Kidneys are vital organs. They filter excess water out of the blood, produce renin, a hormone involved in blood pressure control, and filter wastes from the blood. They make vitamin D, which is needed for bone and metabolic health, and they produce erythropoietin, a chemical involved with red blood cell production.
The kidneys can be damaged either acutely or chronically. In this blog, I will focus on chronic kidney disease (CKD) which is the loss of kidney function over time. Symptoms and signs of CKD are often not evident until the condition is advanced.
Kidneys are generally underappreciated and receive insufficient attention and funding for CKD treatment and prevention. For example, the World Health Organization does not include kidney disease on its list of priority non-communicable diseases. This situation has not helped the silent epidemic of kidney disease that is spreading globally.
CKD is a One Health issue. The kidneys are exquisitely sensitive to environmental (i.e., abiotic) and ecosystem (i.e., biotic) insults. Early detection to prevent CKD progression should be a top priority for global public health.
In this blog, I will use the One Health matrix tool as a framework to examine CKD in humans, cats, and dogs. Cats and dogs share people’s homes, receive veterinary medical care, and generate epidemiologically relevant data, so analyzing CKD in them might provide useful information to benefit humans and other animals.
Because CKD is so complex, and this blog is so long, I will divide it into 3 separate parts.
Today, in Part I, I will examine CKD at the microbial, cellular, and individual (i.e., dogs, cats, and humans) levels. Next week, in Part II, I will discuss the epidemiology of CDK, focusing on environmental (i.e., diet, drugs, chemicals, heavy metals, and per- & polyfluoroalkyl) and ecosystem (i.e., microbial) exposures. In the subsequent week, I will discuss the economic, social, and psychological aspects of CKD in Part III at the national and international levels and will conclude with some recommendations.
There is no cure for CKD, and treatment for end stage kidney disease remains limited to either hemodialysis, peritoneal dialysis, or kidney transplantation. Approximately 2.6 million people worldwide rely on these modalities for renal replacement therapy. Treatment access varies from country to country with low- and middle- income countries having sizeable gaps in care. In the U.S., black Americans are three-times more likely to need renal replacement therapy compared to non-Hispanic whites but suffer disparities in access to care.
Breakthroughs in novel kidney failure treatments have been lacking in recent years. Dialysis was developed in 1943. Eleven years later, the first successful kidney transplant took place using the kidney of the subject’s identical twin. While advances in immunosuppression management have greatly improved the success rate of kidney transplantation, complications such as osteoporotic fractures, infections, and recurrent primary disease continue to occur. In addition, the supply of kidneys has not met demand. The average wait time for a deceased donor kidney is 5 years, and over half of CKD patients die or are removed from wait lists before receiving their transplant organs.
One Health Matrix Tool Analysis
Microbial Level
Microbes, their genes, and metabolites are as important to health and well-being as any organ. The NIH’s Human Microbiome Project revealed that bacterial cells outnumber human cells by about ten to one. The gut has varying concentrations of microbes culminating in the colon where primarily anaerobic bacterial communities up to 100 billion cells per gram reside for several days before being expelled. The composition of the gut microbiota varies, but Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia represent the major phyla.
An imbalance of gut bacterial species, known as dysbiosis, appears to increase disease risk including CKD in susceptible individuals and might contribute to disease progression. Altered patterns of gut bacteria might provide useful diagnostic and prognostic tests as well as potential therapeutic strategies for CKD. Pro-inflammatory mediators and dysbiosis-related uremic toxins appear to contribute to deteriorating renal function. One study found that healthy controls had higher levels of Prevotella in their feces, which produce anti-inflammatory short chain fatty acids compared to individuals with type 2 diabetes mellitus. Individuals with diabetic nephropathy had elevated levels of Escherichia-Shigella that release ethanol, potentially increasing gut ‘leakiness.’
Gut dysbiosis might be modifiable using prebiotics, probiotics, or fecal microbiota transplants to reduce uremic toxins. Prebiotics consist of high-fiber foods that benefit gut bacterial health. Probiotics are supplements or foods that contain live microbes meant to improve gut microbiome composition. For example, the lack of Akkermansia muciniphila in the gut microbiome has been associated with obesity, type 2 diabetes, inflammation, and other maladies. Probiotics containing this bacterium might be beneficial for restoring health. However, most studies of gut microbiome manipulation involve laboratory rodents which might limit their applicability to humans.
The small intestine features the largest semi-permeable mucosal surface in the body and might, theoretically, be used for nitrogenous waste breakdown and elimination, a potentially useful adjunct or substitute for dialysis. One group of researchers manipulated mouse gut microbes, selecting those that breakdown urea and creatinine, the nitrogenous waste products of metabolism that become elevated with renal disease. The advantage of this approach is that the administered microbial therapeutic cocktails could be administered orally bypassing the risk of infection that occurs with peritoneal or hemodialysis, which are designed to filter out the nitrogenous waste products rather than break them down. Escherichia and Bacillus strains efficiently metabolize urea and creatinine into ammonia and strains of Enterobacter convert ammonia into amino acids. These bacteria were selected from murine fecal microbiota and encapsulated in an artificial microenvironment. Mice orally treated with these microbial cocktails experienced a reduction in their blood urea and creatinine levels like those treated with peritoneal dialysis—but without the side effects. Manipulating human gut microbiomes to breakdown urea and creatinine as a CKD treatment strategy has been proposed.
Cellular Level
Kidneys are complex organs containing approximately one million nephrons, each of which consists of over twenty specialized cells. Kidney in utero organogenesis involves the migration of endothelial and stromal cells from different embryonic regions. Cellular differentiation involves spatiotemporal signaling between cells. Renal organogenesis also requires support from a heterogenous group of interstitial stroma cells that secrete an extracellular matrix and paracrine factors. In other words, growing kidneys is complicated.
Kidney diseases involve the loss of nephrons, usually irreversibly. The goal of regenerative medicine is to replace damaged renal cells either through promoting in vivo endogenous regeneration, replacing damaged tissue, or growing in vitro organs from patient stem or progenitor cells. Normal nephron functioning requires correct anatomical positioning and cellular sequencing for osmotic gradients to work. Simply introducing new nephrons without ensuring correct architecture might not suffice.
So far, identifying adult stem cells that can regenerate kidney cells has remained elusive and using fetal pluripotent stem cells to grow functional renal structures in vitro has proven difficult when attempted in animal models. Most efforts to create three-dimensional “organoids” from pluripotent stem cells have lacked higher order structure and function. However, one study using mouse and human pluripotent stem cells conducted an in vivo analysis of renal differentiation systems, identified the key intercellular signals, and induced “ureteric buds” to branch into collecting duct trees.
An alternative strategy might be to grow kidneys in pigs that had been genetically modified to have human-like immune systems. In July 2023, surgeons at NYU Langone Medical Center in New York City transplanted a genetically modified pig kidney into a brain-dead human as a proof-of-concept project. The kidney functioned normally for a month with no evidence of rejection. The pig’s thymus had also been transplanted to help prevent rejection.
Artificial intelligence (AI) conducted by the London-based company DeepMind’s AlphaFold revolutionized the science of protein folding. This breakthrough occurred through a Critical Assessment of Structure Prediction (CASP) competition that began in 1994, helping to accelerate life sciences research. As knowledge about organ development increases, a similar competition using artificial intelligence and machine learning using proper inputs such as transcriptomics, nutrition, growth factors, and instructive signals might lead to an analogous breakthrough in kidney organogenesis.
Three dimensional bioprinting is another technology being explored to create usable bioengineered kidneys. Instead of using plastic, however, scientists use cells suspended in “bioink” to deposit onto receiving substrates. While prone to contamination, expensive, and potentially damaging to the cells during the bioprinting process, it has been used to print viable tissues.
Some organs, such as the liver, can regenerate after injury. The kidneys generally respond to injury with inflammation leading to fibrosis. After an insult, macrophages and T-cells release inflammatory cytokines such as interleukin 6 and 8 (IL-6, IL-8) and tumor necrosis factor-α (TNF-α) that promote further cellular injury. Several studies have found evidence of renal repair after acute injury through paracrine growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor (TGF-ß) secreted by mesenchymal stem cells. These growth factors have been proposed to have therapeutic potential during acute renal injury.
Besides cell-based regenerative strategies, there are efforts to develop wearable or implantable artificial kidneys. These artificial kidneys can be made either entirely from synthetic materials or combine both synthetic materials and renal cells. For example, implantable artificial kidneys, combining silicon nanopore membranes and renal cells, were surgically inserted into pigs without the use of immunosuppressive therapy or systemic anticoagulation. For 7 days, the cells within the units retained greater than 90% functionality and viability with minimal evidence of rejection. Whether these units provide effective renal replacement therapy, however, remains to be seen.
Individual Level
Dogs and Cats
According to the Merck Veterinary Manual, approximately 10 percent of dogs and 60 percent of cats get CKD. The process is usually progressive, irreversible, and clinically silent for many years, like in humans. CKD can be an acquired condition from infections, nephrotoxic exposures, neoplasia, but most frequently, it’s idiopathic. Some dog breeds such as Alaskan Malamutes, Bedlington Terriers, and Chow Chows are genetically predisposed to renal anomalies that can lead to CKD.
Both dogs and cats are vulnerable to obesity and diabetes. The prevalence of canine and feline obesity and type 2 diabetes is increasing, and type 2 diabetes might be associated with CKD in both species. However, the links between obesity, type 2 diabetes, and CKD appear to be stronger in dogs than in cats. One study found no difference in renal damage between cats with or without type 2 diabetes. The researchers hypothesized that the cats might have died before developing renal damage.
Nevertheless, CKD is the most common metabolic disease in geriatric cats and is the most common cause of death in cats presenting to veterinarians. The prevalence rate of CKD in geriatric cats appears to have increased 25-fold from the 1980s to the 2000s, but it is unclear if these figures represent a true increase in prevalence or simply an increase in diagnosis. Since cats share home environments with their owners, researching the epidemiology of CKD in cats is warranted. If the cause is due to toxic environmental exposures, it might have important implications for human health. It would not be the first time that cats served as health sentinels to environmental hazards. The “dancing cats of Minamata Bay” in the early 1950s in Japan provided the crucial link between environmental mercury exposure and severe neurological disease in humans.
Investigating type 2 diabetes and CKD in dogs and their owners might also provide useful information. One study found that Swedish owners of dogs with type 2 diabetes were more likely to develop type 2 diabetes themselves. No such association was found with cat owners and their cats. Shared lifestyle behaviors and obesity have been proposed as possible contributing factors. Behavioral modification weight loss programs for dogs and their owners have been shown to have therapeutic health benefits for both.
Diseases in canines have received increasing attention recently because of the recognized links between canine and human genomes. Dog breeds are analogous to geographically isolated human populations. For example, German shepherds inherit a gene for hereditary multifocal renal cystadenocarcinoma which involves bilateral, multifocal tumors in kidneys that is like the Birt-Hogg-Dube syndrome in humans. After the dog gene was identified, the corresponding human gene was found.
CKD treatment for dogs and cats is primarily supportive with the goal to correct fluid and electrolyte imbalances to enhance the animal’s quality of life. Dietary modification includes protein, phosphorus, and sodium restrictions. Increases in dietary fiber, B vitamins, and omega 3 fatty acids are recommended. Cost constraints as well as animal welfare considerations prohibit dialysis.
Humans
Modifiable and non-modifiable risk factors for CKD are well recognized. Modifiable risk factors include obesity, type 2 diabetes mellitus, hypertension, smoking, alcohol, and recreational drug use. Obstructive sleep apnea and periodontal disease are recently recognized potential risk factors. Non-modifiable risk factors include genetic mutations, male sex, ethnicity, age, and low birth weight. Low socioeconomic status, unemployment, and not graduating from high school increase CKD risk as well.
Early CKD in humans is clinically silent with symptoms typically not manifesting until stage G3 or greater. Symptoms include loss of appetite, fatigue, swollen ankles, feet, and hands, pruritis, muscle cramps, and bone or joint pain. In some cases, decreased urine output or dark or bloody urine appears. High blood pressure or anemia are signs of CKD.
Historically, diagnosis was based on ultrasound, renal biopsy, urinalysis, serum creatinine concentrations, and blood urea nitrogen (BUN) levels. Unfortunately, these biomarkers have been found to be insufficient to detect early-stage disease. Current practice relies on the estimated glomerular filtration rate (eGFR) which is based on age, sex, race, and serum creatinine levels. The eGFR equation uses creatinine which is influenced by patient muscle mass and metabolism and is vulnerable to inaccuracies.
Directly measuring GFR (mGFR) would be a gold standard were it not cumbersome, expensive, and reliant upon inulin, an exogenous filtration marker. These challenges have prompted a search for other endogenous biomarkers besides creatinine that would ideally be produced by the body at a constant rate, be freely filtered through the glomerulus, not be metabolized outside of the kidneys, not be protein bound, or be secreted or reabsorbed in the renal tubular system. Potential candidates for improving estimated glomerular filtration rates include low molecular weight proteins such as cystatin C, B2-microglobulin (B2-M) and beta-trace protein (BTP).
Additional novel biomarkers, potentially useful to assess CKD, have been identified. The desired characteristics of these biomarkers would include reliable and rapid response to kidney injury or insult, sensitive and specific for kidney disease, relevant across age, sex, and race, measured through non-invasive means, and not affected by exogenous drug use. For example, kidney injury molecule (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and liver-type fatty acid-binding protein have been proposed to identify acute kidney injury (AKI) and CKD.
Another preventive strategy might be the use of “smart toilets” to screen urine for glucose, blood, and albumin and other potential early signs of kidney disease. People eliminate body wastes into toilets every day. Wastewater is already being used by health officials to screen for infectious agents such as SARS-CoV-2, providing important early warning data for developing outbreaks. At the individual health level, technology companies are developing urinalysis devices that would fit inside toilets in healthcare settings or in people’s homes. The data can be delivered to smartphone apps and tracked over time.
CKD is divided into six stages based on eGFR rates and gradations of increasing urine albumin levels (i.e., albuminuria). Stages 1-2 have normal to mildly reduced eGFR levels. Stage 3 is split into 3A and 3B, and each succeeding stage has decreasing eGFR levels. CKD is defined as pathologically confirmed kidney damage for three or more months and/or an eGFR less than 60 mL/min per 1.73 m2. Stage 5 represents the lowest eGFR level of < 15 mL/min, signifying End Stage Renal Disease (i.e., ESRD).
As CKD worsens, cardiovascular disease risk increases markedly. Approximately 50 percent of patients with CKD stages 4 to 5 have cardiovascular disease and are more likely to die from cardiovascular complications than from CKD. CKD patients with atrial fibrillation have a threefold greater risk of developing end stage renal failure compared to those who don’t. Those with heart failure have a greater risk of CKD progression and death.
CKD management strategies focus on preserving kidney function to improve long term outcomes. Behavior modification recommendations include low-protein, low sodium, phosphate, and potassium, plant dominant diets, smoking cessation, increase physical activity, and weight reduction. Similarly, medications that treat the known risk factors such as type 2 diabetes, hypertension, and cholesterol help to protect and preserve kidney function. Potential nephrotoxins such as nonsteroidal anti-inflammatory drugs and some antibiotics should be avoided or have the doses reduced.
Approved in 1994, metformin is the current drug of choice for type 2 diabetes mellitus management. However, its use is not recommended in patients with eGFRs < 45 and is contraindicated with eGFRs below 30mL per minute per body surface area. The FDA has approved several new classes of medications to treat type 2 diabetes that also reduce CKD progression. In March 2013, it approved canagliflozin, the first sodium-glucose transport-2 inhibitor (SGLT-2 inhibitor) which increases urinary excretion of glucose in the proximal tubules, reduces major cardiovascular events, and reduces the progression of CDK. However, people with impaired kidney function develop more side effects from the drug. A common side effect is vulvovaginal candidiasis in women.
Steroidal and non-steroidal mineralocorticoid receptor antagonists (MRA) are used to treat type 2 diabetes and cardiovascular disease with or without CKD. These drugs inhibit the renin-angiotensin-aldosterone system (RAAS) which regulates electrolyte balance, blood volume, and systemic vascular resistance by elevating blood pressure in response to decreased renal blood flow and by increasing salt delivery to the nephron’s distal tubule. First and second generation steroidal MRA drugs include spironolactone and eplerenone, respectively. Both risk inducing severe hyperkalemia (i.e., elevated blood potassium levels) and worsening renal function, which lowers their therapeutic utility and use. The novel non-steroidal MRAs, including finerenone, which the FDA approved in July 2021, have been shown to reduce the risk of CKD and cardiovascular death in patients with type 2 diabetes. Like the steroidal MRAs, there is a risk of hyperkalemia.
Novel medications such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase IV (DPP 4) inhibitors, known as incretin analogues, act like gut hormones that increase insulin secretion in response to food consumption. Both have relatively strong safety profiles and are not contraindicated in patients with CKD. GLP-1 RA appear to have renal protective effects. Some DPP-4 inhibitors require dose adjustments for patients with low GFRs. Further studies are needed to determine if DPP 4 inhibitors benefit kidneys.
Both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used to treat hypertension. They are also effective in decreasing proteinuria and delaying CKD progression in patients with and without type 2 diabetes. Combined use is not recommended because of increased risk of hyperkalemia and acute kidney injury. Statins, which treat hypercholesterolemia, a risk factor for cardiovascular disease, appear to be renal protective in advanced stages of CKD but not during the early stages.
Next week, I will post Part II.