Clinical characteristics and risk factors for kidney involvement in children with immunoglobulin A vasculitis.

BACKGROUND: Immumoglobulin A (IgA) vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is a self-limiting systemic vasculitis in children. Kidney involvement is associated with a long-term unfavorable outcome and can lead to significant morbidity. This study was conducted to describe the clinical and laboratory characteristics of childhood IgAV with kidney involvement and to identify risk factors associated with IgAV nephritis (IgAVN). METHODS: This was an ambidirectional descriptive study of 77 children with IgAV. All demographic data, clinical features, and laboratory tests were collected from electronic medical records from January 2010 to December 2022. Risk factors for kidney involvement in IgAV were assessed using multivariate logistic regression. Kaplan-Meier survival analysis was used to calculate the time to commencement of kidney involvement. RESULTS: Twenty-five children (32.4% of the IgAV patients) developed IgAVN. The common findings in IgAV with kidney involvement were microscopic hematuria (100%), nephrotic range proteinuria (44%), and non-nephrotic range proteinuria (40%). Multivariate logistic regression showed that age greater than 10 years (adjusted hazard ratio, AHR 4.66; 95% confidence interval, CI, 1.91-11.41; p = 0.001), obesity (body mass index, BMI, z-score ≥ +2 standard deviations, SDs) (AHR 3.59; 95% CI 1.41-9.17; p = 0.007), and hypertension at onset (AHR 4.78; 95% CI 1.76-12.95; p = 0.002) were associated significantly with kidney involvement. During follow up, most IgAV patients developed nephritis within the first 9 months. CONCLUSION: Age greater than 10 years, obesity, and hypertension at presentation were predictive factors for IgAVN. Our study emphasized that IgAV patients with risk factors should be closely monitored for at least 1 year after the onset of the disease.

Quantitative assessment of glomerular basement membrane collagen IV α chains in paraffin sections from patients with focal segmental glomerulosclerosis and Alport gene variants.

Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.

Pathogenic variant detection rate by whole exome sequencing in Thai patients with biopsy-proven focal segmental glomerulosclerosis.

The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.

Incidence of healthcare-associated urinary tract infections in Thai children.

BACKGROUND: Urinary tract infection is one of the commonest types of healthcare-associated infections. There are currently limited data regarding the incidence and characteristics of healthcare-associated urinary tract infections (HA-UTIs) in children. This study was conducted to determine the incidence of HA-UTIs and their characteristics and associated risk factors. METHODS: A case-control study was performed from 2016 to 2020 on children under 15 years old who were diagnosed with HA-UTI. Patients who had HA-UTI were compared with non-UTI patients. The incidence rate of HA-UTIs was calculated and reported as events per 1000 patient days. Potential associated risk factors were analyzed using multivariate logistic regression. RESULTS: Eighty cases and 80 controls were included in the study. The incidence of HA-UTIs was 0.32 events per 1000 patient days. The median time to UTI was 18 days. The most common causative organism was Escherichia coli (43.2%) and the rates of third-generation cephalosporin resistance and carbapenem resistance were 75.6% and 4.9%, respectively. Admission longer than 7 days (OR = 21.61, 95% CI: 6.30-74.11; p < 0.001), neurogenic bladder (OR = 26.24, 95% CI: 3.77-182.87; p < 0.001), mechanical ventilation (OR = 3.60, 95% CI: 1.23-10.54; p = 0.019), and immunosuppressants (OR = 2.59; 95% CI: 1.01-6.60; p = 0.047) were the risk factors significantly associated with HA-UTIs. CONCLUSIONS: The incidence of HA-UTIs was low in this single-center experience. Identifying patients with the risk factor is imperative for preventing the development of HA-UTIs.

Novel CNNM4 variant and clinical features of Jalili syndrome.

The study identifies a non-consanguineous multigenerational family of the Lua ethnic group in Northern Thailand with three members affected with hypoplastic-hypocalcified amelogenesis imperfecta, cone-rod dystrophy, and harboring a novel homozygous missense variant, c.1475G>A p.(Gly492Asp), in CNNM4, indicating Jalili syndrome. We report features including advanced dental age, crossbite, developmental delay, expanding genotypic and phenotypic spectra of Jalili syndrome, and perform the prenatal genetic testing that helps avoid unnecessary pregnancy termination.

Therapeutic Plasma Exchange with Continuous Renal Replacement Therapy for Pediatric Acute Liver Failure: A Case Series from Thailand.

AIM AND OBJECTIVE: Pediatric acute liver failure (PALF) is a life-threatening condition. Extracorporeal support has been applied for toxic metabolite clearance and serves as a bridging therapy to liver transplantation (LT) or to the regeneration of the liver, but evidence for treatment approaches is still lacking in the pediatric population. We aim to report our experience on therapeutic plasma exchange with high-volume continuous renal replacement therapy (TPE + HV-CRRT) as a promising supportive treatment for PALF. MATERIALS AND METHODS: A total of eight PALF cases aged 9 months to 14 years, weighing 10-50 kg., who were admitted to PICU King Chulalongkorn Memorial Hospital, Thailand and treated with TPE + HV-CRRT from January 2016 to September 2019 were reviewed. Patient demographic data, indications, technical aspects, and clinical outcomes were recorded. RESULTS: All patients who underwent TPE + HV-CRRT showed clinical improvement regarding serum bilirubin levels and coagulation studies after the therapy. Complications from the therapy were hemodynamic instability, symptomatic fluid overload, and bleeding from catheter sites. Among these, 6 (75%) patients survived with 4 (50%) successful LTs and 2 (25%) spontaneous recovery. Two children (25%) died while on the transplantation list. CONCLUSION: TPE + HV-CRRT can be used safely as a bridging therapy in children with PALF. As opposed to the adult population, higher volume of TPE or higher blood flow rate in pediatric patients might associate with hemodynamic instability during the procedure. HOW TO CITE THIS ARTICLE: Trepatchayakorn S, Chaijitraruch N, Chongsrisawat V, Chanakul A, Kongkiattikul L, Samransamruajkit R. Therapeutic Plasma Exchange with Continuous Renal Replacement Therapy for Pediatric Acute Liver Failure: A Case Series from Thailand. Indian J Crit Care Med 2021;25(7):812-816.

No increased acute kidney injury rate through giving an intravenous colistin loading dose in pediatric patients.

OBJECTIVES: A colistin loading dose is required to achieve adequate drug exposure for the treatment of multidrug-resistant Gram-negative bacteria. However, data on acute kidney injury (AKI) rates associated with this approach in children have been unavailable. The aim of this study was to examine AKI rates in children who were prescribed a colistin loading dose. METHODS: A retrospective study was conducted in patients aged 1 month to 18 years who had received intravenous colistin for ≥48 h. Loading dose (LD) was defined as colistin methanesulfonate at 4-5 mg of colistin base activity/kg/dose. AKI was defined according to KDIGO serum creatinine (SCr) criteria - SCr ≥ 1.5 times the baseline, measured 3-7 days after colistin initiation. Augmented renal clearance (ARC) was defined as an estimated glomerular filtration rate (eGFR) >150 mL/min/1.73 m2. The rates of AKI were compared between children receiving or not receiving an LD, and between different eGFR groups. RESULTS: In total, 181 children were enrolled. The mean age was 4.3 years (95% confidence interval [CI], 3.6-4.9 years). Ninety-five of the subjects (52.5%) were male. There were 157 children with a baseline eGFR of ≥ 80 mL/min/1.73 m2. The overall AKI rate within the first week in this group was 20.4% (95% CI, 14.4-27.6%): LD, 16.1% vs no LD, 23.2% (p = 0.29). Subgroup analysis, excluding patients with ARC, showed a lower AKI rate of 12.8% (95% CI, 6.8-21.3%): LD, 9.7% vs no LD, 14.3% (p = 0.53). CONCLUSIONS: AKI rate was not different among children who received an intravenous colistin loading dose. This approach should be implemented to ensure the necessary drug exposure required for good treatment outcomes.

Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma.

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

Low bone mineral density in Thai children with systemic lupus erythematosus: prevalence and risk factors.

Background: Improvement of disease recognition and management has increased the survival of children with systemic lupus erythematosus (SLE), but has shifted the morbidity focus toward long-term complications, such as low bone mass and osteoporosis. Studies in adults with SLE show older age, chronic inflammation, and corticosteroid therapy are risk factors for low bone mineral density (BMD) and osteoporosis. Objectives: To determine the prevalence of and identify risk factors associated with low BMD in Thai children with SLE. Methods: We conducted a retrospective review of demographic data and clinical variables for a cohort of 60 Thai children with SLE who underwent 2 dual-energy X-ray absorptiometry (DXA) at their initial examination and later follow-up. We considered a BMD z score ≤ -2.0 to indicate low BMD. Binary logistic regression was used to assess risk factors potentially associated with low BMD. Results: The prevalence of low BMD at the first visit was 40% and increased to 55% over follow-up. We found a significantly decreased hip BMD z score (median difference -0.25, 95% confidence interval [CI] -0.40 to -0.05; P = 0.016) and lumbar BMD z score (median difference -0.49, 95% CI -0.69 to -0.28; P < 0.001) over time. The cumulative steroid dose tended to be higher for patients with low BMD (adjusted odds ratio [OR] = 1.08, 95% CI 1.00 to 1.17; P = 0.050). Conclusion: Low BMD has a 40% prevalence in Thai children newly diagnosed with SLE and progresses significantly over time. Higher cumulative corticosteroid dose tended to be associated with a low BMD, but we did not find a significant risk in this small sample.

Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients.

Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12-24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2-18 years) with normal renal function. Patients (n = 20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5-11.3) years and 21.5 (13.5-20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: Cmax, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC0-t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; Vd, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.

Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents.

BACKGROUND: Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages. METHODS: We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age ≥10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6-12 months. PRD was defined as having ≥2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60-89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria ≥1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis. RESULTS: This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5-18.8) and ART duration of 10.3 (7.1-12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)-based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1-19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10-15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1-25.2), male (aOR: 3.2, 95% CI: 1.4-7.7), CD4 nadir <150 cells/mm (aOR: 2.6, 95% CI: 1.1-6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2-28.9). CONCLUSIONS: PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring.

Exhaled nitric oxide, pulmonary function, and disease activity in children with systemic lupus erythematosus.

AIM: To determine the association among fractional exhaled nitric oxide (FENO), pulmonary function, and disease activity in children with systemic lupus erythematosus (SLE). METHODS: Children aged 7-18 years, diagnosed with SLE under the criteria of the American Rheumatism Association (revised 2012), were enrolled. All eligible participants had disease activity, FENO, and pulmonary function evaluated and re-evaluated at 6-month follow-up. RESULTS: Twenty-four children (95.8% female; mean age 15.2 ± 2 years; median disease duration 2.4 years) were studied. The mean FENO1 and FENO2 were 19.6 ± 7.2 parts per billion (ppb) and 17.4 ± 4.5 ppb, respectively. At baseline, 20.8% had abnormal pulmonary functions (all restrictive defects) and increased to 29.2% at follow-up (isolated restrictive defect 25% and restrictive with diffusion defect 4.2%). Most of their disease activities at baseline and second assessment were non-active (58.3%, 70.8%) or mild disease activities (20.8% both). There was significant correlation between FENO and disease activity (r = 0.49; P-value = 0.02). The significant negative correlation between total lung capacity (TLC) and disease activity was detected in children with active SLE (r = -0.71; P-value = 0.02). CONCLUSION: Decreased TLC and high FENO were common in SLE children who had no respiratory symptoms and correlated with disease activity. FENO should be considered as an additional pulmonary function to evaluate disease activity in children with SLE.

Early stage of vascular disease and diabetic kidney disease: an under-recognized entity.

Early stage of vascular disease and diabetic kidney disease (DKD stages 1 and 2) has been under-recognized, under common practice worldwide. The lack of sensitive diagnostic marker leads to late diagnosis and a progression of underlying vascular disease associated with chronic renal ischemia, which eventually intensifies the magnitude of DKD damage. Treatment at this late stage fails to correct the renal ischemia, or restore renal function, due to the altered vascular homeostasis associated with an impaired nitric oxide production. In contrast to the above information, early recognition of vascular disease and DKD with sensitive diagnostic markers would be able to implement an effective prevention of progression of vascular disease and DKD. Treatment at early stage under environment favorable for adequate vascular homeostasis is able to correct the renal ischemia and improve the renal function.

FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues.

The mitochondrial enzyme 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by the CYP27B1 gene, converts 25OHD to the biological active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Renal 1α-hydroxylase activity is the principal determinant of the circulating 1,25(OH)2D concentration and enzyme activity is tightly regulated by several factors. Fibroblast growth factor-23 (FGF-23) decreases serum 1,25(OH)2D concentrations by suppressing CYP27B1 mRNA abundance in mice. In extra-renal tissues, 1α-hydroxylase is responsible for local 1,25(OH)2D synthesis, which has important paracrine actions, but whether FGF-23 regulates CYP27B1 gene expression in extra-renal tissues is unknown. We sought to determine whether FGF-23 regulates CYP27B1 transcription in the kidney and whether extra-renal tissues are target sites for FGF-23-induced suppression of CYP27B1. In HEK293 cells transfected with the human CYP27B1 promoter, FGF-23 suppressed promoter activity by 70%, and the suppressive effect was blocked by CI-1040, a specific inhibitor of extracellular signal regulated kinase 1/2. To examine CYP27B1 transcriptional activity in vivo, we crossed fgf-23 null mice with mice bearing the CYP27B1 promoter-driven luciferase transgene (1α-Luc). In the kidney of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity was increased by 3-fold compared to that in wild-type/1α-Luc mice. Intraperitoneal injection of FGF-23 suppressed renal CYP27B1 promoter activity and protein expression by 26% and 60% respectively, and the suppressive effect was blocked by PD0325901, an ERK1/2 inhibitor. These findings provide evidence that FGF-23 suppresses CYP27B1 transcription in the kidney. Furthermore, we demonstrate that in FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA abundance are increased in several extra-renal sites. In the heart of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA were 2- and 5-fold higher, respectively, than in control mice. We also observed a 3- to 10-fold increase in CYP27B1 mRNA abundance in the lung, spleen, aorta and testis of FGF-23 null/1α-Luc mice. Thus, we have identified novel extra-renal target sites for FGF-23-mediated regulation of CYP27B1.