MEDICAL RESEARCH BLOG
INFORMATION FOR DOCTORS AND RESEARCHERS
Dear reader, thank you for your interest in this page, which is intended for healthcare professionals and researchers seeking to learn about the latest discoveries and advances in treatments for End-Stage Renal Disease (ESRD), such as intermediate metabolites of the Krebs Cycle. Since this blog focuses on ESRD, it is appropriate to clarify the difference between it and Chronic Kidney Disease (CKD). CKD encompasses the entire spectrum of the disease, while ESRD limits to the latest stages 4 and 5.
Classification for Chronic Kidney Disease
According to the KDIGO guidelines—which are the evaluation and treatment standards for CKD used practically worldwide—the latest 2024 edition classifies the disease based on 3 factors, abbreviated as CGA:
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Cause
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Glomerular filtration rate
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Albuminuria
Cause
There are multiple causes of Chronic Kidney Disease (CKD); however, the most frequent worldwide are: Type 2 Diabetes Mellitus and Systemic Arterial Hypertension. These two diseases account for 60% to 70% of CKD cases globally. The remaining causes include:
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Systemic Lupus Erythematosus (SLE), IgA Nephropathy, or other glomerulopathies (accounting for approx. 20% of cases).
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Renal Hypoplasia.
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Nephrolithiasis (kidney stones).
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Polycystic Kidney Disease (accounts for approx. 5% of CKD).
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Chronic use of NSAIDs (ketorolac, naproxen, diclofenac, ketoprofen, ibuprofen, indomethacin, among others).
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Use of contrast media.
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Hereditary diseases such as Alport Syndrome, Fabry Disease, among others.
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Other uncommon diseases.
Glomerular Filtration Rate (GFR)
Considering the Glomerular Filtration Rate (GFR), the KDIGO guidelines classify CKD into 5 stages:
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Stage 1: GFR is normal (greater than 90 ml/min/1.73 m²), but abnormalities have been detected. these may be structural (renal hypoplasia, kidney stones) or laboratory-based (proteinuria, hematuria), lasting for more than 3 months.
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Stage 2: GFR is between 60 and 90 ml/min/1.73 m².
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Stage 3: GFR is between 30 and 60 ml/min/1.73 m². This stage is subdivided into:
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Stage 3a GFR from 45 to 60
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Stage 3b GFR from 30 to 45
Important Note: Up to this point (Stage 3b), the patient has Chronic Kidney Disease (CKD) but not yet Chronic Renal Failure (CRF). In Stage 3b, the patient is generally asymptomatic.
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Stage 4: GFR is between 15 and 29 ml/min/1.73 m²; the kidneys have severely lost function, working at only 15% to 29% of their capacity.
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Stage 5: GFR is less than 15 ml/min/1.73 m²; the kidneys have severe damage; this stage is also known as End-Stage Renal Disease (ESRD). The patient must begin Renal Replacement Therapy (dialysis or transplant).
It is when the GFR drops below 30 ml/min/1.73 m² that Chronic Renal Failure begins, as the kidneys become unable to perform some or all of their functions, including:
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Blood pressure control.
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Production of erythropoietin.
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Regulation of calcium and phosphorus levels.
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Regulation of other electrolytes: sodium, chloride, potassium, and magnesium.
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Generation of the active form of Vitamin D (1,25-dihydroxycholecalciferol).
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Acid-base balance regulation.
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Normal urine formation through filtration and secretion.
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Elimination of toxic waste (ammonia, urea, uric acid, creatinine).
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Metabolism and excretion of medications.
In a span as short as 2 to 3 years, kidney capacity can deteriorate from 30% down to 15%. At this point, the body cannot regulate itself, and serious problems begin: anemia, fatigue, swelling (edema), paleness, shortness of breath, foamy urine, and poor appetite. This is why it is extremely important to prevent and avoid the kidneys continued deterioration, even when they're still working above 50%.
The Baltimore Longitudinal Study of Aging evaluated people without kidney disease over 23 years. It concluded that the average annual decline in creatinine clearance was -0.75 ml/min/1.73 m². However, 35% of the participants experienced no decline in kidney function at all. [see Ref. 1].
Albuminuria
Measuring albumin in the urine is crucial as it is a sign of kidney disease and other complications, even when the GFR is normal. It is classified into 3 grades:
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A1 - "Normal": Less than 30 mg/g per day
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A2 - "Moderately increased": Between 30 mg/g and 300 mg/g per day
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A3 - "Severely increased": More than 300 mg/g per day
Treatment of Renal Failure
Renal Failure has several forms of treatment, including:
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Diet
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Medication
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Nutritional supplements
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Renal replacement therapies: peritoneal dialysis, hemodialysis, and kidney transplant
Diet
Diet is fundamental in the treatment of CKD. Malnutrition is a prognostic factor for the progression of kidney damage as well as for morbidity and mortality in kidney failure.
Regarding protein intake, it should ideally be around 0.6 to 0.8 grams of protein per kilogram of body weight per day, preferably high biological value proteins due to their essential amino acid content, such as whey protein (WPC) and egg whites.
As for sodium, in daily intake:
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10% comes from its natural presence in foods
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15% from what is added during food preparation
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Approximately 75% comes from processed foods and salt added at the table
Total sodium intake should be equal to or less than 2 grams per day.
Regarding phosphorus, milk and dairy products, as well as processed meats, contain high amounts due to additives used during processing. As CKD progresses, restriction of high-potassium foods is also necessary.
To achieve these goals, patients and their families should consult a nutritionist specialized in renal diets.
Medication
Various medications may be required depending on the patient’s conditions and laboratory results:
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Anemia treatment: erythropoietins, folic acid, B-complex vitamins, and more recently, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), such as roxadustat (brand name Evrenzo).
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Hyperphosphatemia treatment: calcium-based phosphate binders (calcium carbonate, calcium lactate, calcium acetate), or non-calcium binders such as sevelamer, lanthanum carbonate, and more recently, sucroferric oxyhydroxide (brand name Velphoro).
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Hyperkalemia treatment: sodium polystyrene sulfonate (kayexalate), and more recently patiromer calcium (brand name Veltassa) and sodium zirconium cyclosilicate (brand name Lokelma).
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Fluid overload treatment: diuretics, usually loop diuretics such as furosemide and bumetanide.
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Management of comorbidities:
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Antihypertensive medications, typically starting with renin-angiotensin system inhibitors due to their renal benefits
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Blood pressure control (target systolic pressure: 120 mmHg)
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If applicable: control of diabetes, hyperuricemia, cholesterol and/or triglycerides, hypocalcemia, and malnutrition (considered when albumin < 3.8 g/dL)
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In cases of secondary hyperparathyroidism, treatment may include calcimimetics such as cinacalcet.
Treatment of Chronic Metabolic Acidosis
The KDIGO 2024 guidelines indicate that in CKD patients, with or without dietary intervention, pharmacological treatment with sodium bicarbonate should be considered when levels are below 18 mmol/L to prevent clinically significant acidosis. The treatment goal is to raise bicarbonate to ≥22 mmol/L.
The study “Bicarbonate supplementation slows progression of CKD and improves nutritional status” [see Ref. 2] included 134 patients with an eGFR between 15 and 30 ml/min/1.73 m² and serum bicarbonate levels of 16 to 20 mmol/L. Patients were randomized to receive either oral sodium bicarbonate (1.82 ± 0.8 g/day) or standard treatment over two years. Results showed:
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Slower decline in creatinine clearance in the bicarbonate group (1.88 ml/min/1.73 m² vs. 5.93 ml/min/1.73 m² in placebo)
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Fewer patients progressed to end-stage renal disease (6.5% vs. 33% in placebo)
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Significant improvement in nutritional parameters
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Increase in serum bicarbonate from 20 to 24 mmol/L
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Metabolic acidosis has several negative health effects, including loss of bone and muscle mass, negative nitrogen balance, possible acceleration of CKD progression, increased protein catabolism, and reduced synthesis of visceral proteins including albumin.
Renal Replacement Therapies
In patients whose kidneys function at an eGFR below 15 ml/min/1.73 m², who present with severe edema, minimal urine output, and high toxin levels (urea, creatinine), the usual therapies are hemodialysis, peritoneal dialysis, or kidney transplantation (from a deceased or compatible living donor), which is considered the best renal replacement option.
Some patients may choose not to undergo these therapies and instead receive conservative palliative care.
What's new...
In recent medical history, there are four groups of medications that help slow or reduce the decline in kidney function.
Click on each button of interest to learn more about each:
Renin-Angiotensin-Aldosterone System Blockers
Medications used to treat cardiovascular diseases, known as ACE inhibitors (ACEIs) and ARBs, with losartan being the most well-known.
Sodium-Glucose Cotransporter Type 2 Inhibitors
Medications used to treat diabetes mellitus, which have also been shown to provide additional benefits in cardiovascular disease and chronic kidney disease. Examples include canagliflozin, dapagliflozin, and empagliflozin.
Non-steroidal selective mineralocorticoid receptor antagonists
The most well-known drug in this class is finerenone, studied in patients with chronic kidney disease and type 2 diabetes.
Glucagon-like peptide-1 receptor agonists
The FLOW study evaluates whether semaglutide can reduce the progression and deterioration of chronic kidney disease in patients with type 2 diabetes.
New evidence highlights the benefits of intermediate metabolites of the Krebs Cycle. The most recent study in 55 patients showed an improvement in eGFR. Click the button to learn more about this formulation:
Cited References
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Muntner P. Longitudinal measurements of renal function. Semin Nephrol. 2009;29(6):650-7. doi: 10.1016/j.semnephrol.2009.07.010. PMID: 20006797
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de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009;20(9):2075-2084. doi:10.1681/ASN.2008111205