✨ This is Akshaya (Akshaya Jayachandran) signing off. Thank you to everyone who joined us from around the world 🌍🌙 This was my team’s final NephJC chat, and it’s been an absolute honor to host this conversation. Until next time 👋 #NephJC

Endless gratitude to our dearest Brian Rifkin, Milagros Flores , @drpallaviprasad.bsky.social, Swapnil Hiremath 🍁🇨🇦 and Cristina Popa and all of our #NephJC mentors who helped in all aspects 🌟to make this level of new learning, incredibly fun and beautiful!

🙏 As we wrap up, I wish to pause and express our deepest thanks to our mentors—for their guidance, patience, and constant encouragement. I'm truly grateful for the opportunity to be here, to learn, to contribute, and to grow through this experience. (Hey I'm just holding my tears ✨🙏!) #NephJC

🙌❤️🩺Truckloads of love and gratitude to my amazing team — Dr SaiVani Yellampalli, Bogdan Agavriloaei Natalia Nombera Aznaran, Janany Sabes Truly the best! 🌟 It’s been an absolute pleasure working & learning alongside all of you. #NephJC The #Nephronauts sign off 👋✨!!

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🩸Up next! We’ll be discussing the 2025 KDIGO Anemia in CKD guidelines, it has been more than 12 years since an update 🩸 #NephJC kdigo.org/wp-content...#NephJC

Great discussion! INFINITI shows SGLT2 inhibitors behave differently—but plausibly beneficially—in transplanted kidneys. What more trial evidence would you like to have before implementing in your practice? #NephJC

❓Would you start an SGLT2 inhibitor💊 in a stable kidney transplant recipient today — despite muted BP and proteinuria effects? Are there a group of KTRs for whom you would avoid #flozination? #NephJC

T3i 📌 Bottom line: INFINITI shows that SGLT2 inhibitors “work differently”but plausibly beneficially in KTRs. The field now needs long-term outcome trials to answer the real question: do they improve graft and patient survival? #NephJC

T3h: ⚠️ Limitations ⏳ Short follow-up duration 🛡️ Low-risk, stable transplant population ⚖️ Underrepresentation of women and minorities 🎯 ❌ No hard clinical outcomes (graft failure, CV events) #NephJC

T3g 💪 Strengths: ✔️ Measured GFR with iohexol ✔️ Lithium clearance for tubular physiology ✔️ Rigorous mechanistic design #NephJC

T3f Safety deserves emphasis. INFINITI adds high-quality RCT data showing short-term SGLT2i use is feasible and well tolerated in stable KTRs. #NephJC

T3e Despite small MAP reductions, there was no improvement in arterial stiffness, SVR, or sympathetic tone. This suggests transplant-specific vascular and tubular physiology may blunt traditional SGLT2i BP mechanisms. Perhaps a longer study may have shown different results?⚠️ #NephJC

T3d 👉 Strong glucosuria without natriuresis. This challenges the classic SGLT2i narrative. Possible explanations: • Calcineurin-inhibitor–mediated sodium retention • Rapid distal sodium reabsorption • Altered tubular signaling in denervated grafts #NephJC

T3c Notably, this occurred without meaningful albuminuria reduction, aligning with growing evidence that SGLT2i benefits go beyond proteinuria. Were you surprised there wasn’t lowering (of already low) albuminuria? #NephJC

T3b 📉The preserved acute GFR dip strongly suggests that intraglomerular pressure unloading still occurs in transplanted kidneys. The magnitude of the dip mirrors non-transplant SGLT2i trials — reinforcing that this is likely a hemodynamic, not toxic, effect. #NephJC

T3a ❌ 🚫 INFINITI did not meet its primary BP endpoint, but that may not be the most important story here. No other #flozin study used BP as a primary endpoint, would you have chosen something else? #NephJC

Not yet finished, at least not without the discussion. #NephJC

T2j Metabolic Parameters: Dapagliflozin was associated with reductions in body weight and body mass index at week 1 and week 12 compared with placebo. Fasting glucose, HbA1c, and lipid parameters did not differ significantly between groups. #NephJC

T2i Vascular & hemodynamic findings: 🫀 No significant change in arterial stiffness (augmentation index, PWV) at 12 weeks. 📊 Cardiac output measures unchanged. ⚡ Renin, aldosterone, catecholamines, HR, and HRV showed no differences vs placebo at 1 or 12 weeks. #NephJC

T2h 🔍🧠📊 Tubular sodium handling was… unexpected. Despite robust glucosuria, FENa, FELi, and distal sodium reabsorption did NOT differ vs placebo. Volume effects were present: ✔️ Increased 24-h urine volume ✔️ Sustained glucosuria at both 1 and 12 weeks. #NephJC

T2g Proteinuria At baseline, participants had low-grade proteinuria -UACR ~2–3 mg/mmol- very low After SGLT2i → NO significant reduction in UACR at 1 or 12 weeks UACR and 24-hour urine protein excretion remained unchanged across timepoints, despite the clear mGFR dip. #NephJC

T2f Creatinine-based eGFR showed directionally similar changes, closely mirroring the early hemodynamic dip seen in native-kidney SGLT2i trials. Crucially, this GFR dip was not accompanied by harm: ❌ No excess AKI ❌ No biochemical instability ❌ No signal for acute rejection #NephJC

T2e Turning to kidney function — the most consistent physiologic effect. Using iohexol clearance, dapagliflozin caused an acute dip in measured GFR. The placebo-adjusted mGFR decline was: – 4.2 ml/min/1.73 m² at 1 week – 3.5 ml/min/1.73 m² at 12 weeks #NephJC

T2d 📉 At 1 week, dapagliflozin led to a placebo-adjusted MAP reduction of ~3.9 mmHg. However, this BP effect was modest and transient. By 12 weeks, MAP and DBP differences were attenuated and not consistently sustained. #NephJC

T2c The primary endpoint was seated systolic BP. 👉 Dapagliflozin did NOT reduce SBP at either 1 week or 12 weeks vs placebo. Is this unexpected? #NephJC

T2b 👥Baseline characteristics: 🗓️Mean age 53 yrs; 🧁 57% diabetes, 💊62% hypertension; 🫘mean eGFR ~68 ml/min/1.73 m². Baseline characteristics were well balanced. #NephJC

T2a ♾️ INFINITI randomized 52 stable kidney transplant recipients, >6 months post-KT. #NephJC

T20: Lets move on to the results #NephJC

T1l Understanding how a drug works in Kidney transplant recipients (KTRs) is a prerequisite to asking whether it improves outcomes—INFINITI sets the stage for that next step. #NephJC

T1k Longitudinal outcomes were analyzed using linear mixed-effects models with fixed effects for treatment, time, and treatment×time interaction, and a participant-level random intercept.

T1j 🔍 Analyses followed an intention-to-treat approach using linear mixed-effects models; secondary outcomes were exploratory and not adjusted for multiple comparisons. 🔎 #NephJC

T1i Integrated assessments included systemic hemodynamics, arterial stiffness, autonomic function, metabolic parameters, and neurohormonal markers. #NephJC 🔍 This is a mechanistic trial, not an outcomes trial. How should that shape how we interpret the results?

T1h Tubular sodium handling was studied using lithium clearance, allowing segment-specific assessment of proximal vs distal sodium handling, moving beyond crude natriuresis and directly testing classic SGLT2i mechanisms. #NephJC

Should proteinuria have been an inclusion criterion, given how central it is to SGLT2i benefit in native CKD? #NephJC

Kidney function was assessed using iohexol-measured GFR, alongside creatinine-based eGFR for clinical context. Any concerns about use of Iohexol (omnipaque) in this setting? #NephJC

T1f The 1° endpoint was seated systolic blood pressure—chosen as a surrogate of vascular and volume effects. Is this a good endpoint given the short length of the study? Do you usually see ⬇️ in BP in patients on #flozins? Do you frequently stop BP meds? #NephJC

T1e ⚔️ Participants were randomized 1:1 to 💊 Dapagliflozin 10 mg daily vs 💊 Placebo Physiologic assessments were performed at baseline, 1 week (acute effects), and 12 weeks (chronic exposure). #NephJC

T1d 🔍Exclusion criteria Any other criteria you would have considered for exclusion? #NephJC

🔍 Inclusion criteria. Any surprises here? #NephJC

T1b Participants were stable kidney transplant recipients, ≥6 months post-transplant. Initially restricted to patients with diabetes, eligibility was later expanded to non-diabetic recipients after publication of DAPA-CKD. #NephJC

T1a ♾️ INFINITI was a randomized, double-blind, placebo-controlled mechanistic trial, designed to study physiology and safety, rather than clinical outcomes. #NephJC

⚡Moving on to the methods.⚡ #NephJC

T0j The INFINITI trial has set out to answer this very question. Let’s see if #Flozins can go to INFINITY AND BEYOND! (Disclaimer: Disney has not specifically endorsed #flozin use) #NephJC

T0i So here comes the quintessential, key unanswered question: 👉 Do SGLT2 inhibitors exert similar, altered, or entirely different physiologic effects in kidney transplant recipients—and more importantly are they safe? 📉 📈 #NephJC

T0h Transplanted kidneys are physiologically distinct from native kidneys. Denervated, exposed to calcineurin inhibitors, and characterized by altered sodium handling and vascular tone are just a few of the significant differences. Can you think of others? #NephJC

T0g However, kidney transplant recipients have been excluded from all major SGLT2i outcome trials—creating a major evidence gap. For better (overly cautious) or worse, we have limited safety and efficacy data for renal transplant patients. #NephJC

T0f 🔍Proposed mechanisms of action of the #flozins include -restoration of tubuloglomerular feedback -intraglomerular pressure reduction -osmotic diuresis -improved tubular energetics. Do these mechanisms also work in transplanted kidneys? #NephJC