Comments for:
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Kidney tubular cells have a high energy demand, dependent on fatty acid oxidation (FAO). Although carnitine is indispensable for FAO, the pathological role of carnitine deficiency in DKD is not fully understood. We showed here that ectopic lipid accumulation owing to impaired FAO increased in patients with DKD and inversely correlated with kidney function. Organic cation/carnitine transporter 2–deficient (OCTN2-deficient) mice exhibited systemic carnitine deficiency with increased renal lipid accumulation. Cell death and inflammation were induced in OCTN2-deficient, but not wild-type, tubular cells exposed to high salt and high glucose. Compared with Spontaneously Diabetic Torii (SDT) fatty rats, uninephrectomized SDT fatty rats fed with 0.3% NaCl showed higher lipid accumulation and increased urinary albumin excretion with kidney dysfunction and tubulointerstitial injury, all of which were ameliorated by l-carnitine supplementation via stimulating FAO and mitochondrial biogenesis. In our single-center randomized control trial with patients undergoing peritoneal dialysis, l-carnitine supplementation preserved residual renal function and increased urine volume, the latter of which was correlated with improvement of tubular injury. The present study demonstrates the pathological role of impairment of carnitine-induced FAO in DKD, suggesting that l-carnitine supplementation is a potent therapeutic strategy for this devastating disorder.
Authors
Sakuya Ito, Kensei Taguchi, Goh Kodama, Saori Kubo, Tomofumi Moriyama, Yuya Yamashita, Yunosuke Yokota, Yosuke Nakayama, Yusuke Kaida, Masami Shinohara, Kyoko Tashiro, Keisuke Ohta, Sho-ichi Yamagishi, Kei Fukami
Diabetic kidney disease beyond L-carnitine deficiency
Submitter: Arduino Arduini | a.arduini@iperboreal.com
Iperboreal Pharma
Published July 28, 2025
Recently, Ito et al. presented evidence that L-carnitine (LC) deficiency is a key factor in the physiopathology of diabetic kidney disease (DKD) (1). DKD exhibited lipid accumulation and decreased LC-induced fatty acid oxidation (FAO), which is linked to tubular damage. The authors found that LC deficiency in various animal models is associated with reduced counts of viable proximal tubular cells (PTC), increased pro-fibrotic and pro-inflammatory cytokines, impaired fatty acid oxidation (FAO), and disrupted mitochondrial structure in uninephrectomized diabetic rats on a high-salt diet, leading to kidney dysfunction, tubular injury, and fibrosis. Most dysfunctions improved with LC treatment. A randomized controlled trial of patients on peritoneal dialysis (PD) demonstrated that LC supplementation preserved residual renal function and increased urine volume, correlating with reduced tubular injury. We have published and conducted several clinical trials in PD patients treated with LC administered along with glucose-based PD solution (2,3). In our multicenter, randomized, controlled clinical trial, we had already demonstrated that carnitine administration in a more homogeneous, non-diabetic population of PD patients not only led to a significant improvement in insulin sensitivity but also maintained residual diuresis (3). Ito et al. ignored our preclinical and clinical studies on LC, either in combination with glucose or as a component of a ternary combination of glucose-sparing PD solution, in Phase III clinical development in Europe (4).
Assuming plasma LC levels reflect organ levels, the beneficial effects reported in the Ito et al. study may not depend on correcting LC deficiency. A previous study argued that higher LC levels in plasma and target organs can positively impact metabolic disturbances like insulin resistance and diabetes, which are common in chronic kidney disease patients and those undergoing dialysis (5). Furthermore, their claim about impaired carnitine-induced FAO doesn’t align with a recent study showing that selective deletion of renal tubules' carnitine palmitoyltransferase (CPT1A) did not significantly affect kidney function or fibrosis, even after aging or chronic injury (6). CPT1A is the rate-limiting step in long-chain fatty acid oxidation (Ceccarelli et al. J Med Chem 2011). A final note, the reference units of plasma LC Figure 7K and Suppl Table 6 are mmol/L, not nmol/L.
Arduino Arduini is a major shareholder of Iperboreal Pharma.
1.Ito et al. Involvement of impaired carnitine-induced fatty acid oxidation in experimental and human diabetic kidney disease. JCI Insight. 2025;10(13):e179362
2. Bonomini M, et al. L-carnitine is an osmotic agent suitable for peritoneal dialysis. Kidney Int. 2011;80(6):645-654.
3. Bonomini M, et al. Effect of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicenter randomized trial. Am J Kidney Dis. 2013;62(5):929-938
4. Bonomini M, et al. Rationale and design of ELIXIR, a randomized, controlled trial to evaluate efficacy and safety of XyloCore, a glucose-sparing solution for peritoneal dialysis. Perit Dial Int. 2025 Jan;45(1):17-25.
5. Arduini et al. Carnitine in metabolic disease: Potential for pharmacological intervention. Pharmacol Ther. 2008;120(2):149-156.
6. Hammoud S, et al. Tubular CPT1A deletion minimally affects aging and chronic kidney injury. JCI Insight. 2024;9(9).
7. Ceccarelli et al. Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011 May 12;54(9):3109-52.
Response to Arduini
Submitter: Kensei Taguchi | taguchi_kensei@kurume-u.ac.jp
Authors: Sakuya Ito and Kensei Taguch
Division of Nephrology, Kurume University School of Medicine
Published July 28, 2025
Diabetic kidney disease (DKD) is the leading cause of end‑stage kidney disease worldwide. In DKD rodent models, we observed carnitine deficiency in kidney tissue and serum, accompanied by mitochondrial fragmentation, tubular injury, and interstitial fibrosis, all of which were prevented by L‑carnitine supplementation. These mechanistic findings resonate with the clinical trials by Bonomini et al., which showed that an L‑carnitine–enriched peritoneal dialysis (PD) solution preserved residual renal function (RRF) and attenuated insulin resistance (1, 2). Consistently, our results demonstrate that oral L‑carnitine confers antioxidant activity and maintains RRF in PD patients, including those with diabetes. These findings indicate that L‑carnitine provides renoprotective effects irrespective of the route of administration.
Accumulating basic and clinical evidence has shown that L-carnitine supplementation exerts pleiotropic effects against oxidative stress, inflammation, and apoptosis. Even in healthy individuals with normal carnitine profiles, L-carnitine supplementation upregulates antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, protecting the organs (3). In line with these actions, L‑carnitine lowered the urinary albumin‑to‑creatinine ratio (UACR) in SDT rats whose carnitine levels were within the normal range, indicating kidney protection independent of overt carnitine deficiency. However, it is also the fact that the reduction in UACR was even more pronounced in the carnitine‑deficient DKD rats. Furthermore, LC‑MS/MS analysis confirmed a significant decline in renal free carnitine in the DKD rats, which was fully restored by the supplementation (Supplementary Fig. 5C). These observations implicate carnitine deficiency as a pathogenic driver of DKD progression and highlight L‑carnitine as a promising therapeutic agent to halt disease progression.
Carnitine palmitoyltransferase 1a (CPT1a) and CPT2 are the rate‑limiting enzyme of mitochondrial long‑chain fatty‑acid oxidation (FAO). Gene expression of FAO-related genes, including CPT1a, CPT2, ACOX1, and ACOX2, was reduced in patients with CKD (4). Conversely, renal overexpression of CPT1a enhances mitochondrial biogenesis and confers renoprotection in CKD rodent models (5). Similar benefits have been reported for CPT2 and CrAT (6, 7). In contrast to the findings of Hammoud et al. (8), we observed marked reductions not only in CPT1a, but also in CPT2 and CrAT in the DKD rats, suggesting that broad suppression of FAO enzymes can cause the disease progression. Please note that carnitine concentrations in some figure panels were mislabeled and will be corrected in an erratum.
[Reference]
1. Bonomini M, et al. L-carnitine is an osmotic agent suitable for peritoneal dialysis. Kidney Int. 2011;80(6):645-654.
2. Bonomini M, et al. Effect of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicenter randomized trial. Am J Kidney Dis. 2013;62(5):929-938.
3. Cao Y, et al. Single Dose Administration of L-Carnitine Improves Antioxidant Activities in Healthy Subjects. The Tohoku Journal of Experimental Medicine. 2011;224(3):209-213.
4. Kang HM, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21(1):37-46.
5. Miguel V, et al. Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J Clin Invest. 2021;131(5).
6. Lee J, et al. Mitochondrial carnitine palmitoyltransferase 2 is involved in N(ε)-(carboxymethyl)-lysine-mediated diabetic nephropathy. Pharmacol Res. 2020;152:104600.
7. Kruger C, et al. Proximal Tubular Cell-Specific Ablation of Carnitine Acetyltransferase Causes Tubular Disease and Secondary Glomerulosclerosis. Diabetes. 2019;68(4):819-831.
8. Hammoud S, et al. Tubular CPT1A deletion minimally affects aging and chronic kidney injury. JCI Insight. 2024;9(9)e181816.
