Vasculitis and Kidney Disease.

Pediatric vasculitis is a complex group of disorders that commonly presents with multisystem involvement. Renal vasculitis can be isolated to the kidneys or can occur as part of a broader multiorgan vasculitis. Depending on severity, renal vasculitis may present as acute glomerulonephritis (AGN) often associated with hypertension and sometimes with a rapidly deteriorating clinical course. Prompt diagnosis and initiation of therapy are key to preserving kidney function and preventing long-term morbidity and mortality. This review focuses on the clinical presentation, diagnosis, and treatment objectives for common forms of renal vasculitis seen in pediatric patients.

Clinical profile of children incidentally found to have advanced kidney failure.

INTRODUCTION: No data exist on the epidemiology of children incidentally diagnosed with advanced kidney failure (KF) during evaluation for non-specific symptoms. This is likely related to unrecognized symptoms and signs of CKD. The objective of our study was to evaluate incidentally diagnosed patients with advanced KF requiring long-term kidney replacement therapy (KRT). METHODS: An IRB-approved retrospective chart review of children who started KRT with dialysis (hemo- or peritoneal) was conducted. Included were children with no prior knowledge or diagnosis of underlying kidney disease with chronic kidney disease (CKD) disease stage 4 (GFR 15-29 mL/min/1.73 m2) or 5 (GFR < 15 mL/min/1.73 m2) at initial presentation and started on chronic KRT within 2 months of presentation. RESULTS: Of 177 patients initiating KRT during the study period, 26 (15%) were categorized as incidental advanced KF. This cohort with mean age 12.25 years consisted of 42% males, 54% African Americans included 46% with glomerular, and 54% with non-glomerular etiology for kidney failure. Vomiting (42%) and fatigue (39%) were most common, while growth failure (19%) and hyperkalemia (7%) were less frequent on initial presentation. Anemia (100%), hypertension (96%), hyperparathyroidism (96%), and hyperphosphatemia (92%) were the most frequently seen CKD comorbidities. Chronic KRT was started within 24 h in 62% and within 2 weeks in 88% of the cohort. CONCLUSION: Under-diagnosis of patients with advanced KF is most likely related to milder non-specific clinical symptoms and normal growth in the majority of patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Acute Kidney Injury in Pediatric Acute SARS-CoV-2 Infection and Multisystem Inflammatory Syndrome in Children (MIS-C): Is There a Difference?

Objective: To evaluate the prevalence and factors associated with the risk of acute kidney injury (AKI) in pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and multisystem inflammatory syndrome in children (MIS-C). Study Design: We performed a retrospective chart review of 113 patients with SARS-CoV-2 infection with or without MIS-C admitted at Children's Hospital of Michigan (CHM) from March to August 2020. Patient demographic details, laboratory data, imaging studies, echocardiography reports, and treatment data were collected. Results: Of the 92 patients included in the final analysis, 22 (24%) developed AKI with 8/22 (36%) developing stage 3 AKI. The prevalence of AKI was much higher in patients with MIS-C 15/28 (54%) vs. those with acute SARS-CoV-2 infection 7/64 (11%), (p < 0.001). Overall, when compared to patients without AKI, patients with AKI were older in age (11 vs. 6.5 years, p = 0.007), African American (86 vs. 58%, p = 0.028), had MIS-C diagnosis (68 vs. 19%, p < 0.001), required ICU admission (91 vs. 20%, p < 0.001), had cardiac dysfunction (63 vs. 16%, p < 0.001), required inotropic support (59 vs. 6%, p < 0.001) and had a greater elevation in inflammatory markers. In a multivariate analysis, requirement of inotropes [Odds Ratio (OR)-22.8, p < 0.001], African American race (OR-8.8, p = 0.023) and MIS-C diagnosis (OR-5.3, p = 0.013) were the most significant predictors for AKI. All patients had recovery of kidney function, and none required kidney replacement therapy. Conclusion: Children with acute SARS-CoV-2 infection and MIS-C are at risk for AKI, with the risk being significantly greater with MIS-C. The pathogenesis of AKI in acute SARS-CoV-2 infection appears to be a combination of both renal hypo-perfusion and direct renal parenchymal damage whereas in MIS-C, the renal injury appears to be predominantly pre-renal from cardiac dysfunction and capillary leak from a hyperinflammatory state. These factors should be considered by clinicians caring for these children with a special focus on renal protective strategies to aid in recovery and prevent additional injury to this high-risk subgroup.

Intraperitoneal vancomycin treatment of multifocal methicillin-resistant Staphylococcus aureus osteomyelitis in a patient on peritoneal dialysis.

PURPOSE: We report the case of a 2-year-old girl with end-stage renal disease managed by peritoneal dialysis (PD) who developed methicillin-resistant staphylococcal osteomyelitis of the left shoulder and was successfully treated with intraperitoneal (IP) administration of vancomycin for 2 weeks followed by oral clindamycin therapy. SUMMARY: The patient was hospitalized with tactile fever and a 3-day history of worsening fussiness. Radiography of the left shoulder showed findings indicative of osteomyelitis. Vancomycin was administered via central venous line for 3 days, during which time the patient underwent PD 24 hours a day. After magnetic resonance imaging revealed proximal humeral osteomyelitis, septic arthritis of the shoulder joint, and osteomyelitis of the scapula, the patient underwent incision and drainage of the left shoulder joint. Both blood and joint drainage cultures grew methicillin-resistant Staphylococcus aureus that was sensitive to vancomycin. The patient's central venous catheter was removed on hospital day 4; due to difficulties with peripheral i.v. access and a desire to avoid placing a peripherally inserted central venous catheter, vancomycin administration was changed to the IP route, with vancomycin added to the PD fluid. During IP treatment, serum vancomycin levels were maintained at 13.5 to 18.5 mg/L, and the calculated ratio of vancomycin area under the curve to minimum inhibitory concentration was maintained above 400. After completing a 14-day course of IP vancomycin therapy, the patient was switched to oral clindamycin, with subsequent complete resolution of osteomyelitis. CONCLUSION: IP vancomycin was effective for treatment of invasive S. aureus infection in this case. This approach should be considered in patients undergoing PD for whom peripheral i.v. access options are limited and/or not preferred.

KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for hemodialysis vascular access since 1996. Since the last update in 2006, there has been a great accumulation of new evidence and sophistication in the guidelines process. The 2019 update to the KDOQI Clinical Practice Guideline for Vascular Access is a comprehensive document intended to assist multidisciplinary practitioners care for chronic kidney disease patients and their vascular access. New topics include the end-stage kidney disease "Life-Plan" and related concepts, guidance on vascular access choice, new targets for arteriovenous access (fistulas and grafts) and central venous catheters, management of specific complications, and renewed approaches to some older topics. Appraisal of the quality of the evidence was independently conducted by using a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and interpretation and application followed the GRADE Evidence to Decision frameworks. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research.

KDOQI Clinical Practice Guideline for vascular access: 2019 update

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidencebased guidelines for hemodialysis vascular access since 1996. Since the last update in 2006, there has been a great accumulation of new evidence and sophistication in the guidelines process. The 2019 update to the KDOQI Clinical Practice Guideline for Vascular Access is a comprehensive document intended to assist multidisciplinary practitioners care for chronic kidney disease patients and their vascular access. New topics include the end-stage kidney disease "Life-Plan" and related concepts, guidance on vascular access choice, new targets for arteriovenous access (fistulas and grafts) and central venous catheters, management of specific complications, and renewed approaches to some older topics. Appraisal of the quality of the evidence was independently conducted by using a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and interpretation and application followed the GRADE Evidence to Decision frameworks. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research

APOL1-Associated Collapsing Focal Segmental Glomerulosclerosis in a Patient With Stimulator of Interferon Genes (STING)-Associated Vasculopathy With Onset in Infancy (SAVI).

Apolipoprotein L1 (APOL1) risk variants G1 and G2 are known to result in risk for kidney disease in patients of African ancestry. APOL1-associated nephropathy typically occurs in association with certain environmental factors or systemic diseases. As such, there has been increasing evidence of the role of interferon (IFN) pathways in the pathogenesis of APOL1-associated collapsing glomerulopathy in patients with human immunodeficiency virus (HIV) infection and systemic lupus erythematosus, 2 conditions that are associated with high IFN levels. Collapsing glomerulopathy has also been described in patients receiving exogenous IFN therapy administered for various medical conditions. We describe a patient with a genetic condition that results in an increased IFN state, stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI), who developed collapsing glomerulopathy during a flare of his disease. The patient was found to have APOL1 G1 and G2 risk variants. This case supports the role of IFN in inducing APOL1-associated collapsing glomerulopathy.

Recommended Clinical Trial End Points for Dialysis Catheters.

Central venous catheters are used frequently in patients on hemodialysis as a bridge to a permanent vascular access. They are prone to frequent complications, including catheter-related bloodstream infection, catheter dysfunction, and central vein obstruction. There is a compelling need to develop new drugs or devices to prevent central venous catheter complications. We convened a multidisciplinary panel of experts to propose standardized definitions of catheter end points to guide the design of future clinical trials seeking approval from the Food and Drug Administration. Our workgroup suggests diagnosing catheter-related bloodstream infection in catheter-dependent patients on hemodialysis with a clinical suspicion of infection (fever, rigors, altered mental status, or unexplained hypotension), blood cultures growing the same organism from the catheter hub and a peripheral vein (or the dialysis bloodline), and absence of evidence for an alternative source of infection. Catheter dysfunction is defined as the inability of a central venous catheter to (1) complete a single dialysis session without triggering recurrent pressure alarms or (2) reproducibly deliver a mean dialysis blood flow of >300 ml/min (with arterial and venous pressures being within the hemodialysis unit parameters) on two consecutive dialysis sessions or provide a Kt/V≥1.2 in 4 hours or less. Catheter dysfunction is defined only if it persists, despite attempts to reposition the patient, reverse the arterial and venous lines, or forcefully flush the catheter. Central vein obstruction is suspected in patients with >70% stenosis of a central vein by contrast venography or the equivalent, ipsilateral upper extremity edema, and an existing or prior history of a central venous catheter. There is some uncertainty about the specific criteria for these diagnoses, and the workgroup has also proposed future high-priority studies to resolve these questions.

Dialysis in Children and Adolescents: The Pediatric Nephrology Perspective.

The care of children with end-stage renal disease (ESRD) is highly specialized and often poorly understood by nonpediatric providers and facility/institution administrators. As such, this position paper has been created to offer provider, facility, and institutional guidance regarding the components of care necessary for children receiving dialysis. Key differences between adult and pediatric dialysis units are highlighted. Responsibilities and expectations of the members of the interdisciplinary dialysis team are outlined as they pertain specifically to the care of pediatric dialysis patients. Physical and staffing requirements of the dialysis facility are reviewed, again focusing on unique needs and challenges faced by the pediatric dialysis care team. Among these, vascular access options and proper planning of ESRD care are underscored. Pediatric quality-of-life metrics differ significantly from adult quality variables, and proper tools for assessment must be used. Endorsed by the Council of the American Society of Pediatric Nephrology (ASPN), this position paper serves as a reference tool for the provision of care to pediatric patients with ESRD.

FAT1 mutations cause a glomerulotubular nephropathy.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Treatment of Hypertension in Children With Catecholamine-Secreting Tumors: A Systematic Approach.

Management of blood pressure in children with pheochromocytoma and other catecholamine-secreting tumors (CSTs) is unique and challenging. The authors report a single-center experience using sequential α-adrenergic blockade (phenoxybenzamine), increased fluid intake, and ß-blockade for presurgical management of 10 CSTs in children. In this retrospective review, mean duration for blood pressure control in preparation for surgery was 4.5±2.6 weeks. Intraoperative hypertension was noted transiently (<2 hours) in eight patients (80%) and was treated with continuous infusion of short-acting antihypertensive agents. Two (20%) patients required vasopressor medication infusion to manage intraoperative hypotension. Only two (20%) patients developed postoperative hypotension and required vasopressor medication infusion for <24 hours. All antihypertensive medications were discontinued in the immediate (≤4 days) postoperative period in 80% of patients. In conclusion, a systematic and multidisciplinary approach utilizing adrenergic blockade is effective in treating children with CSTs.

Barriers, biases, and beliefs about arteriovenous fistula placement in children: a survey of the International Pediatric Fistula First Initiative (IPFFI) within the Midwest Pediatric Nephrology Consortium (MWPNC).

There has been recent emphasis on increased arteriovenous fistula (AVF) use and decreased central venous catheter use in hemodialysis (HD) patients. The International Pediatric Fistula First Initiative was founded via collaborative effort with the Midwest Pediatric Nephrology Consortium to alert nephrologists, surgeons, and dialysis staff to consider fistulae as the best access in pediatric HD patients. A multidisciplinary educational DVD outlining expectations and strategies to increase AVF placement and usage in children was created. Participants were administered a survey previewing and postviewing to identify barriers to placement and usage of AVF in children. A total of 52 surveys were subdivided as either "dialysis staff" or "proceduralist" at five centers. Thirty-three percent of respondents were unaware if their practice was following published guidelines. Sixty-five percent of respondents stated they referred to a dedicated vascular access surgeon at their respective institutions. Methods used to monitor AVF function included physical exam, venous pressure monitoring, and ultrasound dilution. Vascular access was placed within 3 months in only 35% of patients. Interdisciplinary communication problems between surgeons, interventional radiologists, and nephrologists were identified as a major barrier. Lack of AVF usage was often due to maturation failure. Routine access rounds did not occur in any centers. Regarding monitoring, 74% of the respondents use physical exam, 26% use venous pressure monitoring, and 9% use ultrasound dilution. Ninety-three percent of dialysis staff stated they would change practice patterns following the intervention; however, 12% of surgeons stated they would alter practice patterns. To our knowledge, this is the first report to identify barriers to placement of AVF in children from the perspectives of multidisciplinary team members including pediatric nephrologists, surgeons, interventional radiologists, and multidisciplinary dialysis staff.

Reducing central venous catheters in chronic hemodialysis--a commitment to arteriovenous fistula creation in children.

BACKGROUND: An internal permanent vascular access [arteriovenous fistula (AVF) or arteriovenous graft (AVG)] is preferred over central venous catheters (CVC) for chronic hemodialysis. However, CVC remain the most commonly used access in children. The objective of this study was to evaluate our experience with AVF. METHODS: We conducted a retrospective chart review of children aged 1-18 years on chronic hemodialysis from 2001 to 2012. Patients were divided into three time periods: 2001-2005, 2006-2009 and 2010-2012. A systematic approach to AVF placement was introduced in our department in 2006 which resulted in a greater number of AVF being placed and used, but the access failure rate was still higher than desired. In 2010, a more experienced vascular surgeon was contacted to perform AVF surgery in our most difficult AVF candidates. RESULTS: Sixty-five AVF were created in 55 patients (67.3 % male). The median age of the patients was 14 (3-18) years. Forty-one (63.1 %) AVF were used successfully, and this number increased from 52.6 to 57.6 to 92.3 % over the three time periods, respectively. Over time, AVF use rates increased and CVC use decreased. By 2012 only 7.7 % of our patients were using a CVC. The primary patency rate was 42.9 % at 1 year; secondary patency rates were 100 and 93.8 % at 1 and 2 years, respectively. Infection and hospitalization rates were higher for CVC than for AVF [0.8 vs. 0.1 infections per access-year (p < 0.001) and 0.9 vs. 0.2 hospitalizations per access-year (p < 0.001)]. CONCLUSIONS: With a dedicated approach and vascular access team it is possible to decrease CVC and increase AVF use in children on hemodialysis. In our study, increased AVF use resulted in decreased access-related infection and hospitalization rates.

Vitamin D deficiency is associated with increased left ventricular mass and diastolic dysfunction in children with chronic kidney disease.

Cardiovascular disease currently is the leading cause of morbidity and mortality among patients with chronic kidney disease (CKD). Abnormalities in arterial compliance, increased left ventricular mass, and diastolic dysfunction are some of the recognized cardiovascular complications observed in these patients. This study explored the relationship between various parameters of calcium-phosphorus metabolism including 25-hydroxy vitamin D and cardiovascular structure and function in pediatric patients with CKD. This cross-sectional study was conducted using a cohort of 34 children with CKD who had no history of underlying congenital or structural cardiac disease. Two-dimensional echocardiography was used to measure the left ventricular mass index (LVMI), E/A ratio, E', E/E' ratio, and myocardial performance index (MPI). The augmentation index (AI), derived via radial artery tonometry, was used as an indirect measure of central aortic stiffness. Serum biochemical markers of calcium-phosphorus metabolism were simultaneously measured. Univariate analysis showed that LVMI correlated with 25-hydroxy vitamin D (r = -0.54; p < 0.05), systolic blood pressure (SBP) (r = 0.36; p < 0.05), and AI (r = 0.26; p < 0.05). Serum-intact parathyroid hormone (PTH) levels correlated with the E/E' ratio (r = 0.63; p < 0.05) and E' (r = -0.61; p < 0.05). Multiple regression analysis showed that 25-hydroxy vitamin D and SBP were independent predictors of increased LVMI and that PTH was an independent predictor of diastolic dysfunction. This is the first study investigating pediatric patients with CKD that suggests an etiology of nutritional vitamin D deficiency associated with increased left ventricular mass and diastolic dysfunction. The cardiovascular changes observed are not easily reversible. Hence, early preventive therapy with vitamin D supplementation is advocated.

Race-specific relationship of birth weight and renal function among healthy young children.

BACKGROUND: Low birth weight is associated with diminished renal function. However, despite African Americans being at increased risk of low birth weight and chronic kidney disease, little is known about the association between birth weight and renal function in diverse groups. We examined racial differences in the relationship of birth weight and renal function among healthy young children. METHODS: Birth weight and serum creatinine data were available on 152 children (61.8% African American; 47.4% female) from a birth cohort. Estimated glomerular filtration rate (eGFR) was calculated using the bedside Schwartz equation and gender- and gestational-age-adjusted birth weight Z-scores using the US population as a reference. Race-specific linear regression models were fit to estimate the association between birth weight Z-score and eGFR. RESULTS: Mean age was 1.5 ± 1.3 years at first eGFR measurement. African Americans had lower eGFR than non-African Americans (median eGFR = 82 vs. 95 ml/min per 1.73 m(2); p = 0.06). Birth weight was significantly and positively associated with eGFR among African American (p = 0.012) but not non-African American children (p = 0.33). CONCLUSIONS: We provide, for the first time, evidence suggesting that birth weight is associated with renal function in African American children. Future work is needed to determine if prenatal programming helps explain racial disparities in adult health.

The impact of change in volume and left-ventricular hypertrophy on left-ventricular mechanical dyssynchrony in children with end-stage renal disease.

Left-ventricular dyssynchrony (LVD) adversely affects systolic performance and has not been previously evaluated in children with end-stage renal disease (ESRD). We hypothesized (1) that LVD in children with ESRD would be significantly increased compared with controls and (2) that volume load and left-ventricular hypertrophy (LVH) would be associated with increased LVD. This was a prospective observational study in which real-time three-dimensional echocardiographic data were acquired in 27 stable children with ESRD (13 peritoneal dialysis [PD] and 14 hemodialysis [HD]) and 29 normal controls. Data were acquired before and after an HD session. Dyssynchrony index (SDI) was defined per standard formulae and was normalized to cardiac cycle duration (SDIp). Left-ventricular mass (LVM) was obtained from M-mode echocardiography and was normalized to height(2.7) (LVM index). The mean age (13.8 vs. 11.3 years) and SDI, SDIp, LVM, and LVM index were significantly greater among children with ESRD than among controls (p < 0.05). Demographics and heart rates were comparable between HD and PD subgroups, whereas SDI 16 and 12 segments, SDIp 16 segments, and LVM were significantly greater in the HD group. SDI and SDIp 16 segments improved after an HD session (p < 0.05); LVM and LVM index remained unchanged. LVD was significantly greater in patients with LVH compared with those without LVH. Children with ESRD had significant LVD and increased LVM compared with controls. Increased LVD in those undergoing HD rather than PD, as well as the improvement in synchrony after HD, suggest that volume may modulate LVD. LVD was increased in children with LVH. LVD in children with ESRD may have pathogenic implications.