Management of pediatric hemolytic uremic syndrome.

Classical clinical triad of hemolytic uremic syndrome (HUS) is microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell injury. Several situations, including infections, medications, malignancies, and transplantation can trigger endothelial damage. On the HUS spectrum, atypical hemolytic uremic syndrome (aHUS) deserves special attention in pediatric patients, as it can cause endstage kidney disease and mortality. A dysfunction in the alternative complement pathway, either acquired or genetic, has been shown to be the main underlying cause. In the last decades, breathtaking advances have been made in understanding the pathophysiology of this rare disease, which has led to more efficient treatment. Recent studies have implicated genes in pathways beyond the alternative complement system, such as DGKE, TSEN2, and INF2 highlighting the importance of personalized management. Eculizumab has brought about dramatic improvements in the treatment of aHUS. Beyond eculizumab, there are many alternative therapeutics in the pipeline that target the complement system. Because of the rarity of aHUS, data from multiple patient registries are very important. The present report aimed to summarize the most important aspects of diagnosing and treating aHUS based on the Turkish national registry and the literature so as to improve clinical practice.

Allelic Variants of the Complement Genes in Acute Postinfectious Glomerulonephritis.

Acute postinfectious glomerulonephritis (APIGN) is one of the most common causes of acute glomerulonephritis in children. It may lead to inflammation and proliferation of glomerular tissue through immunologic mechanisms (Balasubramanian R, Paediatr Int Child Health 2017;37:240-247).

Spontaneous tendon or ligament ruptures in patients undergoing dialysis: First pediatric case report and literature review.

Spontaneous tendon or ligament ruptures are quite rare and mostly associated with chronic systemic diseases such as diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, and chronic kidney disease (CKD). In this study, we present the first documented case of a spontaneous rupture of the medial patellofemoral ligament (MPFL) in a pediatric patient. The patient was undergoing long-term peritoneal dialysis (PD) and had a history of severe secondary hyperparathyroidism. Additionally, we discussed spontaneous tendon and ligament ruptures associated with CKD or dialysis through a comprehensive literature review. This case report highlights the importance of recognizing that spontaneous tendon or ligament injuries are not exclusive to adults; children with CKD can also be affected. Several factors including poor parathyroid hormone (PTH) and metabolic acidosis control, prolonged CKD duration and presence of malnutrition play role in the pathogenesis. Early diagnosis is crucial as it allows for timely surgical intervention and leads to a favorable functional recovery.

Long-term Effects of Kidney Transplantation Compared With Dialysis on Intima-media Thickness in Children-Results From the 4C-T Study.

BACKGROUND: Children requiring kidney replacement therapy experience high burden of cardiovascular (CV) disease leading to increased mortality. Intima-media thickness (IMT) indicating atherosclerosis is a validated surrogate marker for future CV events. METHODS: We investigated the effect of different treatment modalities (dialysis, preemptive kidney transplantation (KTx), late KTx after dialysis) on IMT by multivariable linear mixed-effect modeling. Patients were enrolled in a prospective cohort study. RESULTS: A total of 261 analyzed children had a mean follow-up of 3 y. Children after preemptive and late KTx had lower levels of IMT when compared with dialysis. Using an interaction term, a significant progression of IMT over time was seen during dialysis (ß = 0.0053 mm/y, P   =  0.004). IMT before the start of therapy was the most influential determinant in all models. Low IMT was associated with maintenance steroid treatment after preemptive KTx. High IMT on dialysis was associated with higher systolic blood pressure, lower body mass index, lower serum albumin, and lower bicarbonate. CONCLUSIONS: IMT remained rather stable in children several years after KTx. In contrast, children on dialysis had higher IMT values, which increased over time. In these children, blood pressure control, calorie and protein intake, and acid-base homeostasis seem important. Taken together, children might profit from early transplantation to limit accumulation of CV risk.

An unusual cause of renal vein thrombosis in a newborn: COVID-19.

There is no information on renal vein thrombosis induced by COVID-19 infection in a neonate. Few cases of renal vein thrombosis caused by COVID-19 infection have been reported in predominantly adult patients. On day 25 after birth, a newborn whose mother was infected with COVID-19 had renal vein thrombosis. We believed that our patient's renal vein thrombosis was caused by postnatal transmission of the COVID-19 infection that the mother had acquired during birth. The clinical and radiologic findings of these unusual renal complications in a neonate, as well as treatment options, are presented.

LAMB2 gene: broad clinical spectrum in Pierson syndrome.

Pierson syndrome (PS) is a rare autosomal recessive disease, characterized by congenital nephrotic syndrome (CNS), and ocular and neurologic abnormalities. In affected cases, there is abnormal b-2 laminin which is compound of the several basement membranes caused by inherited mutations in the LAMB2 gene. Although patients have mutations in the same gene, the phenotype is highly variable. In this case series, the relationship between genotype and phenotype is emphasized, and information about the clinical follow-up of the patients is presented. Hereby, we report four pediatric cases with PS as a result of mutation in the LAMB2 gene. Clinical spectrum of LAMB2-associated disorders varies from mild-to-severe ocular, kidney, and neurologic involvement. Since genotype-phenotype correlation in PS has not been clearly demonstrated, we recommend that all patients with ophthalmic anomalies and glomerular proteinuria should be tested for LAMB2 mutations.

Efficacy and safety of anti-interleukin-1 in children with colchicine-resistant familial Mediterranean fever.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of anti-interleukin-1 (IL-1) therapies in colchicine-resistant pediatric patients with familial Mediterranean fever (FMF). METHODS: In this study, we retrospectively evaluated 656 children with FMF and 27 patients who had been treated with anti-IL-1 therapies (anakinra/canakinumab) . Clinical and laboratory features, MEFV gene mutations, treatment responses were investigated. RESULTS: Twenty of the patients were treated with anakinra (the treatment of 6 patients who initially used anakinra was switched to canakinumab in the follow-up period), and 13 patients were treated with canakinumab. Clinical symptom and severity scores decreased in all patients A decrease in acute phase reactants was also observed in patients. A total of 18 (66%) patients had a M694V homozygous mutation, while 24 (89%) patients had a M694V mutation, at least in one allele. CONCLUSIONS: FMF patients with colchicine resistance may progress to amyloidosis. IL-1 antagonist treatment could be used safely with a favorable outcome in pediatric patients with FMF resistance to colchicine therapy and/or who have renal amyloidosis.

Electrocardiographic measurements in children with pre-dialysis chronic kidney disease and undergoing kidney replacement therapy.

Cardiovascular diseases are the main causes of morbidity in children with chronic kidney disease (CKD). Electrocardiography (ECG) can provide important information about cardiac functions and parameters associated with sudden cardiac death. This study aims to evaluate the potentially dangerous changes in CKD and kidney replacement therapies by ECG and to determine the value of ECG in predicting cardiovascular outcome compared with echocardiography. 101 patients with CKD were divided into subgroups according to treatment modalities as pre-dialysis CKD, hemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation (KTx). Differences in anthropometric measurements, laboratory results, blood pressures, ECG monitoring were compared within groups as well as with 40 healthy controls. Available echocardiographic findings were noted. In the patients, HD group had highest frequency of hypertension. ECG revealed prolonged QTc as more frequent (16.8% vs 0%, p = 0.006) and higher QTcD (56.7 ± 6.5 vs 39.9 ± 5.1 ms, p = 0.001) in the patients compared to controls, especially in dialysis patients, whereas lowest values were in KTx subgroup. Left ventricular (LV) hypertrophy (LVH) was more frequent (47.1%) in HD compared to other CKD subgroups in ECG (p = 0.052). Echocardiography also showed LV mass index as highest in HD and lowest in KTx (121.4 ± 55.7 vs 63.7 ± 18.3 g/m2, p = 0.000), with numerically highest LVH in HD (58.3%, p = 0.063).  Conclusion: ECG can be used to detect cardiovascular problems in patients with CKD, especially in HD. As ECG results were in line with echocardiography, patients with ECG abnormalities suggestive of LVH should be referred for echocardiographic assessment. What is Known: • Cardiovascular diseases such as coronary artery disease, congestive heart failure, arrhythmias and sudden cardiac death are major causes of morbidity and mortality in chronic kidney disease. • Electrocardiography has significant advantages in demonstrating cardiac functions in children because it is readily available, non-invasive and often non-experts can interpret the results. What is New: • The heart rate is higher, QTc is longer and QTcD is higher in dialysis patients and the prolonged QTc is more frequent in patients with underlying glomerular diseases. • Left ventricular hypertrophy is more common in HD patients and those with hypertension, hypercalcemia, anemia or glomerular etiology. The cardiovascular risky conditions are less frequent in the patients with kidney transplantation.

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.

A Well-Intentioned Enemy in Autoimmune and Autoinflammatory Diseases: NETosis.

Neutrophils are an essential member of the innate immune system derived from the myeloid stem cell series and develop in the bone marrow. The action of neutrophils defined in immune response includes phagocytosis, degranulation, cytokine production, and neutrophil extracellular traps. The success of the host immune defense depends on effective neutrophil activation. Recent studies have shown that neutrophils that have completed their task in the field of inflammation rejoin circulation. Uncontrolled inflammatory response and dysregulated immune responses to the host are important factors in the development of acute and chronic diseases. Neutrophils are the first cells to be drawn into the field at the time of inflammation. They have developed response strategies that produce proinflammatory cytokines and are known as neutrophil extracellular traps since they create mesh-like structures with their DNA contents into the external environment and release their granular proteins in this way. This article summarizes numerous recent studies and reviews the role of neutrophil extracellular traps in autoimmune and autoinflammatory diseases in the hope, that this will lead to the development of more effective treatments. In addition, in this review, the role of neutrophil extracellular trap formation in some pediatric autoimmune diseases is emphasized.

The Clinical and Mutational Spectrum of 69 Turkish Children with Autosomal Recessive or Autosomal Dominant Polycystic Kidney Disease: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) is associated with pathogenic variants in the PKHD1 gene. Autosomal dominant polycystic kidney disease (ADPKD) is mainly associated with pathogenic variants in PKD1 or PKD2. The present study aimed to identify the clinical and genetic features of Turkish pediatric ARPKD and ADPKD patients. METHODS: This multicenter, retrospective cohort study included 21 genetically confirmed ARPKD and 48 genetically confirmed ADPKD patients from 7 pediatric nephrology centers. Demographic features, clinical, and laboratory findings at presentation and during 12-month intervals were recorded. RESULTS: The median age of the ARPKD patients at diagnosis was lower than the median age of ADPKD patients (10.5 months [range: 0-15 years] vs. 5.2 years [range: 0.1-16 years], respectively, [p = 0.014]). At the time of diagnosis, the median eGFR in the ARPKD patients was lower compared to that of ADPKD patients (81.6 [IQR: 28.7-110.5] mL/min/1.73 m2 and 118 [IQR: 91.2-139.8] mL/min/1.73 m2, respectively, [p = 0.0001]). In total, 11 (52.4%) ARPKD patients had malnutrition; 7 (33.3%) patients had growth retardation at presentation; and 4 (19%) patients had both malnutrition and growth retardation. At diagnosis, 8 (16.7%) of the ADPKD patients had malnutrition, and 5 (10.4%) patients had growth retardation. The malnutrition, growth retardation, and hypertension rates at diagnosis were higher in the ARPKD patients than the ADPKD patients (p = 0.002, p = 0.02, and p = 0.0001, respectively). ARPKD patients with malnutrition and growth retardation had worse renal survival compared to the patients without (p = 0.03 and p = 0.01). Similarly, ADPKD patients with malnutrition had worse renal survival compared to the patients without (p = 0.002). ARPKD patients with truncating variants had poorer 3- and 6-year renal outcome than those carrying non-truncating variants (p = 0.017). CONCLUSION: Based on renal survival analysis, type of genetic variant, growth retardation, and/or malnutrition at presentation were observed to be factors associated with progression to chronic kidney disease (CKD). Differentiation of ARPKD and ADPKD, and identification of the predictors of the development of CKD are vital for optimal management of patients with ARPKD or ADPKD.

A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature.

BACKGROUND: Recently, recessive mutations in SGPL1 (sphingosine-1-phosphate lyase), which encodes the final enzyme of sphingolipid metabolism, have been reported to cause steroid-resistant nephrotic syndrome, adrenal insufficiency, and many other organ/system involvements. We aimed to determine the clinical and genetic characteristics, and outcomes in patients with SGPL1 mutations. METHODS: The study included 6 patients with bi-allelic SGPL1 mutation. Clinical, genetic, and laboratory characteristics, and outcomes of the patients were evaluated retrospectively. We also reviewed previously reported patients with SGPL1 mutations and compared them to the presented patients. RESULTS: The median age at kidney presentation was 5 months. Four patients (67%) were diagnosed before age 1 year. Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient. Steroids were given to 3 patients, but they did not respond. All 6 patients progressed to chronic kidney disease; 5 required kidney replacement therapy (KRT) at a median age of 6 months. Deceased kidney transplantation was performed in one patient. All 6 patients had adrenal insufficiency, of which 5 were diagnosed at age < 6 months. Three patients had hypothyroidism, 2 had ichthyosis, 4 had immunodeficiency, 5 had neurological findings, and 2 had genitourinary system anomalies. Four patients died at a median age of 30.5 months. Two patients are being followed up with KRT. One patient had a novel mutation. CONCLUSIONS: Patients with SGPL1 mutations have a poor prognosis, and many types of extrarenal organ/system involvement beyond adrenal insufficiency can be seen. Genetic diagnosis of such patients is important for treatment, genetic counseling, and screening for comorbid conditions. A higher resolution version of the Graphical abstract is available as Supplementary information.

Chest pain in children with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common and autosomal recessive inherited autoinflammatory disease. The most common signs and symptoms are fever, abdominal pain, chest pain, and arthritis. The aim of this study was to describe the clinical, laboratory and genetic differences between pediatric FMF patients with and without chest pain. METHODS: Between January 2006 and January 2022, 1134 patients with FMF were analyzed retrospectively. Patients were divided into two groups including those with and without recurrent chest pain. These groups were compared in demographic, clinical, treatment, and MEFV gene analyses. RESULTS: A hundred and sixty-two (14.3%) patients had recurrent chest pain. In patients with recurrent chest pain, the age of onset of symptoms was younger (p=0.003), and the family history of FMF was higher (p=0.002). Patients with chest pain had a higher annual attack frequency (p < 0.001), a longer attack duration (p < 0.001), and higher Pras disease activity scores (p < 0.001). The colchicine dose used in the treatment was higher in FMF patients with chest pain (p=0.005), and anti-IL-1treatment was higher (p < 0.001). M694V homozygous mutation was found more frequently (p=0.001), whereas M694V/V726A mutation was found less frequently in patients with recurrent chest pain (p=0.017). CONCLUSIONS: Patients with recurrent chest pain seem to have early onset symptoms, often are more likely to have family history, and have a higher disease severity. In addition, the presence of homozygous M694V mutation is more common in patients with chest pain.

Encapsulated Peritoneal Sclerosis in an Adolescent With Kidney Transplant After Long-Term Peritoneal Dialysis.

Encapsulated peritoneal sclerosis is a rare complication of long-term peritoneal dialysis that has a high rate of morbidity and mortality. We present an 18-year-old female patient who was first diagnosed with renal failure at 8 years of age and who had 7 years of peritoneal dialysis and then hemodialysis before kidney transplant from a deceased donor. Before transplant, the patient developed encapsulated peritoneal sclerosis and was treated with tamoxifen and steroids. Three years after transplant, the patient presented with complaints of vomiting, abdominal pain, and abdominal distension and was again diagnosed with encapsulated peritoneal sclerosis. The patient required excretory paracentesis, pulse steroid treatment for 3 days, and treatment with methylprednisone and tamoxifen, which resulted in regression of signs and symptoms. Factors such as long-term peritoneal dialysis, a history of bacterial peritonitis, and use of high-concentration dialysate may cause encapsulated peritoneal sclerosis, but symptoms can recur after transplant, as shown in our patient. Thus, it is important to recognize that encapsulated peritoneal sclerosis may cause graft loss due to the various complications that it can cause.

Value of Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios in the Evaluation of Acute Rejection and Chronic Allograft Nephropathy in Children With Kidney Transplantation.

OBJECTIVES: Neutrophil-to-lymphocyte ratio and platelet (thrombocyte)-to-lymphocyte ratio have become accepted markers of inflammation in recent years and are used to assess disease activity in some diseases. In this study, we investigated the relationship between these values and acute rejection attacks, as well as their role in determining chronic allograft nephropathy, in follow-up of pediatric kidney transplant recipients. MATERIALS AND METHODS: Our study included 58 kidney transplant recipients (age 5-18 years) with at least 5-year follow-up at our center. Patients with history of secondary transplant, concomitant malignancy, and shorter follow-up were excluded. Medical history and laboratory parameters pretransplant and at 1, 3, and 6 months and 1, 2, 3, 4, and 5 years posttransplant, as well as kidney biopsy reports, were reviewed. RESULTS: Both neutrophil-to-lymphocyte (P = .003) and thrombocyte-to-lymphocyte (P = .002) ratios were significantly higher during acute rejection attacks. Although both values were higher in patients with chronic allograft nephropathy at 5 years posttransplant, differences were not statistically significant (P = .69 and P = .55). When patients with and without chronic allograft nephropathy within 5 years were compared, those who developed chronic allograft nephropathy had significantly higher neutrophil- tolymphocyte and thrombocyte-to-lymphocyte ratios at all periods in the first 2 and 4 years posttransplant, respectively. Among patients who had acute rejection attacks, those who subsequently developed chronic allograft nephropathy had higher neutrophil-tolymphocyte ratio in the first 3 years posttransplant, with higher thrombocyte-to-lymphocyte ratio at all posttransplant periods. CONCLUSIONS: This is the first study on neutrophil- tolymphocyte and thrombocyte-to-lymphocyte ratios in pediatric kidney transplant recipients. Our results indicated that both values can be useful and easily accessible markers in acute rejection diagnosis and determining chronic allograft nephropathy development risk, which are 2 major causes of kidney graft loss posttransplant. Pediatric studies with larger populations are needed to support our findings.