Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome.

Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.

[Spontaneous femoral arterio-venous fistula in an 80-year-old female patient as an incidental finding]. / Spontane femorale arterio-venöse Fistel bei einer 80-jährigen Patientin als Zufallsbefund.

INTRODUCTION: Spontaneous arteriovenous fistulas (AVF), in contrast to iatrogenic or post-traumatic ones, are extremely rare and only sporadically published in the literature. In the absence of exposure risk, the diagnosis of AVF can be challenging, especially if it is an incidental finding. CASE HISTORY: An 80-year-old female patient presented to our vascular consultation because of swelling of the left leg due to varicosis. For years, she had also noticed that the right foot seemed to be cooler. Percutaneous catheter examinations via the groin had not been performed, and she could not remember any groin injuries. EXAMINATION AND FINDINGS: Truncal varicosis of the great saphenous vein confirmed clinically and sonographically. In addition, with peripheral pulses obtained, the right foot appeared slightly cooler but not discolored. On auscultation, a systolic-diastolic murmur accompanied by palpable buzzing was heard in the right groin. Color duplex sonography showed a coarse color mosaic pattern between the common femoral artery (AFC) and the anterior saphenous vein (VSAA) in the sense of aliasing ("confetti phenomenon"). A fistula channel between the AFC and VSAA could be visualized, in which very high systolic-diastolic flow velocities prevailed; pulsatile and turbulent flow was present in the region of the crosse-near femoral vein. THERAPY AND COURSE: Endovenous laser ablation was performed for symptomatic truncal varicosis of the left leg. Under ultrasound-guided compression of the afferent artery and fistula at the right groin, the fistula flow did not stop. The patient was reluctant to undergo a proposed interventional closure of the AVF. In follow-up over 4 years, no signs of cardiac insufficiency or critical limb ischemia developed. DISCUSSION: Spontaneous femoral AVF is a rarity. Characteristic clinical findings lead to a targeted use of color duplex sonography with correct interpretation of artifacts that can otherwise be easily missed.

Correction: Stämmler et al. Estimating Glomerular Filtration Rate from Serum Myo-Inositol, Valine, Creatinine and Cystatin C. Diagnostics 2021, 11, 2291.

In the original publication [...].

[Rare cause of calf pain in a 56-year-old female patient: cystic adventitial degeneration of the popliteal artery]. / Seltene Ursache von Wadenschmerzen bei einer 56-jährigen Patientin: die zystische Adventitiadegeneration.

INTRODUCTION: Cystic adventitial degeneration (CAD) is a rare vascular disease, affects mostly middle-aged men, and as a nonatherosclerotic disease, is an uncommon differential diagnosis of intermittent claudication. CASE HISTORY: A 56-year-old female patient presented to our medical office because of unexplained right-sided calf pain that was not constantly load-dependent. The complaints fluctuated considerably with longer symptom-free intervals. EXAMINATION AND FINDINGS: Clinically, the patient presented regular pulses, which were maintained even with provocative maneuvers such as plantar flexion and knee flexion. Duplex sonography showed cystic masses around the popliteal artery. On MRI examination, a tubular tortuous connection to the knee joint capsule also appeared to be visualizable. A diagnosis of cystic adventitial degeneration was made. THERAPY AND COURSE: In the absence of constant impairment of walking performance with symptom-free intervals as well as morphological and functional signs of stenosis, interventional or surgical therapy was not desired by the patient. Short-term follow-up revealed stable clinical and sonomorphologic findings over an observation period of 6 months so far. DISCUSSION: CAD should also be considered in female patients with atypical leg symptoms. There are no uniform treatment recommendations for CAD, which is why it is a challenge to select the optimal, usually interventional procedure. In patients with few symptoms and no critical ischemia, a conservative approach with close follow-up may be justified, as in our case report.

Serum myo-inositol and valine improve metabolomic-based estimated glomerular filtration rate among kidney transplant recipients.

Background: Close monitoring of glomerular filtration rate (GFR) is essential for the management of patients post kidney transplantation. Measured GFR (mGFR), the gold standard, is not readily accessible in most centers. Furthermore, the performance of new estimated GFR (eGFR) equations based upon creatinine and/or cystatin C have not been validated in kidney transplant patients. Here we evaluate a recently published eGFR equation using cystatin C, creatinine, myo-inositol and valine as measured by nuclear magnetic resonance (eGFRNMR). Methods: Residual sera was obtained from a cohort of patients with clinically ordered iothalamate renal clearance mGFR (n = 602). Kidney transplant recipients accounted for 220 (37%) of participants. Results: Compared to mGFR, there was no significant bias for eGFRcr or eGFRNMR, while eGFRcr-cys significantly underestimated mGFR. P30 values were similar for all eGFR. P15 was significantly higher for eGFRNMR compared to eGFRcr, while the P15 for eGFRcr-cys only improved among patients without a kidney transplant. Agreement with mGFR CKD stages of <15, 30, 45, 60, and 90 ml/min/1.73 m2 was identical for eGFRcr and eGFRcr-cys (61.8%, both cases) while eGFRNMR was significantly higher (66.4%) among patients with a kidney transplant. Conclusion: The 2021 CKD-EPI eGFRcr and eGFRcr-cys have similar bias, P15, and agreement while eGFRNMR more closely matched mGFR with the strongest improvement among kidney transplant recipients.

Analytical Validation of GFRNMR: A Blood-Based Multiple Biomarker Assay for Accurate Estimation of Glomerular Filtration Rate.

Accurate and precise monitoring of kidney function is critical for a timely and reliable diagnosis of chronic kidney disease (CKD). The determination of kidney function usually involves the estimation of the glomerular filtration rate (eGFR). We recently reported the clinical performance of a new eGFR equation (GFRNMR) based on the nuclear magnetic resonance (NMR) measurement of serum myo-inositol, valine, and creatinine, in addition to the immunoturbidometric quantification of serum cystatin C, age and sex. We now describe the analytical performance evaluation of GFRNMR according to the Clinical and Laboratory Standards Institute guidelines. Within-laboratory coefficients of variation (CV%) of the GFRNMR equation did not exceed 4.3%, with a maximum CV% for repeatability of 3.7%. Between-site reproducibility (three sites) demonstrated a maximum CV% of 5.9%. GFRNMR stability was demonstrated for sera stored for up to 8 days at 2-10°C and for NMR samples stored for up to 10 days in the NMR device at 6 ± 2°C. Substance interference was limited to 4/40 (10.0%) of the investigated substances, resulting in an underestimated GFRNMR (for glucose and metformin) or a loss of results (for naproxen and ribavirin) for concentrations twice as high as usual clinical doses. The analytical performances of GFRNMR, combined with its previously reported clinical performance, support the potential integration of this NMR method into clinical practice.

Estimating Glomerular Filtration Rate from Serum Myo-Inositol, Valine, Creatinine and Cystatin C.

Assessment of renal function relies on the estimation of the glomerular filtration rate (eGFR). Existing eGFR equations, usually based on serum levels of creatinine and/or cystatin C, are not uniformly accurate across patient populations. In the present study, we expanded a recent proof-of-concept approach to optimize an eGFR equation targeting the adult population with and without chronic kidney disease (CKD), based on a nuclear magnetic resonance spectroscopy (NMR) derived 'metabolite constellation' (GFRNMR). A total of 1855 serum samples were partitioned into development, internal validation and external validation datasets. The new GFRNMR equation used serum myo-inositol, valine, creatinine and cystatin C plus age and sex. GFRNMR had a lower bias to tracer measured GFR (mGFR) than existing eGFR equations, with a median bias (95% confidence interval [CI]) of 0.0 (-1.0; 1.0) mL/min/1.73 m2 for GFRNMR vs. -6.0 (-7.0; -5.0) mL/min/1.73 m2 for the Chronic Kidney Disease Epidemiology Collaboration equation that combines creatinine and cystatin C (CKD-EPI2012) (p < 0.0001). Accuracy (95% CI) within 15% of mGFR (1-P15) was 38.8% (34.3; 42.5) for GFRNMR vs. 47.3% (43.2; 51.5) for CKD-EPI2012 (p < 0.010). Thus, GFRNMR holds promise as an alternative way to assess eGFR with superior accuracy in adult patients with and without CKD.

Adjusting microbiome profiles for differences in microbial load by spike-in bacteria.

BACKGROUND: Next-generation 16S ribosomal RNA gene sequencing is widely used to determine the relative composition of the mammalian gut microbiomes. However, in the absence of a reference, this does not reveal alterations in absolute abundance of specific operational taxonomic units if microbial loads vary across specimens. RESULTS: Here we suggest the spiking of exogenous bacteria into crude specimens to quantify ratios of absolute bacterial abundances. We use the 16S rDNA read counts of the spike-in bacteria to adjust the read counts of endogenous bacteria for changes in total microbial loads. Using a series of dilutions of pooled faecal samples from mice containing defined amounts of the spike-in bacteria Salinibacter ruber, Rhizobium radiobacter and Alicyclobacillus acidiphilus, we demonstrate that spike-in-based calibration to microbial loads allows accurate estimation of ratios of absolute endogenous bacteria abundances. Applied to stool specimens of patients undergoing allogeneic stem cell transplantation, we were able to determine changes in both relative and absolute abundances of various phyla, especially the genus Enterococcus, in response to antibiotic treatment and radio-chemotherapeutic conditioning. CONCLUSION: Exogenous spike-in bacteria in gut microbiome studies enable estimation of ratios of absolute OTU abundances, providing novel insights into the structure and the dynamics of intestinal microbiomes.