Author: Payal Bhandari, M.D., Abraham Tejeda-Martinez 

Contributors: Vivi Chador, Nigella Umali Ruguian  

Key Insights

The kidneys are two fist-sized, bean-shaped organs located below the rib cage on either side of the spine. They remove waste from protein metabolism, balance fluids and electrolytes, and produce hormones that regulate blood pressure, red blood cells, and bone health. Healthy kidneys filter about half a cup of blood per minute (150 quarts daily) and remove 1 to 2 quarts of waste and excess water as urine. Each kidney has millions of tiny filters (glomeruli) and tubules that regulate water, proteins, salts, and minerals like sodium, calcium, and potassium. Urine travels through ureters to the bladder, where it is stored until excretion.

Figure 1: The Genitourinary Tract

The Glomerular Filtration Rate (GFR) and creatinine tests check how well your kidneys work. GFR shows how efficiently your kidneys filter blood, while creatinine levels reflect how well they remove waste. High creatinine and low GFR can signal kidney problems. Tracking these markers helps detect and manage chronic kidney disease. Factors like diet, hydration, muscle mass, medications, and stress can affect these levels. Research suggests a plant-based, nutrient-rich diet, proper hydration, and stress reduction support kidney health and improve protein metabolism.

What is the Glomerular Filtration Rate (GFR) and Creatinine? 

The creatinine (Cr) test measures the breakdown of muscle protein (like creatine phosphate) and how well the kidneys filter protein waste, including creatinine and urea. Serum creatinine levels reflect total muscle mass and are affected by factors like age (lower in children), gender (lower in women), ethnicity (higher in Black individuals), medications, and diet (lower in plant-based diets, higher with cooked meat consumption).

The eGFR test estimates how much blood the kidneys filter through the glomeruli per minute. Glomeruli, tiny kidney filters, receive blood through the afferent arteriole and remove waste via the efferent arteriole. eGFR depends on protein metabolism and is calculated using creatinine levels, age, sex, and ethnicity. eGFR provides a more accurate measure of kidney function than creatinine alone. As GFR decreases, creatinine levels rise, indicating reduced kidney filtration. Aging naturally lowers GFR, so older adults often have reduced filtration rates.

What are your Kidney Numbers? uACR and eGFR Explained | CKD Heat Map | NKF

Figure 2: The Definition of Chronic Kidney Disease. Worsening kidney function correlates inversely with lower GFR and higher creatinine levels. The diagnosis of CKD is made after regularly monitoring the GFR and/or creatinine levels for 3 or more months.[1]

Regulation of Creatinine and GFR Levels 

Kidney function, measured by GFR, is closely tied to skeletal muscle protein (creatine) metabolism and the kidney’s ability to clear toxic byproducts like creatinine. It is also linked to the body’s energy production (ATP) through cellular respiration, which supports essential cellular functions.[51] Creatinine levels are influenced by muscle mass and dietary protein intake, reflecting variations in metabolism. Recognizing these factors is essential for accurately interpreting creatinine and GFR results in clinical settings.

Cellular Respiration and Ketogenesis 

Figure 3: Cellular respiration is a set of metabolic reactions that convert electrons from plants that do direct photosynthesis into high-energy, electron-carrying molecules like adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NADH), and flavin mononucleotide-FMN (FADH), and release the waste product CO2 during exhalation by the lungs. The three-step process generates the greatest amount of energy via the electron transport chain in the mitochondria of cells (34 ATP + 2 ATP each from glycolysis and the Krebs cycle). 

Energy is typically derived from digested food, but during low-energy states (like prolonged fasting or intense exercise) or when the brain’s energy needs are high, ATP is produced by breaking down skeletal muscle protein and stored fat. The brain cannot directly use fat for energy unless it is converted into ketone bodies through ketogenesis. This process turns the glycerol from fat into glucose, reducing the brain’s reliance on carbohydrates and proteins, stabilizing protein metabolism and fat storage, and helping the kidneys clear toxic protein byproducts.

Ketogenesis also increases ATP production per glucose molecule while reducing reactive oxygen species (ROS), which can otherwise cause cell damage and gene mutations, leading to metabolic inflammatory disorders. However, ketogenesis can also occur when glucagon production exceeds insulin secretion, as seen in diabetes.[51]

Figure 4: The breakdown of fatty acids, amino acids, glycerol, and other substrates in adipocytes, the liver, and skeletal muscle helps regulate glucose and ketone production in the liver. Ketones serve as an alternative energy source during prolonged fasting, intense exercise, insulin deficiency, excess glucagon production, or when the brain’s energy demands surpass those of the body. Ketone synthesis produces significantly more energy (34 ATP) compared to glucose synthesis (2–4 ATP). This process is closely influenced by circadian rhythm (sleep-wake cycle) genes.

Dietary Protein Metabolism

Unlike dietary fat, protein cannot be stored and must be broken down daily into amino acids. The body breaks down and rebuilds about 250 grams of protein each day, with over 90% of dietary protein processed into amino acids. Excess protein not used for energy is converted to glycogen and eventually stored as fat. To avoid breaking down muscle protein for energy, it is important to maintain the amino acid pool by consuming plant-based meals rich in essential amino acids.

Figure 5:  Amino acids derived from food and muscle protein metabolism are placed into a “pool” and used to form new proteins and other nitrogen-containing compounds. 

When we chew food, healthy bacteria in the mouth interact with saliva to convert about 40% of the nitrates and nitrites in dietary protein into nitric oxide (NO), while the remaining 60% are excreted in urine . NO enters the bloodstream and helps keep arteries flexible, maintain blood pressure, and protect blood vessels from inflammation caused by oxidative stress (atherosclerosis).

The remaining protein travels down the esophagus to the stomach, where it mixes with hydrochloric acid (HCl) and the enzyme pepsin to form a mixture called chyme. The stomach’s acidic environment breaks proteins into smaller units called amino acids (AA).Chyme then moves to the small intestine, where bacteria like Veillonella, Neisseria, and Lactobacillus play a vital role in protein metabolism. These bacteria help protect the gut lining by:

• Breaking down undigested proteins further.

• Neutralizing stomach acid to prevent damage.

• Supporting gut health and nutrient absorption.

Figure 6: The conversion of nitrates and nitrites in dietary plant-based proteins to nitric oxide (NO) by healthy bacteria in the mouth, small intestine, and skin play a critical role in enhancing blood vessel function, regulating blood pressure, and protecting tissues against oxidative stress. From the small intestine nitrates and nitrites are transported back to the mouth and either stored in the salivary glands or under the skin, where healthy bacteria convert it to NO. NO helps maintain flexible arteries, promotes proper communication in nerve cells, and mitigates inflammation, infection, and cancer growth. 

Figure 7: Ingested protein metabolism involves bacteria in the mouth and small intestine, stomach acid [hydrochloric acid (HCl)], and digestive enzymes to break it down into its subunits (amino acids, nitrates, and nitrites), which are then transported to the liver and various organs. Chemicals secreted by the pancreas and small intestine protect the inside lining of the gut from being damaged by HCl and undigested proteins that would otherwise mount an inflammatory response and enable toxins (like pathogenic microorganisms, tumor cells, and other foreign invaders) to leak out into the bloodstream (a process known as leaky gut syndrome) and cause systemic inflammation. 

Without enough gut bacteria, digestive enzymes, or HCl, undigested particles build up, triggering an immune response. White blood cells release inflammatory proteins and ROS, while platelets and smooth muscle cells form clots and scar tissue. This leads to vascular inflammation and impaired blood vessel function.

Figure 8: Rising blood protein levels reduce arterial blood flow, causing fat (especially LDL cholesterol) and plaque deposition, along with red blood cell clotting by white blood cells, platelets, and smooth muscle cells. Atherosclerosis, an inflammatory process, thickens and hardens arteries to prevent excess RBC destruction and ROS production. However, it restricts blood flow, raises blood pressure, and causes blood to back up into organs like the pancreas, heart, and lower extremities. Persistent atherosclerosis damages cells, mutates genes, disrupts metabolism, and increases the risk of severe health conditions by impairing organ function and hormonal balance.

Hormones

Glucagon and insulin promote fat metabolism and prevent skeletal muscle breakdown, efficiently producing energy while minimizing ROS and heat. In contrast, stress hormones like cortisol and catecholamines shift the body toward skeletal muscle breakdown and glucose production, reducing fat metabolism and increasing ROS, proinflammatory proteins, and cell damage.

During acute or chronic stress (e.g., trauma, surgery, or illness), cortisol increases glucose production by breaking down muscle protein into amino acids, raising blood creatinine without reducing GFR. High nighttime cortisol, especially with sleep deprivation, suppresses insulin, raises blood glucose, and impairs oxygen delivery (hypoxia), disrupting cell functions and increasing toxic byproducts like cholesterol and hemoglobin.

Cortisol also increases thyroid hormone (T3) levels, promoting protein breakdown and inflammation. T3 aids energy production but elevates ROS and proinflammatory proteins, contributing to inflammation and metabolic strain, particularly in liver cells. Excess T3 activity recycles damaged cells but worsens imbalances and inflammation.

Clinical Significance of High Creatinine and Decreased to Normal eGFR Levels

Elevated creatinine levels, along with a slightly decreased or normal GFR, often indicate increased skeletal muscle protein breakdown and the excretion of waste products like creatinine and cystatin C by the kidneys. This can result from shifts in metabolism caused by excessive dietary protein intake, reduced fat metabolism (the body’s main energy source), and increased reactive oxygen species (ROS), which generate excess heat and damage cells.

Additionally, partial or complete obstruction of urine flow in the genitourinary (GU) system can trigger an immune response, allowing GU bacteria to spread through the bloodstream and cause infections. It also raises the risk of kidney stones, blocks urine flow, and damages the ureters. 

The leading drivers of high creatinine blood levels and decreased to normal eGFR are reduced blood flow states, medications, and drug use. 

Low Blood Flow States

Blood plasma is 90% water, so dehydration makes blood thicker and less able to carry oxygen efficiently by binding to hemoglobin. Dehydration also raises ion concentration outside cells, causing water to move out of cells, shrinking them and impairing energy production. The brain detects this shrinkage with sensors that control thirst and urine production, releasing antidiuretic hormone (vasopressin) to reduce urine output and concentrate it. Chronic dehydration or severe fluid loss, such as from trauma, major surgery, or gastrointestinal bleeding, can lead to hypovolemic shock. This condition critically lowers blood pressure and reduces blood flow to organs, including the kidneys. In response, the kidneys increase erythropoietin (EPO) production to boost red blood cell (RBC) production and improve tissue oxygenation. Meanwhile, the liver breaks down muscle protein to maintain vital functions, raising blood creatinine levels without significantly changing GFR.

Chronic dehydration destroys red blood cells (RBCs), reduces blood flow to organs like the kidneys, liver, and heart, and accelerates muscle protein breakdown, raising creatinine levels and lowering GFR. It impairs kidney functions, including fluid balance, acid-base regulation, erythropoietin production, vitamin D3 activation, and blood pressure control. The liver struggles to detoxify blood, regulate hormones, break down nutrients, and produce energy. Gut microbiota disruption hinders digestion, nutrient absorption, and nitric oxide production, affecting artery flexibility, blood flow, and nerve function. Reduced blood volume impacts all systems, triggering inflammation and contributing to atherosclerosis, autoimmune disorders, infections, cancers, organ damage, and early death.

Impact of Medications

Many medications interfere with the kidneys’ ability to function properly, thereby reducing GFR. For instance, reduced production of the hormone erythropoietin decreases red blood cell synthesis and cellular oxygenation, thereby reducing tissues’ ability to harvest enough energy and maintain normal physiologic functions. The most widely cited drug group associated with rising blood creatinine levels and reduced GFR are :

Corticosteroids: Increase fat/cholesterol deposition, causing vascular inflammation and kidney damage.

Anabolic Steroids/Androgens: Raise cholesterol levels and promote kidney fat deposition, worsening CKD.72,73,74,75,76

Diuretics: Cause electrolyte imbalances, reducing energy production and damaging kidney structure.

Antibiotics:

• Sulfonamides: Disrupt gut microbiota, cause urine crystals, and induce kidney inflammation..

• Cephalosporins: Reduce microbiota diversity, impair metabolism, and risk tubular damage.

• Aminoglycosides: Directly damage kidney cells and mitochondria, causing acute injury

Cholesterol-Lowering Drugs: Impair liver enzymes, reduce coenzyme Q10, and cause muscle-related kidney stress.  

NSAIDs: Reduce blood flow by narrowing vessels, leading to kidney injury or CKD progression.

Antacids: Lower stomach acid, increase protein waste, and cause kidney inflammation.

Clinical Significance of Low Creatinine and Decreased GFR Levels

When creatinine levels are lower than the normal range and the GFR is decreased, several potential causes may be at play. 

Low Animal Protein Diet 

A diet rich in plant-based proteins but low in animal protein can reduce creatinine levels by decreasing muscle protein metabolism. Plant-based proteins, when balanced, support essential physiological processes like nutrient absorption and energy production without overburdening the kidneys.

Reduced Muscle Mass

Low muscle mass or body weight leads to reduced creatinine production, as it is closely tied to skeletal muscle metabolism. In cases of severe malnutrition or muscle wasting, creatinine levels drop further.

Chronic Kidney Dysfunction and Disease

Dehydration and poor blood flow impair kidney function, reducing toxin clearance and essential processes like protein synthesis and nutrient absorption. This leads to energy depletion, malnutrition, and accumulation of ROS, which damage the kidneys and worsen filtration capacity.

Kidney Stones

Obstructions like kidney stones block urine flow, causing renal swelling and damage to filtering units (glomeruli). This reduces GFR, impairs waste removal, and disrupts fluid and electrolyte balance, increasing the risk of UTIs, cancers, and progressive kidney damage.18

Stress

Obstructions like kidney stones block urine flow, causing renal swelling and damage to filtering units (glomeruli). This reduces GFR, impairs waste removal, and disrupts fluid and electrolyte balance, increasing the risk of UTIs, cancers, and progressive kidney damage.

Figure 9: Distribution of eGFR Categories by ACR Levels. This figure presents the distribution of different eGFR categories (G1-G5) based on their corresponding albumin-to-creatinine ratio (ACR) levels. The eGFR categories range from G1 (Normal or high: eGFR ≥90 mL/min/1.73m²) to G5 (Kidney failure: eGFR <15 mL/min/1.73m²). Each eGFR category is further subdivided by ACR levels: A1 (ACR <30 mg/g, normal to mildly increased), A2 (ACR 30-299 mg/g, moderately increased), and A3 (ACR ≥300 mg/g, severely increased). The majority of individuals fall into G1 with A1 ACR (59.8 percent), while only a small percentage fall into G5 with severe kidney failure (0.15 percent). ACR measures the amount of albumin (a type of protein) in the urine, indicating how much protein is leaking from the kidneys. Higher ACR levels suggest greater kidney damage, and is measured in conjunction with their eGFR levels.

Prevalence and Statistics of Abnormal GFR and Creatinine Levels

Chronic kidney disease (CKD) is a growing public health issue with high rates of illness and death, increasing significantly over the past 20 years. According to the CDC, low eGFR prevalence rose from 8.5% in 2000 to 11.2% in 2020. NIH data also highlight this trend, linking it to aging populations and rising CKD risk factors such as diabetes, obesity, high blood pressure, and vascular diseases.

Public health programs like the Kidney Early Evaluation Program (KEEP) and campaigns for diabetes and hypertension awareness have improved early CKD detection, with a 15% rise in early-stage diagnosis between 2014 and 2024. However, advanced CKD progression rates remain unchanged, likely due to increasing risk factors like chronic anemia, diabetes, and obesity.

Conclusion

Expanding eGFR and creatinine testing in routine screenings supports preventive medicine and provides a cost-effective way to manage chronic diseases like obesity, hypertension, diabetes, vascular diseases, cancers, and infections. Early detection of kidney dysfunction—through increased creatinine or decreased eGFR—enables timely intervention to prevent CKD progression and renal failure.The global rise in CKD is linked to conditions like anemia, immune dysfunction, and organ damage. Regular kidney function monitoring helps guide management strategies. Proactive steps, such as dietary changes, reducing medication use, and stress management, offer a holistic approach to disease prevention. Early lifestyle modifications can improve quality of life, reduce healthcare costs, and lower the societal burden of chronic diseases.

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