Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. METHODS: A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10 years and <18 years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. RESULTS: The mean age at diagnosis was 12.8±2.3 years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p = 0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6 years. At the last visit, adolescent patients had lower eGFR levels (p = 0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p = 0.04). CONCLUSIONS: Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

Crush Syndrome of Children in Kahramanmaras Earthquake: A Single Center Experience in Malatya.

OBJECTIVE: Natural disasters cause enormous environmental, economic, and human losses. Children are the most vulnerable group and face severe consequences. While the primary cause of post-traumatic death is direct injury, the secondary cause is crush syndrome (CS). In this study, we aimed to share our experience in the management of children with CS during disasters by evaluating the clinical and laboratory outcomes of a group of 26 paediatric patients. MATERIALS AND METHODS: Age, weight, length of time under rubble, laboratory results, and characteristics of crush injuries were assessed in 26 paediatric patients admitted to the emergency department after the earthquake. Diagnostic criteria for CS were established and the need for dialysis, hyperbaric oxygen or amputation and its determinants were assessed. RESULTS: Crush syndrome was observed in 10 of the 26 patients. Significant differences in creatinine, aspartate aminotransferase, alanine aminotransferase, creatine kinase, hematocrit, pH, HCO3, and myoglobin levels were observed between patients with and without CS. None of the individuals rescued from the rubble within the first 6 hours had symptoms associated with CS. These 10 patients who developed CS were rescued within the first 48 hours of the earthquake, while 2 siblings were rescued after 81 hours and did not develop CS. CONCLUSION: The fact that the children were rescued from the rubble after 81 hours without developing CS shows the importance of patience in rescue operations. In addition, the very cold weather conditions during this earthquake may have prevented the development of dehydration and acute kidney injury and reduced the possibility of CS.

Pediatric kidney care experience after the 2023 Turkey/Syria earthquake.

BACKGROUND/AIMS: Two earthquakes on February 6th, 2023 destroyed ten cities in Türkiye. We report our experience with pediatric victims during these catastrophes, with a focus on crush syndrome related-acute kidney injury (Crush-AKI) and death. METHOD: A web-based software was prepared. Patient demographics, time under rubble (TUR), admission laboratory data, dialysis, and kidney and overall outcomes were asked. RESULTS: 903 injured children (median age: 11.62 years) were evaluated. Mean TUR was 13 h (Interquartile range-IQR: 32.5), max 240 h). 31 of 32 patients with a TUR of >120 h survived. The patient who rescued after ten days survived.Two-thirds of the patients were given 50 mEq/L sodium-bicarbonate in 0.45% sodium-chloride solution on admission day. 58% of patients were given intravenous fluid (IVF) at a volume of 2000-3000 mL/m2 body surface area (BSA), 40% of 3000-4000 mL/m2 BSA, and only 2% of >4000 mL/m2 BSA. 425 patients had surgeries, 48 suffered from major bleeding. Amputations were recorded in 96 patients. Eighty-two and 66 patients required ventilator and inotropic support, respectively.Crush-AKI developed in 314 patients (36% of all patients). 189 patients were dialyzed. Age > 15 years, creatine phosphokinase (CK)≥20 950 U/L, TUR≥10 h, and the first-day IVF volume < 3000-4000 mL/m2 BSA were associated with Crush-AKI development. 22 deaths were recorded, 20 of 22 occurred in patients with Crush-AKI and within the first 4 days of admission. All patients admitted after 7 days survived. CONCLUSIONS: This is the most extensive pediatric kidney disaster data after an earthquake. Serum CK level was significantly associated with Crush-AKI at the levels of >20 950 U/L, but not with death. Adolescent age and initial IVF of less than 3000-4000 mL/m2 BSA were also asscoiated with Crush-AKI. Given that mildly injured victims can survive longer periods in the disaster field, we suggest uninterrupted rescue activity for at least 10 days.

Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Characteristics and predictors of chronic kidney disease in children with myelomeningocele: a nationwide cohort study.

BACKGROUND: Myelomeningocele (MMC) is highly prevalent in developing countries, and MMC-related neurogenic bladder is an important cause of childhood chronic kidney disease (CKD). This nationwide study aimed to evaluate demographic and clinical features of pediatric patients with MMC in Turkey and risk factors associated with CKD stage 5. METHODS: Data from children aged 0-19 years old, living with MMC in 2022, were retrospectively collected from 27 pediatric nephrology centers. Patients > 1 year of age without pre-existing kidney abnormalities were divided into five groups according to eGFR; CKD stages 1-5. Patients on dialysis, kidney transplant recipients, and those with eGFR < 15 ml/min/1.73 m2 but not on kidney replacement therapy at time of study constituted the CKD stage 5 group. RESULTS: A total of 911 (57.8% female) patients were enrolled, most of whom were expectantly managed. Stages 1-4 CKD were found in 34.3%, 4.2%, 4.1%, and 2.4%, respectively. CKD stage 5 was observed in 5.3% of patients at median 13 years old (range 2-18 years). Current age, age at first abnormal DMSA scan, moderate-to-severe trabeculated bladder on US and/or VCUG, and VUR history were independent risk factors for development of CKD stage 5 (OR 0.752; 95%; CI 0.658-0.859; p < 0.001; OR 1.187; 95% CI 1.031-1.367; p = 0.017; OR 10.031; 95% CI 2.210-45.544; p = 0.003; OR 2.722; 95% CI 1.215-6.102; p = 0.015, respectively). Only eight CKD stage 5 patients underwent surgery related to a hostile bladder between 1 and 15 years old. CONCLUSION: MMC-related CKD is common in childhood in Turkey. A proactive approach to neurogenic bladder management and early protective surgery in selected cases where conservative treatment has failed should be implemented to prevent progressive kidney failure in the pediatric MMC population in our country.

Uroflowmetry parameters in healthy children between 5 and 15 years old.

OBJECTIVES: Uroflowmetry (UFM) is the first-line noninvasive screening test employed in the diagnosis of lower urinary tract dysfunction (LUTD). The purpose of this study was to determine normal UFM values in healthy Turkish children among our local population. METHODS: A total of 100 healthy girls and 62 healthy boys aged 5-15 years, who applied to Inönü University Turgut Özal Medical Center Pediatrics Polyclinic between February 2021 and January 2022, were included in the present study. The UFM parameters, including maximum flow rate (Qmax), average flow rate (Qavg), voided volume (VV), time to maximum flow, and voiding time, were measured using the Inoflow Smart System UFM Device and the resulting urine flow curve was recorded. The children were compared in terms of the UFM parameters based on their gender and age groups (5-10 years and 11-15 years). RESULTS: The mean Qmax value in healthy female children aged 5-15 years (21.8 ± 8.6 mL/s) was significantly higher than in male children (17.98 ± 6.1 mL/s) (p = .003). VV, Qmax, and Qavg values of the children in the 11-15 age group were significantly higher than those in the age group of 5-10 years (p > .05 for each). VV, Qmax, and Qavg values were directly proportional to age (p = .0001, for each). CONCLUSIONS: We believe that this study adds to the limited knowledge base regarding normal flow patterns in healthy children.

The outcomes of renin-angiotensin-aldosterone system inhibition and immunosuppressive therapy in children with X-linked Alport syndrome.

BACKGROUND: Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy. METHODS: Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively. RESULTS: Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased < 60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003). CONCLUSIONS: RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD.

Acute kidney injury and peritoneal dialysis in extremely low birth weight newborns.

BACKGROUND: In 12.5-56% of extremely low birth weight (ELBW) infants treated in newborn units, acute kidney injury (AKI) develops. Some of these infants may need renal replacement therapy for several reasons including hyperkalemia, hypovolemia and resistant acidosis. METHODS: All ELBW infants who were followed in our hospital between January 2015 and December 2017 and who lived longer than 48 hours were assessed. Patients were followed for AKI and peritoneal dialysis (PD). RESULTS: AKI developed in 25 of 201 ELBW infants. PD was administered to nine patients. PD was initiated at a median of 11 days (2-22 days) for all patients due to hyperkalemia which did not respond to medical treatment. Three of the nine infants who received PD died while dialysis was ongoing. The remaining six patients completed PD successfully. In these patients, the serum potassium value returned to normal in three days, and dialysis was continued for a median of 93 hours (40-172 hours). Dialysis leakage occurred in two patients, and hyperglycemia developed in two patients. On average, diuresis started at the 25th hour (8-40th hour). CONCLUSIONS: In the renal failure treatment of ELBW infants, PD is the only option which can be used for many units. It was found that in ELBW infants, who had wider peritoneal surface when compared to their body weight, biochemical values recovered rapidly with PD, and diuresis started a short while later in most patients.

Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study.

BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney disease profile and encountered problems during follow-up in Syrian refugee children: a multicenter retrospective study.

BACKGROUND: Children are one of the most vulnerable groups in conflict zones, especially those with chronic diseases. This study aimed to investigate kidney disease profiles and problems during follow-up in a population of Syrian refugee children residing in Turkey. METHODS: Syrian refugee children aged between 0 and 18 years were included in the study. Demographic data, diagnosis, particular interventions due to nephrological problems, and problems encountered during follow-up were obtained from all participating pediatric nephrology centers. RESULTS: Data from 633 children from 22 pediatric nephrology centers were included. Mean age of the children was 94.8 ± 61.7 months and 375 were male (59%). 57.7% had parental consanguinity and 23.3% had a close relative(s) with kidney disease. The most common kidney diseases were congenital anomalies of the kidney and urinary tract (CAKUT) (31.0%), glomerular disease (19.9%), chronic kidney disease (CKD) (14.8%), and urolithiasis (10.7%). Frequent reasons for CAKUT were nonobstructive hydronephrosis (23.0%), vesico-ureteral reflux (18.4%), and neurogenic bladder (15.8%). The most common etiology of glomerular diseases was nephrotic syndrome (69%). Ninety-four children had CKD, and 58 children were on chronic dialysis. Six children had kidney transplantation. Surgical intervention was performed on 111 patients. The language barrier, lack of medical records, and frequent disruptions in periodic follow-ups were the main problems noted. CONCLUSIONS: CAKUT, glomerular disease, and CKD were highly prevalent in Syrian refugee children. Knowing the frequency of chronic diseases and the problems encountered in refugees would facilitate better treatment options and preventive measures.

Evaluation of arterial hypertension by ambulatory blood pressure monitoring in pediatric liver transplant recipients.

OBJECTIVE: Many cardiovascular complications, including hypertension, are seen in pediatric liver transplantation. The purpose of this study was to analyze the frequency of arterial hypertension of pediatric liver transplant recipients and also to determine the related risk factors. METHODS: Thirty-six pediatric liver transplant recipients aged 8-17 years were prospectively studied by manual and ambulatory blood pressure measurement (ABPM) technique. RESULTS: The mean age of patients was 12.42 ± 2.74 years and the mean ABPM measurement time after transplantation was 2 years (3 months-5.9 years). Only one (2.7%) patient was detected as hypertensive by casual measurement, but 17 (47.2%) patients were found to be hypertensive when measured through ABPM. Of children that were found to be hypertensive as a result of ABPM, 64.7% were observed to have a nondipper pattern. Considering the time passed after the transplantation, patients were found to be more hypertensive in the first 2 years posttransplant although it was not found statistically significant. CONCLUSIONS: In this study, it has been shown that it is possible to diagnose hypertension at an earlier period of transplantation using ABPM in pediatric liver transplant patients. ABPM is needed to detect masked hypertension that may develop following liver transplantation.

Prevalence of Familial Mediterranean Fever in Children with Cryptogenic Cirrhosis.

BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by abdominal and chest pain and recurrent fever due to inflammation in the serosal membranes such as peritoneum, pleura and synovia. In FMF, recurrent inflammatory cytokine production may lead to cirrhosis. The aim of this study was to determine the prevalence of FMF in children with cryptogenic cirrhosis and it was found to be high, to add FMF among the etiological causes of cirrhosis. MATERIALS AND METHODS: This prospective cohort study conducted at the Hospital of Inönü University, Malatya, Turkey. In this study, 44 patients diagnosed with cryptogenic cirrhosis by biopsy, in the Pediatric Gastroenterology, Hepatology and Nutrition Clinic, were included, after the other reasons that may cause chronic liver disease were excluded. MEVF gene analysis was performed for all patients with cryptogenic cirrhosis. RESULTS: FMF genetic mutation was detected in 9 (20%) of 44 patients. M694V mutation was detected in one patient (2.27%) and E148Q homozygous mutation was detected in one patient (2.27%). Various other heterozygous mutations were detected in seven other patients. Homozygous and heterozygous R202Q mutations were detected in one patient. CONCLUSION: We suggest that FMF plays a role in the etiologic differential diagnosis of cryptogenic cirrhosis.

Comparison of Urinary Tract Dilatation and Society of Fetal Urology systems in the detection of vesicourethral reflux and renal scar.

PURPOSE: The presence and degree of hydronephrosis is very important in the management of many diseases of the urinary tract. In this study, we aim to compare the sensitivity and specificity of 2 classification systems that are used for hydro-nephrosis grading in ultrasound, for reflux and scar detection. The classification systems were the Society of Fetal Urology (SFU) and Urinary Tract Dilatation (UTD). MATERIAL AND METHODS: Ultrasounds and dimercaptosuccinic acid scintigraphies (DMSA) of all patients who underwent voiding cystourethrogram (VCUG) due to urinary tract infection were examined retrospectively. DMSA was accepted for scar detection and VCUG for reflux detection as reference methods. SFU classification was used for hydronephrosis in ultrasound reports, and UTD classification was made over the reports. Sensitivity, specificity, and positive and negative predictive values of UTD and SFU classification systems for reflux and scar detection were calculated, and these 2 systems were compared. RESULTS: 103 (39%) of the patients were male and 162 (61%) were female. Pathologies were detected in 192 (35%) of 530 kidneys in ultrasound. In 110 (42%) of the children, reflux was detected in VCUG. Scars in DMSA were detected in only 16% (44) of 266 kidneys. Sensitivity, positive and negative predictive values of the UTD classification system were statistically significantly higher than the SFU system for scar and reflux detection (p < 0.01). CONCLUSIONS: If we use the UTD system in ultrasounds of patients with urinary tract infections, children reported as UTD 0 may not need VCUG, which reduces radiation exposure to children and the cost of the diagnostic interventions.

Prevalence estimates of voiding disorders in Turkish school-age children.

OBJECTIVES: This study aims to investigate the prevalence of voiding disorders and identify the associated risk factors for school-age children in East Anatolia, Turkey. METHODS: We randomly selected six primary schools in Malatya in East Anatolia, and 907 students from 6 to 14 years old were involved. Data were obtained using the dysfunctional voiding and incontinence scoring system (DVISS) scale, and children who scored 8.5 or above on that scale were considered as having voiding disorders. RESULTS: Voiding disorders were detected in 175 (19.2%) of 907 children. One hundred and fifty-two (16.8%) had day-time urinary incontinence, and 131 (14.5%) had night-time incontinence. The findings showed a significant relationship between voiding disorder and daytime/night-time incontinence, and fecal incontinence. Voiding disorders decreased as the age increased. There was a significant relationship between voiding disorder and positive family history, and the quality of life of these children was significantly affected. CONCLUSION: Voiding disorder is a common disease among school-age children. By identifying and treating voiding disorders and related risk factors in children in the early period, these children can be protected from possible medical or social complications.

Predictors of poor kidney outcome in children with C3 glomerulopathy.

BACKGROUND: C3 glomerulopathy (C3G) is characterized by heterogeneous clinical presentation, outcome, and predominant C3 accumulation in glomeruli without significant IgG. There is scarce outcome data regarding childhood C3G. We describe clinical and pathological features, treatment and outcomes, and risk factors for progression to chronic kidney disease stage 5 (CKD5) in the largest pediatric series with biopsy-proven C3G. METHODS: Sixty pediatric patients with C3G from 21 referral centers in Turkey were included in this retrospective study. Patients were categorized according to CKD stage at last visit as CKD5 or non-CKD5. Demographic data, clinicopathologic findings, treatment, and outcome data were compared and possible risk factors for CKD5 progression determined using Cox proportional hazards model. RESULTS: Mean age at diagnosis was 10.6 ± 3.0 years and follow-up time 48.3 ± 36.3 months. Almost half the patients had gross hematuria and hypertension at diagnosis. Nephritic-nephrotic syndrome was the commonest presenting feature (41.6%) and 1/5 of patients presented with nephrotic syndrome. Membranoproliferative glomerulonephritis was the leading injury pattern, while 40 patients had only C3 staining. Patients with DDD had significantly lower baseline serum albumin compared with C3GN. Eighteen patients received eculizumab. Clinical remission was achieved in 68.3%. At last follow-up, 10 patients (16.6%) developed CKD5: they had lower baseline eGFR and albumin and higher frequency of nephrotic syndrome and dialysis requirement than non-CKD5 patients. Lower serum albumin and eGFR at diagnosis were independent predictors for CKD5 development. CONCLUSIONS: Children with C3G who have impaired kidney function and hypoalbuminemia at diagnosis should be carefully monitored for risk of progression to CKD5. Graphical abstract.

The Change in the Renal Pelvis Anterior-Posterior Diameter Between Prevoiding and Postvoiding Status, and Its Correlation With Vesicoureteral Reflux.

In this study, our aim was to evaluate the significance of the change in renal pelvis anterior-posterior diameter (RPAPD) before and after micturition between vesicoureteral reflux (VUR)-positive and -negative patients to whom had voiding cystourethrography (VCUG) was performed.In this study, 69 children, age ranging from 0 to 12 years, were included. Before the VCUG imaging, the RPAPD was measured first with a full bladder and then after urination via ultrasound (US). The differences between in RPAPD measurements were noted and values compared made among VUR-positive and -negative children. Data distribution was inhomogeneous, and the Wilcoxon Sign Rank test was utilized instead of Student t test. There was no statistically significant difference in prevoiding and postvoiding RPAPD in VUR (+) and VUR (-) patients (P = 0.672). There was no statistically significant relation between VUR and the presence of hydronephrosis (P = 0.126). Vesicoureteral reflux is more common in patients with urinary tract infections (UTI) (P = 0.001). There was no statistically significant relationship between prevoiding and postvoiding RPAPD change and VUR diagnosis (P = 0,164).Ultrasound is the modality of choice for urinary system evaluation. Diagnosis of hydronephrosis via US is not sufficient in predicting VUR; however, indirect findings may reveal the diagnosis. A decrease in RPAPD in postvoiding US evaluation may not rule out the VUR diagnosis for this reason further imaging modalities, such as VCUG, should be taken into consideration for the patients with clinical suspicion.