Persistent, low-grade inflammation is now considered a hallmark feature of chronic kidney disease (CKD), being involved in the development of all-cause mortality of these patients Although substantial improvements have been made in clinical care, CKD remains a major public health burden, affecting 10-15% of the population, and its prevalence is constantly growing Due to its insidious nature, CKD is rarely diagnosed in early stages, and once developed, its progression is unfortunately irreversible There are many factors that contribute to the setting of the inflammatory status in CKD, including increased production of proinflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, altered metabolism of adipose tissue, and last but not least, gut microbiota dysbiosis, an underestimated source of microinflammation In this scenario, a huge step forward was made by the increasing progression of omics approaches, specially designed for identification of biomarkers useful for early diagnostic and follow-up Recent omics advances could provide novel insights in deciphering the disease pathophysiology; thus, identification of circulating biomarker panels using state-of-the-art proteomic technologies could improve CKD early diagnosis, monitoring, and prognostics This review aims to summarize the recent knowledge regarding the relationship between inflammation and CKD, highlighting the current proteomic approaches, as well as the inflammasomes and gut microbiota dysbiosis involvement in the setting of CKD, culminating with the troubling bidirectional connection between CKD and renal malignancy, raised on the background of an inflammatory condition

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Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome.

Germin and germin-like proteins (GLPs) are encoded by a family of genes found in all plants. They are part of the cupin superfamily of biochemically diverse proteins, a superfamily that has a conserved tertiary structure, though with limited similarity in primary sequence. The subgroups of GLPs have different enzyme functions that include the two hydrogen peroxide-generating enzymes, oxalate oxidase (OxO) and superoxide dismutase. This review summarizes the sequence and structural details of GLPs and also discusses their evolutionary progression, particularly their amplification in gene number during the evolution of the land plants. In terms of function, the GLPs are known to be differentially expressed during specific periods of plant growth and development, a pattern of evolutionary subfunctionalization. They are also implicated in the response of plants to biotic (viruses, bacteria, mycorrhizae, fungi, insects, nematodes, and parasitic plants) and abiotic (salt, heat/cold, drought, nutrient, and metal) stress. Most detailed data come from studies of fungal pathogenesis in cereals. This involvement with the protection of plants from environmental stress of various types has led to numerous plant breeding studies that have found links between GLPs and QTLs for disease and stress resistance. In addition the OxO enzyme has considerable commercial significance, based principally on its use in the medical diagnosis of oxalate concentration in plasma and urine. Finally, this review provides information on the nutritional importance of these proteins in the human diet, as several members are known to be allergenic, a feature related to their thermal stability and evolutionary connection to the seed storage proteins, also members of the cupin superfamily.

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Germin and Germin-like Proteins: Evolution, Structure, and Function

Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) are toxic, non‐proteinogenic amino acids formed by post‐translational modification and are uremic toxins that inhibit nitric oxide (NO) production and play multifunctional roles in many human diseases. Both ADMA and SDMA have emerged as strong predictors of cardiovascular events and death in a range of illnesses. Major progress has been made in research on ADMA‐lowering therapies in animal studies; however, further studies are required to fill the translational gap between animal models and clinical trials in order to treat human diseases related to elevated ADMA/SDMA levels. Here, we review the reported impacts of ADMA and SDMA on human health and disease, focusing on the synthesis and metabolism of ADMA and SDMA; the pathophysiological roles of these dimethylarginines; clinical conditions and animal models associated with elevated ADMA and SDMA levels; and potential therapies against ADMA and SDMA. There is currently no specific pharmacological therapy for lowering the levels and counteracting the deleterious effects of ADMA and SDMA. A better understanding of the mechanisms underlying the impact of ADMA and SDMA on a wide range of human diseases is essential to the development of specific therapies against diseases related to ADMA and SDMA.

https://www.mdpi.com/2072-6651/9/3/92/pdf

Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA).

Recurrent urinary tract infections (UTIs) are common among girls and young women who are healthy and have anatomically normal urinary tracts. These infections are a main source of morbidity and health-care costs in this population. The interaction between specific infecting bacteria and urinary tract epithelium characteristics underlies the pathogenesis of this disease. Several pathogen-related factors predispose people to recurrent UTI, including periurethral bacterial colonisation and Escherichia coli virulence. Host behavioural risk factors include voiding dysfunction, high intercourse frequency, and oral contraceptive and spermicide use. The role of vesicoureteral reflux in recurrent childhood UTI is probably overestimated in the medical literature and is important only in a small group of children with high-grade reflux. Family pedigree analysis suggests a familial genetic predisposition for UTI among young females. Animal models show the multigenic nature of recurrent UTI. Putative candidate genes for the disease include ABH blood groups, interleukin-8 receptor (CXCR1), the human leucocyte antigen locus, toll-like receptors, tumour necrosis factor, and Tamm-Horsfall protein.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(04)01147-8.pdf

Pathogenesis of urinary tract infections with normal female anatomy

Current conventional tests of kidney damage and function in blood (serum creatinine and urea nitrogen) and urine (urine protein creatinine ratio and urine specific gravity) are widely used for diagnosis and monitoring of kidney disease. However, they all have important limitations, and additional markers of glomerular filtration rate and glomerular and tubular damage are desirable, particularly for earlier detection of renal disease when therapy is most effective. Additionally, urinary markers of kidney damage and function may help localize damage to the affected portion of the kidney. In general, the presence of high- and intermediate-molecular weight proteins in the urine are indicative of glomerular damage, while low-molecular weight proteins and enzymes in the urine suggest tubular damage due to decreased reabsorption of proteins, direct tubular damage, or both. This review aims to discuss many of these new blood and urinary biomarkers in domestic veterinary species, focusing primarily on dogs and cats, how they may be used for diagnosis of renal disease, and their limitations. Additionally, a brief discussion of serum creatinine is presented, highlighting its limitations and important considerations for its improved interpretation in domestic species based on past literature and recent studies.

Renal biomarkers in domestic species.

BACKGROUND: The study was undertaken to develop a potential new markers for distinguishing minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) in children. We hypothesized that matrix metalloproteinase9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) is a better marker of focal sclerosis in the glomerulus then matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) and matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-2 MMP2/TIMP-2. METHODS: The present study used a sample of 36 children and adolescents subdivided into two groups: I – 20 children with MCNS, subjected to examination twice: A – in relapse of nephrotic syndrome, before treatment and B – after regression of proteinuria; II – 16 children with FSGS. MMPs and TIMPs and NGAL levels were measured in the urine using ELISA kit. MMP-9/TIMP-1, MMP-2/TIMP-2 and MMP-9/NGAL ratios were calculated. RESULTS: Median NGAL/cr. was significantly higher in MCNS and FSGS patients when compared to healthy controls. Both, NGAL and MMP-9 urinary levels were significantly elevated in FSGS subjects, as compared with control subjects. Contrary to FSGS children, in MCNS group, before treatment only NGAL/cr., but not MMP-9/cr. was increased. Urinary concentrations of NGAL and MMP-9 were highly associated with each other (NGAL/cr. vs. MMP-9/cr., r = 0.485, p< 0.01). Median urine MMP-9/NGAL ratio in FSGS patients was significantly higher than in patients with MCNS. We also found that significant increase in MMP-9/NGAL was associated with FSGS [odds ratio (OR) – 9.0; confidence interval (CI) 1.97–41.07]. CONCLUSION: MMP-9/NGAL ratio may serve as differentiation marker between MCNS and FSGS in nephrotic children.

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Urinary MMP-9/NGAL ratio as a potential marker of FSGS in nephrotic children

Aim

There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status and lipid disturbances on urinary lithogenic factors and the risk of kidney stone formation in children and adolescents from three to 18 years of age.



Methods

We carried out serum lipid profile evaluations and 24-h urine chemistry analyses on 493 overweight/obese paediatric participants (mean age 13 years) without nephrolithiasis and 492 healthy normal weight sex and age-matched controls.



Results

A third (33%) of the study group had blood lipid disturbances, with more acidic urine, lower urinary citrate excretion and a higher fraction of ionised calcium and higher Bonn Risk Index than the controls. The participants' body mass index standard deviation score (BMI Z-score) was positively correlated with urinary oxalate and uric acid and negatively correlated with citrate excretion. Total cholesterol, low-density lipoprotein cholesterol and triglycerides correlated negatively with citraturia, while high-density lipoprotein cholesterol correlated positively.



Conclusion

The main factor that predisposed overweight and obese children to kidney stones was hypocitraturia. Urinary citrate excretion was related to both BMI Z-scores and all lipid fraction abnormalities. However, hypercholesterolaemia and particularly low-density lipoprotein hypercholesterolaemia seemed to play a major role.

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

Oxalate homeostasis is a derivative of absorption and transportation in the digestive system and renal/intestinal excretion of oxalate. The objective of this cross-sectional study was to determine normative values of plasma oxalate in relation to age, gender, and body size. A group of 1,260 healthy Caucasian children and adolescents aged 3 months to 18 years [mean ± standard deviation (SD) 10.5 ± 4.3] was studied. Each 1-year group comprised 70 subjects. Oxalate levels were assessed in blood plasma samples obtained from fasted individuals using the precipitation–enzymatic method with oxalate oxidase. Median oxalate levels in healthy infants was 3.20 µmol/L (5th–95th percentiles: 1.56–5.58) and was higher compared with older children [2.50 µmol/L (5th–95th percentiles: 0.95–5.74); p < 0.01]. No differences were found in plasma oxalate levels between boys and girls. There were no associations between plasma oxalate levels and anthropometric traits. In the healthy population aged 1–18 years, plasma oxalate concentration is independent of age, gender, and body size. Infants demonstrate higher plasma oxalate levels compared with older children, which suggests possible immature mechanisms of renal excretion. This study appears to be the first extensive report providing normative data for plasma oxalate in children and adolescents.

Reference values of plasma oxalate in children and adolescents.

Objective. Myelomeningocele is the most common physically disabling birth defect in humans. It is caused by the failure of the neural tube to close and is most common in the lumbosacral area. Because of associated neurogenic bladder dysfunction, children with myelomeningocele have an increased risk of urinary tract infections and, ultimately, of kidney damage. Nerve growth factor (NGF) is an important mediator inducing bladder overactivity in many pathological conditions. The aim of this study was to evaluate urinary NGF excretion in children with neurogenic bladder caused by myelomeningocele. Material and methods. The investigation was conducted into two groups. Group 1 comprised 28 children with neurogenic bladder, and group 2 comprised 20 healthy children with no abnormalities in the urinary and nervous systems. Urinary NGF levels were measured by enzyme-linked immunosorbent assay. Results. Median urinary NGF concentration in group 1 was higher when compared with healthy controls. Positive cor...

Urinary nerve growth factor level in children with neurogenic bladder due to myelomeningocele.

Objective To assess functional day-time bladder capacity (DBC) and urine osmolality in children with primary monosymptomatic nocturnal enuresis (PMNE) according to age and sex. Material and methods A total of 263 children with PMNE were divided into two groups: Group I, 160 children (63 girls, 97 boys) aged 5–9 years (mean age 7.14±1.47 years); and Ggroup II, 103 children (25 girls, 78 boys) aged 10–15 years (mean age 12.26±1.52 years). DBC (milliliters) was the largest void of the day measured over four 24-h periods, irrespective of the diet applied. Urine osmolality was determined three times: in the evening before bed-time; at night, 2–4 h after falling asleep; and in the morning in the nocturnal void. Results DBC was smaller in Group I than in Group II (151.27 vs 199.46 ml; p 0.05). The mean osmolality of the nocturnal void in the morning was 854.15 and 909.22 mOsmol/kg H2O in Groups I and II, respectively (p>0.05). Diffe...

Agata Korzeniecka-Kozerska

Papers

Urinary MMP-9/NGAL ratio as a potential marker of FSGS in nephrotic children

Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones.

Reference values of plasma oxalate in children and adolescents.

Urinary nerve growth factor level in children with neurogenic bladder due to myelomeningocele.

Functional bladder capacity and urine osmolality in children with primary monosymptomatic nocturnal enuresis.