Gut Microbiota as a Source of Uremic Toxins

Uremic retention solutes are the compounds that accumulate in the blood when kidney excretory function is impaired. Some of these compounds are toxic at high concentrations and are usually known as “uremic toxins”. The cumulative detrimental effect of uremic toxins results in numerous health problems and eventually mortality during acute or chronic uremia, especially in end-stage renal disease. More than 100 different solutes increase during uremia; however, the exact origin for most of them is still debatable. There are three main sources for such compounds: exogenous ones are consumed with food, whereas endogenous ones are produced by the host metabolism or by symbiotic microbiota metabolism. In this article, we identify uremic retention solutes presumably of gut microbiota origin. We used database analysis to obtain data on the enzymatic reactions in bacteria and human organisms that potentially yield uremic retention solutes and hence to determine what toxins could be synthesized in bacteria residing in the human gut. We selected biochemical pathways resulting in uremic retention solutes synthesis related to specific bacterial strains and revealed links between toxin concentration in uremia and the proportion of different bacteria species which can synthesize the toxin. The detected bacterial species essential for the synthesis of uremic retention solutes were then verified using the Human Microbiome Project database. Moreover, we defined the relative abundance of human toxin-generating enzymes as well as the possibility of the synthesis of a particular toxin by the human metabolism. Our study presents a novel bioinformatics approach for the elucidation of the origin of both uremic retention solutes and uremic toxins and for searching for the most likely human microbiome producers of toxins that can be targeted and used for the therapy of adverse consequences of uremia.

KIM-1 and GADDI-153 gene expression in paracetamol-induced acute kidney injury: effects of N-acetylcysteine, N-acetylmethionine, and N-acetylglucosamine

Objectives Acute kidney injury (AKI) is a critical clinical event characterized by a reduction in the excretory function of the kidneys. N-acetylcysteine (NAC), N-acetylmethionine (NAM) and N-acetylglucosamine (NAG) are antioxidants with scanty known genetic mechanisms. We aimed to assess both kidney injury molecule-1 (KIM-1) and growth-arrested DNA damage-inducible gene-153 (GADD-153) genes expression in paracetamol (PA) induced AKI. Also, to recognize whether NAC, NAM and/or NAG have roles in altering the expression of these genes for ameliorating the AKI induced by PA. Methods The present preliminary study achieved the AKI model by oral administration of PA therapeutic dose for 15 days in experimental male rats. Serum urea, creatinine, and renal oxidative stress parameters were analyzed. Genetic expression of KIM-1 and GADD-153 were determined using real time-PCR. Results Significant elevations of serum urea, creatinine and nitric oxide in renal tissue after PA administration; however, total thiol content was reduced. In addition, both KIM-1 and GADD-153 were upregulated. These biochemical alterations were improved after using NAC and partially after NAM; however, NAG had little effect. Conclusions Up-regulation of both KIM-1 and GADD-153 occur in AKI induced by PA, which was significantly reversed by NAC.

Vitamin D levels in patients with diabetes mellitus in combination with chronic kidney disease

BACKGROUND. Vitamin D has been known since 1928. The wide range of its metabolic effects paradoxically contrasts with the high prevalence of insufficiency and deficiency in the population of different regions of the world. A number of publications have demonstrated information about the relationship between vitamin D and insulin production by beta cells of the pancreas, as well as the excretory function of the kidneys.THE AIM: to assess the level of vitamin D in patients with diabetes mellitus in combination with chronic kidney disease (CKD).PATIENTS AND METHODS. A questionnaire and a study of the level of 25-hydroxyvitamin D, creatinine, urea, and glucose in the blood were conducted in 117 patients aged 18 to 84 years who gave voluntary consent. All patients were divided into three study groups: group 1 - patients with long-term DM, group 2 - patients with newly diagnosed DM, and 3 - control group. The glomerular filtration rate (GFR) is calculated by the formula CKD-EPI.RESULTS. As a result of the study, it was found that patients with DM, regardless of the duration of its course, were more likely to suffer from vitamin D deficiency, compared with the control group, where D-deficiency and D-deficiency occurred with the same frequency. In addition, patients with DM were more likely to have stage 2-3A CKD, in contrast to the control group, where preserved kidney function prevailed. We also identified and confirmed the direct dependence of GFR on the level of vitamin D in the blood of patients with DM.CONCLUSION. In the patients studied by us, a clear association was found between a lower vitamin D index in the blood serum and the presence of a history of diabetes. They also showed a tendency to decrease the excretory function of the kidneys and the formation of CKD. Consequently, a full-fledged diagnosis of vitamin D-deficient conditions and timely initiated therapy can prevent or at least slow down the progression of CKD in these patients, which will certainly improve their quality of life and reduce the costs of health services for renal replacement therapy and rehabilitation of this group of patients.

The Effects of Two Different Dietary Regimens During Exercise On Outcome of Experimental Acute Kidney Injury

Introduction: Acute kidney injury (AKI) is a syndrome characterized by rapid loss of excretory function of kidney. One of the molecules considered in the treatment of renal failure is the silent information regulator (SIRT1). In this study, the effect of two different diets during exercise on AKI was investigated. Materials and Methods: A number of rats were randomly divided into four groups; control without exercise, control with exercise, exercise + calorie restriction (CR), and exercise + time restriction (TR). Each group was divided into two subgroups of without AKI and with AKI (six rats in each group). Endurance exercise and diets were implemented before AKI. Serum urea and creatinine, urinary albumin, kidney malondialdehyde (MDA), total antioxidant capacity (TAC), transforming growth factor (TGF-β1), and SIRT1 levels, glomerular filtration rate (GFR) and relative kidney weight were measured before and 48 h after AKI induction.Results: After induction of kidney injury, serum urea and creatinine, urinary albumin, kidney MDA and TGF-β1 levels and relative kidney weight increased in rats with both previous exercise and no previous exercise (p <0.001), while GFR, and kidney TAC and SIRT1 levels decreased (p <0.001). These changes after AKI were less in the group with previous exercise than in the group that had no exercise (p <0.001). The TR diet during exercise caused a less increase in serum urea (p <0.001) and creatinine (p <0.05), and urinary albumin (p <0.01) levels after injury compared to the just exercise group. Also, both CR and TR diets during exercise caused less change in MDA (p <0.01, p <0.05, respectively) and TAC (p <0.001, p <0.05, respectively) levels compared to just exercise group. Conclusion: The results showed that exercise alone had no effect on preventing function impairment of kidney, oxidative stress, inflammation and also SIRT1 alteration following AKI in athletes, although these indexes were less among those with exercise than those without exercise. However, when the CR and TR diets were implemented during exercise, strong renoprotective effects appeared, and the protective effect of TR diet was greater.

Renal function in chronic lung diseases of non-tuberculous etiology

We investigated the functional state of the kidneys in 20 patients with bronchiectasis, 13 with bronchial asthma and 7 with lung abscesses. Zimnitsky's test was normal in 12 patients, isogppostenuria and nocturia were found in 9, and nocturia in 19. Fonno's test was carried out in 31 patients. In 18 it turned out to be normal, in 13 patients a violation of the excretory function was revealed. Albuminuria was observed in 8, microhematuria - in 4, urobilinuria - in 17. The level of residual nitrogen was normal in 39 and increased in one patient.

Placental Cryoextract and Renin-Angiotensin-Aldosterone System Blockade Mitigate Renal Failure in Rats

Here, we have studied the impact of administration of rat placental cryoextract (PCE), drug blockade of the renin-angiotensin-aldosterone system (RAAS) with enalapril and spironolactone and their combination on the rat kidney tissue structure and excretory function at different stages of chronic renal failure (CRF) development using the glycerol model. In 3 weeks after glycerol introduction, the animals from all the groups showed low values of glomerular filtration rate, impaired blood flow in renal cortex, tubular epithelial dystrophy, inflammation and edema of interstitium, indicating the onset of CRF development. Tubulo-interstitial nephritis and nephrosclerosis were dominated in untreated rats 16 weeks later. The use of RAAS drug blockade, as well as a comprehensive therapy with RAAS blockers and placental cryoextract stopped the inflammatory processes in renal tissue, restored blood circulation and normalized excretory function, which persisted for up to 16 weeks of observation.

How to potentialize the effect of renin-angiotensin-aldosterone system inhibitors?

The scientific review presents a practical analysis of the properties of Lespedeza capitata in terms of its attractiveness for nephrological practice. Lespedeza shows many effects on ectoderm derivatives, including skin and the kidneys. Thus, the results of studies showed significant stimulation of the growth of fibroblasts and keratinocytes, as well as increased collagen synthesis with a lipolytic effect on adipocytes. The researchers concluded the possibility of using herbal medicinal preparations of Lespedeza capitata to stimulate skin cells and tissue regeneration, for anti-aging therapy and induction of lipolysis due to flavonoid extract. Lespedeza capitata extract enhances diuresis, eliminates edema, reduces azotaemia and albuminuria, increases sodium excretion, and to lesser extent potassium, promotes renal filtration and excretion of nitrogenous products in the urine. The advantages of phytotherapy in normalizing the capillary permeability of the glomeruli are a mild diuretic effect, which prevents a significant loss of electrolytes in contrast to synthetic diuretics. These effects are now considered as potentiating the action of inhibitors of the renin-angiotensin system, which is the basis of renoprotection in modern nephrology. Lespedeza flavonoids improve protein-energy metabolism, which has been demonstrated in many models of acute renal failure. Correction of protein metabolism has a favourable nephroprotective effect and slows the progression of chronic kidney disease (CKD) while maintaining normal excretory function. Lespedeza extract can be considered as a substance that enhances the action of renin-angiotensin-aldosterone system inhibitors (RAASi), acting synergistically in inhibiting the activity of the renin-angiotensin system. This property of the drug becomes very relevant in patients with CKD stage 5 when the abolition of RAASi today corresponds to the current trend. Maintaining a small dose of RAASi in stage 10 CKD, or the use of RAASi with extrarenal elimination in combination with Lespedeza extract demonstrates encouraging results in clinical practice.

Role of renal sympathetic nerve activity in volatile anesthesia's effect on renal excretory function

Regulation of fluid balance is pivotal during surgery and anesthesia and affects patient morbidity, mortality and hospital length of stay. Retention of sodium and water is known to occur during surgery but the mechanisms are poorly defined. In this study, we explore how the volatile anesthetic sevoflurane influences renal function by affecting renal sympathetic nerve activity (RSNA). Our results demonstrate that sevoflurane induces renal sodium and water retention during pediatric anesthesia in association with elevated plasma concentration of renin but not arginine-vasopressin. The mechanisms are further explored in conscious and anesthetized ewes where we show that RSNA is increased by sevoflurane compared with when conscious. This is accompanied by renal sodium and water retention and decreased renal blood flow. Finally, we demonstrate that renal denervation normalizes renal excretory function and improves renal blood flow during sevoflurane anesthesia in sheep. Taken together this study describes a novel role of the renal sympathetic nerves in regulating renal function and blood flow during sevoflurane anesthesia.

Blunted natriuretic response to saline loading in sheep with hypertensive kidney disease following radiofrequency catheter-based renal denervation

Renal sympathetic nerves contribute to renal excretory function during volume expansion. We hypothesized that intact renal innervation is required for excretion of a fluid/electrolyte load in hypertensive chronic kidney disease (CKD) and normotensive healthy settings. Blood pressure, kidney hemodynamic and excretory response to 180 min of isotonic saline loading (0.13 ml/kg/min) were examined in female normotensive (control) and hypertensive CKD sheep at 2 and 11 months after sham (control-intact, CKD-intact) or radiofrequency catheter-based RDN (control-RDN, CKD-RDN) procedure. Basal blood pressure was ~ 7 to 9 mmHg lower at 2, and 11 months in CKD-RDN compared with CKD-intact sheep. Saline loading did not alter glomerular filtration rate in any group. At 2 months, in response to saline loading, total urine and sodium excretion were ~ 40 to 50% less, in control-RDN and CKD-RDN than intact groups. At 11 months, the natriuretic and diuretic response to saline loading were similar between control-intact, control-RDN and CKD-intact groups but sodium excretion was ~ 42% less in CKD-RDN compared with CKD-intact at this time-point. These findings indicate that chronic withdrawal of basal renal sympathetic activity impairs fluid/electrolyte excretion during volume expansion. Clinically, a reduced ability to excrete a saline load following RDN may contribute to disturbances in body fluid balance in hypertensive CKD.