More CVRM to learn

• Has anyone used isglt2 and glp1a in patients without diabetes, for overweight? the risk of hypoglycemia is high?

  • Have used dapa few times. And started using semaglutide in some for morbid obesity and borderline diabetes and hypertension

• And there is a lot of evidence of dapa in heart failure without diabetes...They do well

  • The use of isglt2, reducing approximately 60-70 g carbohydrates (70 x 4 kcal = 280) approximately per day for 7 days = 2000 kcal less per week

• Semaglutide or liraglutide at high doses are effective for weight loss. Dapa has minimal or null effect on weight. Overweight + OSA or HFpEF could be an indication for combination SGLT2 and GLP1.

• Oral semaglutide demonstrated weight loss of 4.2 kg compared with 3.8 kg for empagliflozin at 26 weeks.

• Do you prefer metformin or SGLT2i as your first choice in treating diabetes in a CKD? KDIGO suggests we can use either.

• By price and accessibility in most places: metformin, if covered SGLT2 for long-term protection

• Personal preference: start with metformin and then SGLT2i. Rationale: metformin is cheap, proven to work, familiarity with side-effects and therapeutics.

• If cost where not being an issue, if the goal is to "treat" diabetic nephropathy then I would start them in combo, using the added benefit of the two drugs in different pathophysiologic pathways.

• I would probably recommend SGlT2 first (after discussing/revising risks vs benefits). But still, with DMII unless you have a disciplined patient it is unlikely that glycemic control will be adequate with just a flozin

• Metformin is still a very wonderful drug. I would start with it. We do not have data comparing others with Metformin. Most are after treatment with Metformin as it is still the standard

• Metformin itself has many pleiotropic effects with much lower adverse effect profile. It does act on many facets of diabetes apart from glucose control. We do not have any data showing advantage of flozins or Metformin. Head to head trials could give us a better info.

• Even if the cost was not an issue (which still is) for flozins, metformin can hold its own. Sure, SGLT2i are the new cool kind on the block but let's not count Metformin out yet. Whatever flozins do, metformin can confer similar benefits from weight loss, heart disease, kidney disease, even some signal towards helping with fatty liver, polycystic ovarian syndrome.

• I tend to use a GLP1RA + SGLT2i for patients with Metabolic Kidney Disease

• And how many cases of lactic acidosis have you seen? I haven’t seen any yet but would know others opinions regarding Metformin safety in advanced ckd.

• Severe lactic acidosis with pH in the ~ 6.9 range, often requiring ICU and emergent HD

• This study shows very few episodes of lactic acidosis

• We offer metformin until dialysis, with reduction of the dose, usually reaching 500 mg day with GFR between 15 to 30

• I agree with metformin as a first treatment option, especially because of its benefits on lowering glucose levels. About safety of using the drug in advanced CKD, I don't discontinue at 30. Also i agree that many times is very difficult to determine if a lactic acidosis in secondary to metformin use, and probably other precipitant factors could be present.

• If BP allows you can go ahead and get the spironolactone. In fact I think is part of the GDMT for heart failure.

• I have a patient new PD patient with whom we are having difficulty draining all of the PD fluid. She had abdominal surgery and lots of adhesions. She ends up being positive 200-300 ml of fluid with each drain. We have ruled out all the reversible causes (constipation, kinks, infection, fibrin). She might be pocketing the fluid or super high transporter. I was thinking to switch her to icodextrin, but someone suggested CT peritoneography.

• Either CT peritoneogram or ask IR or interventional nephrologist to run some dye in to look for flow patterns - omental trapping is often the issue.

Source: https://pubmed.ncbi.nlm.nih.gov/20630641/

• How do you care for covid patients in outpatient clinics early after kidney transplantation re barrier precautions?

• Telehealth + n95 masks at attendance. Early sotrovimab or iv Remdesivir (3 doses within first 7 days) for Rx after positivity.

• IMS reduction - especially MMF/Aza. Despite remaining an Outpatient without O2 reqt,

• Often pcr positive for 3 weeks or longer. Clearance criteria- asymptomatic+ 2 negative PCR or positive but with high Cycle threshold values (>30) are being used in Australia.

• These rules are all centre specific and checking PCR is to ensure that patients who may still be actively shedding virus don't come in contact with other vulnerable patients in hospitals like those on chemotherapy or immunosuppression. It does not necessarily affect their own management i think if they are largely asymptomatic.

• Is it really "virus shedding" though? Won't you get positive PCR if there are dead viral particles? Don't get me wrong, I am all for taking extra measures to protect the vulnerable, but not sure if you get much bang for your buck for checking PCR. Can't they be monitored and managed mostly by Tele visits?

• PCR does not affect their management. But if they let's say need a biopsy or a surgery, then this is to ensure they are placed in isolation from other vulnerable patients to prevent Hospital transmission

• They are most often and most certainly can be managed as outpatients via Telehealth

• Do you guys also give IV remdesivir as outpatient?

• Sotrovimab is less effective against B.a.2 variant. So yes we plan to give iv Remdesivir soon when b.a.2 variant proportion grows in the community. See the PINETREE study below.

• DI in ICU (5 liter of urine, UOsm 30) Is there anything else other than DDAVP to treat it and how long? And what's your starting dose for DDAVP? Do you hold it after a few days and reassess the response?

• Assuming this is central DI desmopressin can be attempted at 0.25 to 1 mcg every 12 to 24h. You assess response until desired UOP. Then withdraw slowly.

Question: In a CKD patient with asymptomatic bacteruria (> 100K CFU), would you start an SGLT2i? Why or why not?

Figure created by Dr. Nasim Wiegley

•67-73% of Players Forum members would administer an SGLT2i. A bit more in favor of flozination compared to the general #NephTwitter population.

• I would go with A. I think all studies show the risk of UTIs is not increased

• Wouldn’t take a risk of UTI. Would prefer GLP1 analogues and RAAS inhibitors instead

• This study used propensity score to compare SGLT2-i with DPP4 & GLP-1 groups of patients, a huge set of pts, but severe CKD patients were excluded from the analysis.

• Still, CREDENCE did not show an increased risk of UTIs, and also this meta- analysis of phase III RCTs confirm an increased risk of genital fungal infections but not of UTIs

• There was a follow up question to SGLT2i use in chronic bacteriuria - consider the immunosuppressed transplant population. A lot more hesitancy with this group

• So what did you end up doing?

• • Didn’t do SGLT2i

  • Transplant pt with chronic E. coli in urine never had symptoms or allograft pain.

  • But surprisingly when had allograft biopsy for slow decline in eGFR- biopsy showed pyelo (plus some CNI toxicity and early diabetic nephropathy)

• Agreed. Have seen few cases of UTI being picked up on evaluation of GDF

• Really makes me wonder if all bacteriuria should be treated in kidney transplant patients 🤔

• Concur with you. Even if not causing UTI, I suspect it does increase the tissue antigenicity

• We need to research see if we can pick up the antigenic exposure via urine markers before onset of overt graft dysfunction. Could help in following up patients with asymptomatic bacteruria

• Response from Dr. Christos Argyropoulos

Chief, Division of Nephrology

University of New Mexico Health Sciences Center

We looked into this with Dr. Mike Johansen in our meta-analysis from a year and a half ago. Relative Risk of symptomatic UTIs (lower track) goes up 9%. Small study from Pakistan suggests that asymptomatic bacteriuria may go up by SGLT2i. Similar odds ratio to an older paper but asymptomatic bacteriuria != (does not equal) UTI, so I would still treat (possibly under cranberry juice 😀)

• Apart from cost, what are some of the barriers you face in prescribing an SGLT2i to your CKD patient?

• Here are some of the barriers that Cardiologists report. How many of these overlap with Nephrologists?

From the 2020 European Society of Cardiology Congress | Courtesy of Dr. Martha Gulati | Study

• The real barrier (at least in #KidneyWk online) is the development of "information bubbles". These bubbles restrict the flow of information. As a result, a large group of people are excluded from the conversations about SGLT2i. This results in a completely different perspectives.

From the 2019 #KidneyWk meeting | Additional data regarding the polarization of KidneyWk found here (tweets 19-30) | Courtesy of Dr. Tejas Desai

• Here is a study from the American College of Cardiology: results of a poll about the barriers that Cardiologists face

• Cultural inertia. That is number 1 followed closely by not wanting to take care of the paperwork and the fact that most of them have (or feel they have) a niche that does not include CKD

Question: Seems like the Qualifying Match for England is a runaway in favor of IV Iron to reduce MI in dialysis patients. How are you using IV iron in your dialysis patients? I for one have been using it ever since PIVOTAL was released (and the paper for England is a pre-specified subgroup analysis of PIVOTAL). I've noticed a drop in my ESA use -- a good thing?

Responses:

• We do follow 1g total iron sucrose (10 consecutive sessions 100mg) in case of absolute Fe deficit and then maintain up to ferritin 800 - usually 200-400mg monthly

  • Maybe I have too much of a simplistic approach, but I aim for Hgb of 10, if it starts to trend up back off Epo and iron. I don't think we know enough to make any other definitive conclusion at this point.

    • Not simplistic at all. I have a similar strategy. I dose IV iron at 62.5 mg x 5 doses if ferritin < 1200 (DRIVE study threshold) or TSAT < 40% (PIVOTAL study threshold). I hold on ESA for as long as I can because of the risk of stroke.

• It’s pity, IMHO, if there are no data about pts’ P, PTH, FGF23 status. In terms of iron Impact on FGF23 level (PMID: 26535997) and FGF23 and P as CVD markers in ESKD patients.

  • This paper looks at inflammation and it’s effect on FGF23 in mice

• Indeed, we did a small study some time ago seeing the impact of iv iron on fgf23 & pth

• Is there a connection between FGF23 and cardiovascular disease (specifically myocardial infarction) in hemodialysis patients?

  • Yes, that’s a controversial issue : in an another study, i.v. Iron reduces intact FGF23 and P, and elevates c-terminal FGF23 in non-iron deficient HD patients. (Roberts et Al. BMC Nephrology, 2016 17:177)

By Dr. Sheldon Chen

Professor, Division of Nephrology
MD Anderson Cancer Center

Texas, United States

You probably already knew that, but when I ask my trainees to apply that principle to ATN, they sometimes have difficulties. What is the problem and what does it teach us about kinetic GFR? I ask my trainees: In ATN, you’ve seen that the creatinine does not keep rising; it eventually levels off. Why is that? A lot of fellows think it’s because the kidney function starts to recover and that keeps the creatinine from rising further. If they go down that path, my follow-up question is: What if ATN did not improve? Would the creatinine keep going up and up?

“I think so,” the fellow says.

My reply: "What if I told you that ATN does not need to improve at all, but the creatinine will still plateau?"

Confused silence.

A lot of confusion, I believe, arises from the conflation of excretion and clearance. They sound like synonyms. But excretion can be high (which is why the creatinine levels off) even though the clearance remains super low (like in severe ATN). How do we reconcile this dissociation? Answer: Clearance is a volume, whereas excretion is an amount. Picture blood being filtered across the glomerulus. A volume (read: clearance) is pushed across the filtration barrier into the urinary space, effectively removing from the body all of its freely filterable substances such as creatinine (read: excretion). Though they are different, how are clearance and excretion related? Logically, volume times its creatinine concentration equals the amount of creatinine the volume contains. In other words, clearance × concentration = excretion. Solve this for clearance, and you’ll glimpse the generic Clearance = U×V (urinary excretion) over P (concentration).

Getting back to ATN, your injured tubule via tubuloglomerular feedback drastically reduces its single nephron GFR. If less blood is pushed across that nephron’s filtration barrier, then less creatinine is excreted into urine. Imagine this occurring in most of your two million nephrons (thanks, ischemia). Creatinine excretion is reduced, but your muscles are happily churning out their daily production of creatinine. That net imbalance (production>excretion) adds creatinine to the body, thereby raising your creatinine concentration. But that worsening azotemia has a bright side. It makes even a low, fixed clearance (thanks, ATN) more “efficient” at excreting creatinine. Sure, less volume is cleared, but if that volume is increasingly full of creatinine, then excretion increases over time. Eventually, you’ll reach a degree of azotemia such that the low clearance is finally able to excrete as much creatinine as the muscles are producing, and then the [creatinine] stops rising—a new steady state! In other words, your clearance may be one-tenth of what it used to be, but now your [creatinine] is ten times what it used to be, and the effects cancel out. That is how you can have a low clearance (ATN) and yet have an intact excretion (as in health).

Is the ATN physiology recapitulated by kinetic GFR? That is, does the kGFR drop precipitously and then remain consistently low? I was recently on service and was consulted on a woman who dropped her blood pressure, and the creatinine promptly bumped up. Her creatinine trend took on a pattern characteristic of ATN that you have all seen before: rapid rise in creatinine at first and then a slower and slower rise over time. You can almost extrapolate where the creatinine curve is going to level off. Knowing the ATN pearls above, we are not fooled on rounds into thinking that each day’s creatinine rise means that the GFR is still getting worse (though a lot of doctors are conditioned to believe this, partly due to the eGFR reporting). No, each day’s creatinine rise in ATN is driven by the same, more or less, low GFR.

How do you treat hypertension in the elderly? Here is a comparison of two randomized trials: STEP versus HYVET. The STEP trial was done in China - so your opinion of this trial will have ramifications for the China Qualifying Match.

• Not sure if we can compare these two trials. HYVET, much older population and much higher BP target.

  • STEP did not have any renal outcome as its primary endpoint. The primary endpoint was a composite of: stroke, ACS, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes

  • To make matters worse (for nephrologists anyways): only 2.3-2.4% of the enrolled patients had renal dysfunction upon entry into the study.

• How do you translate this in our CKD population? Do we have to be liberal with BP in CKD population?

  • This is a trickier question to answer. There isn't good data to say one way or the other. KDIGO has some recommendations about treatment of BP in the elderly CKD population.

The patient is a 21-year-old female medical student, with a history of hematuria during last year and 1g daily proteinuria, without hypertension or edema. Past medical history is not relevant, just being obese during the childhood and underweight now. The hematuria worsens by standing up, also back pain sometimes. Standard US is "normal".

The response