MIXTURE OF CARBOXYLIC ACIDS FOR TREATING PATIENTS WITH KIDNEY FAILURE

Abstract

A mixture of carboxylic acids: citric acid, succinic acid, fumaric acid and malic acid, and any possible combinations thereof. This product is used orally or also intravenously, in the treatment of patients with chronic renal failure, hyperammonemia or human conditions having negative nitrogen balance. This product is beneficial in decreasing the serum values of urea and serum ammonium, while promoting by transamination of the oxalacetate formed via succinate, fumarate and malate, the biosynthesis of non-essential amino acids; by transamination of the alpha ketoglutarate formed via citrate, it generates glutamic acid and related amino acids such as glutamine. This treatment prevents, preserves and even improves kidney function. In other patients it delays deterioration of renal function and the urgent need for renal replacement therapy. In others, it is used as a supplemental renal replacement treatment to improve the patient's quality of life and improve laboratory parameters.

Claims

1. A method of reducing uremia and hyperphosphatemia in patients with chronic renal failure, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising citric acid, succinic acid, fumaric acid, and malic acid, in combination with sodium bicarbonate, calcium carbonate and calcium lactate.

2. The method according to claim 1, wherein the therapeutically effective amount of the composition administers to said patient is 12 to 1800 millimoles (2.304 grams to 345.6 grams) of citric acid per day.

3. The method according to claim 1, wherein the therapeutically effective amount of the composition administers to said patient is 10 to 1800 millimoles (1.18 grams to 212.4 grams) of succinic acid per day.

4. The method according to claim 1, wherein the therapeutically effective amount of the composition administers to said patient is 10 to 1800 millimoles (1.16 grams to 208.8 grams) of fumaric acid per day.

5. The method according to claim 1, wherein the therapeutically effective amount of the composition administers to said patient is 10 to 1800 millimoles (1.34 grams to 241 grams) of malic acid per day.

6. The method according to claim 1, wherein the composition is formulated: (i) as a powder to be reconstituted in drinking water or fruit juice; (ii) as effervescent tablets; or (iii) to be premixed or pre-constituted in fruit juices or ingestible drinks.

7. The method according to claim 1, wherein the composition further comprises vitamin C, folic acid, ferrous sulfate, B complex and/or calcitriol.

8. The method according to claim 1, wherein the composition further comprises artificial sweeteners of acesulfame, aspartame and/or sucralose.

9. The method according to claim 1, wherein the composition further comprises monosaccharides of fructose and/or glucose; disaccharides of sucrose and/or lactose; and/or oligosaccharides of inulin and/or maguey honey.

10. The method according to claim 1, wherein the composition further comprises taurine and/or L carnitine.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 is a Citric acid cycle (Krebs cycle).

[0022] FIG. 2 is an Anaplerotic pathways for replacement of Krebs cycle intermediates.

[0023] FIG. 3 is an External replacement of intermediates of the citric acid cycle.

[0024] 1.Tricarboxylic acid cycle where it is seen that the entry to the cycle is via the acetyl coenzyme A (see FIG. 1), which, together with oxaloacetate, regenerates citric acid, the first target of our invention. After some intermediate steps the citrate generates alpha-ketoglutarate, which subsequently generates succinyl coenzyme-A, which in turn generates succinate, the second target of our invention. Succinate loses two electrons by oxidation and creates fumarate, third objective of our invention. In the immediate metabolic step, the fumarate is hydrated to form malate, the fourth objective of our invention. It should be noted that the salts, among others, citrate, succinate, fumarate and malate are mentioned in the tricarboxylic acid cycle. Our invention consists of mixtures of citric, succinic, fumaric and malic acids, which in the aqueous environment of the organism dissociate into their corresponding citrate, succinate, fumarate and malate ions. Of special interest is that the cycle of citric acid is a universal cycle that takes place not only in the human being, but in the three domains of life on earth, i.e., in 1) domain eukarya where animalia, plantae, fungi and protista kingdoms are included, 2) domain archaea and 3) domain bacteria. This cycle is a universal cycle and constitutes the center or axis of the general metabolism of any cell, be it eukaryote with true nucleus, as is the case with all the cells of the human being, or prokaryotic cell, as is the case with bacteria that do not possess true nucleus. Said citric acid cycle is an amphibole cycle involving two very important general functions or pathways that are interrelated, namely:

[0025] 1.a) Function or catabolic pathway, in which nutrients such as proteins via amino acids, carbohydrates via glucose, triacylglycerols via glycerol and fatty acids, end up as pyruvate before entering the cycle of tricarboxylic acid. By losing a carbon and generating CO.sub.2, pyruvate is converted to acetyl coenzyme A and when it binds with the oxalacetate it regenerates the citrate to enter the citric acid cycle through the catabolic pathway, generating energy through the formation of ATP and various electron carriers like NAD and FAD.

[0026] 1.b) Function or anabolic pathway, in which certain intermediates of the citric acid cycle are used for the biosynthesis of monomeric molecules. Thus, for glucose biosynthesis (gluconeogenesis), oxalacetate is used, and for biosynthesis of fatty acids we use acetyl coenzyme A. For the biosynthesis of non-essential amino acids (glycine, L alanine, L asparagine, L aspartate, L cysteine, L glutamate, L glutamine, L proline, L serine and L tyrosine) the oxalacetate intermediate is used as the initiator of synthesis, which will be formed through the acids of our invention: succinic acid, fumaric acid and malic acid, which in the aqueous medium of our body form the corresponding succinate, fumarate and malate. Thus succinate, by the action of the enzyme succinate dehydrogenase, generates fumarate. In turn, fumarate, by action of the enzyme fumarase, generates L malate. Finally, L malate, by the action of the enzyme malate dehydrogenase, produces oxaloacetate. Another cycle intermediate is alpha-ketoglutarate which serves as the initiator to form glutamic acid by reversible transamination. Then, by additional transamination, form glutamine, as well as other related amino acids. Said alpha ketoglutarate is generated by metabolic reactions exerted on the citric acid, which in the aqueous environment of the organism is dissociated in citrate, which is part of our invention. These methabolic reactions involve the action of the enzyme aconitase on the citrate to generate cis-aconitate. In a second reaction, the same enzyme aconitase acts on the cis-aconitate to form isocitrate. In the next metabolic step, the enzyme isocitrate dehydrogenase acts on the isocitrate to generate alpha ketoglutarate.

[0027] As shown in FIG. 2, these amino acid biosynthetic pathways, glucose and fatty acids, are pathways that extract intermediates from the cycle and are known as cataplerotic pathways or reactions, which hypothetically speaking, when extracting intermediates from the cycle would exhaust it. This is not the case because, in return for this cataplerotic pathway, and since the citric acid cycle cannot be interrupted, there are replacement pathways or reactions of these intermediaries known as anaplerotic pathways or reactions, of which the most important is the catabolized by the enzyme pyruvate carboxylase that generates oxalacetate from pyruvate (reaction 1). Another anaplerotic reaction for the replacement of cycle intermediates involves the direct conversion of phosphoenolpyruvate by the action of the enzyme phosphoenolpyruvate carboxylase to oxalacetate (reaction 2). Another involves reversible transamination from aspartate to oxalacetate (reaction 3). Furthermore, by the action of the malic enzyme or malate dehydrogenase on pyruvate, it catalyzes the reductive carboxylation thereof to generate malate (reaction 4). Finally, glutamate generates alpha ketoglutarate by reversible transamination (reaction 5). To sum up, so far 3 anaplerotic reactions generate and replenish oxaloacetate, namely, anaplerotic reaction from phosphoenolpyruvate to oxalacetate, anaplerotic reaction from pyruvate to oxalacetate and anaplerotic reaction from aspartate to oxaloacetate. A fourth anaplerotic reaction generates malate from pyruvate, and a last and fifth anaplerotic reaction generates alpha ketoglutarate from glutamate.

[0028] In conclusion, the citric acid cycle is:

a) A universal metabolic cycle that takes place in all living beings and includes the three domains: eukaria, which in turn includes animalia and the human beingpurpose of our inventionplantae, fungi, protist, and other two domains, the domain archaea and the domain bacteria.
b) A metabolic cycle that is situated at the axis of the general metabolism.
c) An amphibole cycle with two interrelated pathways, a catabolic pathway involving the use of carbon compounds to generate energy via ATP, as well as electron carriers such as NAD and FAD; and an anabolic pathway in which cycle intermediates, more specifically oxalacetate and alpha ketoglutarate, are used as initiator compounds for building other molecules, most notably non-essential amino acidssubject and consideration of the scientific basis of our patent.
d) In turn, the anabolic pathway, which involves subtracting certain intermediates (oxalacetate, alpha-ketoglutarate and acetyl coenzyme A) to form new molecules different from the compounds of the cycle, known as cataplerotic reactions, is compensated by reactions of replenishment or filling of intermediates, called anaplerotic reactions.
2.Another scientific basis of our invention involves the knowledge that in the urea cycle arginine is used to generate urea and ornithine by the action of arginase. This cycle is energy-dependent, consuming ATP in the formation of urea.

[0029] Urea, the main product of excretion of nitrogen compounds in ureotelic animals, as is the case of humans, is a small molecule with a molecular weight of 48, which by the action of intestinal urease is split into carbon dioxide and ammonium.

[0030] Non-ureotelic animals, such as fish, remove their nitrogenous waste products to the aquatic environment in the form of ammonium, not requiring conversion to urea.

[0031] Animals such as the bear in the wintering period do not form urine, so there must be alternate metabolic pathways to reuse the formed urea.

[0032] The Dalmatian dog, being ureotelic, eliminates its nitrogenous wastes via uric acid.

[0033] Reptiles and birds eliminate their nitrogenous waste via uric acid formation.

[0034] In the insects there are Malpighian tubeles, which consist of tubular structures in which the blind end of the tube is in contact with the hemolymph and the other end leads into the final part of the insect's intestine.

[0035] From the anatomical point of view, in flat worms or plathelminthes the first structures specialized in excretion are given: protonephridia that on the one hand connect with the coelom and on the other they open to the outside of the animal through the nephridiopores. An even more advantageous structure in the evolution are the metanephridia appearing in mollusks and annelids. This consists of an open tubele in which the inner end opens into the coelom and the outer end is opened to the outside by means of a nephridiopore.

[0036] With the above we notice a metabolic diversity regarding the elimination of nitrogenous waste products: ammonium in fish, uric acid in reptiles and birds, and urea in ureothelial animals. There is also an anatomical diversity that remotely targets the relationship between the urinary system, the digestive system and the skin. By this we refer to the Malpighian tubules that connect to the intestine of insects, which explains the transfer of a certain amount of urea to the intestine, about 25% of the serum urea, as well as the elimination of approximately 10% of serum urea through sweat, perhaps a reminder of the time when life on Earth was at the stage of mollusks and annelids.

[0037] Our invention consists or implies (see FIG. 3): first objective, the replacement of citrate from citric acid which, in subsequent metabolic steps, will first generate cis aconitate, then isocitrate and finally alpha keto glutarate; second objective, replacement of succinate from succinic acid, which in subsequent steps will generate fumarate, then malate, and then oxaloacetate; third objective of our invention, replacement of fumarate through fumaric acid which in a subsequent step will generate malate, and this, in turn, will generate oxaloacetate; fourth objective, replacement of malate through malic acid, which in the subsequent step will generate oxaloacetate. Thus, in comparing the five anaplerotic reactions of the citric acid cycle, two of them, for our interest, are not considered since they involve transamination from aspartate to oxalacetate and transamination from glutamate to alfacetoglutarate, since they lead to deamination of existing amino acids. Then, there are three intermediate replacement routes left that do not involve transamination. Two of them replenish oxalacetate via pyruvate and phosphoenolpyruvate, and one of them replaces malate via pyruvate.

[0038] Our invention, unlike prior patents based on the administration of essential amino acids orally or intravenously, or the use of alpha keto analogs of essential branched-chain amino acids in combination with essential amino acids, as well as unlike what happens in vivo inside the cell, and more specifically at the mitochondrial levelbecause the citric acid cycle is performed at the mitochondrial level, our first objective involves the replacement of citrate through citric acid, which in subsequent reactions results in the formation of carbon dioxide and alpha keto glutarate, in molar proportions; thus, one mole of citrate generates one mole of carbon dioxide and one mole of alpha keto glutarate. This does not occur in nature because under biological conditions citrate is regenerated by the reaction of acetyl Coenzyme A, catalyzed by the enzyme citrate synthase on the oxaloacetate to generate citrate. Second objective, replacement of succinate through succinic acid, which will give fumarate, then malate and finally oxalacetate, replacement condition of our invention that does not occur in biological systems either. Third objective, consisting of the replacement of fumarate through fumaric acid that will give malate and finally oxalacetate, replacement of our invention which, like the replacement of succinate, does not occur in biological systems. Fourth objective, consisting of the replacement of malate through malic acid, which in the case of biological systems is carried out by action on the pyruvate of the malic enzyme to generate malate, but in the case of our invention, a direct replacement is provided without intervening or acting on any substrate or by the action of specific enzyme.

[0039] In addition, our invention consists in the option of adding other dicarboxylic acids such as tartaric acid and/or cream of tartar to the mixture to improve the palatability and solubility of said mixture, and additionally phosphorus chelating agents such as calcium carbonate and/or calcium acetate and/or calcium gluconate and/or calcium lactate, which are extremely beneficial in the treatment of patients with chronic renal failure in stages 4 and 5, because in this condition hyperphosphataemia is extremely common, especially in patients with chronic long-term renal failure.

[0040] An additional element of the present patent is the incorporation of sodium bicarbonate into the mixture of dicarboxylic acids (succinic acid, fumaric acid, malic acid and tricarboxylic citric acid). Sodium bicarbonate is beneficial in patients with renal failure, as these occur with chronic metabolic acidosis. In addition, it serves to balance the pH of the mixture or the carboxylic acids used in a unique way and as an antacid effect.

[0041] Another optional element or elements (may be present or not) additional to the mixtures of this patent, is the addition of food additives to improve patient adherence to medical treatment: (1) Artificial sweeteners such as aspartame, acesulfame and/or sucralose, and (2) natural sweeteners such as disaccharides: sucrose and/or lactose, or monosaccharides: glucose and/or fructose.

[0042] In addition, optional additional nutraceutical substances (which may or may not be present) are incorporated into the mixtures of this invention, such as: inulin, maguey honey, taurine, msm (methylsulfonylmethane), alpha lipoic acid and L carnitine.

[0043] As part of the oral treatment of the patient with chronic renal failure, in addition to the specific medications for each patient, supplements consisting of ascorbic acid, folic acid, ferrous sulfate, calcitriol and complex b are routinely prescribed, so that in order to reduce to the maximum and as much as possible the number and diversity of the different and various medicines referred to, the latter, ascorbic acid, folic acid, ferrous sulfate, calcitriol and b complex, are optionally incorporated into the carboxylic acid mixture, a possible condition given the high solubility of these as well as their pleasant palatability.

[0044] In order to calculate the amount of dicarboxylic acids to be used which are sufficient to finally generate oxalacetate and alpha keto glutarate, and to capture ammonium via transamination derived from the metabolism of amino acids, and on a much smaller scale of the metabolism of the pyrimidine bases and other compounds carrying amino, amido or imino groups, we will resort to the following data:

1.A restricted diet of 0.6 to 0.8 grams per kilo of patient weight per day is suggested; then in a man of 70 kilos, the amount of protein to be consumed will be 42 to 56 grams per day, ideally high quality biological proteins.
2.The average amino acids for a large number of proteinsthe same ones to be ingestedis as follows: see Table 1column 4. Of these twenty amino acids, 14 have a nitrogen (N), 4 of them carry 2 nitrogens, 1 of them 3 nitrogens and 1 of them 4 nitrogens. Their atomic weights are expressed in column 6. Correlating the above data we have that one mole of average proteins would weigh 125.76 grams and would contain 18.802 grams of nitrogen.

TABLE-US-00001 TABLE 1 Average composition of the amino acids constituent of the average proteins. N PROPOR- EMPIRICAL PRESENCE IN ATOMS PER ATOMIC TIONAL N N NAME OF A.A. FORMULA PROTEINS.sup.0 A.A. MASS.sup.1 MASS.sup.2 ATOMS.sup.3 ATOMS.sup.4 ALANINE O2C3H8N1 .sup.9% 1 90 8.1 0.09 1.26 ARGININE O2C6H16N4 4.7% 4 168 7.896 0.188 2.632 ASPARAGINE O2C4H9N2 4.4% 2 117 5.148 0.088 1.232 ASPARTIC O2C4H8N1 5.5% 1 102 5.61 0.055 0.77 ACID CYSTEINE O2C3H8S1N1 2.8% 1 122 3.416 0.028 0.392 GLUTAMINE O3C5H11N2 3.9% 2 147 5.733 0.078 1.092 GLUTAMIC O4C5H10N1 6.2% 1 148 9.176 0.062 0.868 ACIDO GLYCINE O2C2H6N1 7.5% 1 76 5.7 0.075 1.05 HISTIDINE O2C6H12N3 2.1% 3 158 3.318 0.063 0.882 ISOLEUCINE O2C6H14N1 4.6% 1 132 6.072 0.046 0.644 LEUCINE O2C6H14N1 7.5% 1 132 9.9 0.075 1.05 LYSINE O2C6H16N2 .sup.7% 2 148 10.36 0.14 1.96 METHIONINE O2C5H12S1N1 1.7% 1 150 2.55 0.017 0.238 PHENYLALANINE O2C9H13N1 3.5% 1 167 5.845 0.035 0.49 PROLINE O2C5H10N1 4.6% 1 116 5.336 0.046 0.644 SERINE O3C3H8N1 7.1% 1 106 7.526 0.071 0.994 THREONINE O3C4H10N1 .sup.6% 1 120 12 0.06 0.84 TRYPTOPHAN O2C11H16N2 1.1% 2 208 2.288 0.022 0.308 TYROSINE O3C9H14N1 3.5% 1 184 6.44 0.035 0.49 VALINE O2C5H12N1 6.9% 1 118 8.142 0.069 0.966 100% 125.76 1.34 18.8 .sup.0Average for a large number of proteins. Individual proteins may exhibit significant variations with respect to these values. .sup.1The atomic masses of the elements constituting amino acids are: Hydrogen 1, Carbon 12, Nitrogen 14, Oxygen 16 and Sulfur 32. .sup.2The proportional mass of each amino acid (A.A.) was obtained by multiplying the percentage of each A.A. found in an average protein by its atomic mass. Hence, by adding up the proportional mass of each amino acid that makes up a protein, we obtain that the weight of an average protein is 125.76 grams. .sup.3The nitrogen atoms of each amino acid in proportion to their appearance in proteins are equivalent to their mass proportional by the number of atoms per amino acid among its atomic mass. The sum of the nitrogen atoms of each A.A. found in an average protein is equal to 1.34. .sup.4Since one mole of nitrogen weighs 14 grams, it can be deduced that 1.34 moles of nitrogen equals 18.8 grams.
According to a diet restricted to 0.6 grams of protein per kilo of weight per day, a person of 70 kilos of weight would ingest 42 grams of protein, which would provide 6.28 grams of nitrogen (equivalent to 448.54 millimoles of nitrogen).
In the case of a diet of 0.8 grams of protein per kilo of weight per day, a person of 70 kilos of weight would ingest 56 grams of protein, which would provide 8.37 grams of nitrogen (equivalent to 598.05 millimoles of nitrogen).
Taking into account the Avogadro's number, where one mole of any substance is equal to 6.02210.sup.23 molecules per mole (gram molecule), we can conclude that:
3.To capture 6.28 grams of nitrogen (448.54 millimoles of nitrogen, as one mole of nitrogen equals 14 grams) contained in 42 grams of protein, we need the same amount of millimoles of dicarboxylic and tricarboxylic acids; this in basal conditions, it is obvious to mention that in situations of stress, such as sepsis, surgery, burns, consumptive diseases and diabetes, the requirements would increase.
Since the carboxylic acid mixture has an average mass of 140 to equal parts (see Table 2), one mole of this mixture is equal to 140 grams. To obtain 448.54 millimoles of such acids, 62.79 grams of these are needed, and to obtain 598.05 millimoles 83.73 grams of dicarboxylic and tricarboxylic acids are needed.

TABLE-US-00002 TABLE 2 Average molar weight of carboxylic acids and their mixtures in equal parts. ATOMIC CARBOXYLIC ACIDS MASS Succinic Acid 118 Fumaric Acid 116 Malic Acid 134 Citric Acid 192 AVERAGE WEIGHT (in equal proportions) 140

[0045] Excretion of urea and other low molecular weight nitrogen compounds is carried out through sweat in 10%, feces in 25%, as ammonium through the urine in 10% and another 10% by residual renal function. This represents about 35% of the removal of nitrogen and nitrogen compounds alternately to renal excretion and 20% renally (10% in ammonium form as such, and 10% as residual renal function). If one takes into account that of the daily intake of proteins about 55% of the nitrogens contained in them are eliminated through these pathways, the need for ingestion of the carboxylic acids can be reduced by half approximately. This would maintain the daily requirement thereof in the order of 31.40 grams to 41.86 grams of carboxylic acids for an intake of 42 and 56 grams of protein respectively.

[0046] The effects and, consequently, the benefits of this invention are:

1.Capture of ammonium before the formation of urea at the liver level, thereby
1.1reducing the concentration of ammonium in the body and the toxic effects thereof and
1.2reducing the concentration of urea in the organism and its toxic effects thereof.
2.Capture of ammonium via dicarboxylic acids: succinic acid, fumaric acid and malic acid, which by enzymatic reactions thereon end up in the ketoacid oxalacetate, which, by transamination, forms aspartate and other related amino acids. In turn, citric acid, after passing to cis-aconitate and isocitrate, loses a carbon generating CO.sub.2 and alpha-ketoglutarate, which by transamination will generate glutamate and related amino acids.
2.1improvement of nitrogen balance,
2.2increase in the synthesis of non-essential amino acids,
2.3improvement of nutritional status and
2.4increase in serum albunim levels in the blood.
3.Improvement of palatability versus prior patents based on mixtures of calcium salts of alpha keto analogs of branched chain amino acids and mixture of L amino acids.
4.Improvement of patient adherence to treatment.
5.Improvement of the quality of life.
6.Decrease in treatment costs.
7.Additionally the phosphate is chelated from food by incorporating calcium carbonate and/or calcium acetate and/or calcium gluconate and/or calcium lactate into the mixture. This incorporation of calcium salts into the mixture contains the following benefits:
7.1Contributes to the mixture pH damping,
7.2gastric protection,
7.3additional cost reduction and overall adherence to the treatment of end-stage renal disease, due to the additional use of phosphorus-chelating drugs, otherwise the patient should consume phosphorus-chelating drugs separately.
8.Improvement of metabolic acidosis, a very common condition of patients with renal failure stages 4 and 5, with the addition of sodium bicarbonate which is added for two purposes:
8.1dampening of the dicarboxylic acids mixture,
8.2improvement of metabolic acidosis characteristic of CRF stages 4 and 5, and
8.3protection against hyperkalemia and the adverse and potentially lethal effects thereof, which is aggravated in the presence of acidosis.
The treatment with dicarboxylic and tricarboxylic acids prevents, preserves and even improves renal function, avoiding renal replacement therapy, poor quality of life of the patient and the extremely high financial costs borne by relatives and/or institutions of the health sector of the States. Finally, it prevents frequent hospitalizations as a consequence of the inherent therapeutic procedures and the complications thereof. In other patients it delays deterioration of renal function and the urgent need for renal replacement therapy. In this group of patients, laboratory parameters and quality of life are maintained favorably while waiting for a kidney transplant. In others, it is used as a treatment complementary to renal replacement therapy to improve the patient's quality of life and improve laboratory parameters.
The following clinical cases illustrate the benefits and achievements of this invention:
Case 1.Retrospective study: A 82-year-old male with a history of Diabetes Mellitus type II of over 25 years of evolution was diagnosed with Terminal Renal Failure Stage V in August 2010 with a serum urea of 129.5, creatinine 3.3, BUN 60.51, hb 11.8, potassium 5.1, phosphorus 4.5, calcium 9.4 and general urine with proteinuria of 250 mg/liter. Nephrology started protocol for initiation of peritoneal dialysis. In November 2010, before starting treatment with oral carboxylic acids, the 24-hour urine creatinine clearance was 16.46 ml/min, with a urinary volume of 17.5 deciliters, serum creatinine of 3.14 and urinary creatinine of 39.82 mg/dl. The patient refused peritoneal dialysis renal replacement therapy and initiated treatment consisting of the current invention, combined with a low protein diet of the order of 0.6 to 0.8 grams of protein per kilo per day. In July 2014, he broke is hip, which resulted in a total prosthesis thereof, blood transfusion of 2 units and his biochemical parameters were: hb 11.5, urea 141, creatinine 3.2, BUN 66, serum ammonium 5 (normal 9-33). In August 2014 his 24-hour urine creatinine clearance was 25.36 ml/min with a urinary volume of 23.7 deciliters, serum creatinine of 2.41 and urinary creatinine of 33.91. In November 2014, the patient completed 4 years in treatment. An improvement in creatinine clearance in the 24-hour urine of an initial pretreatment value of 16.46 ml/min is observed, which even 4 years later remains above these values, the last clearance being 25.36 ml/min.
Case 2.Retrospective study: a 50-year-old female with a history of severe arterial hypertension with a previous figure of 240/140 mmHg. In September 2013 she started renal replacement therapy with hemodialysis, 3 sessions per week for 2 consecutive months. After 2 months of hemodialysis, the laboratory parameters are: hb 10, serum creatinine 6.7, urea 133, 24-hour urine creatinine clearance 10.84 ml/min. In November 2013, she started treatment with oral carboxylic acids, as well as a low-protein diet of 0.6 to 0.8 grams/kilo/day. She did not continue attending the hemodialysis sessions, so at the end of January 2014 the central catheter was removed. The last assessment of the patient was in September 2014. It is should be mentioned that during the last two months the patient had suspended treatment with carboxylic acids because they did not have them. Her laboratory tests in September 2014 are: hb 9.6, serum creatinine 5.1, urea 200, BUN 84, potassium 5.2, phosphorus 6.8, calcium 8.2, albumin 4.4. After 60 days of hemodialysis, one year without dialytic treatment and 2 months of discontinuation of carboxylic acid treatment, the patient showed a decrease of 0.4 in hemoglobin, reduction in serum creatinine from 6.7 to 5.1, and a moderate increase in urea from 133 to 200.
Case 3.Retrospective Study: A 72-year-old male with a history of systemic arterial hypertension, diabetes mellitus of 40 years of evolution and ESRD. In November 2012 the laboratory analysis showed: hb 12.2, serum creatinine 5.3, urea 127, BUN 59. He refused renal replacement therapy and in November 2012 he began with treatment of oral carboxylic acids. At this time he had a serum creatinine of 6.74, urea 209, BUN 97.7. In November 2013, the date of his last visit, his laboratory tests were: serum creatinine of 3.9, urea of 58, BUN 27. Eight months later he had pneumonia and myocardial infarction, endotracheal intubation was performed and he died as a consequence of myocardial infarction. In a year of treatment with carboxylic acids, the patient's nitrogen levels were improved: serum creatinine was reduced by more than 42% and urea decreased by 72%.
Case 4Retrospective study: 35-year-old male diagnosed with end-stage renal disease secondary to hypoplastic kidneys. In May 2014, he started renal replacement therapy with acute dialysis; his laboratory tests at that date were hb of 6.9, serum creatinine 21.3, urea 216 and potassium 4.4. One month later he started with intermittent peritoneal dialysis consisting of 20 sessions each week. At the onset of IPD, his laboratory tests showed hb of 7.4, serum creatinine 17, urea 226, uric acid 10.1, urine creatinine clearance of 24 hours of 2.65 ml/minute. In July 2014, laboratory tests show: hb 8.4, serum creatinine 17.7, urea 215. On September 2 he started treatment with oral carboxylic acids, coupled with a low protein diet. On Sep. 22, 2014, 20 days after initiating such treatment, he began with continuous ambulatory peritoneal dialysis consisting of 4 sessions per day. On Oct. 20, 2014, two months after starting treatment with carboxylic acids and one month after starting ambulatory peritoneal dialysis, he showed dramatic laboratory studies: hb 12.7, serum creatinine 12.77, and urea 86.2.