Chronic kidney disease in children: an update.

Chronic kidney disease (CKD) is a major healthcare issue worldwide. However, the prevalence of pediatric CKD has never been systematically assessed and consistent information is lacking in this population. The current definition of CKD is based on glomerular filtration rate (GFR) and the extent of albuminuria. Given the physiological age-related modification of GFR in the first years of life, the definition of CKD is challenging per se in the pediatric population, resulting in high risk of underdiagnosis in this population, treatment delays and untailored clinical management. The advent and spreading of massive-parallel sequencing technology has prompted a profound revision of the epidemiology and the causes of CKD in children, supporting the hypothesis that CKD is much more frequent than currently reported in children and adolescents. This acquired knowledge will eventually converge in the identification of the molecular pathways and cellular response to damage, with new specific therapeutic targets to control disease progression and clinical features of children with CKD. In this review, we will focus on recent innovations in the field of pediatric CKD and in particular those where advances in knowledge have become available in the last years, with the aim of providing a new perspective on CKD in children and adolescents.

Associations of longitudinal height and weight with clinical outcomes in pediatric kidney replacement therapy: results from the ESPN/ERA Registry.

BACKGROUND: Associations between anthropometric measures and patient outcomes in children are inconsistent and mainly based on data at kidney replacement therapy (KRT) initiation. We studied associations of height and body mass index (BMI) with access to kidney transplantation, graft failure, and death during childhood KRT. METHODS: We included patients < 20 years starting KRT in 33 European countries from 1995-2019 with height and weight data recorded to the ESPN/ERA Registry. We defined short stature as height standard deviation scores (SDS) < -1.88 and tall stature as height SDS > 1.88. Underweight, overweight and obesity were calculated using age and sex-specific BMI for height-age criteria. Associations with outcomes were assessed using multivariable Cox models with time-dependent covariates. RESULTS: We included 11,873 patients. Likelihood of transplantation was lower for short (aHR: 0.82, 95% CI: 0.78-0.86), tall (aHR: 0.65, 95% CI: 0.56-0.75), and underweight patients (aHR: 0.79, 95%CI: 0.71-0.87). Compared with normal height, patients with short and tall statures showed higher graft failure risk. All-cause mortality risk was higher in short (aHR: 2.30, 95% CI: 1.92-2.74), but not in tall stature. Underweight (aHR: 1.76, 95% CI: 1.38-2.23) and obese (aHR: 1.49, 95% CI: 1.11-1.99) patients showed higher all-cause mortality risk than normal weight subjects. CONCLUSIONS: Short and tall stature and being underweight were associated with a lower likelihood of receiving a kidney allograft. Mortality risk was higher among pediatric KRT patients with a short stature or those being underweight or obese. Our results highlight the need for careful nutritional management and multidisciplinary approach for these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome.

Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype-phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.

Expectations in children with glomerular diseases from SGLT2 inhibitors.

Chronic kidney disease (CKD) is a global public healthcare concern in the pediatric population, where glomerulopathies represent the second most common cause. Although classification and diagnosis of glomerulopathies still rely mostly on histopathological patterns, patient stratification should complement information supplied by kidney biopsy with clinical data and etiological criteria. Genetic determinants of glomerular injury are particularly relevant in children, with important implications for prognosis and treatment. Targeted therapies addressing the primary cause of the disease are available for a limited number of glomerular diseases. Consequently, in the majority of cases, the treatment of glomerulopathies is actually the treatment of CKD. The efficacy of the currently available strategies is limited, but new prospects evolve. Although the exact mechanisms of action are still under investigation, accumulating data in adults demonstrate the efficacy of sodium-glucose transporter 2 inhibitors (SGLT2i) in slowing the progression of CKD due to diabetic and non-diabetic kidney disease. SGLT2i has proved effective on other comorbidities, such as obesity, glycemic control, and cardiovascular risk that frequently accompany CKD. The use of SGLT2i is not yet approved in children. However, no pathophysiological clues theoretically exclude their application. The hallmark of pediatric CKD is the inevitable imbalance between the metabolic needs of a growing child and the functional capacity of a failing kidney to handle those needs. In this view, developing better strategies to address any modifiable progressor in kidney disease is mandatory, especially considering the long lifespan typical of the pediatric population. By improving the hemodynamic adaptation of the kidney and providing additional beneficial effects on the overall complications of CKD, SGLT2i is a candidate as a potentially innovative drug for the treatment of CKD and glomerular diseases in children.

Guidelines for Genetic Testing and Management of Alport Syndrome.

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.

Summary of Expert Opinion on the Management of Children With Chronic Kidney Disease and Growth Failure With Human Growth Hormone.

Background: The management of children and adolescents with chronic kidney disease (CKD) and growth failure candidate for recombinant human growth hormone therapy (rhGH) is based on an appraisal of the literature established on a 2006 consensus statement and 2019 Clinical practice recommendations. The performance of these guidelines has never been tested. Aims: The objective of this study was to establish the level of adherence to international guidelines based on the 2006 consensus and the 2019 criteria that lead to the initiation of growth hormone treatment by both pediatric endocrinologists and pediatric nephrologists. Methods: A multidisciplinary team of pediatric endocrinologists and pediatric nephrologists, members of the Italian Society of Pediatric Endocrinology or of the Italian Society of Pediatric Nephrology, discussed and reviewed the main issues related to the management of pediatric patients with CKD who need treatment with rhGH. Experts developed 11 questions focusing on risk assessment and decision makings in October 2019 and a survey was sent to forty pediatric endocrinologists (n = 20) and nephrologists (n = 20) covering the whole national territory. The results were then analyzed and discussed in light of current clinical practice guidelines and recent recommendations. Results: Responses were received from 32 of the 40 invited specialists, 17 of whom were pediatric endocrinologists (42.5%) and 15 pediatric nephrologists (37.5%). Although all the centers that participated in the survey agreed to follow the clinical and biochemical diagnostic work-up and the criteria for the treatment of patients with CKD, among the Italian centers there was a wide variety of decision-making processes. Conclusions: Despite current guidelines for the management of children with CKD and growth failure, its use varies widely between centers and rhGH is prescribed in a relatively small number of patients and rarely after kidney transplantation. Several raised issues are not taken into account by international guidelines and a multidisciplinary approach with mutual collaboration between specialists will improve patient care based on their unmet needs.

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review.

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from January 1, 2015 to May 31, 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.

Hypokalemia After Rituximab Administration in Steroid-Dependent Nephrotic Syndrome: A Case Report.

The monoclonal antibody rituximab is a commonly used steroid sparing agent for steroid-dependent idiopathic nephrotic syndrome of childhood. With this brief report, we describe the first case of symptomatic hypokalemia after intravenous rituximab administration in a young woman. The sudden onset of dizziness and palpitation prompted acute life-threatening hypokalemia recognition by blood gas analysis and electrocardiography. Her symptoms were rapidly controlled by intravenous potassium administration. Such adverse drug reactions, when mild and self-limiting, can easily be overlooked if not expected or investigated. Health professionals should take into account the possibility of acute hypokalemia after rituximab administration in order to promptly setup the appropriate treatment and limit potentially severe complications.

[Dystrophic Calcinosis Cutis: a rare fearsome issue of Chronic Kidney Disease].

Disorders of calcium-phosphate-parathormone balance, are very important issues in ESRD patients, that may lead to severe complications, as dystrophic calcinosis cutis, a rare disease, caused by calcium salt deposits in cutaneous or subcutaneous tissues and many organs. We present the case of a 47 years old woman, in ESRD due to membranous glomerulopathy, treated by peritoneal dialysis, who, after 7 months of dialysis, developed painful masses on second finger and fifth metacarpus of the right hand. Laboratory and instrumental data showed hyperparathyroidism with a parathyroid mass consistent with adenoma. Increasing of therapy with phosphate binders and cinacalcet only, was not effective to solve cutaneous masses, that were biopsied. Histological exam revealed deposition of amorphic material with calcific component, consistent with cutaneous dystrophic calcinosis. We further increased dialysis and therapy and we observed complete regression of masses in 2 months.

Parathyroid hormone may be an early predictor of low serum hemoglobin concentration in patients with not advanced stages of chronic kidney disease.

BACKGROUND: Parathyroid hormone (PTH) has been associated with anemia only in dialysis patients with severe hyperparathyroidism. Whether an association between PTH and hemoglobin also exists in patients with chronic kidney disease not on dialysis (CKD-patients) is still unclear. In this study we evaluated the association between PTH and hemoglobin in CKD-patients without severe secondary hyperparathyroidism. METHODS: Hospitalized patients and outpatients (N = 979) were retrospectively evaluated and categorized according to PTH quartile and serum hemoglobin (<12.0, <11.0, <10.0 g/dl). Gender, diabetes, glomerular filtration rate (GFR), hemoglobin, PTH, markers of mineral metabolism, inflammation, iron status and nutrition were variables of adjustment in univariate and multivariate analysis. RESULTS: An inverse association (p = 0.001) was observed between PTH and hemoglobin in patients as a whole, in diabetics, and in patients with GFR ≤60 ml/min. PTH was the single predictor of low hemoglobin in patients as a whole (unstandardized beta -2.12; p = 0.005), in diabetics (unstandardized beta -8.86; p = 0.007) and in patients with GFR ≤60 ml/min (unstandardized beta -2.52; p = 0.006). For each increase of quartile of PTH the risk of having hemoglobin level <10.0 mg/dl was more than doubled [hazard ratio (HR) 2.79, 95% confidence interval (CI) 2.00-3.88; p = 0.001]. The receiver operating characteristic curve showed that PTH ≥122 pg/ml had 67% sensitivity and 75% specificity in predicting hemoglobin level <10.0 g/dl with area under the curve of 0.758 (95% CI 0.73-0.78). CONCLUSIONS: This study shows a significant inverse association between PTH and hemoglobin levels across the whole spectrum of non-dialysis CKD and a doubled risk of having serum hemoglobin <10.0 mg/dl in the absence of severely deranged PTH concentration. These findings may have clinical relevance in ascertaining the cause of unexplained low hemoglobin levels in CKD-patients.

Impact of BMI on cardiovascular events, renal function, and coronary artery calcification.

BACKGROUND/AIMS: High BMI increases the risk of cardiovascular events (CVEs) in the general population. Conflicting results have been reported on the role of BMI on CVEs and on decline of renal function in patients with chronic kidney disease not on dialysis (CKD). This study evaluates the impact of BMI on CVEs, dialysis initiation, and coronary artery calcification (CAC) in CKD patients. METHODS: CKD patients were divided in normal-BMI and high-BMI patients. CVEs, initiation of dialysis, and extent and progression of CAC were assessed. Univariate and multivariable analysis were performed (adjustment variables: age, diabetes, hypertension, gender, CKD stage, serum concentration of hemoglobin, parathyroid hormone, calcium, phosphorus, albumin, C-reactive protein, LDL-cholesterol, total calcium score, 24-hour proteinuria). Patients were followed to the first event (CVE, dialysis) or for 2 years. RESULTS: 471 patients were evaluated. A CVE occurred in 13.5 and 21.3% (p < 0.05) of normal-BMI and high-BMI patients, respectively. High BMI did not increase the risk for CVEs in univariate (HR: 1.86; 95% CI: 0.97-3.54; p = 0.06) or multivariable analysis (HR: 1.36; 95% CI: 0.57-3.14; p = 0.50). High BMI did not increase the risk for initiation of dialysis in univariate (HR: 0.96; 95% CI: 0.58-1.60; p = 0.9) or multivariable analysis (HR: 1.77; 95% CI: 0.82-3.81; p = 0.14). Adding the interaction term (between BMI and glomerular filtration rate) to other variables, the risk of dialysis initiation significantly increased (HR: 3.06; 95% CI: 1.31-7.18; p = 0.01) in high-BMI patients. High BMI was not a predictor of CAC extent or progression. CONCLUSIONS: High BMI was not a predictor of CVEs. High BMI increased the risk for dialysis initiation, but high BMI was not associated to CAC extent and progression. The presence of confounders may underestimate the impact of high BMI on dialysis initiation.