Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus (DM). Diabetic nephropathy occurs in about 20% to 40% of diabetic patients, and it is the main cause of end-stage renal disease (ESRD) and one of the main causes of increased morbidity, mortality and disability in diabetic patients. Clinically, once diabetic nephropathy develops persistent proteinuria, its renal function will decline progressively, and about 25% of patients will develop end-stage renal failure within 6 years, 50% within 10 years, and 75% within 15 years, and the average duration of the disease is 10 years from the appearance of proteinuria to death from uremia.
Over the years, many clinical studies have been conducted to explore various therapeutic means to stop the development of diabetic nephropathy, but with little success. In recent years, compound alpha-keto acid (Kaito) nutritional therapy has been attracting attention and high expectation because of its unique mechanism to effectively reduce proteinuria and treat both the “symptoms” and the “root” of the disease, which is effective in slowing down the progression of diabetic nephropathy.
The clinical situation of DN is serious
In China, DN is a common cause of secondary glomerular diseases, and with the improvement of people’s living standard and the advent of aging society, the incidence of DM is increasing rapidly, and the number of DM patients in China is expected to reach 80 million in 2015, so it is expected that DN will increase rapidly and the rate of DN leading to ESRD will become higher.
The results of the study showed that 25.7% of the DM population in China had albuminuria, 12% of the pre-diabetic population had microalbuminuria, 9% of DM patients had renal insufficiency, and about 8% of pre-diabetic patients had renal insufficiency, i.e. about 16% of the hyperglycemic population had a moderate decrease in renal function. In patients with type 1 and type 2 DM, the incidence of DN is as high as 25% to 40%. Even in patients with diabetic nephropathy who receive optimal control of blood glucose, blood pressure and lipids, the morbidity and mortality rates are still at unacceptably high levels.
What is the constraint of DN treatment?
The earliest pathophysiological changes in diabetic nephropathy are glomerular hyperfiltration and glomerular hypertrophy. Persistent glomerular hyperfiltration causes damage to the glomerular thylakoid, basement membrane and capillary endothelium; deposition of various proteins (albumin, globulin and fibrin) and lipid mucopolysaccharides in the basement membrane promotes glomerulosclerosis; the presence of proteinuria further activates the RAS system, exacerbates intrarenal hemodynamic disturbances, activates a large number of inflammatory factors, and aggravates renal injury.
Persistent microalbuminuria (30-229 mg/24h) is a marker for the development of nephropathy in DM. Baseline proteinuria levels in patients significantly increase the incidence of renal events, and in patients with type 1 or type 2 diabetes, the presence of microalbuminuria not only marks the presence of early nephropathy, but also greatly increases the prevalence of cardiovascular disease and the risk of death. The risk of death due to proteinuria is higher compared to hypertension. Patients who progress from microalbuminuria to macroalbuminuria (≥300 mg/24h) are likely to progress to ESRD several years later.
Low-protein diet (LPD) can block the core part of proteinuria formation process and avoid glomerular hyperperfusion and hyperfiltration, but when LPD is applied, due to insulin deficiency, insulin resistance, weakened muscle protein synthesis, severe protein loss due to massive proteinuria and gastrointestinal dysfunction in diabetic patients, it will definitely cause essential amino acid deficiency, which will easily lead to negative nitrogen balance and protein It is easy to lead to negative nitrogen balance and protein malnutrition, thus further aggravating the deterioration of renal function.
There is a way to treat the “root” of the problem, and the compound α-keto acid is another way
The unique pharmacological mechanism of proteinuria inhibition
Compound α-keto acid is a compound preparation of α-keto acid and essential amino acids, which contains one α-hydroxy acid (hydroxymethionine) and five essential amino acids in addition to four α-keto acids (keto-leucine, keto-isoleucine, keto-phenylalanine and keto-valine). α-keto acid does not contain NH2 group and can be combined with NH2 in the body and converted into corresponding essential amino acids through corresponding transaminases, thus promoting the synthesis of amino acids in the body. It is also used to reduce blood urea nitrogen and improve azotemia.
The alteration of renal tubular transport function in renal lesions reduces tubular reabsorption, increases urinary excretion of branched-chain amino acids, and produces proteinuria. Protein degradation and oxidation of branched-chain amino acids are increased and synthesis is decreased in patients with renal disease. Studies have shown that branched-chain amino acids do not trigger renal hyperfiltration and directly reduce proteinuria, whereas other amino acids injected increase GFR and renal plasma flow.
Ketoacid improves renal tubular transport function and enhances renal tubular reabsorption of branched-chain amino acids such as leucine, isoleucine, and valine, thereby reducing urinary excretion of branched-chain amino acids, decreasing proteinuria, and correcting disorders of protein synthesis. When compound α-keto acid + LPD is given under the condition of adequate caloric guarantee, the body will adapt to increase protein synthesis, reduce amino acid oxidation and protein degradation, adjust protein metabolism, and indirectly treat proteinuria. The combination of compounded alpha-keto acid and LPD thus has the dual effect of treating proteinuria and ensuring nutritional status, and inhibiting the progression of diabetic nephropathy by “treating both the symptoms and the root cause”.
Strong support from clinical research evidence
The use of compounded alpha-keto acid plus LPD in patients with chronic kidney disease began in the late 1970s. Over 30 years of clinical practice have shown that compounded alpha-keto acid significantly reduces the rate of progression from microalbuminuria to macroalbuminuria and end-stage renal disease, and has gradually become a routine treatment for patients with chronic renal insufficiency.
A meta-analysis of six studies showed that LPD + compounded alpha-keto acid significantly reduced proteinuria in patients with diabetic nephropathy. a meta-analysis by Pedrini et al. showed that treatment with LPD + compounded alpha-keto acid in patients with diabetic nephropathy significantly reduced urinary protein and delayed the decline in GFR and a 46% reduction in the risk of ESRD onset or all-cause mortality.
Teplan et al. showed that the treatment group (LPD 0.6 g/kg/d + perindopril + cotrimoxazole) was significantly better than the control group (LPD 0.6 g/kg/d + perindopril) in reducing proteinuria and slowing the rate of decline in glomerular filtration rate, suggesting that cotrimoxazole has an independent effect in reducing proteinuria. was most effective in reducing proteinuria and significantly delayed the progression of diabetic nephropathy.
The results of the study conducted by Walser et al. on the treatment of nephrotic syndrome with compounded α-keto acid + VLPD showed that the mean 24-hour proteinuria of patients decreased from 9.3 g/d to 1.9 g/d, the mean serum protein level increased from 2.5 g/dl to 3.8 g/dl, and the mean serum cholesterol level decreased from 415 mg/dl to 255 mg/dl. The patients’ proteinuria, hypoprotein Proteinuria, hypoproteinemia and hyperlipidemia were significantly improved. Another study using keto acid for nephrotic syndrome yielded similar results, with urinary protein excretion decreasing from (5.7±2.8)g/24h at baseline to (3.0±2.1)g/24h (P.