Moderate Renal Impairment and Toxic Metabolites Produced by the Intestinal Microbiome: Dietary Implications.

OBJECTIVE: Toxic metabolites produced by the intestinal microbiome from animal proteins, carnitine (mainly from red meat), or phosphatidylcholine (mainly from egg yolk), have important adverse effects on cardiovascular disease. These are renally eliminated and may be termed gut-derived uremic toxins (GDUT). We hypothesized that even moderate renal impairment and intake of nutrient precursors would raise plasma levels of GDUT. DESIGN: A cohort study. SETTING: Academic medical center. SUBJECTS: Patients attending stroke prevention clinics at a university medical center were recruited. MAIN OUTCOME MEASURE: Nutrient intake was assessed by the 131-item Harvard Food Frequency Questionnaire; estimated glomerular filtration rate (eGFR) was caculated using the Chronic Kidney Disease-Epidemiology (EPI) equations. Plasma levels of trimethylamine n-oxide, p-cresyl sulfate, hippuric acid, p-cresyl glucuronide, pheny acetyl glutamine, and phenyl sulfate were measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Among 316 patients recruited, the mean (standard deviation [SD]) age was 66.74 (10.42) years; 59.7% were men. Mean eGFR was 76.03 ± 20.01; 57 (18%) had eGFR<60 mL/min/1.73 m2. Plasma levels of all GDUT were significantly higher even with moderate reduction of eGFR. Nutrient intake affected plasma levels of some GDUT; the effects differed by eGFR above and below 60 mL/min/1.73 m2. Plasma levels were obtained fasting, so we probably underestimated the effect of nutrient intake. CONCLUSIONS: Even moderate impairment of renal function was associated with higher plasma levels of GDUT. This has dietary implications for patients at risk of atherosclerosis, particularly in those with impaired renal function (including the elderly): they should limit intake of animal protein, red meat, and egg yolk. It also points the way to novel approaches to vascular prevention, including more intensive dialysis, renal transplantation, and modification of the intestinal microbiome with probiotics or fecal transplantation.

Penile fibrosis-still scarring urologists today: a narrative review.

Background and Objective: Implantation of penile prosthesis (PP) into scarred and fibrotic corpora can be a difficult challenge. In this review article, we provide a review of penile fibrosis, discuss current medical and surgical management and summarize preventative strategies. Methods: In this study, we searched PubMed between the years 2000-2023 for publications with search strategy: "penile fibrosis" OR "scarred corpora" OR "fibrosed corpora". Key Content and Findings: This search returned a total of 137 articles. We examine the evidence for preoperative patient evaluation and penile ultrasound (US), oral phosphodiesterase-5 inhibitors, pentoxifylline, and L-arginine, vacuum device therapy and the use of surgical approaches and tools in the context of complex penile fibrosis cases. Severe penile fibrosis is most associated with priapism and infection. Estimating the degree of fibrosis via preoperative US may help set realistic patient expectations. Phosphodiesterase inhibitors and L-arginine reduce fibrosis in animal models however their impact in humans remains unclear despite theoretical advantage for their use. Vacuum device therapy may preserve penile length following priapism and infected PP cases. The use of Coloplast Narrow-Based or AMS-700 CXR implants are used primarily for severe fibrosis. Various surgical excisional/incisional techniques, the Carrion-Rossello, Mooreville Uramix cavernotomes and reverse cutting scissors are all options, and their use varies from case to case. Finally, prevention of penile fibrosis in patients with history of penile implant infection and the safety of early implantation of a penile implant in patients with refractory priapism is encouraged. Conclusions: The management of penile fibrosis remains a challenge but there are multiple options to assist clinicians. Complex cases should be managed and studied at high volume centers.

Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function.

Metabolic products of the intestinal microbiome such as trimethylamine N-oxide (TMAO) that accumulate in renal failure (gut-derived uremic toxins, GDUTs) affect atherosclerosis and increase cardiovascular risk. We hypothesized that patients on a Mediterranean diet and those consuming lower amounts of dietary precursors would have lower levels of GDUTs. Patients attending vascular prevention clinics completed a Harvard Food Frequency Questionnaire (FFQ) and had plasma levels of TMAO, p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresyl glucuronide, phenyl acetyl glutamine, and phenyl sulfate measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Carotid plaque burden was measured by ultrasound; CKD-Epi equations were used to estimate the glomerular filtration rate. In total, 276 patients completed the study. Even moderate renal function significantly increased plasma GDUTs, which were significantly associated with higher carotid plaque burden. There was no significant difference in plasma levels of any GDUT associated with a Mediterranean diet score or with intake of dietary precursors. In omnivorous patients with vascular disease, the intake of dietary precursors of intestinal metabolites or adherence to a Mediterranean diet did not change plasma GDUT. Approaches other than diet, such as probiotics and repopulation of the intestinal microbiome, may be required to mitigate the adverse effects of GDUTs.

Data on the gut and saliva microbiota from a cohort of atherosclerosis patients determined by 16S rRNA gene sequencing.

This work was conducted to characterize the 16S rRNA gene profile of a cohort of patients with traditional risk factors for developing atherosclerosis. The patients in the cohort were divided into two extremes; those predicted to develop extreme atherosclerosis who did not (Protected), and those predicted not to develop atherosclerosis who did (Unexplained). Bacterial DNA was isolated from stool and saliva and this was used to determine the V4 variable region of the 16S rRNA gene sequence composition of the samples in triplicate.

Metabolic products of the intestinal microbiome and extremes of atherosclerosis.

BACKGROUND AND AIMS: There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area. METHODS: Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <-2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure - gut-derived uremic toxins (GDUT) - were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden. CONCLUSIONS: The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.