Column: Cool Beans

Getting to Know the Uremics: Attending to Early and Moderate CKD Detoxicology

Robin Rose, MD, FNP, RN

This column”s intent is to deepen primary care vision and understanding of early and moderate chronic kidney disease (CKD). The CKD epidemic is growing. Many patients report their diagnosis was delayed and their care neglectful. While we may offhandedly portray Stage 3 as asymptomatic, patients beg to differ.¹

Nephrologist Amanda Raff explains that the concept of uremia, historically described as late stage CKD, is expanding. Uremia literally means “urine in the blood.” Now, it is understood that uremia begins at the onset of declining glomerular filtration, long before the end stage.² Uremic toxicity is a systemic syndrome; uremic toxins can affect all tissues – and do so early in the course of the disease.³

Uremia, known as a state of chronic inflammation, can cause acute phase reactants to increase (CRP, IL6, fibrinogen, ferritin, serum amyloid A) or decrease (albumin, prealbumin, and transferrin). Gut-Kidney-related dysbiosis – with endotoxin-induced inflammation – contributes to the multifactorial choir of uremic toxic assault on body functions.

Uremic toxemia is fraught with complexity, whether the source of toxins is endogenous or exogenous. Deficient glomerular filtration results in diminished renal excretory capacity. This, combined with disordered renal tubular metabolism and renal endocrine disarray, perpetuates many dysfunctional processes.³

Already by Stage 3, elevated solutes (hippuric acid, indole-3-acetic acid, kynurenic acid) may inhibit tubular excretion. These compete for organic anion uptake transporters and efflux pumps, resulting in increased risk of drug interactions and toxicity.⁴

Uremic toxins can induce apoptosis, with nephron-damaging and fibrosis-inviting “epithelial-to-mesenchymal transition” (EMT) in the proximal tubules. With inhibited tubular transport proteins, the excretion of drugs, solutes, and waste products is compromised. So too, is the patients’ quality of life compromised – with notable risk for comorbidities.⁴

Engaging preventive uremia thinking, one observes impaired defensive ability and superimposed deficiency states of CKD. There is a synergy of toxins with maladaptive consequences. Many uremic toxins, already elevated in patients with less advanced cases, often go under the radar without astute laboratory exploration.² Thus, renal detoxicology.

The European Uremic Toxins (EUTox) Work Group, established by biochemists and clinicians working with uremic toxicity and its therapies, collaborated to develop the Uremic Toxins DATA BASE, an encyclopedic overview of uremic toxins and comprehensive reviews on all uremic solutes.⁵

Uremic retention solutes are many. Some of these solutes have more recently been recognized as uremic toxins because they negatively impact normal biological functions. Combined with the mal-effects of their toxic metabolites, these toxins cause a broad range of cellular and molecular patho-biological damage.^3,6

Several sort-systems for categorizing uremic toxins have been proposed. This illustrates why primary care can step way beyond the BUN, creatinine, and protein in urine to assess the status of this population. (See Sidebar 1.)

Barb, this sidebar placement really breaks up the text. If possible, please place it near but not directly underneath the preceding paragraph. Thank you.

Sidebar

1.

Uremic Toxin Types Based on Pathobiological Mechanisms

Type I

: Normally produced endogenous substance, accumulates due to impaired excretion (i.e., urea).

Type II

: Excess endogenous production and impaired degradation of normal substance (i.e., PTH, ADMA, urea).

Type III

: Exogenous toxin accumulates due to decreased excretory capacity and persistent intake (i.e., aluminum).

Type IV

: Normally produced endogenous substance – decreased synthesis, enhanced degradation.

(Normally, there is a combination of more than one.)²

• Low-molecular-weight, water-soluble uremic toxins (< 500 Da): EUTox found 68 in this group, many familiar: ADMA, SDMA, creatine, creatinine, hyaluronic acid, guanidine, urea, uric acid, oxalates.

• Protein-bound solutes comprise 27.8% of EUTox uremic toxins, < 500 Da. This includes AGEs, cytokines, interleukins, TNFa, homocysteine, indoxyl sulfate, kynurenic acid, leptin, p-cresyl sulfate, etc.

• Middle-molecular-weight molecules (>500 Da); more than 50 found to cause and effect pathophysiology: Adiponectin, cystatin C, leptin, gherlin, prolactin, cholecystokinin, B2 microglobulin, etc.

• Uremic toxins with similar chemical structures – ie Guanidines: small water soluble compounds that resemble urea and creatinine, also urea derivatives like ADMA.⁶ Bugnicourt et al. write that these cause neuroexcitation in CKD, increase Homocycreine, and cause cerebral endothelial dysfunction – all associated with the well-recognized CKD cognitive disorder.⁷ See Sidebar 2.

  Sidebar 2. Uremic Toxins with Similarities

Purine Derivatives

: Cytidine, hypoxanthine, xanthine, uric acid

Pyrimidine Derivatives

: Thymine, orotic acid, orotidine, uridine

Methyl amine Derivatives

: Methylamine, dimethylamine, trimethylamine

Indole Derivatives

: Kynurenine, indole-3-acetate, kynurenic acid, melatonin, indoxyl sulfate, quinolinic acid.⁶

Some Examples of Uremic Toxins and Their Effects

AGEs: An example of a familiar uremic toxin is advanced glycation end products – AGEs. These exogenous uremics, absorbed 30% by digestion, are too large for filtration at Bowman’s capsule. AGE proteolysis in cells can result in metabolites that are even more toxic. Inadequate removal leads to accumulation; five-times-increased concentrations can be found in mild CKD.⁶ Teaching patients to change cooking habits helps decrease this risk.

ADMA, another example, is a highly protein-bound methylated amino acid, increased in uremic plasma. As a potent NOS inhibitor, endothelial damage is the concern (recall CKD’s dramatically increased cardiorenal risk). It is the inhibition of kidney-derived metabolizing enzymes – NOT decreased excretion – that causes this facet of uremic inflammation.² Lifestyle strategies may offer patients lowered risk for this issue.

Cardio-renal effects. Premature uremic vascular disease is well recognized at all CKD stages. The phenotype of uremia and its complex dysmetabolism presents an imbalanced relationship with DNA methylation; there’s a combination of environmental and heritable factors. Manipulating the epigenome in early/moderate CKD with an individualized lifestyle prescription, guided by functional medicine lab explorations, can impact and lessen the assault of this dire morbidity and mortality.^8,9

Gut-kidney effects. Functional gastroenterology has a place in remediating uremic dysbiosis with its well-honed inflammation awareness.

Uremia is a significant cause of dysbiosis. The gut is an extension of the external environment. The large intestine produces toxic uremic compounds, even from normal dietary macromolecules. Toxic substances ingested with food can affect intestinal bacterial products. Marked disintegration of colonic epithelial barrier structure, significant alterations in the colonic bacterial flora,¹⁰ and disruption of tight junctions occur as a direct result of uremic toxin damage. Endotoxin influx causes systemic inflammation, even without infection. Oxidative stress recruits immune cells. Impaired Nrf2 compromises cytoprotection, disabling natural antioxidants.¹¹

Decreased glomerular filtration rate (GFR) leads to increased concentration of urea. Urea influxes into the gut, hydrolyzes to ammonia, then to ammonium hydroxide (increasing intestinal lumen pH), causing mucosal irritation (accompanied by aberrations in uric acid and oxalate). These metabolites, substituting as food for microbes in place of indigestible carbohydrates, cause a shift, disturbing normal symbiotic microbe/host relationships. Pro-oxidant, pro-inflammatory harmful byproducts form. Compromised tight junctions and efflux of toxins ultimately causes the nephron-sclerosing heralding end stage.

Basic Treatment Approach – Renal Detoxicology

The search for therapies to improve removal of toxins has focused on pharmacological strategies to block pertinent pathways. Due to limited space, I can merely point out familiar areas of functional holistic medicine to mitigate CKD metabolic toxic derangements.

Exogenous Detox. Toxic food and environment significantly effect CKD patients. Heavy metals, pesticides, prepared foods, hygiene products, and household, garden and cleaning chemicals are known to harbor uremia-triggering qualities. Initiating the arduous process of encouraging elimination of potentially toxic and common “products” from kitchen, bathroom, garage, garden, and work offers a program with strong secondary prevention benefit.

Stress illustrates another category of toxics. Reducing life and social stresses reduces toxic catecholamines. Stress reduction is medicine: PTSD, abuse, psychopathology, and eating disorders are all appropriate targets.

Diet specifications for early moderate CKD are individualized. Encouraging a shift to organic, non-GMO fare is a start. Using basic labs can provide insight into potential uremic toxins – creatinine, potassium, phosphorus, albumin, bicarbonate levels, etc. – and easily guide renal diet. Begin by optimizing amount (max 0.8 grams of protein per kilo daily) and type of protein (plant-based choices offer CKD benefits). More sophisticated testing provides a more optimal health status: amino acid testing, organic acid testing, nutrient panels, hormone panels, inflammation markers, etc.

Medication awareness and supplement awareness, including binders, incipients etc., is important, as some contribute to renal toxicity.

Endogenous Detox impacts how internally-derived toxins are formed and processed. It includes engaging well-honed skills and proactively evaluating and addressing inflammation, SNPs, coagulation, oxygenation, and acidification. Early subtle findings can be used to guide the long-term arduous process of making healthy changes. Practices to aid endogenous detox include the following:

1. Prebiotics, dietary resistant starch, and probiotics can support healthy gut microbe symbiosis. Elimination of GMO products, unnecessary antibiotics, steroids, and sugars offer balance to urea-induced dysbiosis. Fermented foods are well-accepted by patients understanding the CKD-dysbiosis association.

2. Low-inflammation lifestyle as Rx, with supplement and nutrient support.

3. Sorbent therapies such as natural toxin barriers like bentonite clay and activated charcoal have been studied and used to block gut absorption of toxins (i.e., phosphorus) Nutrient monitoring and supplementing might be necessary.

4. Prevention of constipation is important as prolonged mucosal contact with gut-microbe-derived toxins exacerbates dysbiosis. Known strategies are useful. Acacia gum, magnesium, and rhubarb root have dual benefits for CKD and gut.

Summary

Uremia starts with early CKD. Lowering the toxic load protects nephrons and offers the potential to slow progression. Diagnosing at Stage 2 CKD can initiate a health-improving journey. Stage 3 patients have multifactorial complaints and symptoms: an excellent portal into which a doctor-patient team can achieve rewarding detoxicology.

References

1. Personal communications.|

2. Raff A, et al. New Insights into Uremic Toxicity. Current Opinion in Nephrology

and Hypertension. 2008Nov; 17(6);560-65.

3. Glassock R. Uremic Toxins: What are they? An integrated Overview of

Pathobiology and Classification. Journal of Renal Nutrition. 2008Jan; 18(1); 2-6.

4. van den Brand JAJG, et al. Uremic Solutes in CKD and their Role in Progression. PLOS ONE.

2016 Dec; 11(12).

5. Uremic Toxin (EUTox) Work Group. Purpose of EUTox. www.uremic-toxins.org.

6. Lisowska-Myjak B. Uremic Toxins and Their Effects on Multiple Organ Systems.

Nephrology Clin Pract. 2014;128:303-311.

7. Bugnicourt J-M, et al. Cogitive Disorders and Dementia in CKD: The neglected

Kidney Brain Axis. JASN. 2013Mar; 24(3); 353-63.

8. Vanholder R, et al. A bench to bedside view of uremic toxins. J Am Soc Nephrol. 2008;19(5):863-870.

9. Stenvinkel P, Ekstrom J. Does the Uremic Milieu Effect the Epigenotype. Journal of

Renal Nutrition. 2009 Jan; 19(1); 82-85.

10. Black AP, Cardozo LF, Mafra D. Effects of Uremic Toxins from the Gut Microbiota on

Bone: A Brief Look at Chronic Kidney Disease. Ther Apher Dial. 2015 Oct;19(5):436-40.

11. Vaziri, Nosratola, Altered intestinal microbial flora and impaired epithelial barrier

structure and function in CKD: the nature, mechanisms, consequences and potential

treatment. Current Opinion in Nephrology and Hypertension. 2015 Nov; 21(6); 587-92.