Reversal of Established CKD by Weekly Subcutaneous Recombinant Human Mutated Angiopoietin-Like 4
Bibliographic record
Abstract
Background: We investigated the therapeutic potential of recombinant mutated human Angiopoietin-like 4 (ANGPTL4), previously shown to reduce proteinuria in diabetic and FSGS (Buffalo Mna) rats (Clement LC Nat. Med. 2014), in established chronic kidney disease (CKD). ANGPTL4 binds integrins β1 and β5 (podocyte α3β1, glomerular endothelial αvβ5, interstitial capillary endothelial α1β1), and has potent anti-apoptotic activity. Methods: Included with results. Results: As a proof of concept, transgenic expression of wild type rat Angptl4 from adipose tissue in Buffalo Mna rats (372-B. Mna) prevented doubling of serum creatinine (measured by LC-MS) between age 6 to 8 months (P<0.001), eliminated tubulo-interstitial fibrosis, and improved glomerular morphology compared to B. Mna rats (n = 4 to 6 rats / group). Interstitial infiltrate in 372-B. Mna rats contained mostly macrophages. Recombinant human mutated ANGPTL4 protein 8520 (Nat. Med. 2014) was purified and ultra-purified from HEK 293 stable cell lines grown in FiberCell systems. In a declining dose study (starting with 500 μg weekly subcutaneous 8520 or control rat albumin, n = 5 ZSF1 diabetic rats / group), serum creatinine was lower in the 8520 group compared to control between week 5 (dose 500 μg; P<0.001) and week 9 (dose 125 μg; P<0.05), but not at subsequent lower doses. Within the 8520 group, serum creatinine was lower on week 9 than Day 0 (P<0.05). Upon euthanasia (week 28), interstitial capillary endothelium apoptosis (TUNEL stain) was lower in 8520 compared to control (P<0.001). Using the lowest effective 8520 dose (125 μg / week) with or without ACE inhibitor (enalapril 5 mg/Kg/day), inulin clearance GFR at 16 weeks was higher in 8520 (P<0.05) and 8520 + enalapril (P<0.01) groups, tubulo-interstitial fibrosis lower (P<0.01 both groups) and interstitial capillary endothelial apoptosis lower (P<0.001 both groups) compared to control treated ZSF1 rats (age on Day 0, 19 weeks; n = 4-5 rats / group). Enalapril alone did not improve GFR. Studies with higher doses of 8520 are in progress. Conclusion: 8520 reverses established CKD to improve GFR via a multi-compartment anti-apoptosis effect that keeps capillaries open for repair. Funding: NIDDK Support
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".