Mild COVID-19 in a pediatric renal transplant recipient.

As of mid-April 2020, the coronavirus disease of 2019 (COVID-19) pandemic has affected more than 2 million people and caused 135 000 deaths worldwide. Not much is known about the effect of this disease in immunosuppressed children with renal transplantation (RT). Here we report a 13-year-old child with multiple comorbidities who acquired COVID-19 5 years post-RT in the United States. Maintenance immunosuppression (IS) consisted of sirolimus and mycophenolate. There was no history of travel or exposure to sick contacts. The presenting features were fever, cough, rhinorrhea, and hypoxemia. Diarrhea was the only extrapulmonary manifestation. Chest X-ray was normal. He did not require intensive care unit care or ventilation. There was a transient rise in his serum creatinine without change in urine output; dialysis was not required. Slight reduction in IS was done. He had an excellent clinical recovery within 4 days and was able to be discharged home. His respiratory symptoms resolved but the diarrhea persisted during a 4-week follow-up period. This report provides a brief perspective on the short-term COVID-19 clinical course in an immunosuppressed child. More reports will add valuable information on the potential variety of spectrum of the illness in this subset of children.

Transplant renal artery stenosis in a child with BK nephropathy.

TRAS and BK nephropathy are known complications of RT, but the association between both has not been reported. A 2-year-old girl underwent a deceased donor renal transplant from a 20-year-old donor, along with bilateral native nephrectomies. She had a DGF due to a renal artery thrombus and required thrombectomy with re-anastomosis. Heparin and aspirin were used. Immunosuppressive agents included thymoglobulin, steroid, tacrolimus, and MMF. CMV and EBV DNA PCRs were negative, but she developed BK viremia at 2 months with stable allograft function. Immunosuppression was reduced, and leflunomide was initiated. Blood pressures were well controlled on low-dose amlodipine. Five months after RT, she presented with hypertensive emergency, following a respiratory infection, and required dialysis for oliguric acute kidney injury. Allograft biopsy showed evidence of BK nephropathy. Immunosuppression was further minimized. Doppler renal US and renal artery duplex studies were both suggestive of TRAS. Angiogram showed severe proximal anastomotic TRAS (>95% occlusion). PTA with stenting was done with immediate improvement in the blood flow and reduction in the pressure gradient. BPs and renal function normalized. Ten months post-RT, she remains normotensive with stable renal function and resolution of BK viremia. Although ureteral stenosis and nephropathy are known to occur with BK infection, TRAS is an interesting association and possibly suggest the tropism of BK virus to the vascular endothelial cells. Timely recognition and management of both is important to prevent uncontrolled hypertension and allograft dysfunction.

BK virus encephalitis and end-stage renal disease in a child with hematopoietic stem cell transplantation.

BK virus encephalitis after HSCT is uncommon. Several reports of native kidney BKVN in patients with HSCT, hematologic malignancies, human immunodeficiency virus infection, and non-renal solid organ transplantation have been described. However, an uncommon combination of BK encephalitis and ESRD of native kidneys secondary to BK virus in a child with HSCT has not been described. We report a 10-year-old boy who presented with a gradually rising serum creatinine during treatment for severe autoimmune hemolytic anemia, which he developed 9 months after receiving an allogeneic HSCT for aplastic anemia. There was no proteinuria or hematuria present. Serum BK virus load was 5 × 106  copies/mL. A renal biopsy showed evidence of BKVN. He developed fever, seizures, and confusion, and the (CSF) showed significant presence of the BK virus (1 × 106  copies/mL) along with biochemical evidence of viral encephalitis. Cerebrospinal fluid cultures were negative. Despite significant clinical symptoms and presence of BK virus in CSF, the magnetic resonance brain imaging findings were minimal. With reduction of immunosuppression, there was resolution of BK encephalitis but BKVN remained resistant to multiple anti-BK virus agents, including leflunomide and cidofovir. He eventually became dialysis-dependent and, 6 years later, received a renal transplant from his mother. This case illustrates that BK virus in severely immunocompromised HSCT recipient may lead to BK encephalitis and BKVN of native kidneys, even without hemorrhagic cystitis, leading to ESRD. Knowledge of such is important for appropriate timely evaluation and management.

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.

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes.

Leptin is a pro-inflammatory cytokine secreted by the adipose tissue. Dopamine D2 receptors (D2Rs) have anti-inflammatory effects in the brain and kidney tissues. Mouse and human adipocytes express D2R; D2R protein was 10-fold greater in adipocytes from human visceral tissue than subcutaneous tissue. However, the function of D2R in adipocytes is not well understood. 3T3-L1 cells were treated with D2-like receptor agonist quinpirole, and immunoblot and quantitative PCR were performed. Quinpirole increased the protein and mRNA expression of leptin and IL-6, but not adiponectin and visfatin (24 h). It also increased the mRNA expression of TNF-α , MCP1, and NFkB-p50. An acute increase in the protein expression of leptin and TNF-α was also found in the cells treated with quinpirole. The leptin concentration in the culture media was increased by quinpirole-bathing the 3T3-L1 adipocytes. These quinpirole effects on leptin and IL-6 expression were prevented by the D2R antagonist L741,626. Similarly, siRNA-mediated silencing of Drd2 decreased the leptin, IL-6, mRNA, and protein expressions. The D2R-mediated increase in leptin expression was prevented by the phosphoinositide 3-kinase inhibitor LY294002. Acute quinpirole treatment in C57Bl/6J mice increased serum leptin concentration and leptin mRNA in visceral adipocyte tissue but not in subcutaneous adipocytes, confirming the stimulatory effect of D2R on leptin in vivo. Our results suggest that the stimulation of D2R increases leptin production and may have a tissue-specific pro-inflammatory effect in adipocytes.

Cytomegalovirus transmission in pediatric renal transplant recipients during the window period.

We report two CMV naïve children who received deceased donor renal transplants from a CMV IgG-negative single donor. CMV IgG in both recipients and the donor were negative immediately prior to transplant. Both recipients had early recurrences of their original disease in their transplants, requiring multiple sessions of plasmapheresis. All blood products used were leukoreduced or CMV seronegative. A few days post-transplant, both recipients developed significant positive CMV viremia. Both required initiation of oral valganciclovir. Case 1 responded to oral valganciclovir only while the case 2 had a delayed response to it and hence required intravenous ganciclovir with good response. When checked retrospectively, CMV IgM in the donor was positive along with positive CMV DNA PCR from the white cells. Here we describe a very unusual scenario of CMV transmission in two pediatric renal transplant recipients from a single donor during the CMV window period.

Anorexia nervosa in a pediatric renal transplant recipient and its reversal with cyclosporine.

We report a 16-yr-old female who developed AN within a month after renal transplantation and its resolution after switching from tacrolimus to cyclosporine. Her initial maintenance immunosuppressive regimen after renal transplantation consisted of tacrolimus, mycophenolate, and steroid. She had 7 kg weight loss within the first month of transplant with subsequent 10, 12, 17, and 19 kg loss after three, five, seven, and nine months of transplant, respectively. Besides weight loss and disturbances in body image, the patient developed alopecia, bradycardia, and persistent secondary amenorrhea. Upon switching to cyclosporine from tacrolimus nine months after transplant, she started regaining weight with 5 kg gain within two months and 10 kg after four months. She restarted her menstrual cycle, alopecia and bradycardia resolved, and her body image disturbance improved. Here, we describe a very unusual neuropsychiatric side effect of tacrolimus and its resolution with another calcineurin inhibitor, cyclosporine, in an adolescent renal transplant recipient.

Solid organ transplantation following end-organ failure in recipients of hematopoietic stem cell transplantation in children.

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment modality for various malignant and non-malignant disorders of the lympho-hematopoietic system. Patient survival rate has increased significantly with the use of this procedure. However, with the increase in disease-free patient survival rates, complications including various organ toxicities are also common. Kidney, liver, lung, heart, and skin are among those solid organs that are commonly affected and frequently lead to organ dysfunction and eventually end-organ disease. Conservative measures may or may not be successful in managing the organ failure in these patients. Solid organ transplantation has been shown to be promising in those patients who fail conservative management. This review will summarize the causes of solid organ (kidney, liver, and lung) dysfunction and the available data on transplantation of these solid organs in post-HSCT recipients.

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.

Our Experience with Sinonasal Glomangiopericytoma in North India: A Case Series.

Glomangiopericytoma (GPC) is a rare benign sinonasal tumor originating from Zimmerman's Pericytes surrounding capillaries and accounting for less than 0.05% of all sinonasal tumors. Glomangiopericytoma has low malignant potential (5-10%) and is mostly diagnosed in the 6th or 7th decade of age with slight female preponderance. We presented here a case series of 5 patients with sinonasal GPC. This research was conducted at a tertiary healthcare centre in North India. In our case series, all the patients were evaluated and underwent endoscopic surgical resection. All patients underwent digital subtraction angiography (DSA) and preoperative embolization. The coblation technique used for haemostasis proved very effective and time-saving. All patients exhibited cytoplasmic SMA positivity (a marker of GPC) and CD34 negativity, while one patient exhibited a high Ki-67 index (> 10%), which is a predictor of aggressive tumor behavior. None of the patients showed any recurrence in follow-up. We recommend performing complete endoscopic surgical excision to prevent recurrence. The use of DSA, preoperative embolization, and intraoperative use of the coblation technique provides a cleaner surgical field and reduced operating time.

DOPAMINE D4 RECEPTOR DOWN-REGULATES RENAL SODIUM CHLORIDE COTRANSPORTER VIA UBIQUITINATION-ASSOCIATED LYSOSOME DEGRADATION.

BACKGROUND: The thiazide-sensitive sodium chloride cotransporter (NCC) is the major apical sodium transporter located in the mammalian renal distal convoluted tubule (DCT). The amount of sodium reabsorbed in the DCT through NCC plays an important role in the regulation of extracellular fluid volume and blood pressure. Dopamine and its receptors constitute a renal antihypertensive system in mammals. The disruption of Drd4 in mice causes kidney-related hypertension. However, the pathogenesis of D4R-deficiency associated hypertension is not well documented. METHOD: We assessed the effects of D4R on NCC protein abundances and activities of DCT in mice with renal or global Drd4-deficiencies and expressing human D4.7 variant and in cultured mouse DCT cells, and explored the molecular mechanism. RESULTS: NCC inhibitor hydrochlorothiazide enhanced the natriuresis in Drd4-/- mice. Renal NCC protein was greater while ubiquitination of NCC was less in Drd4-/- than Drd4+/+ mice. Silencing of D4R in cultured mouse DCT cells increased NCC protein but decreased NCC ubiquitination. D4R agonist had opposite effects that were blocked by the antagonist. In mouse kidneys and DCT cells D4R and NCC colocalized and co-immunoprecipitated. Moreover, D4R-agonist promoted the binding between the two proteins demonstrated by fluorescence resonance energy transfer. D4R agonism internalized NCC, decreased NCC in the plasma membrane, increased NCC in lysosomes and reduced NCC-dependent-intracellular-sodium transport. The lysosomal inhibitor chloroquine prevented the D4R-induced NCC-reduction. A shortened NCC half-life was suggested by its decay under cycloheximide-chase. Ubiquitin-specific-protease 48 (USP48, a deubiquitinating enzyme) was increased in the kidneys and cells with Drd4-deficiency while D4R stimulation decreased it in vitro and reduction of USP48 with siRNA decreased NCC expression. The mice carrying human D4.7 variant or with renal supcapsular-Drd4-siRNA-delivery developed hypertension with increased NCC. CONCLUSION: Our data demonstrates that D4R downregulates NCC by promoting USP48-associated deubiquitination and subsequent internalization, lysosome relocation and degradation.

Ultra-Early Hemostatic Therapy for Acute Intracerebral Hemorrhage: An Updated Review.

Intracerebral hemorrhage (ICH) is the second most common type of stroke, accounting for approximately 10-20% of all strokes, and is linked to severe neurological disability and death. Since the most accurate predictor of outcome in patients with ICH is hematoma volume, there is a great need for pharmacologic therapy that can reduce hematoma expansion and resultant mass effect and edema. This is especially critical within the ultra-early window of 3-4 hours after the presentation. Hemostatic therapies are exceptionally important for those patients taking antiplatelet or anticoagulant medications to reverse the effects of these medications and therefore prevent hematoma expansion. Furthermore, the recent publication of the 2023 Guideline for the Management of Patients with Aneurysmal Subarachnoid Hemorrhage by the American Heart Association/American Stroke Association, the first update to the guidelines since 2012, underscores the importance of optimizing anticoagulation reversal for this population. The purpose of this selective, nonsystematic review is to examine current literature regarding the use of hemostatic therapies in ICH, with particular attention paid to antiplatelet, anticoagulation, and antifibrinolytic therapies.

Early recurrence of focal segmental glomerulosclerosis in a kidney transplant recipient with APOL1 one risk variant.

Apolipoprotein 1 (APOL1) risk variants (G1 and G2) are associated with focal segmental glomerulosclerosis (FSGS) in patients of African ancestry. The prevalence of APOL1 two risk variants is lower in Hispanics and very rare in European and Asian populations. APOL1 two risk variants in donor kidneys is associated with recipient kidney graft loss, however the effect of recipient risk variant in the kidney transplant outcome is unclear. Here, we present a late adolescent male with FSGS and end stage renal disease with one APOL1 risk variant (G2) who had immediate recurrence of FSGS in the post-KT period. There was an excellent response to few sessions of plasmapheresis and Rituximab with no further recurrence of FSGS in the 1 year follow-up period. It needs to be seen whether the recipient APOL1 single risk variant causes increased susceptibility to kidney graft loss on a long run via recurrent or de novo pathologies.

Short-Term Outcome of Isolated Kidney Transplantation in Children with Autosomal Recessive Polycystic Kidney Disease: A Case Series and Literature Review.

Autosomal recessive polycystic kidney disease (ARPKD) is often associated with hepatobiliary disease in the form of hepatic fibrosis and/or Caroli disease. Combined liver-kidney transplantation (CLKT) is a transplant modality of choice in children with both end-stage renal disease (ESRD) and severe hepatic disease. However, there is no consensus on whether children with ARPKD-associated ESRD without severe hepatic disease can be treated with isolated kidney transplantation (KT) without the need for CLKT. We retrospectively studied the efficacy of isolated KT in children with ARPKD without severe hepatic disease, and followed the course of hepatic disease post KT. This is a single-center study of three children with ARPKD and ESRD who underwent isolated KT. None of them had severe hepatic disease at the time of KT. All children were clinically diagnosed with ARPKD in the immediate postnatal period. All had hepatic fibrosis of varying degrees and two had intrahepatic biliary duct (IHBD) dilatation. None had gastrointestinal (GI) bleed, portal hypertension or cholangitis. Two children had preemptive KT. Pre-transplant unilateral or bilateral native nephrectomy were performed for two children, and one underwent unilateral native nephrectomy at the time of KT. The median creatinine clearance at a median post-KT follow-up of 24 months was 60.3 mL/min/1.73 m2. The two-year graft and patient survival were both 100%. Post KT, all three patients continued to demonstrate evidence of hepatic fibrosis and IHBD on sonogram; however, none of them were either evaluated for or required liver transplantation given normal synthetic liver function and absence of portal hypertension or other severe hepatobiliary disease. There were no adverse events observed such as cholangitis, GI bleed, or multiorgan failure. Hence, an excellent short-term graft and patient survival was demonstrated in this study of children with ARPKD and mild to moderate hepatic disease who received isolated KT. Long-term follow-up and larger studies are important to assess the efficacy of isolated KT in this subset of children with ARPKD.

An Exploration of the Relationship Between Atrial Fibrillation and Obesity.

In the past 40 years, the prevalence of atrial fibrillation and obesity have skyrocketed. It has long been established that obesity can lead to adverse cardiovascular outcomes due to its myriad of effects on cardiovascular architecture, cardiovascular hemodynamics, and electrical conduction interference. The goal of this article is to explore the pathogenesis of atrial fibrillation in obese patients and examine the role of atrial enlargement, increased adipose deposits surrounding the pericardium, interstitial fibrosis, and inflammation in the development and worsening of atrial fibrillation in obese patients.

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.

Efficacy and safety of local candida immunotherapy in recalcitrant warts in pediatric kidney transplantation: A case report.

BACKGROUND: Warts are common in recipients of kidney transplantation (KT). Resistant warts which are not amenable to conventional therapies may lead to significant mor bidity. Limited data exists on safety and efficacy of local immunotherapy among immunocompromised KT recipients. CASE SUMMARY: We report a seven-year-old child who presented with recalcitrant plantar per iungual warts in the early KT period. Immunosuppression consisted of tacrolimus, mycophenolate and steroid. Due to failure of conventional anti-wart therapies, he was treated with two sessions of intralesional (IL) candida immunotherapy along with liquid nitrogen cryotherapy leading to complete resolution of the warts. Interestingly, de novo BK viremia was seen about three weeks following the last candida immunotherapy. This required reduction of immu nosuppression and other anti-BK viral therapies. Allograft function remained stable but there were donor specific antibodies detected. There also was elevated level of plasma donor derived cell-free DNA. A pneumocystis jirovecii pneumonia occurred ten months following completion of immunotherapy that was successfully treated with trimethoprim-sulfamethoxazole. During this ten-month follow-up period, there have been no recurrence of warts, and transplant kidney function has remained stable. CONCLUSION: Stimulation of cell-mediated immunity against the human papilloma virus induced by the IL candida immunotherapy is thought to be a cause for wart resolution. With this therapy, whether it is necessary to augment the immunosuppression to prevent rejection is unclear as that may come with a risk of infectious complications. Larger, prospective studies in pediatric KT recipients are needed to explore these important issues.