Chronic Kidney Disease

@ckd_ce on Twitter

1) Welcome to our new #accredited #tweetorial on the Pathophysiology of #DKD in #T2D: Traditional Teaching and New Insights. Our expert author is Hans-Joachim Anders, MD, @hjanders_hans from @LMU_Uniklinikum of @LMU_Muenchen

2) This #accredited #tweetorial series on the foundations of #kidneydisease #DKD through the lens of #T2D is supported by an independent educational grant from the Boehringer Ingelheim/Lilly Alliance and is intended for healthcare providers.

3) This activity is accredited for #physicians #physicianassociates #nurses #NPs #pharmacists ๐Ÿ‡บ๐Ÿ‡ธ๐Ÿ‡ช๐Ÿ‡บ๐Ÿ‡ฌ๐Ÿ‡ง๐Ÿ‡จ๐Ÿ‡ฆ. Past programs still eligible for credit are at http://www.ckd-ce.com. Faculty disclosures are at https://ckd-ce.com/disclosures/. FOLLOW US for regular programs by expert faculty!

4a) Letโ€™s start with a case. 53โ™‚๏ธ with new onset #T2D 2Y ago is referred for suspected #DKD in light of 3mos’ dipstick proteinuria. Meds include metformin/sitagliptin. BP 143/85. BMI 31.

4b) Labs: Na 138, K 4.6, Creat 1.4, A1c 7.1%, no free LC, MG or autoantibodies, #UACR 690mg/g, sediment: 10 RBC/hpf.
Ultrasound imaging: both kidneys 10cm, 1 cyst 3 cm, cortex hyperechoic. Duplex: homogeneous perfusion

5) What is your diagnosis?

A. Definite #DKD because pt has #T2D + #macroproteinuria + #hypertension
B. Suspected #DKD but #kidney biopsy should rule out #GN or #FSGS
C. #CKD. Unlikely #DKD because at that age #CKD is usually multifactorial

6) Maybe we can all agree that the pt has #CKD plus #T2D.
In the past this combo was referred to as #DKD or #diabetic nephropathy/#DN but the 2020 @goKDIGO guidelines ๐Ÿ”“https://kdigo.org/wp-content/uploads/2020/10/KDIGO-2020-Diabetes-in-CKD-GL.pdf avoid the use of these terms because …

7) The global prevalences of both #CKD & #T2D are high & concomitance ๐Ÿšซ necessarily imply causality when #CKD may be caused by e.g., #genetics, #ischemia, toxins, #autoimmunity or obstruction. In addition, example, obesity can be an upstream cause of both #CKD and of #T2D.

8) Naming any of these โ€ž#DKDโ€œ would be misleading.

9) Wait: Researchers have spent billions ๐Ÿ’ฒ๐Ÿ’ถ๐Ÿ’ดin research funds to understand #DKD, and companies spent billions ๐Ÿ’ฒ๐Ÿ’ถ๐Ÿ’ดin private investments to develop cures for #DKD and the disease does not even exist?
No, there are still pts with #DKD, e.g.:

Kermit Worried GIF

10) DKD
๐Ÿ‘‰ longstanding #T1D w/o #insulinpump, poorly-controlled A1c w/o other RF for #CKD
๐Ÿ‘‰ younger non-obese adults with a decade of #T2D and no other RF for #CKD
๐Ÿ‘‰ #kidneybiopsy can rule out many DD and enforce #DKD, although many histo features are unspecific

11a) From a clinical perspective, #CKD +/- #diabetes is preferred also because no #DKD-specific cures exist. All approved drugs target either #DM, #CKD, or both:

11b)
#Antidiabetic drugs: #insulin, #biguanides, #sulfonylureas, inhibitors of #ฮฑ-glucosidase, #DPP4, #SGLT2, #GLP-1 agonists
#CKD drugs: #ACEi, #ARBs, #SGLT2i, #MRA

https://www.nature.com/articles/s41581-018-0001-y

12) Now, we better understand (and overcome) the previous hurdles for progress.
Let`s have a look @ the decades of #DKD research concepts about #DKD pathophysiology from the different angles .

13) The perspective of the #clinician:
๐Ÿ‘‰ focus on albuminuria as a hallmark of #DKD
๐Ÿ‘‰ no appreciation of progressive #CKD in absence of #proteinuria
๐Ÿ‘‰ ignoring that the concept fits almost all forms of #CKD
๐Ÿ”“

https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002989

14) Perspective of the #cellculture expert:
๐Ÿ‘‰ #glucocentric view
๐Ÿ‘‰ static models of #kidney cell stress
๐Ÿ‘‰ missing #hemodynamics, #pressures, #metabolism, #shearstress, and adaptive mechanisms

https://pubmed.ncbi.nlm.nih.gov/23313806/

15a) Perspective of the pathologist:
#Tervaert classification (๐Ÿ”“https://jasn.asnjournals.org/content/21/4/556):
๐Ÿ‘‰Lesion pattern-based view but most lesions unspecific
๐Ÿ‘‰Extent of global #glomerulosclerosis mirrors no more than clinical #CKD stage . . .

15b) … but, an advantage of the pathologist’s perspective:
๐Ÿ‘#kidneybiopsy can identify alternative upstream causes of #CKD that may benefit from specific treatments

https://www.nature.com/articles/s41581-018-0001-y

16a) Perspective of #omics systems biologist (๐Ÿ”“https://jasn.asnjournals.org/content/28/4/1050):
๐Ÿ‘‰Kidney transcriptomics: #inflammation & #fibrosis per #path
๐Ÿ‘‰Urinary #proteomicsโžก๏ธstress responses
๐Ÿ‘‰Hierarchy & directional causality can’t be determined
(cont)

16b) ๐Ÿ‘‰Missed #RAAS #SGLT2 & #MRA as key tx targets
๐Ÿ”“

https://jasn.asnjournals.org/content/28/4/1050

17a) Perspective of the #genetic expert: consider that genome-wide studies comparing #diabetes +/- #DKD or other comparisons revealed genetic #CKD RF unrelated to #diabetes, e.g.,
๐Ÿ‘‰#Alport-like COL4 gene variants (=GBM weakness; see ๐Ÿ”“https://jasn.asnjournals.org/content/30/10/2000) …

17b) … &
๐Ÿ‘‰APOL-1 gene variants (=podocyte weakness; see ๐Ÿ”“https://www.karger.com/Article/FullText/326763), suggesting that #DM promotes onset & progression of #CKD in #CKD-susceptible individuals, thus #diabetes = a RF for accelerated #CKD progression, esp when #CKD develops shortly after #DM onset

18) Whew! That’s a lot of perspectives. Think on these–their relative strengths/weaknesses–and return tomorrow for more education & your link to ๐Ÿ†“CE/#CME! ๐Ÿ‘to @kidneydoc101 @RenalFellowNtwk @swissnephro @RealDr_Pepper @KSusztak @SethiRenalPath @drjosflynn @StuartShankland

19) Thank you for coming back! You are learning from @hjanders_hans all about #CKD + #T2D while you earn ๐Ÿ†“CE/#CME! Hello to @kdjhaveri @KuppeChristoph @Tiff_Caza @AstridWeins @suz_allison @LinusButt @Renalpathsoc @JeanHouMD @ChristophWanne4 @mvaduganathan @KidneyPath

20) So considering all those perspectives confirms how complicated looking at #CKD through a lens of #T2D can be! The multifactorial origin of #CKD +/- #diabetes in adults: And then there's #aging, during which numerous RF for the onset of #CKD accumulate

https://www.nature.com/articles/nrdp201788

21) Thus, with increasing age it becomes less and less likely that the origin of #CKD is a single disease. Thus in adults, targeting the unspecific mechanisms of #CKD progression and minimizing all RF for #CKD progression has become a management priority.

https://www.nature.com/articles/nrdp201788

22) Frequently, multiple factors combine that enhance single nephron #hyperfiltration & require structural #adaptation, for which human capacity is quite limited before irreversible injury occurs, e.g., #podocyte detachment from intolerable shear stress.

https://pubmed.ncbi.nlm.nih.gov/28992221/

23a) Learned from recent RCTs with unprecedented large effect sizes:
#Diabetes accelerates onset & progression of #CKD viaโ€ฆ
๐Ÿ‘‰forced โ†‘ #glucose reabsorption in the PT= โ†‘ metabolic PT stress = #hypoxia & #cytokine signaling & irreversible loss of PT cells
(cont)

23b)
๐Ÿ‘‰increasing hemodynamic shear stress on #podocytes because SGLT2-mediated disabling of the #tubuloglomerularfeedback. Ultimately leads to #podocyte loss = #glomerulosclerosis
๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/24334175/

24) An integrated view of mechanisms leading to the structural changes of #CKD that are all accelerated by the presence of persistent hyperglycemia (= #diabetes) is also shown here:
See

https://www.nature.com/articles/s41581-018-0001-y

25) Loss of #podocytes & PT cells both โ†‘ workload (hemodynamic & metabolic) to remaining #podocytes & PT cells, respectively, ending in an autoamplification loop of functional overload & progressive epithelial cell loss = #CKD progression = BAD NEWS

https://www.nature.com/articles/s41581-021-00510-7

26) These mechanisms apply to all forms of #CKD. #Diabetes is just one of many RF that create a dysbalance between #nephron no./capacity & metabolic demands of the body.

https://www.nature.com/articles/s41581-021-00510-7

27) This concept is poorly addressable in:
๐Ÿ‘‰Cell culture studies (no hemodynamics, pressures, shear stress)
๐Ÿ‘‰Rodent models (โ†‘โ†‘โ†‘capacity to adapt to nephron overload vs. Humans

28a) What is the evidence for hemodynamic and metabolic nephron overload as key drivers of #CKD +/- #diabetes?
๐Ÿ‘‰Rodents with #diabetes: identical overload but capacity for adaption โ†‘โ†‘โ†‘ prevents progressive #CKD: Reducing overload is key in humans
(cont)

28b)
๐Ÿ‘‰#Pathology: glomerulomegaly in #diabetes = adaptation to #hyperfiltration
๐Ÿ‘‰#RCTs: dual RAS/SGLT2 inhibition prevents progression of #CKD +/- #diabetes at unprecedented effect size (๐Ÿ”“https://www.nejm.org/doi/full/10.1056/NEJMoa2024816)

29a) How do #RAASi affect #nephron overload in #CKD +/- #diabetes?
๐Ÿ‘‰The #RAS is a key stress response pathway activated in #diabetes, #kidneydisease and #heartfailure
(cont)

29b)
๐Ÿ‘‰#RAASi open eff. arteriole = filtration pressure โ†“ = #podocyte shear stress โ†“ = #proteinuria โ†“ = metabolic load to PT โ†“
๐Ÿ‘‰Better resilience of #podocytes & PT= remnant nephrons last little longer
๐Ÿ‘‰#RAASi block profibrotic effects of #AT2
See

https://www.nejm.org/doi/full/10.1056/NEJMcibr1608564

30a) How do #SGLT2i affect #nephron overload in #CKD +/- #diabetes beyond #RAASi?
๐Ÿ‘‰Block Na+/glucose reabsorption in PT = less metabolic PT workload
(cont)

30b)
๐Ÿ‘‰Reactivation of TG feedback = constriction of aff. arteriole = filtration pressure โ†“ = #podocyte shear stress โ†“ = #proteinuria โ†“
๐Ÿ‘‰Better resilience of #podocytes and PT = remnant nephrons last a lot longer
๐Ÿ‘‰Proximal diuretic effect improves #diabetes & #heartfailure

31) More insights from human #RCT about the pathophysiology of #CKD + #diabetes?
๐Ÿ‘‰Mineralocorticoid receptor signaling, another pleiotrophic stress pathway, has non-redundant contributions to #CKD + #diabetes
See ๐Ÿ”“https://pubmed.ncbi.nlm.nih.gov/33264825/
(cont)

32)
๐Ÿ‘‰Endothelin receptor signaling contributes to #CKD + #diabetes
See https://pubmed.ncbi.nlm.nih.gov/30995972/
๐Ÿ‘‰CCL2/CCR2-related #kidney #inflammation is a downstream pathomechanism (low effect size)
See https://pubmed.ncbi.nlm.nih.gov/26268910/ and ๐Ÿ”“

https://pubmed.ncbi.nlm.nih.gov/28186566/

33a) Let me summarize:
๐Ÿ‘‰#DKD as a term should be used only for pts where #diabetes is the only or predominant cause of #CKD, which is rare in older adults w/#T2D.
๐Ÿ‘‰Global epidemic & unmet need = #CKD + #diabetes
– Check @goKDIGO guidelines for tx of #diabetes in this setting

33b)
๐Ÿ‘‰Reduce hemodynamic & metabolic overload of the remaining #nephrons to maximize #kidney lifespan. For this: (a) control all RF for hyperfiltration of the remaining #nephrons & (b) minimize tubular reabsorption of #salt, #glucose, & #protein

33c) Finally,
๐Ÿ‘‰#Inflammation and #fibrosis are downstream pathomechanisms, & whether targeting these beyond dual #RAASi/SGLT2i will have additional effects is possible but currently unknown

34a) And let us conclude with our patient:
In an obese 53 YO w/proteinuria & #CKD after only 2Y of #T2D, #DKD is unlikely. More likely diagnosis: #CKD + #T2D (consider work-up for proteinuria, e.g., COL4 variants/IgAN)

34b) Therapy: Dual #RAASi/SGLT2i, consider triple #CKD therapy by adding #MRA. The #SGLT2i could improve A1c, BMI, BP & reduce the risk of #hyperkalemia

34c) Target-BMI <25, -BP 120/80 w/o dihydropyridine CCB, minimize dietary salt, no smoking, regular physical activity, avoid #NSAID, #PPI or other nephrotoxins. Comprehensive care!

35) And that’s it! YOU MADE IT! 0.5h CE/#CME credit. Go claim your certificate at https://ckd-ce.com/dkd9/. I am @hjanders_hans and I invite you to FOLLOW @ckd_ce (and @cardiomet_CE) for more outstanding education and credit for ๐Ÿ‡ช๐Ÿ‡บ๐Ÿ‡ฌ๐Ÿ‡ง๐Ÿ‡จ๐Ÿ‡ฆ๐Ÿ‡บ๐Ÿ‡ธ clinicians!

Originally tweeted by @CKD_ce (@ckd_ce) on April 27, 2022.