ubiquinone and Nephritis--Interstitial

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Antioxidants; Biomarkers; Blotting, Western; Disease Models, Animal; DNA Primers; Enzyme-Linked Immunosorbent Assay; Fluorescein-5-isothiocyanate; Genotype; Glomerular Filtration Rate; Humans; Immunohistochemistry; Kidney Tubules, Proximal; Methylmalonyl-CoA Mutase; Mice; Mice, Knockout; Microarray Analysis; Microscopy, Electron, Transmission; Nephritis, Interstitial; Real-Time Polymerase Chain Reaction; Transgenes; Ubiquinone

Coenzyme Q10 belongs to important antioxidants and it has a key role in the synthesis of adenosinetriphosphate. Its beneficial effect was proved in several diseases, e.g. in mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial cardiomyopathy.. All 15 patients of the studied group (5 with tubulopathy and 10 with chronic tubulointersticial nephritis) received antioxidative therapy for three months (E vitamin, C vitamin, riboflavin) and for the last two months coenzyme Q10 was added. Renal functions, spectrum of lipids, parameters of lipid peroxidation (malondialdehyde), levels of alpha-tocopherol, beta-carotene, coenzyme Q10.. Before the substitutive antioxidative treatment, coenzyme Q10 levels reached in blood 0.11 +/- 0.03 mumol/l and 0.15 +/- 0.04 mumol/l in plasma. These values were well below the reference range (rr) is 0.4 +/- 1.0 mumol/l). After the substitution coenzyme Q10 levels significantly increased (p < 0.001) to the values of 1.66 +/- 0.16 mumol/l in blood and to 1.78 +/- 0.27 mumol/l in plasma. Plasma levels of beta-carotene increased from the markedly subnormal values 0.25 +/- 0.07 mumol/l (rr > 0.8 mumol/l) to 0.56 +/- 0.02 mumol/l (no statistical difference). Plasma levels of alpha-tocopherol remained within the reference range 32.15 +/- 4.73 mumol/l (rr 15-30 mumol/l) and they increased up to the plasma level of 44.83 +/- 5.82 mumol/l during the period of testing. Malondialdehyde levels did not significantly change within the testing period. No changes in renal functions and parameters of lipid metabolism were described. Patients well tolerated the treatment and no adverse effects were seen during the period of observation.. Our results ascertained that levels of antioxidant CoQ10 were lower in patients with nephropathy who underwent conservative treatment with peroral substation. Such deficit can be amended by CoQ10 administration, which could be therefore taken as complementary treatment of nephrology.

Topics: Acidosis, Renal Tubular; Adult; Aged; Aged, 80 and over; Antioxidants; Coenzymes; Female; Humans; Kidney; Kidney Diseases; Male; Malondialdehyde; Middle Aged; Nephritis, Interstitial; Ubiquinone; Vitamins

MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers.. Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years.. MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear.

Topics: Amino Acid Metabolism, Inborn Errors; Carnitine; Child; Child, Preschool; Creatinine; Cystatin C; Disease Progression; Female; Glomerular Filtration Rate; Humans; Infant; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Nephritis, Interstitial; Postoperative Complications; Renal Dialysis; Retrospective Studies; Ubiquinone; Vitamin B 12; Vitamin E

Oxidation stress and decreased antioxidative capacity participate in the progression and complications of renal diseases such as hyperlipoproteinemia or cardiovascular diseases. Many data have been collected on oxidation stress in dialysed patients, however a shortage of information is evident in conservatively treated patients.. To determine the blood and/or plasma levels of MDA and the selected antioxidants, i.e. Coenzyme Q10 (CoQ), alpha-tocoferol, beta-carotene in conservatively treated patients with kidney diseases.. Fifty five patients (45 with interstitial nephritis and 10 with glomerulonephritis) were included. They were divided into 3 subgroups on the basis of their clearance of creatinine (Ckr). Only validated methods have been exploited for the determination of variables.. MDA plasma levels were increased (5.37 +/- 0.10, reference range (rr.) < 4.5 mumol/l) with the highest levels in patients treated by immunosuppression. CoQ plasma (0.35 +/- 0.04, rr. 0.4-1.0 mumol/l) and blood (0.30 +/- 0.03 mol/l) were decreased, notably in patients with interstitial nephritis. No correlation with Ckr was apparent. alpha-tocopherol plasma levels (42.1 +/- 3.04, rr. 15-40 mumol/l) were increased, but the concentrations increased further with the decreasing kidney function. beta-carotene plasma (2.14 +/- 0.39, rr. > 0.8 mumol/l) were in reference range but decreased with the decrease of kidney function.. CoQ plasma levels are decreased and MDA levels increased in conservatively treated kidney disease patients even in just slightly decreased renal function. beta-carotene levels decrease only in advanced renal failure. These changes could participate in kidney disease progression and it is suggested that their correction opens the possibility of progression inhibition. (Tab. 3, Ref. 27.)

Topics: Adolescent; Adult; Aged; Antioxidants; beta Carotene; Chronic Disease; Glomerulonephritis; Humans; Immunosuppressive Agents; Malondialdehyde; Middle Aged; Nephritis, Interstitial; Ubiquinone; Vitamin E