Population Level
Epidemiology of Chronic Kidney Disease
Chronic kidney disease is increasing globally. From 1990 to 2017, the global all-age mortality rate from CKD increased approximately 41.5 percent. Another study, assessing global CKD shifts from 1990 to 2019, found an upward trend of CKD with age-standardized incidence rates highest in North Africa, the Middle East, and Central and South America. In 2019, there were almost 19 million cases of CKD globally. China, India, and the U.S. had the highest number of reported cases.
While most cases of CKD are due to known risk factors, such as obesity and diabetes mellitus, over the past two decades, severe CKD has been reported in individuals with no identifiable risk factors living in Sri Lanka, Central America, and in regions of Egypt and India. Urinalyses and kidney function test surveillance data have been limited. Men living in poor, rural areas who do agricultural work appear to be most at risk. Occupational and environmental exposures to heavy metals combined with glyphosate have been hypothesized as possible risk factors.
In 2020, around 37 million people, over 14 percent of the US population, had CKD. It is more common in people over age 65 years, many of whom might not have been diagnosed. Obesity and type 2 diabetes mellitus prevalence rates have been increasing. For example, from 2009 to 2022, obesity rates increased from 32.7 to 40.9 percent, and type 2 diabetes mellitus rates increased from 3 to 4.1 percent in adults aged 20 to 44 years.
The CDC's Kidney Disease Surveillance System 2019 data suggests that regions with the highest prevalence rates of CKD in individuals aged 65 years and older were in Appalachia, Florida, the Midwest, and Southern California. In contrast, the Rocky Mountain region had the lowest CKD prevalence rate. Notably, Colorado had the lowest prevalence rate of type 2 diabetes (17%) among Medicare fee-for-service beneficiaries.
Environments
Diet/Nutrition
The quantity and quality of the carbohydrates, fats, and proteins that people eat influence their health. While the debate regarding what constitutes the "healthiest" diet has been ongoing for decades, no single "best" diet appears to exist. Instead, health experts agree that diets low in refined grains and sugars help to maintain healthy weight and reduce chronic disease risk. Diets vary according to culture, level of affluence, and food availability.
In 2004, a study found that people living in the central, mountainous areas of Sardinia, an island off the coast of Italy, routinely claimed to live over 100 years of age, especially the males. The study authors named this region, a "Blue Zone," suggesting that something about the inhabitants' diet, genetics, or environment promoted such health and longevity. To investigate further, National Geographic hired Dan Buettner, a journalist, to travel the world looking for other "Blue Zones." He identified 4 others besides Sardinia: Icaria, a small Greek island, Okinawa, a Japanese island, Nicoya Peninsula, a peninsula in eastern Costa Rica, and Loma Linda, California, a Seventh-day Adventist community. For all the Blue Zones, lifestyle factors such as physical activity, social connections, and a sense of purpose appeared to be as important for longevity as the foods consumed. The diets were primarily plant-based, including vegetables, fruits, legumes, seeds, and nuts, with no more than 4-5% total food consumption consisting of animal proteins, primarily lean meats, poultry, seafood, and low-fat dairy products, along with unsaturated oils such as olive oil.
Gut microbes, which influence metabolism and immunity among other bodily functions, are fed by the foods that people consume. These microbes prefer high fiber—not highly processed foods. Firmicutes and Bacteroidetes constitute most of the bacterial phyla in the gut. The gut bacteria phyla include: Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), Actinobacteria (3%), as well as Fusobacteria and Verrucomicrobia. They breakdown undigested carbohydrates such as fiber and starches, a process known as saccharolytic fermentation.
The Firmicutes are Gram-positive bacteria that include Bacillus, Clostridium, Enterococcus, Lactobacillus, and Ruminococcus. Many of them breakdown flavonoids, phenolic compounds found in fruits and vegetables, to produce short-chain fatty acids (SCFA), notably butyrate, which has been found to have anti-inflammatory, anti-carcinogenic, antioxidant, and anti-viral properties. Most importantly, butyrate increases insulin sensitivity and might have anti-obesity activity. Metagenomic studies suggest that people with type 2 and pre-type 2 diabetes have a deficiency of butyrate-producing gut microbes such as Roseburia and Faecalibacterium prausnitzii.
In mice fed a high-fat diet, butyrate supplements were found to prevent and treat obesity and insulin-resistance. Butyrate supplementation as a preventive or treatment strategy for human obesity and type 2 diabetes has been proposed but remains unrealized. Oral administration of butyrate appears to be absorbed in the proximal intestine, making it less accessible to the colon where it is used. Rectal administration might provide a viable strategy if this approach were acceptable to patients. Dietary starches as prebiotics or butyrate-producing microbes as probiotics might provide alternative therapeutic options in addition to decreased consumption of highly processed foods and increased consumption of high fiber foods. Fecal transplants from healthy, lean donors might be another intervention strategy if shown to be effective.
Bacteroidetes are Gram-negative bacteria that include the genera Alistripes, Bacteroides, Parabacteroides, and Prevotella. They function as 'commensal' bacteria meaning that their presence is generally beneficial for the host but can also be detrimental. They digest polysaccharides, provide nutrients to other microbes, and help prevent the overgrowth of harmful bacteria such as Clostridium difficile. Bacteroidetes species are prevalent in the colons of people consuming high animal protein and high fat diets. Unfortunately, if these bacteria proliferate excessively, such as from excessive antibiotic use, they can cause disease by breaking down gut mucus which can lead to intestinal inflammation, abscess formation, and toxin-mediated diarrhea. With increasing age and genetic susceptibility, long-term excessive meat and fat consumption could lead to inflammatory bowel disease, intra-abdominal abscesses, intestinal wall breach, extra-intestinal infections, and bacteremia.
In general, a healthy microbiome consists of a balance between Firmicutes and Bacteroidetes bacteria, known as the F/B ratio. Dysbiosis occurs when there is an imbalance in the ratios. However, determining the exact ratio imbalances that lead to disease has proven challenging. Some studies found increased body weight in mice and humans associated with an increased F/B ratio. Others found decreased F/B ratios in overweight adults compared to normal controls. In general, obesity appears to be associated with alterations with microbial ratios and reduced bacterial diversity. The science of gut microbiome analysis for use as diagnostic, therapeutic, or prognostic tools remains in its infancy.
For much of the world, particularly in low- and middle- income countries, carbohydrates provide 50% or more daily calories with far less consumption of fats or proteins. These countries have lower rates of obesity and chronic diseases. However, if these individuals move to affluent countries, then their incidence of chronic diseases increases. One study found that Africans who ate minimally processed carbohydrates had gut microbiomes dominated by healthy butyrate-producing bacteria resulting in reduced colon cancer risk. In contrast, African Americans who consumed high-fat diets possessed less healthy gut microbial communities. Their diets resulted in higher fecal secondary bile acid concentrations that potentially promoted tumorigenesis.
Another study conducted in 2018 determined that poor diet, namely excess consumption of refined rice, wheat, processed and unprocessed meats, potatoes, and fruit juices contributed to over 70% of type 2 diabetes in 184 countries. These findings translated to over 14 million incident cases of the disease. Poor diet was more common in men and inversely correlated with age.
For people living with CKD, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) and the National Kidney Foundation recommended limiting the intake of sodium, potassium, and phosphorus. Consumption of high-quality proteins including egg whites, lean poultry, fish, beans, and lentils as well as minimally processed whole grains, fruits, and vegetables was also recommended. However, despite these recommendations, evidence suggests that few people with CKD actually receive nutritional advice from registered dietitian nutritionists. One study found that 88% of patients with CKD received no care from dietitians. Another study found that lack of insurance coverage and increased out-of-pocket costs contributed to the paucity of nutritional advice for CKD patients. Of the CKD patients who do receive dietary recommendations, evidence suggests that they do not adhere to the recommended dietary regimens, potentially contributing to CKD progression. The recommended diets might be difficult to follow because of their restrictions.
Drugs/Herbs/Dietary Supplements
Some prescription drugs are known to be renal toxic. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, antibiotics such as aminoglycosides, and antifungal agents such as amphotericin B can cause interstitial nephritis or damage proximal tubular cells, altering the glomerular filtration rate. Antiviral drugs can cause crystal nephropathy. Some chemotherapeutic agents like methotrexate and cisplatin can damage kidneys. Radiocontrast agents can cause acute kidney injuries. Prescribers should discuss the risks of these drugs and agents, particularly with patients at increased risk, before prescribing them.
In the US, the FDA does not have the authority to regulate herbs or dietary supplements. As a result, many herbs and supplements with unknown safety and efficacy profiles are sold over the counter directly to consumers without warning labels. If the manufacturers of these products voluntarily submit adverse event reports, then the FDA can monitor them along with any submitted consumer complaints.
One study examined surveillance data from 63 emergency departments from 2004 to 2013 and found 3667 cases of adverse events related to dietary supplements. Over half of the cases involved the use of weight-loss supplements used by young women. Acute kidney injuries were not mentioned.
A South Korean study used National Health and Nutrition Examination survey data from 2015 to 2017 to evaluate any association between CKD and dietary supplement use in over 13,000 Korean adults. They found that the prevalence of CKD was significantly higher among respondents who consumed amino acids and proteins, ginseng and red ginseng, and herbal medicines (i.e., berry extracts) compared to those who did not. Only the berry extracts group revealed an independent association with CKD incidence after adjusting for covariates. (The types of berry extracts were not noted.) Individuals who consumed probiotics were found to have a significantly reduced prevalence of CKD. The authors concluded that dietary supplements might affect long term kidney function and that improving the gut microbiome might slow CKD progression. Dietary consumption of specific berries on kidney function should be studied, and given the increasing global use of supplements, epidemiologic surveillance of their potential risks to kidneys should be conducted.
Case reports of adverse reactions causing kidney injuries from herbs or dietary supplements are occasionally published in the medical literature. One study assessed PubMed case reports in the medical literature over the past 50 years (1966 to 2016) and found 7 herbs and 10 dietary supplements, currently available over the counter in the US, that have caused a spectrum of kidney injuries including acute renal failure, chronic kidney disease, and death. The 7 herbs are St. John's wort (Hypericum perforatum), thundergod vine (Tripterygium wilfordii hook F), Tribulus (Tribulus terrestris), wormwood (Artemisia herba-alba), Chinese yew extract (Taxus celbica), impila (Callilepis laureola), and morning cypress (Cupressus funebris Endl). The 10 dietary supplements are chromium, CKLS (Colon, Kidney, Liver, Spleen), bile (sheep), chlorella, creatine, fish gallbladder, glucosamine, hydrazine, N.O.-Xplode, Spanish fly, as well as the excessive use of vitamins A, C, and D. Additional dietary supplements reported to cause kidney injuries include chaparral and aristolochic acid, which is found in some Chinese herbs.
Kidney-toxic foods include uncooked yam powder or juice, djenkol bean, the gallbladders of carp fish, pufferfish, and snakes, and star fruit (in CKD patients). Excessive licorice consumption, lemongrass tea, oleander, and rhubarb can also have nephrotoxic effects.
Heavy Metals/Chemicals
Industries producing batteries, pesticides, textile dyes and agricultural products among other goods use heavy metals which can enter bodies through inhalation of contaminated air or vapors, consumption of contaminated food or water, or contact through the skin. Exposure to these compounds can damage many organs including the kidneys. Acute kidney injury occurs through ionized (diffusible) bloodstream forms whereas, chronic kidney injury happens via protein bound (non-diffusible) bloodstream formulations. Exposure typically occurs occupationally, accidentally, or therapeutically. Heavy metals most implicated include platinum, mercury, lithium, lead, copper, cobalt, cadmium, barium, and arsenic. Kidney reabsorption of protein-bound heavy metals can lead to chronic inflammation, fibrosis, CKD, and kidney failure.
Rice readily absorbs arsenic in the soil, and rice grown in the south-central U.S. contains almost 1.8 times more arsenic than in other regions because of the historical use of arsenic-based pesticides to control boll weevils. Jasmine and basmati rice grown in Thailand, Pakistan, and India contain the least amount of arsenic. Rinsing rice appears to have minimal effect in removing arsenic. Public education about the potential risk of eating rice from high arsenic containing regions is lacking.
Pets are also exposed to heavy metals. One Italian study conducted necropsies of 38 dogs that had lived in urban areas and died from various causes. Half the dogs had been living in homes as pets and the other half had been strays. Liver and kidney samples were taken from each animal and tested for cadmium, lead, and mercury. Lead was found in all the samples. Cadmium was present in all kidney samples and 95% of liver samples, and mercury was found in 71% of liver and 55% of kidney samples. The highest mercury concentrations were found in the household dogs. The authors concluded that while the heavy metals concentration levels were generally low, the risk of potential long-term effects should not be dismissed.
Pet food might be another potential source of heavy metal exposure in dogs and cats. One study done in Brazil surveyed 100 pet foods from 29 manufacturers for heavy metal contamination. They found high concentrations of aluminum, vanadium, uranium, lead, and mercury in dog and cat food. Mercury, a nephrotoxic agent, was found in 100% of the samples.
Melamine, a by-product of the coal industry, is used in many products such as plastic cups, plates, and bowls. If ingested as a powder, it can cause kidney damage like when it was used in 2008 as an adulterant in baby formula in China. The incident affected approximately 300,000 Chinese infants and young children, causing an increased incidence of kidney stones, renal failure, and 6 deaths. One year earlier, melamine had contaminated some pet foods in North America that sickened and killed dogs and cats. The pet food had been imported from China. It was recalled and destroyed.
Per and Polyfluoroalkyl chemicals (PFASs)
Over 3000 compounds make up the class of chemicals known as per- and polyfluoroalkyl substances (PFASs). These compounds have grease-repelling and stain-resisting properties and are widely used in consumer products like textiles, non-stick cookware, aqueous fire-fighting foams, food packaging, and papers. Because they are so widely used, they have been detected in virtually all soils, waters, and air and are considered global pollutants. Exposure occurs through the ingestion of contaminated foods and fluids as well as the inhalation of tainted air. These substances have been linked to endocrine disruption, carcinogenesis, teratogenesis, and metabolic and immunologic pathogenesis. Growing evidence suggests that they adversely impact kidney health and might play a key role in CKD of unknown etiology.
Humans are not alone in PFASs exposures. Domestic cats are also being exposed and might serve as important sentinels. Their exposures are likely due to self-grooming leading to inhalation/ingestion of contaminated dust. One study of 72 pet and feral cats, including 11 healthy and 61 sick with a variety of diseases, surveyed the cats presenting for veterinary care over a 4-month period in 2008 in North Carolina. The researchers found that all but one had blood serum specimens with detectable levels of PFASs. The highest concentrations were found in the indoor cats.
PFASs were found in every serum sample taken from 31 dogs and 32 horses living in Gray's Creek, North Carolina, located near a flurochemical production site. On average, the dogs had higher PFAS serum concentrations than the horses. Drinking water in the area had been documented to be contaminated with PFASs.
Heavy metal and PFAS exposure in utero might adversely impact fetal growth and development—including the kidneys. Fetal kidneys are vulnerable during specific periods of gestation which could lead to permanent modifications known as 'renal programming' resulting in subsequent hypertension and kidney disease in adulthood. Prenatal chemical exposures might lead to reduced nephron numbers per kidney among other insults.
Other chemicals potentially affecting prenatal kidney development include dioxins (synthetic hydrocarbons used to make pesticides), bisphenol A (used to line cans and in plastics), phthalates (used in personal hygiene products), polycyclic aromatic hydrocarbons (PAHs—organic pollutants from many manufacturing processes), and air pollution. Additional epidemiologic studies are needed to better understand prenatal chemical exposures and subsequent kidney disease risk to develop preventive strategies.
Ecosystems
Microbial Exposures
Viruses, bacteria, fungi, and parasites can cause either direct or indirect kidney injuries. Direct injuries occur through the effects of microbial infection. Indirect injuries occur via immune-mediated mechanisms in response to infections such as post-infectious glomerulonephritis. Any microbe has the potential to injure kidneys, but some cause harm more commonly than others.
Viruses
Viral agents known to injure kidneys include dengue, hepatitis A, hepatitis B, hepatitis C, hepatitis E, Epstein-Barr virus, cytomegalovirus, hantavirus, parvovirus, polyoma virus, varicella-zoster virus, and human immunodeficiency virus. As of May 11, 2025, there have been approximately 778 million confirmed COVID-19 cases and 7.1 million deaths. Since the emergence of the COVID-19 pandemic, the SARS-CoV-2 virus has become a recognized cause of acute and chronic kidney damage. Approximately 28% of patients hospitalized with COVID-19 developed acute kidney injury (AKI), and of those, around 9% required renal replacement therapy. Patients that developed acute kidney injuries from SARS-CoV-2 were more likely to have a history of hypertension, diabetes, and hyperlipidemia than those who did not. Severe COVID-19 infections associated with acute kidney injury led to a worse overall prognosis.
SARS-CoV-2 infection can cause direct renal endothelial damage, local inflammation, and glomerulopathy. Systemic inflammation, complement activation, hypercoagulability, and thromboembolic disease can lead to indirect damage. Severe acute kidney damage can result in CKD and potentially the need for renal replacement therapy. Causes for CKD progression from COVID-19 infection has been hypothesized to be multifactorial. Understanding the risks of COVID-19 infection- induced CKD requires large clinical and laboratory datasets from multiple institutions such as those provided by the National COVID Cohort Collaborative (N3C). The N3C project is currently studying the epidemiology of acute and chronic kidney injury associated with SARS-CoV-2 infection and other related projects.
Individuals living with CKD and requiring renal replacement therapy appear to have been disproportionately affected by COVID-19 infections. A review of 348 studies involving over 380,000 participants living with CKD found that the incidence of COVID-19 was higher in those receiving dialysis than in those who didn't require renal replacement therapies. Individuals requiring renal replacement therapy appeared to have a 10-fold higher incidence of death from COVID-19 compared to people with CKD who weren't infected with COVID-19.
Bacteria
All bacteria have the capability of infecting kidneys. For example, bacteria can ascend the urethra, bladder, and ureters, resulting in pyelonephritis. Septicemia is another route that bacteria can gain access to the kidneys. Renal damage from bacterial infection can lead to CKD.
Bacterial species associated with nephropathies include Brucella species, Escherichia coli, Campylobacter jejuni, Corynebacterium diptheriae, Leptospira, Legionella species, Mycobacteria species, Salmonella species, Staphylococcus species, and Streptococcus pyogenes. For example, post-streptococcal glomerulonephritis (PSGN) is an immune-mediated process involving complexes of immune cells and bacterial components deposited in the kidneys. While rare in affluent countries, it can develop in children with respiratory or skin infections who lack access to antibiotic therapy. Adults in poverty-stricken regions can also develop infection-related glomerulonephritis. Staphylococcus is the more common offending pathogen in adults rather than streptococcus, which primarily affects children.
Tuberculosis (Tb) is a global concern. According to the 2024 WHO Global Tuberculosis Report, an estimated 10.8 million people were infected with Tb in 2023, two-thirds of whom lived in 8 countries: India (26%), Indonesia (10%), China (6.8%), the Philippines (6.8%), Pakistan (6.3%), Nigeria (4.6%), Bangladesh (3.5%), and Democratic Republic of the Congo (3.1%). Between 15 to 40% of newly diagnosed Tb patients present with extrapulmonary disease, many of which involve urogenital infections. Tuberculosis of the kidneys can remain clinically silent for months until non-specific signs and symptoms such as hematuria, dysuria, and flank pain develop. Renal Tb can lead to hypertension and CKD. Pulmonary Tb might be the only the clue that undiagnosed kidney disease might be due to the bacteria.
Some antibiotics are nephrotoxic, which limits their usefulness in patients with CKD. As the global antimicrobial resistance (AMR) threat worsens, people living with CKD and are dependent on renal replacement therapy or immunosuppressive drugs for prevention of organ transplant rejection, are particularly vulnerable to resistant bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species (VRE), and multi-drug resistant Gram-negative organisms.
Bacteriophage therapy has the potential to ameliorate the crisis, providing treatment options for multi-drug-resistant bacteria in renal transplant recipients. For example, one case report involving a 70-year-old female liver/kidney transplant recipient who developed recurrent resistant infections requiring multiple hospitalizations over a 1½ year period, demonstrated the potential of bacteriophage therapy. She received intravenous bacteriophage therapy that successfully cured her for almost 6 months. Regulatory, financial, and clinical hurdles currently limit widespread bacteriophage therapy use. Its potential, however, for CKD patients might be substantial.
Fungi and Parasites
Renal fungal infections occur primarily in hospitalized, immunosuppressed patients with risk factors such as diabetes, older age, indwelling catheters, mechanical ventilation, and parenteral (i.e., intravenous) nutrition. Candida species are the most common cause of fungal infections, typically originating in urinary tracts. Filamentous fungi such as Aspergillus and Mucor can also cause kidney infections. Blastomycosis, Coccidiomycosis, and Histoplasmosis rarely cause kidney infections, but when they do occur, it's primarily by bloodstream spread.
Parasites such as malaria, leishmaniasis, Chagas disease, filariasis, and schistosomiasis can infect the kidneys. The highest incidence occurs in tropical regions, primarily Africa, Asia, and South America, but with climate change, the pathogens might expand their geographic range. Kidney damage can result from direct or in-direct, immune-mediated inflammation and complex deposition.
According to WHO, in 2023, there were 263 million cases and 597 thousand deaths from malaria. Africa carried a disproportionate share of the burden. Acute kidney injury is one of the most severe complications of malarial infections. The prevalence of malarial AKI ranges from an estimated 20 to 40% of severe cases, increasing the risk of mortality.
Next week: Part III will cover the Economic, Social, and Psychological Factors of CKD