Colchicine for CKD!
In a multi-center, nested, case-control study in three Korean hospitals, patients with CKD stage 3 and 4 who are using drugs including colchicine, allopurinol, and febuxostat for high uric acid or chronic gout were studied over a period of 10 years. The progression of CKD was compared between 3085 compared to 11715 control patients.
Colchicine use was associated with a lower risk of adverse kidney outcomes in CKD patients with hyperuricemia, or chronic gout.
Unlike a study published two years ago in NEJM which excluded patients with advanced CKD, this study included patients with kidney function as low as 15 ml/min. Colchicine is known to anti-inflammatory. It also protects against kidney fibrosis.
There are concerns about myopathy and neuropathy with the intake of colchicine. It is, therefore, important to adjust the dose with advanced kidney disease and to be cautious when using it with patients who are on other myopathy-inducing drugs such as statin drugs.
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Long sleep duration is associated with decline in kidney function
This study is retrospective, longitudinal cohort study included 82,001 participants who visited a primary care center in Japan. Patients were categorized into CKD risk groups and sleep duration categories according to their self-reported average nightly sleep duration. The relationship between average nightly sleep duration and the incidence of composite renal outcome was studied.
Researchers found that an average sleep durations ≥8 h/night were associated with an increased risk of kidney function decline over time.
There are many reasons that connect sleep problems with poor kidney function. We summarized these in this blog.
Risk of environmental heavy metal toxicity is higher in CKD
In a study of 5,638 NHANES participants, lead and cadmium levels were higher in patients with CKD than those without it. This was also associated with decreased urinary lead excretion. Each decrease in estimated GFR by 10 ml/min/1.73m2 was associated with 0.05 mcg/dL increase in lead levels and 0.02 mcg/dL of cadmium levels. This association was even stronger among black participants.
The study concluded that CKD increases the susceptibility to heavy metal environmental exposure by reducing its elimination.
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The root cause of IgA nephropathy
IgA nephropathy is a kidney disease that is defined by the pathologic appearance of glomerular deposition of IgA immune complexes. However, this definition does not address the root cause of the disease.
It has been increasingly recognized that IgA immune complex that deposit in the kidneys predominantly contain polymeric IgA1 lacking galactose within its O-glycosylated hinge region.
In this study, researchers found that patients with IgA nephropathy have elevated levels of certain B cells that are enriched for λ light chains. These cells are predestined for homing to upper respiratory and digestive tract mucosal tissues. In the mucosal tissues, these B cells mature and excrete abnormal IgA in the setting of upper respiratory or digestive infection. You can read more IgA nephropathy by reading our blog here.
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Metformin: Some people love it and some people hate it… But it sure is getting a lot of attention lately
This study was done in rats with “non-diabetic kidney disease.” CKD was established in these rats by feeding them high adenine diet. Then they were randomized to receive either metformin or canagliflozin (an SGLT-2 inhibitor).
Metformin, but not canagliflozin, halted the decline in kidney function. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group.
Metformin is increasingly being studied in humans for various kidney diseases. If used judiciously it may be a cheap alternative to preserving kidney function.
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Tremor + gum disease + nephrotic Syndrome = ?
In this study, investigators in Beijing looked into the manifestation of mercury poisoning in 172 patients. 26.74% of these patients had kidney injury (3/4 were women) and most of them had nephrotic syndrome. The most common finding on the biopsy was membranous nephropathy.
Other findings of chronic mercury poisoning were neurotoxicity and gingivitis. Chelation with DMPS alone was as effective as chelation and prednisone in reversing kidney injury.
The most common source of exposure without kidney disease was industrial exposure. Interestingly, the most common source of exposure leading to kidney disease was cosmetics containing ionic mercury (mercury concentration in one of the patients cosmetic was 4600 mg/kg – national standards are < 1 mg/kg).
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Air pollution is linked to kidney disease
PM 2.5 refers to particulate matters that are up to 2.5 microns in size. Because of their small size, they are considered to be the worst of all air pollutants. They reach the alveoli and enter the blood stream. This study looked at the link between PM 2.5 and chronic kidney disease (CKD) in the Twin-cities area of Minnesota. Researchers found that the risk of CKD increases with higher levels of PM 2.5. This remained true after adjusting to all other variable.
It is, therefore, important to think of air pollution as a mediator of CKD and minimize exposure to it.
Block "fundamentals" not found
A Study reaffirms the role of the gut kidney connection in diabetic kidney disease
You know we discussed the role of the gut-kidney connection in the progression of CKD. You can find many of our blogs discussing this here. Dysbiosis can be a predisposing factor or a mediator when it comes to kidney disease. This study looked at the contribution of impairment in the intestinal barrier (leaky gut) to kidney injury in diabetic kidney disease (DKD). In diabetic mice with impaired intestinal integrity intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation. This was associated with epithelial renal tubular injury and faster progression to kidney failure as compared to control.
So, always think about the gut when it comes to kidney disease. A personalized comprehensive gut restoration protocol is a must to heal the gut.
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A gut-derived uremic toxin is associated with inflammation
Speaking of the gut, we discussed monocyte to HDL ration (MHR) in a previous email. If you missed it, you can read about it on our Instagram page. This study looked at the connection between Indole-3-acetic acid which is a gut-derived uremic toxin and MHR in patients with kidney disease. The study was conducted on 67 patients with CKD. Researchers found that Indole-3-acetic acid levels are directly related to MHR levels. The latter was associated with higher levels of fibrinogen, arterial hypertension, CRP.
So, as they say, when in doubt think about the gut.
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FAQs about genetic testing for kidney disease
What can I learn from genetic testing?
Genetic testing for kidney disease can help diagnose unknown causes of chronic kidney disease (CKD) and help identify changes in the genome that may increase CKD risk. Results from the tests can even help providers correct improper diagnoses. In addition, genetic testing can determine kidney disease severity. Identifying specific gene variants can help guide treatment for specific types of CKD as well as proper dosing of medications.
How does it work?
In order to perform the test, a sample of DNA is required, usually obtained through a saliva or blood sample. The cells from the sample are processed and analyzed in a database, obtained from Genome Wide Association studies (GWAS), of currently known genetic variants associated with CKD. These studies looked at multiple genetic variants and linked them statistically to specific kidney diseases in established patients.
Does genetic testing help diagnose specific kidney disease?
As mentioned above, genetic testing can help identify genetic variants associated with certain kidney diseases. However, carrying a genetic variant does not necessarily mean a person will develop the disease. Other factors can play a role in the genes’ ability to express themselves. Genetic tests should always be interpreted in consultation with an experienced nephrologist or genetic counselor.
Will these tests identify all genetic variants associated with CKD?
No, our knowledge about the genetic basis for CKD is still evolving. To date, mutations in more than 500 genes have been associated with different forms of kidney disease. The specific genetic mutations identified on the panel varies depending on the genetic testing company used. In addition, genetic testing cannot tell you everything about inherited diseases. Diet, lifestyle, and environment all influence how genes are expressed, a field known as epigenetics.
Why do I need genetic testing for kidney disease if I am already doing regular physicals and lab checks?
Kidney disease is a silent disease and patients usually don’t develop symptoms until later stages of CKD. In addition to laboratory testing, genetic testing provides information for those at increased risk of CKD. Knowing your genetic risk provides you with an opportunity to modify your lifestyle in order to decrease the chance of kidney disease and failure in the future.
Is this test covered by my health insurance?
Depending on the test performed, your insurance may or may not cover a portion of the cost. Some small panel tests implemented by a few pharmaceutical companies are free. These companies hope to recoup the cost by identifying patients who will benefit from their products. In general, broad panel genetic tests are now much more affordable than they used to be.
Will I be discriminated against based on my results?
Federal law prohibits health insurance providers and employers from discriminating against a person based on genetic information. However, unfortunately, this law does not apply to long-term care, disability, or life insurance providers. It is crucial that you choose a testing company that values your privacy.
The Bottom Line
Genetics are one factor that plays a significant role in the development of kidney disease. Genome-wide association studies (GWAS) have identified several hundred genes that are associated with kidney diseases. Therefore, genetic testing may play a crucial role in the management of kidney disease patients.
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Current evidence suggests that genetics play a role in the development of kidney disease. Common genetic disorders associated with kidney disease include polycystic kidney disease, Alport’s Syndrome and Fabry’s disease. The advances of genome-wide association studies (GWAS) helped identify several hundred other genes linked to kidney diseases. This made genetic testing a useful tool in the management of kidney disease patients. In this blog, we will detail the benefits of broad-panel genetic testing in kidney disease management.
Next Generation Sequencing
Various methods for identifying genetic variants have been used in the past. The exome is that 2% of the genome that codes for all biological proteins. Next generation sequencing is a new technology that allows DNA sequencing of the entire human exome within a single day. It also captures a broader spectrum of variations that can affect the genetic code. This revolutionary technology can identify mutations associated with CKD. It can also recognize variants associated with an increase in risk or severity of CKD. It is now available for kidney disease patients. This type of “broad-panel genetic testing” can transform care for patients with kidney disease.
Clinical benefits of genetic testing in kidney disease management
Identify diagnosis of unknown causes
While diabetic and hypertensive kidney diseases are the most common causes of kidney failure, there are others. There are instances when providers find themselves unable to identify the cause of kidney disease. Indeed, in some cases, urinalysis is actually “bland” and the workup to identify the cause of kidney disease is negative.
Even a kidney biopsy may not be helpful. It may show glomerulosclerosis and fibrosis (scarring). This does not help identify the original cause of kidney disease. Genetic testing can have a tremendous value in these cases. In fact, whole exome sequencing was able to diagnose up to one third of the patients who had unknown causes of kidney disease.
Reclassify a clinical diagnosis
It is common for providers to label kidney disease patients with unknown causes as hypertensive kidney disease or “nephrosclerosis”. This is because hypertension is common in kidney disease patients. Studies have shown that 60-90% of patients with chronic kidney diseases have high blood pressure. It is often not clear which came first, hypertension or kidney disease. It is possible that patients who were diagnosed with hypertensive kidney disease have another cause. In fact, studies have shown that up to a quarter of kidney diseases can be reclassified with a broad-panel genetic testing.
Target the therapy and workup
Broad-panel genetic testing can help providers avoid unnecessary procedures, tests, and treatments. It gives accurate and “molecular level diagnosis”. It provides a better idea of the outcome of the specific kidney disease. It also helps providers avoid the use of immunosuppressive medications in patients with genetic causes of kidney disease. Furthermore, it can guide therapy for specific genetic causes that we currently have treatment for such as Fabry’s disease. This type of testing may, indeed, eliminate the need for a kidney biopsy.
Role in kidney transplant
Genetic testing can have a tremendous impact in guiding kidney transplant and in the care of kidney transplant recipients. Kidney transplant donors can be pre-screened by broad panel genetic testing to assess if they carry any genetic kidney disease risk. While carrying the genes does not necessarily indicate that the donor will have the disease, it can play an important role in selection. This is especially true for living donor kidney transplant when the recipient has a known genetic kidney disease, and the donor is too young to have any manifestations.
In addition, many immunosuppressive medications that are used by kidney transplant patients are metabolized by well-established pathways that can be affected by genetic SNPs.
Having this genetic information can help providers prescribe the proper dose of immunosuppressive medications which is critical in transplant patients to avoid rejection or toxicity. This evolving field is called pharmacogenomics.
Help with management of kidney patients
Broad panel genetic testing can identify patients who are at risk for kidney disease, reclassify the exact cause of kidney disease, and guide treatment. Knowing the molecular basis of some kidney diseases can guide lifestyle modification interventions, future development of drugs, and gene therapy. It can also identify early complications outside the kidneys that can be related to the specific genetic disease and prompt early interventions.
Available broad panel genetic tests
Broad panel genetic tests are now available for providers and patients, and are relatively inexpensive. Many of them are covered by insurance companies. We have utilized Natera’s Renasight broad panel genetic test for this purpose. It provides next generation sequencing for 382 genes that are associated with kidney disease. There are also other genetic testing companies that test a small panel of genes for free to identify patients for drug or gene therapy.
The Bottom Line
We are at the dawn of a new era in nephrology and kidney care. Broad panel genetic testing will revolutionize kidney disease management. Our genes are not our destiny, but we cannot change our destiny without knowing our genes.
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In this series we’re focusing on the integrative approach to preventing kidney stone formation.
Conventional approaches to kidney stones tend to focus on medications, surgical removal, and using ultrasonic waves to break up stone. It rarely approaches the root cause including risk factors to prevent stone formation.
We covered the impact of diet, the microbiome and gut health, and electrolyte imbalances on kidney stones in previous blogs. Here we will discuss the role genetics play in kidney stone formation.
The Genetics of Kidney Stones
There seems to be a familial link when it comes to the development of kidney stones. In fact, two thirds of patients with calcium-containing kidney stones have a relative with kidney stones. Recently, genome-wide association studies uncovered several genetic sequence variants (SNPs) that lead to increased risk of kidney stone development. Although we are still scratching the surface in understanding the contribution of genetic factors to stone formation, we do know that we can modulate these risks through environmental and dietary modifications.
Genetic Variations in Calcium Handling
In a previous blog, we discussed the role of the kidney filtration units (specifically the nephrons). The kidneys are responsible for filtering large volumes of blood daily. This function is crucial, and, the unique design of the nephrons make it able to adjust this filtrate and prevent dehydration. This intricate design also makes the kidneys crucial in the balance of water and many electrolytes.
Calcium is one of the electrolytes filtered and reabsorbed in the kidneys. Calcium sensing receptors (CaSR) are present in kidney cells and are essential for the reabsorption of calcium. These receptors increase and decrease the amount of calcium reabsorbed based on the calcium level in the blood. In other words, activating these receptors increases the amount of calcium lost in the urine.
Single nucleotide polymorphisms (SNPs) in CaSR have been found to alter the function of these receptors leading to increased urinary excretion of calcium. Of particular interest, SNPs in rs7652589 and rs1501899 were associated with kidney stones in patients with normal citrate excretion. SNPS in rs1801725, rs1042636 of the CaSR gene were also associated with kidney stones in various populations.
Another gene that has been associated with increased calcium in the urine is the gene coding for the protein Claudin-14, responsible for forming tight junctions. This protein helps connect adjacent cells to form a barrier which acts like a gate, separating blood from urine. Tight junctions are also responsible for ensuring that minerals don’t pass between the cells. SNPs in the genes that code Claudin-14 (CLDN14) alters the integrity of these “gates” and allows for calcium to “sneak” between cells into the urine, increasing the risk for kidney stone formation. Specifically, SNPs at the locations rs219778, and rs219780 of the CLDN14 gene were significantly associated with kidney stones.
Genetic Variations in Vitamin D Receptors (VDR)
Vitamin D plays a crucial role in calcium balance. Studies have shown that vitamin D increases the absorption of calcium from the gut and also increases calcium excretion in the urine. Vitamin D receptors are essential for vitamin D to exert its action on calcium balance.
Some mutations or SNPs in the VDR are associated with increased absorption and excretion of calcium, significantly increasing the risk of kidney stones. It is worth mentioning here that there is some controversy about the link between vitamin D supplementation and kidney stone formation. Vitamin D deficiency appears to be common among kidney stone formers. This is likely because low vitamin D causes calcium loss from the bone in order to maintain normal calcium range in the blood for cardiovascular protection. Even though vitamin D3 supplementation may increase calcium excretion in the urine, it has not been conclusively found to increase the risk of kidney stone formation.
Therefore, genetic assessment may be a key to identify patients who are at risk of kidney stone formation from taking vitamin D supplements.
Genetic Variations in the Handling of Other Minerals
The kidneys are crucial for balancing many minerals in our bodies such as magnesium, phosphate, oxalate and others. Genetic mutation or SNPs affecting the genes that code for the channels or receptors that regulate these minerals can also impact the risk of kidney stones. Some SNPs on the other hand can be protective against kidney stones such as SNPs in the UMOD gene. Discussion of this long list of SNPs requires details beyond the scope of this blog, but we summarized most of the genes that have been associated with kidney stones in the table below.
| Gene symbol | Gene name | Phenotype |
| ADCT10 | Adenylate cyclase 10 | Increased calcium excretion |
| AGXT | Alanine-glyoxylate aminotransferase | Increased oxalate excretion |
| CA2 | Carbonic anhydrase II | Osteoporosis + decreased acid excretion |
| CASR | Calcium-sensing receptor | Increased calcium excretion |
| CLCN5 | Chloride channel, voltage-sensitive 5 | Dent disease |
| CLCNKB | Chloride channel, voltage-sensitive Kb | Bartter Syndrome, type 3 |
| CLDN14 | Claudin 14 | Increased calcium excretion |
| CLDN16 | Claudin 16 | Increased calcium and magnesium excretion |
| CLDN19 | Claudin 19 | Increased calcium and magnesium excretion |
| CYP24A1 | Cytochrome P450 | Decreased breakdown of vitamin D3 |
| GRHPR | Glyoxylate reductase | Increased oxalate excretion |
| HOGA1 | 4-Hydroxy-2-oxoglutarate aldolase 1 | Increased oxalate excretion |
| HPRT1 | Hypoxanthine phosphoribosyltransferase 1 | Increased uric acid excretion |
| SLC12A1 | Solute carrier family 12, member 1 | Bartter syndrome, type 1 |
| SLC26A1 | Solute carrier family 26, member 1 | Calcium oxalate kidney stones |
| SLC22A12 | Solute carrier family 22, member 12 | Decrease uric acid excretion |
| SLC2A9 | Solute carrier family 2, member 9 | Decreased uric acid excretion |
| SLC34A1 | Solute carrier family 34, member 1 | Calcium phosphate kidney stones |
| SLC34A3 | Solute carrier family 34, member 3 | Calcium phosphate kidney stones |
| SCL3A1 | Solute carrier family 3, member 1 | Increased Cystine excretion |
| SLC4A1 | Solute carrier family 4, member 1 | Decrease acid excretion (dRTA) |
| SLC7A9 | Solute carrier family 7, member 9 | Increased Cystine excretion |
| SLC9A3R1 | Solute carrier family 9, subfamily A, member 3, regulator 1 | Calcium phosphate kidney stones |
| UMOD | Uromodulin (most common urine protein) | Protective against kidney stones |
| VDR | Vitamin D (1,25-dihydroxy D3) receptor | Increased calcium excretion |
| XDH | Xanthine dehydrogenase | Increased xanthine excretion |
The Bottom Line
There are many factors that impact the risk of kidney stone development. Although there are pure genetic diseases that are associated with kidney stones, often the increased risk is subtle or offset by other factors. Increased risk, when combined with other factors including nutrient depletion, dysbiosis, electrolyte imbalances and dehydration, may lead to the development of kidney stones in some. Assessing the genetic profile of kidney stone patients can help identify the root cause of the disease to tailor appropriate, personalized management. Practitioners working with individuals to prevent kidney stone formation should formulate a comprehensive and individualized intervention that modifies all relevant components in their integrative approach.
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