amazon.com/Must-Betray-You-Ruta-Sepetys/dp/1984836048/ref=asc_df_1984836048?mcid=d3c09a725eca38d8b48ee05239b1adff&hvocijid=11413289357258037967-1984836048-&hvexpln=73&tag=hyprod-20&linkCode=df0&hvadid=721245378154&hvpos=&hvnetw=g&hvrand=11413289357258037967&hvpone=&hvptwo=&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9016826&hvtargid=pla-2281435179778&psc=1]) Koyal: Taekwondo (Wikipedia [https://en.wikipedia.org/wiki/Taekwondo]) Jennie: these unprecedented times Trump NYT: Administration Freezes $1 Billion for Cornell and $790 Million for Northwestern, Officials Say [https://www.nytimes.com/2025/04/08/us/politics/cornell-northwestern-university-funds-trump.html] Al: Acquired Podcast [https://www.acquired.fm] Brad: The Feather Thief by Kirk Wallace Johnson (Amazon [https://www.amazon.com/Feather-Thief-Obsession-Natural-History/dp/110198161X]) Joel: Paradise on Hulu (Wikipedia [https://en.wikipedia.org/wiki/Paradise_(2025_TV_series)])