Safety and Efficacy of Very Early Conversion to Belatacept in Pediatric Kidney Transplantation with Transplant-Associated Thrombotic Microangiopathy: Case Study and Review of Literature.

The inhibition of co-stimulation during T-cell activation has been shown to provide effective immunosuppression in kidney transplantation (KT). Hence, the conversion from calcineurin inhibitor (CNI) to belatacept is emerging as a potential alternate maintenance immunosuppressive therapy in those with transplant-associated thrombotic microangiopathy (TA-TMA) or in the prevention of TA-TMA. We present a 17-year-old male who presented with biopsy-proven CNI-associated TA-TMA immediately post-KT. The administration of eculizumab led to the reversal of TMA. Tacrolimus was converted to belatacept with excellent efficacy and safety during a short-term follow-up of one year. Further larger controlled studies are required to demonstrate the efficacy of this approach in children who present with early-onset TMA post-KT.

Efficacy and Safety of Eculizumab in Enteroaggregative E. coli Associated Hemolytic Uremic Syndrome.

BACKGROUND: Hemolytic uremic syndrome (HUS) may present atypically without the full triad of classical HUS. Eculizumab has been shown to be efficacious in complement-mediated atypical HUS and some cases of Shiga-toxin (ST) associated HUS. We report the utility of eculizumab in enteroaggregative E. coli (EAEC) associated HUS. CASE SUMMARY: A female toddler presented with hemolytic anemia, oliguric acute kidney injury (AKI) without thrombocytopenia, and peripheral schistocytes. The stool examination for ST was negative but positive for EAEC. She required several hemodialysis sessions and received one dosage of eculizumab with rapid reversal of AKI and hemolytic markers. A kidney biopsy revealed acute tubular injury and segmental glomerular basement membrane splitting. Genetic testing was negative for complement mutations or deficiencies. A follow-up six months later showed persistently normal renal function and hematological markers. CONCLUSION: The clinical and histological manifestations of non-ST-associated diarrheal HUS and the role of eculizumab in this condition warrant future larger studies.

Synthetic cannabinoid-associated acute interstitial nephritis: An emerging cause of pediatric acute kidney injury?

Synthetic cannabinoid (SCB) usage among children is a rapidly emerging public health concern in the United States. Acute kidney injury (AKI) is an uncommon manifestation of SCB usage, with acute tubular necrosis (ATN) as the predominant histology. Here we describe a 16-year-old adolescent who sustained severe non-oliguric AKI in association with SCB usage. Emesis, right flank pain, and hypertension were the presenting clinical features. There was no uveitis, skin rash, joint pains, or eosinophilia. Urinalysis showed absence of proteinuria or hematuria. Urine toxicology was negative. Renal sonogram showed bilateral echogenic kidneys. Renal biopsy demonstrated severe acute interstitial nephritis (AIN), mild tubulitis, and absence of ATN. AIN responded with pulse steroid followed by oral steroid. Renal replacement therapy was not required. Although the exact pathophysiology of SCB-associated AIN is not known, immune response elicited by the renal tubulointerstitial cells against the antigens present in the SCB is the most likely mechanism. A high index of suspicion for SCB-induced AKI is necessary in adolescents who present with AKI of unclear etiology.

Severe hypertriglyceridemia in an infant on chronic hemodialysis.

Severe hyperlipidemia is a risk factor for cardiovascular disease. Children with chronic kidney disease and end stage renal disease are at risk for development of hyperlipidemia. In this report, we describe a 7-month-old male infant with Denys-Drash syndrome who was found to have a "milky-layer" floating on the deaerator of the hemodialysis machine. Investigations showed severe hypertriglyceridemia of >1000 mg/dl. The patient had been on chronic continuous manual peritoneal dialysis until 6 months of age and recently had been switched to hemodialysis. Management included lowering of caloric intake and addition of medium chain triglyceride with reduction of the serum triglyceride levels to 300-400 mg/dl. Close monitoring of serum lipids and timely intervention is important to prevent serious complications associated with dyslipidemia. Observation of the "milky layer" in the deaerator of the hemodialysis machine may be an interesting visual clue of underlying severe hypertriglyceridemia.

Hyperinsulinemic Hypoglycemia Due to PMM2 Mutation in Two Siblings with Autosomal Recessive Polycystic Kidney Disease.

Background: Hyperinsulinemic hypoglycemia (HH) is an important cause of persistent hypoglycemia in newborns and infants. Recently, PMM2 (phosphomannomutase 2) mutation has been associated with HH, especially in conjunction with polycystic kidney disease (PKD). PMM2 deficiency is one of the most common causes of congenital disorder of glycosylation (CDG). Renal involvement in PMM2-CDG manifests as cystic kidney disease, echogenic kidneys, nephrotic syndrome or mild proteinuria. Case Summary: Here, we describe a pair of siblings with HH associated with autosomal recessive polycystic kidney disease (ARPKD) and PMM2 mutation. Two siblings with ARPKD presented during infancy and early toddler years with severe hypoglycemia. Both had inappropriately elevated serum insulin, low ß-hydroxybutyrate, a need for a high glucose infusion rate, positive glycemic response to glucagon, positive diazoxide response and PMM2 mutation. Conclusions: Although this combination of HH and PKD was recently described in patients of European descent who also had PMM2 mutation, our report is unique given that these non-consanguineous siblings were not exclusively of European descent. PMM2 mutation leading to abnormal glycosylation and causing cystic kidneys and the alteration of insulin secretion is the most likely pathogenesis of this clinical spectrum.

Polyethylene Glycol 3350 Crystal Nephropathy in Association With Glomerular Mesangial Immunoglobin A Deposition.

Polyethylene glycol (PEG) 3350, an active ingredient of over-the-counter MiraLAX, is a commonly used laxative in children and is produced by polymerization of ethylene glycol (EG). Masked EG toxicity secondary to contamination of PEG 3350 could occur. We present a 7-year-old child with developmental delay who presented with altered mental status and acute kidney injury (AKI) following intake of generic PEG 3350 for few days prior to presentation. There was high anion gap metabolic acidosis, hypernatremia, elevated osmolar gap, lactic acidosis, and AKI. Urinalysis showed tubular proteinuria, microscopic hematuria, and calcium oxalate crystals. Prior urinalyses were normal without hematuria or proteinuria. Renal biopsy revealed evidence of mesangial dominant immunoglobulin A (IgA) and complement 3 (C3) deposits along with dense tubular deposition of calcium oxalate crystals. He subsequently developed worsening oliguric AKI and required hemodialysis (HD) for several sessions. The AKI resolved within 2 weeks and further HD was not required. Mental status improved in few days. Follow-up urinalyses showed resolution of microscopic hematuria and crystalluria. We hypothesized that the generic PEG 3350 most likely was contaminated with EG leading to the presentation. A high index of suspicion of contamination of PEG 3350 with EG is required in patients presenting with unexplained high anion gap metabolic acidosis, elevated osmolar gap, lactic acidosis, AKI, calcium oxalate crystalluria, and oxalate crystals on renal biopsy. Further studies are needed to determine whether there is an association between transient glomerular mesangial IgA deposition and crystal nephropathy.

Collapsing Focal Segmental Glomerulosclerosis and Acute Kidney Injury Associated With Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: A Case Report.

Chimeric antigen receptor T (CAR-T) cell treatment is a rapidly emerging therapy for relapsed/refractory hematologic malignancies. Although cytokine release syndrome is a common complication, a concomitant development of biopsy-proven collapsing glomerulopathy and acute kidney injury (AKI) has not been described with CAR-T cell therapy. We report a man in his early 20s with relapsed/refractory pre-B-cell acute lymphoblastic leukemia and compensated liver cirrhosis who received 3 courses of CD19-directed CAR-T cells. After the third CAR-T cell therapy, he developed severe cytokine release syndrome accompanied by new onset of nephrotic syndrome and AKI. Cytokine release syndrome was treated with tocilizumab. His kidney biopsy showed collapsing glomerulopathy, glomerulitis, and interstitial nephritis along with complete podocyte foot-process effacement. Due to disease progression, he was subsequently treated with bispecific CD19-directed CD3 T-cell engager antibody, blinatumomab, during which he developed another episode of cytokine release syndrome with exacerbation of nephrotic-range proteinuria and his AKI progressed to stage 3 chronic kidney disease. Excess cytokine-induced podocyte and renal tubulointerstitial injury and/or "on-target off-tumor" direct renal cell toxicity are the probable mechanisms of kidney injury. Further such reports will increase our understanding of the pathophysiologic basis of kidney injury with CAR-T treatment.

Delayed Onset Minimal Change Disease as a Manifestation of Lupus Podocytopathy.

Lupus podocytopathy (LP) is an uncommon manifestation of systemic lupus erythematosus (SLE) and is not included in the classification of lupus nephritis. The diagnosis of LP is confirmed by the presence of diffuse foot process effacement in the absence of capillary wall deposits with or without mesangial immune deposits in a patient with SLE. Here we describe a 13-year-old female who presented with nephrotic syndrome (NS) seven years after the diagnosis of SLE. The renal function had been stable for seven years since the SLE diagnosis, as manifested by the normal serum creatinine, serum albumin and absence of proteinuria. Renal biopsy showed evidence of minimal change disease without immune complex deposits or features of membranous nephropathy. Renal function was normal. The patient had an excellent response to steroid therapy with remission within two weeks. The patient remained in remission five months later during the most recent follow-up. This report highlights the importance of renal histology to determine the accurate etiology of NS in patients with SLE. Circulating factors, including cytokines such as interleukin 13, may play a role in the pathophysiology of LP and needs to be studied further in future larger studies.

An Unusual Occurrence of Erythrocytosis in a Child with Nephrotic Syndrome and Advanced Chronic Kidney Disease.

Background: Anemia is common in patients with nephrotic syndrome (NS) for various reasons. Furthermore, anemia can occur in patients with chronic kidney disease (CKD) predominantly owing to inappropriately low erythropoietin (EPO) production relative to the degree of anemia. However, erythrocytosis is uncommon in patients with NS and advanced CKD who are not treated with exogenous erythropoietin stimulating agents, and when present, will necessitate exploration of the other etiologies. Case summary: Here, we describe an 8-year-old girl with erythrocytosis in association with NS and advanced CKD. The patient was found to have erythrocytosis during the evaluation for hypertensive urgency. She also had nephrotic range proteinuria without edema. Serum hemoglobin and hematocrit were 17 gm/dL and 51%, respectively, despite hydration. Renal function test showed an estimated glomerular filtration rate of 30 mL/min/1.73 m2. There was mild iron deficiency anemia with serum iron saturation of 18%. Serum EPO level was normal. Urine EPO was not measured. Renal biopsy showed evidence of focal segmental glomerulosclerosis. Genetic testing for NS showed mutations in podocyte genes: NUP93, INF2, KANK1, and ACTN4. Gene sequence analysis of genes associated with erythrocytosis showed no variants in any of these genes. She required chronic dialysis ten months later and, subsequently, a renal transplantation 14 months after the initial presentation. Conclusion: Since the serum EPO level was normal, an increased sensitivity to EPO is the most probable mechanism of erythrocytosis. The unusual association of erythrocytosis in patients with NS and advanced CKD needs to be studied further in larger studies.

Concomitant nephrotic syndrome and tubulointerstitial nephritis in a child with Epstein-Barr virus mononucleosis.

Acute kidney injury (AKI) and nephrotic syndrome (NS) are uncommon manifestations of Epstein-Barr virus (EBV) mononucleosis. We report a 4-year-old boy with Infectious mononucleosis (IM) who presented with dialysis-requiring AKI and NS. Renal biopsy showed severe acute tubular necrosis, mild chronic interstitial nephritis and focal podocyte foot processes effacement. EBV early RNA was not detected in the renal tissue. However, immunophenotyping of peripheral lymphocytes showed increased cytotoxic T cell activity and increased memory B cells. Treatment with steroid led to rapid resolution of NS within 3 weeks. Renal function stabilised. EBV viral capsid antigen (VCA) IgM remained elevated until 4 months before starting to decline when VCA IgG and nuclear antigen started appearing. B lymphocytes are the predominant target cells in EBV infection and additionally may also act as antigen presenting cells to T lymphocytes, thereby eliciting the strong immune response and leading to podocyte and tubulointerstitial injury.

Hereditary hemorrhagic telangiectasia presenting as a recurrent epistaxis in an adolescent: A case report.

BACKGROUND: Epistaxis can be an isolated finding or a manifestation of a systemic disease. Some of the potential etiologies are usage of anticoagulants, bleeding disorders, vascular aneurysms, nasal neoplasm, hypertension and nasal steroids. Hereditary hemorrhagic telangiectasia (HHT) as a cause of recurrent epistaxis is uncommon. CASE SUMMARY: In this report, we describe an 18-year-old adolescent with recurrent epistaxis, mucocutaneous telangiectasia and family history of HHT, consistent with HHT. CONCLUSION: Timely diagnosis is needed not only to treat the epistaxis but also to be vigilant for other serious manifestations of this condition.

IgA vasculitis with nephritis in cirrhotic Wilson disease: Is there an association?

INTRODUCTION: IgA vasculitis (IgA-V) predominantly involves skin, gastrointestinal (GI) tract, joints, and kidneys. Wilson disease (WD) is a hepatolenticular degenerative disease caused by ATP7B gene mutation. CASE REPORT: Here we describe an unusual association of IgA-V with nephritis (IgA-VN) in an 11-year-old child with WD. He presented with palpable purpura without arthritis and GI involvement. Renal function was normal. Urinalysis showed microscopic hematuria and tubular proteinuria. Evaluation showed transaminitis, hypoalbuminemia, IgA hyperglobulinemia, and coagulation abnormalities. Serum ceruloplasmin and copper were low and 24-hour urine copper was extremely elevated. Liver biopsy showed stage IV cirrhosis with increased quantitative liver copper content. Skin and renal biopsy showed IgA-positive leukocytoclastic vasculitis and mesangial hyperplasia with IgA deposition, respectively. Quantitative renal copper content was normal. Homozygous pathogenic variant c.3207C>A (p.His1069Gln) of ATP7B was detected. There were no Kayser-Fleischer rings in the eyes, and neuropsychiatric examination was normal. Treatment with zinc and trientine led to normalization of hepatic function and serum IgA level with resolution of the rash and maintenance of renal function. CONCLUSION: Defective hepatic processing and/or clearance of IgA/IgA immune complexes probably led to the IgA-mediated skin and renal injury. Further such reports will help augment our understanding on the pathophysiology of IgA-VN in WD.

Efficacy of Antihypertensive Therapy in a Child with Unilateral Focal Fibromuscular Dysplasia of the Renal Artery: A Case Study and Review of Literature.

Background: Fibromuscular dysplasia (FMD) is one of the important etiologies of renovascular hypertension in children. It is usually resistant to multiple antihypertensive agents and can cause extreme elevation in blood pressures, which can lead to end organ damage if not promptly diagnosed and treated. Treatment options include medical management with antihypertensive agents, balloon or stent angioplasties, surgical revascularization, and nephrectomy. The aim of the study was to review the efficacy of antihypertensive therapy only in the management of FMD in a very young child. Methods: This is a retrospective chart study with review of literature. Results: Here, we report a 22-month-old toddler who presented with severe resistant hypertension and cardiomyopathy who was found to have focal FMD of the right renal artery. She also presented with proteinuria, hyponatremia that was probably secondary to pressure natriuresis, hypokalemia, hyperaldosteronism, and elevated plasma renin activity. The stabilization of blood pressures was done medically with the usage of antihypertensive medications only, without the need for angioplasty or surgical revascularization. Conclusions: We demonstrate that surgical intervention may not always be necessary in the treatment of all cases of FMD, especially in a small child where such intervention may be technically challenging and lead to potential complications. Hence, medical management alone may be sufficient, at least for the short-term, in small children with controlled hypertension and normal renal function, with surgical intervention reserved for FMD with medication-refractory hypertension and/or compromised renal function.

Renal dysplasia masquerading as a renal mass in a child on hemodialysis.

Pathological renal mass is uncommon in children. It is important to differentiate this from a benign mass or mass-like lesion (pseudomass) for proper management. Renal dysplasia is a common finding in patients with end stage renal disease and can mimic a renal mass. Here, we report a 16-year-old girl on hemodialysis who was found to have a nodular right renal mass in the sonogram. Magnetic resonance imaging confirmed the nodular mass. She underwent right nephrectomy and the histopathology revealed features of renal dysplasia and end stage kidney disease without any evidence of malignancy. No further treatments were necessary. This case demonstrates that a nodular renal mass in dialysis patients does not always mean malignancy and could be a pseudomass from severe renal dysplasia. Since a sonogram may not be able to clearly define the etiology of solid mass in these patients, further evaluations including a renal histology and/or other imaging modalities are often necessary.

Isolated abdominal nocardiosis in a pediatric renal transplant recipient.

Nocardia infection after RT is uncommon. The most common modes of exposure are inhalation of dust containing nocardia or contaminated soil/water and surgical instruments. Isolated abdominal nocardiosis following RT has not been reported. We report an 11-year-old female who developed nocardia abscesses of the abdomen post-RT. ESRD was secondary to FSGS and she had received multiple immunosuppressive agents prior to transplant. Induction immunosuppression consisted of thymoglobulin and maintenance was with tacrolimus, mycophenolate, and prednisone. There were construction activities in the hospital ward during her hospital stay. Due to immediate recurrence of FSGS in the allograft, she received plasma exchange, rituximab, and IVIG. Anti-infective prophylaxis consisted of TMP-SMX, valganciclovir, and nystatin. She developed multiple loculated fluid collections in the abdomen 6 weeks later. Histology of lesions demonstrated suppurative caseating granulomatous inflammation and the AFB culture showed Nocardia farcinica. With the reduction of immunosuppressive agents along with usage of TMP-SMX, imipenem-cilastatin, and linezolid, she had a partial recovery after 9 months with persistent small abscesses but remained asymptomatic clinically. There was no evidence of nocardia infection in lungs and brain. Repeat AFB culture from the lesions was negative. Allograft function remained stable throughout. She remains on oral TMP-SMX therapy. We postulated that she could have acquired nocardia either from the contaminated air particles in the hospital from the construction activities or reactivation of nocardia from prior colonization. Nocardia infection should be suspected in immunocompromised patients with unexplained fever and abdominal pain.