Background
Damage-associated molecular patterns | HMGB1, HSPs, fibronectin Advanced glycation end-products IL-33 |
Pattern-recognition molecules | TLR2, TLR4 NLR RAGE MBL (complement) |
Intracellular signaling | JAK/STAT, NF-kB, Nrf2 NLRP3 inflammasome |
Chemokines | CCL2, CCL5, CSF1, CXCL1, CXCL16, CXCL-10, CXCL-16, IL-8 |
Cytokines | IL-6, TNF-α, IL-1β, IL-18, IL-17A, TGF-β1, CX3CL1 |
Adhesion molecules | ICAM-1, VCAM-1, Galectin-3, Integrin αVβ3, LFA-1, VAP-1 |
Pro-fibrotic mediators | PDGF, TGF-β |
Five-compartment model of diabetic kidney disease immunopathology
Immune cell recruitment and activation
Filtration
Resorption and secretion
Extracellular matrix regulation
Perfusion
Pre-clinical research using the five-compartment model
Rodent models
Strain | Model compartments (see Fig. 1) | Diabetogenic mechanism | Reported features |
---|---|---|---|
Type 1 diabetes | |||
C57BL/6 | Immune cell recruitment, resorption, filtration | Streptozotocin | Mild glomerular and tubulointerstitial damage, mild albuminuria, GFR increase, hyperglycemia |
Akita (Ins2C96Y) on C57BL/6 | Immune cell recruitment, structural support, filtration | Toxic mutation in insulin 2 gene | GBM thickening, mesangial expansion, albuminuria, hyperglycemia, hypertension |
ApoE−/− on C57BL/6 | Immune cell recruitment, resorption, filtration | Streptozotocin + hyperlipidemia | Glomerular and tubulointerstitial damage, albuminuria, hyperglycemia |
Nos3−/− on C57BL/6 | Immune cell recruitment, filtration | STZ + NO deficiency | Glomerular fibrosis, albuminuria, hyperglycemia |
BALB/c | Immune cell recruitment, filtration | Streptozotocin | Glomerular damage, hyperglycemia; no change in GFR |
DBA/2 J | Immune cell recruitment, resorption, structural support | Streptozotocin | Glomerular fibrosis, tubulointerstitial damage, hyperglycemia |
Akita (Ins2C96Y) on DBA/2 J | Immune cell recruitment, resorption, filtration, structural support | Toxic mutation in insulin 2 gene | Albuminuria, hyperglycemia |
OVE on FVB | Immune cell recruitment, resorption, filtration, structural support | Calmodulin mutation and toxic protein accumulation | Glomerular and tubulointerstitial fibrosis, albuminuria, GFR reduction, hyperglycemia, hypertension |
TTRhRen on FVB | Immune cell recruitment, resorption, structural support | Hypertension + streptozotocin | Tubulointerstitial fibrosis, mesangial expansion, albuminuria, GFR decrease, hyperglycemia, hypertension |
CD1 | Immune cell recruitment, resorption, structural support | Streptozotocin | Tubulointerstitial fibrosis, mesangial expansion, albuminuria, hyperglycemia |
129/SV | Immune cell recruitment, filtration | Streptozotocin + 2 renin receptors | Albuminuria, hyperglycemia |
Akita (Ins2C96Y) on 129/SV | Immune cell recruitment, structural support | Toxic mutation in insulin 2 gene | Mesangial expansion, albuminuria, hyperglycemia, hypertension |
KKH1J | Immune cell recruitment, filtration | Streptozotocin | Glomerular damage, albuminuria, hyperglycemia |
NOD Mice | Filtration, structural support | Genetic obesity + streptozotocin | Hyperglycemia |
Type 2 diabetes | |||
Db/db on C57BL/Ks | Immune cell recruitment, structural support | Leptin resistance | Mesangial expansion, albuminuria, hyperglycemia |
Db/db Nos3−/− on C57BL/Ks | Immune cell recruitment, filtration, and structural support | Leptin resistance + NO deficiency | Albuminuria, GFR decrease, hyperglycemia |
Ob/ob | Immune cell recruitment, filtration, and structural support | Leptin deficiency | Hyperglycemia |
Ob/ob on BTBR | Immune cell recruitment, filtration, and structural support | Leptin deficiency + hyperinsulinemia | Hyperglycemia |
KK and KKay | Immune cell recruitment, filtration, and structural support | Agouti gene | Albuminuria, hyperglycemia, hypertension |
Non-rodent models
Organoids
Clinical trial design using the five-compartment model
Patient selection and endpoints in published and ongoing studies
Drug (target) | Study design | Intervention and comparison | Model compartment (Fig. 2) | Primary efficacy outcome | Remarks |
---|---|---|---|---|---|
Phase 3, randomized,double-blind trial (BEACON) in adults with T2DM and eGFR of 15 to < 30 mL/min/1.73 m2 | Bardoxolone 20 mg/day or placebo plus background conventional therapy | Filtration Resorption | No effect on rate of ESRD or death from cardiovascular causes (HR, 0.98; 95% CI: 0.70, 1.37; P = 0.92) | Terminated because of higher rate of cardiovascular events than placebo, but GFR improved vs placebo | |
Bardoxolone (Nrf2 activator)a [109] | Phase 2, randomized, double-blind, placebo-controlled study (TSUBAKI) in adults with T2DM, CKD stage 3–4, and UACR < 300 or < 2000 mg/g | Bardoxolone 15 mg/day or placebo for 16 weeks plus ACEi and/or ARB | Filtration Resorption | Improved GFR from baseline to week 16 (mean, 5.95 [95% CI: 2.29, 9.60] vs –0.69 [–3.83, 2.45)] mL/min/1.73 m2; P = 0.008) | Improved GFR; no safety signals of concern detected |
Finerenone (mineralocorticoid receptor antagonist)b [38] | Phase 3, randomized, double-blind, placebo-controlled study (FIDELIO-DKD) in adults with T2DM and CKD receiving ACEi or ARB | Finerenone 10 or 20 mg/day or placebo plus guideline-directed therapy | Filtration Resorption | Reduced risk of kidney failure, sustained eGFR decrease or death from renal causes (HR, 0.82; 95% CI: 0.73, 0.93; P = 0.001) | Discontinuation due to hyperkalemia in 2.3% of patients receiving finerenone |
Selonsertib (ASK1 inhibitor) [129] | Phase 2, randomized, placebo-controlled study in adults with T2DM and treatment-refractory moderate-to-advanced DKD | Selonsertib 2, 6, or 18 mg/day or placebo | Filtration Resorption Immune cell recruitment | No improvement in eGFR from baseline to week 48. Week 4 to 48 post hoc difference vs placebo: 3.11 mL/min/1.73 m2/year (95% CI: 0.10, 6.13; nominal P = 0.043) | Acute inhibitory effects on creatinine secretion confounded eGFR differences from baseline |
Baricitinib (JAK1/JAK2 inhibitor) [94] | Phase 2, randomized, double-blind, placebo-controlled study in adults with T2DM, eGFR or 25–70 mL/min/1.73 m2, UACR of 300–5000 mg/g on ACEi or ARB | Baricitinib 0.75, 1.5 or 4 mg/day or 0.75 mg twice daily or placebo | Immune cell recruitment | Improvement in UACR at week 24 at highest dose (ratio to baseline, 0.59; 95% CI: 0.38, 0.93; P = 0.022), but effects not dose-dependent | Increased risk of anaemia. Terminated for business reasons |
MEDI3506 (IL-33 mAb) NCT04170543 | Phase 2b, randomized, double-blind, placebo-controlled study in patients with DKD and eGFR of 30–75 mL/min/1.73 m2 on ACEi or ARB | MEDI3506 or placebo for 24 weeks, plus dapagliflozin in weeks 12–24 | Filtration Resorption Immune cell recruitment | Change in UACR from baseline to week 24 | Recruiting |
AZD5718 (FLAP inhibitor) NCT04492722 | Phase 2b, randomized, double-blind, placebo-controlled study in patients with eGFR of 20–75 mL/min/1.73 m2 and UACR of 200–5000 mg/g (DKD in a subgroup) | AZD5718 or placebo for 20 weeks, plus dapagliflozin in weeks 12–20 | Immune cell recruitment Filtration Resorption | Change in UACR from baseline to week 20 | Recruiting |
ASP8232 (VAP1 inhibitor) [110] | Phase 2, randomized, double-blind, placebo-controlled study in adults with T2DM, CKD, UACR of 200–3000 mg/g, eGFR of 25–75 mL/min/1.73 m2, HbA1c of < 11·0% (< 97 mmol/mol) on ACEi or ARB and anti-diabetic medication | ASP8232 40 mg/day or placebo for 12 weeks | Immune cell recruitment | Improvement in UACR at week 12 (difference versus placebo, –19.5% 95% CI: –34.0, –1.8; P = 0·033) | Increased risk of peripheral oedema and anaemia. Terminated for business reasons |
PF-04634817 (CCR2 and CCR5 receptor dual antagonist) [130] | Phase 2 randomized, double-blind, placebo-controlled study in patients with T2DM, eGFR of 20–75 mL/min/1.73 m2 and UACR ≥ 30 mg/g | PF-04634817 150 or 200 mg/day (depending on eGFR) or placebo | Immune cell recruitment | Placebo-adjusted improvement in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75, 1.09) at week 12 | Clinical development halted owing to insufficient efficacy |
Propagermanium / DMX-200 (CCR2 inhibitor) [131] | Randomized, open-label, pilot trial in patients with T2DM, dipstick proteinuria ≥ 1 + or UACR of ≥ 30 mg/g and eGFR of ≥ 30 mL/min/1.73 m2 | Propagermanium 30 mg/day for 12 months plus usual care or usual care alone | Immune cell recruitment | No change in UACR from baseline to 12 months (change, 25.0%; 95% CI: − 20.4, 96.5; P = 0.33) | Ineffective |
Propagermanium / DMX-200 (CCR2 inhibitor) NCT03627715 [132] | Phase 2 randomized, double-blind, placebo-controlled crossover trial in patients with DKD already on irbesartan 30 mg/day and an eGFR of 25–90 mL/min/1.73 m2 and UACR of 30–500 mg/mmol | Propagermanium twice daily or placebo for 12 weeks | Immune cell recruitment | 22% placebo-adjusted reduction in albuminuria from baseline (not powered for inferential statistical analysis) | Positive efficacy data announced in press release |
CCX140-B (CCR2 inhibitor) [133] | Phase 2 randomized, double-blind, placebo-controlled trial in patients with T2DM, proteinuria and eGFR ≥ 25 mL/min/1.73 m2 on anti-diabetic medication and ACEi or ARBs | CCX140-B 5 mg/day or 10 mg/day or placebo for 12 weeks (amended to 52 weeks) | Immune cell recruitment | Improvement in UACR from baseline to week 52 (placebo-adjusted difference of –16% for 5 mg [one-sided upper 95% CI –5%; P = 0.01] and –10% for 10 mg [+ 2%; Pp = 0.08]) | Authors concluded potential renoprotective effects, but these were not dose-dependent. No further studies in patients with DKD |
Bindarit (NF-κB modulator) [134] NCT01109212 | Phase 2, randomized, double-blind, placebo-controlled study in patients with DKD receiving irbesartan | Bindarit 600 mg twice daily or placebo plus irbesartan 300 mg/day for 12 weeks | Immune cell recruitment | Change in urinary albumin excretion (µg/mL) from baseline | Reduced albuminuria reported in congress abstract, but full results not published and no further studies |
Gevokizumab (IL-1β mAb) 2013–003,610-41 | Phase 2, randomized, double-blind, placebo-controlled study in patients with DKD and eGFR of 20–60 mL/min/1.73 m2 and UACR > 300 mg/g | Gevokizumab 3, 10, 30 or 60 mg or placebo for 52 weeks | Immune cell recruitment | Change in measured GFR from baseline | Terminated for ‘strategic reasons unrelated to safety’ |
Canakinumab (IL-1β mAb) [135] | Subgroup analysis of phase 3 trial (CANTOS) in patients who were stable after myocardial infarction with hsCRP ≥ 2 mg/mL and eGFR < 60 mL/min/1.73m2 | Canakinumab 50, 150 or 300 mg or placebo | Immune cell recruitment | Reduced risk of major adverse cardiovascular events (HR, 0.82; 95% CI: 0.53, 0.86; P = 0.0015) | No clinically meaningful improvement or worsening of eGFR or UACR or renal AEs |
Emapticap pegol (CCL2 binding aptamer) [136] | Phase 2, randomized, double-blind, placebo-controlled study in patients with eGFR > 25 mL/min/1.73 m2 and UACR > 100 mg/g | Emapticap 0.5 mg/kg twice weekly or placebo for 12 weeks | Immune cell recruitment | No significant improvement in UACR from baseline to week 12 or to 8 weeks after discontinuation | Suggestion of efficacy in a post hoc analysis excluding some patients, but no further studies |