Review of childhood genetic nephrolithiasis and nephrocalcinosis.

Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.

Genetic testing in children with nephrolithiasis and nephrocalcinosis.

BACKGROUND: Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC). METHODS: This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing. RESULTS: One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32% overall (29% NL, 40% NC) with definite diagnoses (had pathogenic variants alone) made in 11.5%, probable diagnoses (carried a combination of pathogenic variants and variants of uncertain significance (VUS) in the same gene) made in 5.4%, and possible diagnoses (had VUS alone) made in 15.0%. Variants were found in 28 genes (most commonly HOGA1 in NL, SLC34A3 in NC) and 20 different conditions were identified. Compared to NL, those with NC were younger and had a higher proportion with developmental delay, hypercalcemia, low serum bicarbonate, hypophosphatemia, and chronic kidney disease. In multivariate analysis, low serum bicarbonate was associated with increased odds of genetic diagnosis (ß 2.2, OR 8.7, 95% CI 1.4-54.7, p = 0.02). CONCLUSIONS: Genetic testing was high-yield with definite, probable, or possible explanatory variants found in up to one-third of children with NL/NC and shows promise to improve clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.

Elevated Levels of Urinary Biomarkers TIMP-2 and IGFBP-7 Predict Acute Kidney Injury in Neonates after Congenital Heart Surgery.

Objectives This article investigated the utility of urine biomarkers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) in identifying acute kidney injury (AKI) in neonates after congenital heart surgery (CHS). TIMP-2 and IGFBP-7 are cell cycle arrest proteins detected in urine during periods of kidney stress/injury. Methods We conducted a single-center, prospective study between September 2017 and May 2019 with neonates undergoing CHS requiring cardiopulmonary bypass (CPB). Urine samples were analyzed using NephroCheck prior to surgery and 6, 12, 24, and 96 hours post-CPB. All patients were evaluated using the Acute Kidney Injury Network (AKIN) criteria. Wilcoxon rank sum tests were used to compare the medians of the [TIMP-2*IGFBP-7] values in the AKIN negative and positive groups at each time point. Receiver operating characteristic curves were used to measure how well the [TIMP-2*IGFBP-7] values predict AKIN status. Results Thirty-six patients were included. No patients met the AKIN criteria for AKI preoperatively. Postoperatively, 19 patients (53%) met the AKIN criteria for AKI diagnosis: 13 (36%) stage 1, 5 (14%) stage 2, and 1 (3%) stage 3. None required renal replacement therapy. At the 24-hour time points, patients who met the AKIN criteria for AKI had a statistically significantly higher [TIMP-2*IGFBP7] values than the patients without AKI (1.1 vs. 0.27 [ng/mL] 2 /1,000) at 24 hours (adj- p = 0.0019). Conclusion AKI is a serious complication associated with adverse outcomes in patients undergoing cardiac surgery. [TIMP-2*IGFBP-7] urinary level 24 hours after CPB is a good predictor of AKI in this population.

Acute kidney injury in pediatric patients hospitalized with acute COVID-19 and multisystem inflammatory syndrome in children associated with COVID-19.

This study describes the incidence, associated clinical characteristics and outcomes of acute kidney injury in a pediatric cohort with COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C). We performed a retrospective study of patients 18 years of age and under admitted to four New York hospitals in the Northwell Health System interned during the height of the COVID-19 pandemic, between March 9 and August 13, 2020. Acute kidney injury was defined and staged according to Kidney Disease: Improving Global Outcomes criteria. The cohort included 152 patients; 97 acute-COVID-19 and 55 with MIS-C associated with COVID-19. Acute kidney injury occurred in 8 with acute-COVID-19 and in 10 with MIS-C. Acute kidney injury, in unadjusted models, was associated with a lower serum albumin level (odds ratio 0.17; 95% confidence interval 0.07, 0.39) and higher white blood cell counts (odds ratio 1.11; 95% confidence interval 1.04, 1.2). Patients with MIS-C and acute kidney injury had significantly greater rates of systolic dysfunction, compared to those without (80% vs 49%). In unadjusted models, patients with acute kidney injury had 8.4 days longer hospitalizations compared to patients without acute kidney injury (95% confidence interval, 4.4-6.7). Acute kidney injury in acute-COVID-19 and MIS-C may be related to inflammation and/or dehydration. Further research in larger pediatric cohorts is needed to better characterize risk factors for acute kidney injury in acute-COVID-19 and with MIS-C consequent to COVID-19.

Pediatric COVID-19-associated rhabdomyolysis: a case report.

COVID-19 is the illness caused by infection with the novel coronavirus SARS-CoV-2. Although myalgia is common in adults, it has not been noted as a common symptom in children. There have been a few reported cases of COVID-19-associated rhabdomyolysis in adults. This case report describes a 16-year-old boy who presented with fever, myalgias, mild shortness of breath with exertion, and dark-colored urine. COVID-19 PCR was positive. His initial creatinine kinase (CK) level was 427,656 U/L. Serum creatinine was normal for age. He was treated with isotonic intravenous fluids containing sodium bicarbonate to maintain urine output of 100-200 mL/h and urine pH > 7.0. His serum creatinine remained normal throughout the hospital stay and he was discharged on hospital day 12 with a CK of 6526 U/L. To our knowledge, no pediatric cases of COVID-19-associated rhabdomyolysis have been previously reported. Adult cases of rhabdomyolysis have been reported and a few reports have noted patients with elevated CK levels without rhabdomyolysis. Given this pediatric case of COVID-19-associated rhabdomyolysis, pediatric clinicians should be aware of this complication and manage fluids appropriately in order to prevent acute kidney injury.

Asymptomatic pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia.

BACKGROUND: Children with Hereditary Hemorrhagic Telangiectasia (HHT) may have pulmonary arteriovenous malformations (AVMs), which can lead to symptoms of shortness of breath, exercise intolerance, clubbing, cyanosis and hemoptysis. However, some patients with pulmonary AVMs may be asymptomatic, placing them at risk for complications such as stroke or brain abscess if they are not identified and treated. This study examines the incidence of signs and symptoms associated with pulmonary AVMs in children with HHT known to have pulmonary AVMs. METHOD: Sixty-one children with HHT and documented pulmonary AVMs were questioned for any symptoms possibly associated with their pulmonary AVMs, prior to embolization. RESULTS: The results show that the majority of these children were asymptomatic (56%), and their AVMs were discovered by routine screening. Those who did experience symptoms most often complained of shortness of breath and exercise intolerance, although there was a tendency to blame other conditions, such as asthma or deconditioning (being out of shape), for these symptoms. Migraine headaches were common in those with pulmonary AVMs, regardless of whether they were symptomatic or not (17 of 61 children, 28%), although they were more common in those who were symptomatic (10 of 27, 37%) versus those who were asymptomatic (7 of 34, 21%). CONCLUSION: Children with HHT and pulmonary AVMs are often asymptomatic. Routine screening for the presence of AVMs should be performed regardless of symptomatology.

Understanding of Meniscus Injury and Expectations of Meniscus Surgery in Patients Presenting for Orthopaedic Care.

PURPOSE: The purpose of this study is to assess orthopaedic patient knowledge and perceptions about the meniscus, meniscal injury, and treatment to identify gaps in orthopaedic patients' understanding and to assess the outcomes most important to these patients. METHODS: A 41-question survey was designed to measure knowledge and perception of meniscal tears regarding anatomy, function, surgical indications, operative techniques, risks, overall benefits of repair or removal, and recovery times. Study participants aged between 18 and 60 years were recruited from an academic orthopaedic sports medicine clinic regardless of their present complaint. Patients aged younger than 18 years were excluded. RESULTS: We surveyed 253 individuals (132 men and 121 women), with a mean age of 38 years. Most respondents (62%) rated their knowledge about the meniscus as little or no knowledge. Participants answered between 49% and 50% of questions regardless of how they self-rated their knowledge base. There was no correlation between perceived knowledge and percent answered correctly or between level of knee injury/surgery exposure and percent answered correctly. Only 28% of respondents knew that partial meniscectomy is the most common type of surgical treatment for meniscal tears. The risk of osteoarthritis developing and the risk of further surgery were the major concerns regarding meniscus surgery. Those who had undergone a previous meniscus surgery performed better on factual questions regarding meniscus structure (P = .0006), function (P = .0001), mechanism of injury (P = .0001), and the need for surgery (P = .0001) than those who had not undergone previous meniscus surgery. CONCLUSIONS: Patients having undergone prior meniscus surgery have better knowledge of meniscus injury and treatment than those who have not had previous meniscus injury. Meniscus repair is believed to be the most common treatment rather than meniscectomy. The risk of needing additional surgery and the risk of arthritis developing after meniscus surgery are the main concerns among respondents.