Freely Filtered, a NephJC Podcast

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)

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)

Join nephrologists Nayan Arora, Jordy Cohen, Katie Kwon, and Mariana Murea as they dive into the latest innovations in dialysis. They discuss the Neff Madness bracket, highlighting breakthroughs in hemodialysis and hemodiafiltration technology. The conversation covers patient-centered care strategies, molecular clearance, and sustainability in dialysis resources. Each guest brings unique insights into the complexities of managing kidney health, balancing humor with serious discussions about improving patient outcomes in the evolving world of nephrology.

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

Mir Melamed, a maternal-fetal medicine expert at the University of Toronto, dives deep into the complexities of preeclampsia. He discusses the collaborative care model uniting nephrology and maternal-fetal specialists to support high-risk pregnancies. The conversation highlights critical biomarkers like S-Fleet and PLGF that aid in diagnosis and management. Melamed also emphasizes the importance of individualized care for renal disease patients, shedding light on the intricate balance of management during pregnancy. Insights into hypertension management and the clinical applications of diagnostic tools are also shared.

Tim Yau, a nephrologist and musical talent, shares his unique blend of music and nephrology. Tom Mueller, author of "How to Make a Killing," discusses the ethical dilemmas in the dialysis industry, shedding light on the struggle between corporate interests and patient care. Graham Abra and Jade Teakall explore the importance of home therapies and the upcoming NephMadness event. They celebrate nephrology achievements with awards, emphasizing social justice and community engagement while enjoying lighthearted musical interludes.

In this engaging discussion, Nephrologists Pedro Teixeira, an expert in clinical trials from the University of New Mexico, and Jay Koyner from the University of Chicago dive into the intriguing role of amino acids in managing acute kidney injury (AKI). They unpack recent clinical trials and explore the complexities of kidney function assessments. The conversation also touches on the relationship between amino acids and renal functional reserve, and the comparison with SGLT2 inhibitors in AKI prevention. Expect insightful analysis and practical implications for patient care!

The draft order:Sophia AmbrusoNayan AroraSwapnil HiremathAC GomezJoel TopfEditor Nayan AroraShow NotesPrevious drafts:2021 KDIGO Hypertension —Joel, Sophia, Swap, Nayan, Josh2021 ASN Kidney Week Draft—Joel, Sophia, Swap, Nayan, Jennie2022 The ISPD Peritonitis Guideline— Joel, Sophia, Swap, Nayan2022 ASN Kidney Week Draft—Joel, Sophia, Swap, Nayan2023 ASN Kidney Week Draft—Joel, Sophia, Swap, Nayan, AC, Josh2024 KDIGO CKD Clinical Practice Guideline —Joel, Sophia, Swap, Nayan, Josh, ACThe guidelineThe NephJC discussion Part 1 | Part 2First RoundSophia’s Pick 3.7.1 We recommend treating patients with type 2 diabetes (T2D), CKD, and an eGFR ≥20 ml/min per 1.73 m2 with an SGLT2i (1A).Not Nayan’s Pick 3.7.3: We suggest treating adults with eGFR 20 to 45 ml/min per 1.73 m2 with urine ACR <200 mg/g (<20 mg/mmol) with an SGLT2i (2B).Nayan’s Pick 2.2.1: In people with CKD G3–G5, we recommend using an externally validated risk equation to estimate the absolute risk of kidney failure (1A).A birdie told me there will not be a Tangri KFRE vs the World debate at Kidney WeekThe action points based on absolute risk results:Practice Point 2.2.1: A 5-year kidney failure risk of 3%–5% can be used to determine need for nephrology referral in addition to criteria based on eGFR or urine ACR, and other clinical considerations.Practice Point 2.2.2: A 2-year kidney failure risk of >10% can be used to determine the timing of multidisciplinary care in addition to eGFR-based criteria and other clinical considerations.Practice Point 2.2.3: A 2-year kidney failure risk threshold of >40% can be used to determine the modality education, timing of preparation for kidney replacement therapy (KRT) including vascular access planning or referral for transplantation, in addition to eGFR-based criteria and other clinical considerations. Swap’s Pick 3.15.1.1: In adults aged ‡50 years with eGFR <60 ml/min per 1.73 m2 but not treated with chronic dialysis or kidney transplantation (GFR categories G3a–G5), we recommend treatment with a statin or statin/ezetimibe combination (1A).AC’s Pick 3.7.2: We recommend treating adults with CKD with an SGLT2i for the following (1A):eGFR ≥20 ml/min per 1.73 m2 with urine ACR ≥200 mg/g (≥20 mg/mmol), orheart failure, irrespective of level of albuminuria. (1A)Joel’s Pick 3.10.1: In people with CKD, consider use of pharmacological treatment with or without dietary intervention to prevent development of acidosis with potential clinical implications (e.g., serum bicarbonate <18 mmol/l in adults).Practice Point 3.10.2: Monitor treatment for metabolic acidosis to ensure it does not result in serum bicarbonate concentrations exceeding the upper limit of normal and does not adversely affect BP control, serum potassium, or fluid status. Freely Filtered 061: Bicarb in Transplant with Nav TangriSecond RoundJoel’s Pick 3.3.1.1: We suggest maintaining a protein intake of 0.8 g/kg body weight/d in adults with CKD G3–G5 (2C).Practice points related to protein intake:3.3.1.1: Avoid high protein intake (>1.3 g/kg body weight/d) in adults with CKD at risk of progression.3.3.1.2: In adults with CKD who are willing and able, and who are at risk of kidney failure, consider prescribing, under close supervision, a very low–protein diet (0.3–0.4 g/kg body weight/d) supplemented with essential amino acids or ketoacid analogs (up to 0.6 g/kg body weight/d). 3.3.1.3: Do not prescribe low- or very low–protein diets in metabolically unstable people with CKD.AC’s Pick 3.9.1: In adults with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT2 inhibitor treatment, or who are unable to use those medications, we recommend a long-acting GLP-1 RA (1B).Swapnil’s Pick Practice Point 5.4.1: Initiate dialysis based on a composite assessment of a person’s symptoms, signs, QoL, preferences, level of GFR, and laboratory abnormalities.IDEAL Trial: A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis NEJMTiming of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study NephJCNayan’s Pick Practice Point 1.1.4.2: Use tests to establish a cause based on resources available (Table 6b).Sophia’s Pick Practice Point 1.1.1.2: Following incidental detection of elevated urinary albumin-to-creatinine ratio (ACR), hematuria, or low estimated GFR (eGFR), repeat tests to confirm presence of CKD.Joel’s cystatin C Tweet The cystatin C guideline recommendation 1.1.2.1: In adults at risk for CKD, we recommend using creatinine-based estimated glomerular filtration rate (eGFRcr). If cystatin C is available, the GFR category should be estimated from the combination of creatinine and cystatin C (creatinine and cystatin C– based estimated glomerular filtration rate [eGFRcr-cys]) (1B).Nayan’s additional thoughts. He is not a fan of Practice Points 3.6.4 and 3.6.5Practice Point 3.6.4 Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation of treatment or an increase in dose.andPractice Point 3.6.5: Consider reducing the dose or discontinuing ACEi or ARB in the setting of either symptomatic hypotension or uncontrolled hyperkalemia despite medical treatment, or to reduce uremic symptoms while treating kidney failure (estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m2).Tubular Secretion Swap The Murderbot Diaries by Martha Wells Nayan Searching for Hobey Baker Narrated by David Duchovny AC Rosie Revere, EngineerSophia BassnectarHow to fix the Apple Music automatically playing when you connect to bluetooth.Joel The Veil with Elizabeth Moss