The Filtrate

Joel Topf Bluesky: @kidneyboy.bsky.social‬

Jordy Cohen Bluesky: @jordybc.bsky.social‬

Swapnil Hiremath Bluesky: @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 | Leiden University Medical Center

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 | BMJ)

Phenformin Wikipedia | Boca Raton News

The metformin black box (as part of the FDA Label)

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

Stopping 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 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 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)

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]

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. 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]

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

Guideline PDF

Executive Summary PDF

NephJC coverage

Consortium 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 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) 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 Secretions

Nayan: Landman on Paramount Plus (IMDB)

Sophia: Pass

Nayan: steps in with The Pitt on HBO (Wikipedia)

Charles: The White Lotus, Yellowstone 1923, Poirot (IMDB)

AC: The Pitt

Michael 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 Topf

Jennie Lin

Swapnil Hiremath

Special Guest

Brad Rovin GN God and second author from The Ohio State

Koyal Jain GN Specialist from UNC

Alfred Kim 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

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

REGENCY: Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis NEJM | NephJC

NOBILITY: B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial Annals of Rheumatic Disease

Comparison of intravenous and subcutaneous exposure supporting dose selection of subcutaneous belimumab systemic lupus erythematosus Phase 3 program PubMed Central

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

Tubular Secretions

Swap: 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 Say

Al: Acquired Podcast

Brad: The Feather Thief by Kirk Wallace Johnson (Amazon)

Joel: Paradise on Hulu (Wikipedia)

The Filtrate

Joel Topf

Jordy Cohen

Nayan Arora

Special Guest

Katie Kwon @katiekwonmd.bsky.social

Mariana Murea @MarianaMurea

Editing by

Simon Topf and Joel Topf

Show Notes

NephMadness at AJKDblog.org

The Hemodialysis Region

Vote for your favorites

The Filtrate

Joel Topf

Swapnil Hiremath

AC Gomez

Sopia Ambruso

Nayan Arora

Special Guests

Michelle Rheault, Director, Division of Pediatric Nephrology, Professor of Medicine

Tiffany Caza, Nephropathologist, Scientist and self-described Freely Filtered fan girl

Editing by

Simon Topf and Sophia Ambruso

Show Notes

10. Healthcare Cyberattacks

9. ApoE in C3 glomerulonephropathy

8. Workforce woes in Adult and Pediatric Nephrology

7. Hyponatremia correction meta-analysis

6. Microvascular inflammation increases risk of graft loss - in all of its forms

5. Xenotransplantation

4. KDIGO CKD Guidelines

3. Hypertension control trials (ESPRIT, BPROAD)

2. The Renaissance of IgAN: IgAN treatment trials

1. FLOW: GLP-1 RAs in CKD

The Filtrate

Joel Topf

Swapnil Hiremath

AC Gomez

Jordy Cohen

Nayan Arora

Special Guest

Brendon Nuen

Editing by

Simon Topf and Nayan Arora

Show Notes

FINEARTS-HF in NEJM

FINEARTS Kidney outcomes in JACC

FINE-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 KidneyWk

Swapnil comes out as a SpiroStan post to NephJC

TOPCAT

TOPCAT primary publication

TOPCAT North American results

TOPCAT funny business explained

AHA/ACC/HFSA Heart Failure Guidelines (PDF)

SGLT2i are 2a

MRA are a 2b

ARBs are a 2b

ARNI are a 2b

Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone

Kansas 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.2635

Why Has it Been Challenging to Modify Kidney Disease Progression in Patients With Heart Failure? (JACC)

Tubular Secretions

Swap: Disclaimer on Apple TV

AC: Duo Lingo Plushy (Amazon)

Nayan: The Puzzle Box

Jordy: Project Hail Mary

Brendon 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 Kurzweil

Closing music, Tim Yau with The Kidney Connection

The Filtrate:

Joel Topf

Swapnil Hiremath

With Special Guest:

Michelle Hladunewich, Nephrologist at the University of Toronto

Mir Melamed, Maternal-Fetal Medicine at the University of Toronto

Editor

Simon Topf

Show Notes

Priscilla 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 entertainment

Tim Yau (@Maximal_Change)

Too Sweet by Hozier

Fairy Tale of New York by written Jem Finer and Shane MacGowan. Hear it performed by the Pogues.

Interview of Tom Mueller

Tom Mueller author of How to Make a Killing

Jade Teakall@jmteakell

Graham Abra@GrahamAbra

Interview of Tom Mueller

Tom Mueller author of How to Make a Killing

Jade Teakall @jmteakell

Graham Abra @GrahamAbra

NephMadness logo reveal

NephJC Kidneys

NephJC blog post

NephJC Manuscript of the Year: Flow accepted by Meg Jardine

Manjula 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 logo

NephJC Social Justice Award: ISN petition to the WHO on Kidney Health

Most Engaged Scientist Award: Michelle Rheault

Rookie of the Year: Milagros Flores

MVP: Christina Popa

NephJC Founders Award: Joshua Waitzman

Nathan Hellman Social Media Project of the Year: Edgar Lerma and the ASN Visual Abstract Team

More Music with Tim

Saginaw, Michigan as performed by Johny Cash

Betty, written by Taylor Swift

The Kidney Connection

Freely Filtered Kidney Week Draft

Previous drafts

2021 ASN Kidney Week Draft

2022 ASN Kidney Week Draft

2023 ASN Kidney Week Draft

List of all the simultaneous publications from Kidney Week 2024

Sophia: SMART Trial (Link goes to the new KidneyCompass podcast that interview lead author Hiddo Heerspink

Jordy’s editorial in the European Heart Journal. Link

Josh: APPLAUSE Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy in the NEJM

APPLAUSE results announcement at The World Congress of Neophrology in Buenos Aries

Iptapocan is a factor B inhibition

Jordy: POISE-3 with simultaneous publication in KI

Mentions she wanted to pick KAT-AKI because she worked with Perry Wilson.

Per Nayan, Amit Garg is the Beyonce of Nephrology

Accord Trial (NEJM)

Joel: HSK21541 for Pruritus

Correction link to source (graph)

Nayan: FINEARTS-HF with simultaneous publication in JACC

BARACH-D: Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial (Nature Medicine)

Swapnil comes out as a SpiroStan

TOPCAT funny business

PATHWAY-2 Trial (NephJC coverage)

Swap: K Bath and cardiac arrhythmia with simultaneous publication in Kidney International

CAST: A study that rocked the cardiology world and became the poster child for evidence-based medicine (Link)

Tubular Secretions

Swap: Late breaking and high impact sessions

Nayan: Intro to…

Joel: Student poster on blood pressure technique

Jordy: The Penguin. A couple of mentee posters

Sophie: Tracks her sessions on paper.

Josh: Quiz and Questionaire session with JC Velez, Bea Concepcione, Anna Burgner, Roger Rodby.