Clinical relevance of membrane attack complex deposition in children with IgA nephropathy and Henoch-Schönlein purpura.

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schönlein purpura are common glomerular disorders in children sharing the same histopathologic pattern of IgA deposits within the mesangium, even if their physiopathology may be different. Repeated exposure to pathogens induces the production of abnormal IgA1. The immune complex deposition in the renal mesangium in IgAN or potentially in small vessels in Henoch-Schönlein purpura induces complement activation via the alternative and lectin pathways. Recent studies suggest that levels of membrane attack complex (MAC) in the urine might be a useful indicator of renal injury. Because of the emerging availability of therapies that selectively block complement activation, the aim of the present study is to investigate whether MAC immunostaining might be a useful marker of IgA-mediated renal injury. METHODS: We conducted immunohistochemistry analysis of the MAC on renal biopsies from 67 pediatric patients with IgAN and Henoch-Schönlein purpura. We classified their renal biopsies according to the Oxford classification, retrieved symptoms, biological parameters, treatment, and follow-up. RESULTS: We found MAC expression was significantly related to impaired renal function and patients whose clinical course required therapy. MAC deposits tend to be more abundant in patients with decreased glomerular filtration rate (p = 0.02), patients with proteinuria > 0.750 g/day/1.73 m2, and with nephrotic syndrome. No correlation with histological alterations was observed. CONCLUSIONS: We conclude that MAC deposition could be a useful additional indicator of renal injury in patients with IgAN and Henoch-Schönlein purpura, independent of other indicators.

The Québec NTBC Study.

In this chapter we describe the current Quebec NTBC Study protocol. Quebec's unique characteristics have influenced the development of the protocol, including a high prevalence of hepatorenal tyrosinemia (HT1), universal newborn screening for HT1, availability of treatment with nitisinone (NTBC) and special diet, a large territory, where HT1 treatment is coordinated by a small number of centers. Screened newborns are seen within 3 weeks of birth. Patients with liver dysfunction (prolonged prothrombin time and/or international normalized ratio (INR) provide sensitive, rapidly available indicators) are treated by NTBC and special diet. The specific diagnosis is confirmed by diagnostic testing for succinylacetone (SA) in plasma and urine samples obtained before treatment. After an initial period of frequent surveillance, stable patients are followed every 3 months by assay of plasma amino acids and NTBC and plasma and urine SA. Abdominal ultrasound is done every 6 months. Patients have an annual visit to the coordinating center that includes multidisciplinary evaluations in metabolic genetics, hepatology, imaging (for abdominal ultrasound and magnetic resonance imaging) and other specialties as necessary. If hepatocellular carcinoma is suspected by imaging and/or because of progressive elevation of alphafetoprotein, liver transplantation is discussed. To date, no patient in whom treatment was started before 1 month of age has developed hepatocellular carcinoma, after surveillance for up to 20 years in some. This patient group is the largest in the world that has been treated rapidly following newborn screening. The protocol continues to evolve to adapt to the challenges of long term surveillance.

Ascending Aorta Elastography After Kawasaki Disease Compared to Systemic Hypertension.

Kawasaki disease (KD) is a systemic vasculitis, classically affecting large- and medium-size arteries. The coronary arteries draw most of the clinical attention, whereas few studies have taken interest in the ascending aorta. Using a proprietary imaging-based mechanical biomarker (ImBioMark), we sought to determine aortic stiffness in KD compared to systemic hypertension (HTN) and healthy children. We evaluated parasternal long-axis views focused on the ascending aorta in 20 controls, 12 KD, and 8 HTN as a comparative clinical model of vascular stiffness. We calculated systolic and diastolic aortic wall strain with ImBioMark. Strain was tested for normality against height, systolic, and diastolic blood pressure in normal subjects. Strain from KD and HTN was normalized (Z score) accordingly. Z score comparisons were performed using nonparametric statistics. Age was similar between KD and HTN (9.1 ± 5.3 and 9.9 ± 5.3 years old; p = NS). Systolic and diastolic strain values were normally distributed against height, systolic blood pressure, and diastolic blood pressure in healthy subjects. HTN subjects had abnormal systolic and diastolic strain values (p < 0.0001). Whereas KD subjects had normal diastolic strain, systolic strain was significantly lower (p < 0.001), and systolic strain was intermediate between controls and HTN. There were no significant differences in aortic strain among KD, however, according to the presence of coronary artery aneurysms. Despite normal blood pressure, the ascending aorta in KD exhibits reduced strain during systole. This may reflect in situ rigidity of the aorta. The normal diastolic strain in KD may, in contrast, reflect normal peripheral vascular resistance.

Vascular access for chronic hemodialysis in children: arteriovenous fistula or central venous catheter?

BACKGROUND: The choice of vascular access (VA) for hemodialysis (HD) in end-stage renal disease (ESRD) is arteriovenous fistula (AVF) or central venous catheter (CVC). Whereas clinical practice guidelines suggest AVF to preserve the vascular bed, pediatric nephrologists tend to favor CVC for shorter-term dialysis. Our objective was to determine whether pediatric priority allocation policies for deceased-donor kidneys affect VA planning. METHODS: Pediatric priority for deceased-donor kidneys was instituted in Quebec in 2004. We retrospectively compared clinical practice on AVF, CVC, wait time on transplant list, HD duration in pre-policy (group A) and post-policy (group B) from 1997-2011. RESULTS: We identified 78 patients with a median age of 14.7 years (range, 0.7-20.5 years) and weight of 46 kg (12.5-95 kg); AVF decreased from 76 % in group A to 41 % in group B (p = 0.002). Wait times on transplant list were significantly reduced: median 413.5 days (range, 2-1,910 days) in group A vs. 89 days (range, 18-692 days) in group B (p = 0.003). Time on HD for deceased-donor recipients was shorter: 705 (range, 51-1,965 days) group A vs. 349.5 days (range, 158-1,060 days) group B (p = 0.01). CONCLUSIONS: This is the first study to document VA changes related to pediatric priority allocation policy. Our fistula-first center saw a shift toward CVC-first.

Molecular Absorbent Recirculating System therapy (MARS®) in pediatric acute liver failure: a single center experience.

BACKGROUND: Supportive care as a bridge to transplant or recovery remains challenging in children suffering from acute liver failure (ALF). We report our experience in children using the Molecular Absorbent Recirculating System (MARS(®)). METHODS: Retrospective data from children receiving therapy using MARS(®) from October 2009 to October 2012 were included in this single-center retrospective study. Patient characteristics, clinical presentation and complications of ALF, clinical and biological data before and after each MARS(®) session, technical modalities and adverse events were recorded. RESULTS: A total of six children underwent 17 MARS(®) sessions during the study period. Two adolescents were treated with the adult filter MARSFLUX(®) and four infants were treated with the MiniMARS(®) filter. The mean PEdiatric Logistic Dysfunction (PELOD) score at admission was 19 (range 11-33). All patients were mechanically ventilated, and four had acute kidney injury. The neurological course improved in one case, judged as stable in two cases and worsened in one case; data were unavailable in two cases. Mean serum ammonia levels decreased significantly following treatment with MARS(®) from an initial 89 ± 29 to 58 ± 35 mcmol/L (p = 0.02). No other significant biological improvement was observed. Hemodynamic status improved/remained unchanged in the adolescent group, but in the infants four of the seven sessions were poorly tolerated and two sessions were aborted. Three patients died, two were successfully transplanted and one recovered without transplantation. CONCLUSION: In our experience, treatment with MARS(®) is associated with encouraging results in adolescents, but it needs modification for very sick infants to improve tolerance.

Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.

BACKGROUND: Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994. METHODS: We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1 month of age (26 patients) and those treated before 1 month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter. FINDINGS: No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26 months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5 years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia. INTERPRETATION: Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1 month had no detectable liver disease after more than 5 years.

Impact of blood volume monitoring on fluid removal during intermittent hemodialysis of critically ill children with acute kidney injury.

BACKGROUND: In chronic pediatric patients treated with intermittent hemodialysis (IHD), blood volume monitoring (BVM) is commonly used to assess and manage volume status during the dialysis session. Minimal data exists on its use during IHD in critically ill children with acute kidney injury (AKI). In these cases, fluid removal may be limited by hemodynamic instability. METHODS: We present a retrospective study conducted in our pediatric intensive care unit. For eligible patients, demographic data and IHD treatment characteristics were recorded including BVM use, ultrafiltration (UF) volume per session, hypotensive episodes and intradialysis interventions. Hypotensive episodes and UF per IHD session were compared between IHD sessions with BVM (BVM group) and IHD sessions without BVM (control group). RESULTS: Twenty-three AKI patients with a median age of 11 years (1.8-18) and body weight of 36 kg (10-85) received 134 IHD sessions (70 with BVM and 64 without BVM). Hypotensive episodes occurred in 34% of all sessions with no significant difference between the BVM group and the control group: (95% CI: 22%, 44%) and 36% (95% CI: 24%, 48%), respectively, but UF per session was higher in the BVM group as compared to control (48 ± 27 mL/kg and 33 ± 26 mL/kg, respectively, P = 0.0001). The mean decrease in BVM did not exceed 13% over an entire dialysis session in patients without hypotension. CONCLUSION: In conclusion, in our experience of IHD sessions in critically ill children with AKI, the use of BVM allowed a higher UF in those with BVM without influencing the frequency of hypotensive episodes. Applying specific guidelines on BVM use may decrease hypotensive episodes during IHD treatment in critically ill patients.

Bartter syndrome in two sisters with a novel mutation of the CLCNKB gene, one with deafness.

This article describes two sisters with type III Bartter syndrome (BS) due to a novel missense variant of the CLCNKB gene. The phenotypic expression of the disease was very different in these two siblings. In one sister, the disease followed a very severe course, especially in the neonatal period and as a toddler. Both the classic symptoms and the biochemical features of the syndrome were striking. In addition, she presented with sensorineural deafness, a complication yet unreported in this subtype of BS In contrast, the least affected sister was symptom free and the biochemical features of the disease although present remained discrete throughout the prolonged follow-up. It is suggested that such a difference in the phenotypic expression of the disease is possibly secondary to the modifier effect of a gene and/or results from environmental factor(s).

Severe Acute Kidney Injury and Multiple Organ Failure in a 17-Day-Old Newborn: When Pathology Makes the Difference.

RATIONALE: Acute tubulointerstitial nephritis (ATIN) in children is most commonly due to allergic drug reactions. In neonates, diagnosis of ATIN is clinically suspected and a kidney biopsy is not routinely performed. PRESENTING CONCERN: A 17-day-old newborn presented with vomiting and dehydration, along with anuric acute kidney injury, severe electrolyte disturbances, hypocomplementemia, and thrombocytopenia. Abdominal ultrasound revealed bilateral nephromegaly and hepatosplenomegaly. The patient was promptly started on intravenous (IV) fluid and broad-spectrum antibiotics. His electrolyte disturbances were corrected as per standard guidelines. The rapid progressive clinical deterioration despite maximal treatment and the unclear etiology influenced the decision to proceed to a kidney biopsy. Histopathological findings revealed diffuse interstitial edema with a massive polymorphic cellular infiltrate and destruction of tubular structures, consistent with severe ATIN. Elements of thrombotic microangiopathy (TMA) were observed. DIAGNOSIS: The clinical presentation combined with imaging and histopathological findings was suggestive of ATIN caused by a severe acute bacterial pyelonephritis. INTERVENTION: Methylprednisolone pulses followed by oral prednisolone were administered. Antibiotics were continued for 10 days. The patient was kept on invasive mechanical ventilation and on peritoneal dialysis for 12 days. OUTCOME: His condition stabilized following steroid pulses. His renal function progressively improved, and renal replacement therapy was weaned off. His renal ultrasound normalized. He has maintained a normal blood pressure, urinalysis, and renal function over the past 5 years. NOVEL FINDING: This case reports a severe presentation of acute bacterial pyelonephritis in a neonate. It highlighted the involvement of complement activation in severe infectious process. Histopathological findings of ATIN and TMA played a crucial role in understanding the physiopathology and severity of the disease.

JUSTIFICATION: La néphrite tubulo-interstitielle aiguë (NTIA) chez l'enfant est le plus souvent attribuée à une réaction allergique aux médicaments. Chez les nouveau-nés, le diagnostic de la NTIA est cliniquement suspecté et une biopsie des reins n'est pas pratiquée de façon systématique. PRÉSENTATION DU CAS: Un nouveau-né âgé de dix-sept jours pris de vomissements et déshydraté qui présentait une insuffisance rénale aiguë anurique, un grave déséquilibre électrolytique, une hypocomplémentémie et une thrombocytopénie. L'échographie abdominale a révélé une hypertrophie rénale bilatérale ainsi qu'une hépatosplénomégalie. Le patient a rapidement été traité avec des antibiotiques à large spectre par voie intraveineuse (IV), et les déséquilibres électrolytiques ont été corrigés conformément aux lignes directrices normalisées. La détérioration clinique rapide et progressive du patient malgré un traitement maximal et une étiologie incertaine a orienté la décision de procéder à une biopsie rénale. Les résultats histopathologiques ont révélé un œdème interstitiel diffus avec infiltrat cellulaire polymorphe et une destruction des structures tubulaires; des observations cohérentes avec une NTIA grave. Des éléments d'une microangiopathie thrombotique (MAT) avaient également été observés. DIAGNOSTIC: Le tableau clinique combiné aux résultats histopathologiques et d'imagerie suggérait une NTIA causée par une pyélonéphrite bactérienne grave. INTERVENTION: Le traitement a consisté en des injections répétées de méthylprednisolone suivies par l'administration orale de prednisolone. Le traitement aux antibiotiques s'est poursuivi sur une période de dix jours. Le patient a également été maintenu sous ventilation mécanique effractive et sous dialyse péritonéale pendant douze jours. RÉSULTATS: L'état du patient s'est stabilisé à la suite des injections répétées de stéroïdes; sa fonction rénale s'est progressivement améliorée et la thérapie de remplacement rénal a pu être cessée. L'échographie rénale s'est normalisée. Le patient a maintenu une tension artérielle, des analyses d'urine et une fonction rénale normales au cours des cinq dernières années. CONSTATATIONS: Ce rapport présente un cas grave de pyélonéphrite bactérienne aiguë chez un nouveau-né et a mis en lumière le rôle de l'activation du complément dans un processus infectieux grave. Les observations histopathologiques de la NTIA et de la MAT ont joué un rôle essentiel dans la compréhension de la physiopathologie et de la gravité de la maladie.

Risk factors of acute renal failure in critically ill children: A prospective descriptive epidemiological study.

OBJECTIVE: Acute renal failure is a serious condition in critically ill patients, but little literature is available on acute renal failure in critically ill children. The aim of the study was to determine incidence rate, identify risk factors, and describe the clinical outcome of acute renal failure in the pediatric intensive care unit (PICU). DESIGN: Prospective, descriptive study. SETTING: A tertiary PICU. PATIENTS: Patients were 1,047 consecutively admitted children over a 1-yr period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute renal failure was defined as doubling of baseline serum creatinine. A comparison between patients with acute renal failure and without acute renal failure was carried out, and the risk factors playing a significant role in the manifestation of acute renal failure were analyzed. There were 985 cases included in the study, with the incidence rate of acute renal failure in PICU being 4.5%. The most common PICU admission diagnoses in acute renal failure cases were hemolytic uremic syndrome (18.2%), oncologic pathologies (18.2%), and cardiac surgery (11.4%). Significant risk factors for acute renal failure following multivariate analysis were thrombocytopenia (odds ratio, 6.3; 95% confidence interval, 2.5, 16.2), age >12 yrs (odds ratio, 4.9; 95% confidence interval, 1.9, 13), hypoxemia (odds ratio, 3.2; 95% confidence interval, 1.3, 8.0), hypotension (odds ratio, 3.0; 95% confidence interval, 1.2, 7.5), and coagulopathy (odds ratio, 2.7; 95% confidence interval, 1.3, 5.6). The mortality rate was estimated to be higher in patients with acute renal failure compared with patients without acute renal failure (29.6% vs. 2.3%, p < .001). CONCLUSIONS: Although not frequent in the PICU, acute renal failure is associated with a significant increase in mortality. The risk factors of acute renal failure are multiple and are often present before PICU admission. A multiple-center study is planned with the intention to confirm these results.

Hemolytic uremic syndrome: late renal injury and changing incidence-a single centre experience in Canada.

Aims. To assess trends in the incidence of pediatric diarrhea-associated hemolytic uremic syndrome (D(+) HUS) and document long-term renal sequelae. Methods. We conducted a retrospective cohort study of children with D(+) HUS admitted to a tertiary care pediatric hospital in Montreal, Canada, from 1976 to 2010. In 2010, we recontacted patients admitted before 2000. Results. Of 337 cases, median age at presentation was 3.01 years (range 0.4-14). Yearly incidence peaked in 1988 and 1994-95, returning to near-1977 levels since 2003. Twelve patients (3.6%) died and 19 (5.6%) experienced long-term renal failure. Almost half (47%) The patients required dialysis. Need for dialysis was the best predictor of renal sequelae, accounting for 100% of severe complications. Of children followed ≥1 year (n = 199, mean follow-up 8.20 ± 6.78 years), 19 had severe and 18 mild-to-moderate kidney injury, a total sequelae rate, of 18.6%. Ten years or more after-HUS (n = 85, mean follow-up 15.4 ± 5.32 years), 8 (9.4%) patients demonstrated serious complications and 22 (25.9%) mild-to-moderate, including 14 (16%) microalbuminuria: total sequelae, 35.3%. Conclusions. Patients with D(+) HUS should be monitored at least 5 years, including microalbuminuria testing, especially if dialysis was required. The cause of the declining incidence of D(+)HUS is elusive. However, conceivably, improved public health education may have played an important role in the prevention of food-borne disease.

Reversible visual evoked potential abnormalities in uremic children.

In this case study, two cystinosis-related uremic children were followed at the Department of Nephrology, University of Montreal Hospital Center Sainte-Justine. Pattern-reversal visual evoked potentials were recorded at two time points, during dialysis treatment (time 1) and after renal transplant (time 2). Data were compared with those obtained from a control group (n = 6). The P1 component was selected and analyzed as the electrophysiologic marker of interest. At time 1, P1 latency was delayed, and P1 amplitude was reduced compared with control subjects. Both responses fell within normal range after kidney transplantation. These results indicate that renal failure and dialysis are associated with abnormal visual evoked potentials in children with chronic renal failure, but such alterations of visual processing are reversible after kidney transplant.

Serum prolactin levels in a uremic child: effects of bilateral nephrectomy and kidney transplantation.

Elevated levels of serum prolactin (PRL) are common and well described in patients with chronic renal failure. We report the case of a 4-year-old girl who also presented with premature thelarche and transient galactorrhea. Neither peritoneal dialysis nor hemodialysis reduced her extremely elevated levels of PRL, which fluctuated from time to time, probably reflecting variations in lactotroph secretion rate. Bilateral nephrectomy (BN) was eventually followed by a progressive and significant rise in PRL levels, suggesting that even uremic kidneys can eliminate PRL through tubular breakdown. Kidney transplantation was responsible for a very abrupt normalization of PRL serum levels, much faster than that observed for creatinine. This confirms animal studies suggesting that elimination of PRL occurs both through glomerular filtration and tubular breakdown. We hypothesized that the seemingly precocious puberty may have resulted from a combination of growth hormone therapy, elevated PRL and a rise in estrogens through the aromatization of adrenal androgens. This case illustrates the impact of dialysis, BN and kidney transplantation on PRL, providing new knowledge on renal PRL metabolism.

Draining Fluids through a Peritoneal Catheter in Newborns after Cardiac Surgery Helps to Control Fluid Balance.

Dialysis can be used in severe cases, but may not be well tolerated. In such patients, peritoneal drainage could be an alternative option for fluid removal. We report the case of a newborn with a truncus arteriosus who developed postoperatively a complicated clinical course with right ventricular dysfunction, prerenal condition as well as fluid overload despite diuretic therapy. Dialysis was indicated for fluid removal. Peritoneal dialysis was started using a surgically placed Tenckhoff catheter and stopped due to inefficacy and leaks and no other modalities of dialysis were used. However, the catheter was left in place over a period of two months for fluid drainage and removed because of unexplained fever. In order to determine the effect of peritoneal drainage, we selected a period of one week before and one week after the removal of the drain to compare daily clinical data, urine electrolytes and renal function and found a positive effect on fluid balance control. We conclude that the fluid removal by continuous peritoneal drainage is a simple and safe alternative that can be used to control fluid balance in infants after cardiac surgery.

[A specialized and integrated outpatient clinic for the care of children with chronic kidney disease: experience of CHU Sainte-Justine]. / Organisation des soins spécialisés et intégrés en ambulatoire pour la prise en charge de la maladie rénale chronique en pédiatrie: expérience du CHU Sainte-Justine.

The management and optimal care for the pediatric patient with chronic kidney disease requires attention not only to medical management, but also special focus on the psychosocial and developmental factors of children which is complicated by the presence of other disease-related complications. In recent years, specialized chronic kidney disease and predialysis clinics have been set up to facilitate and improve the quality of care of these patients with a multidisciplinary organisation and coordinated management approaches of a renal team. We present our experience in establishing such a renal management clinic named "Prévoir" for children with chronic kidney disease at Sainte-Justine Hospital.

Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations.

Atypical hemolytic uremic syndrome (aHUS) frequently results in end-stage renal failure and can be lethal. Several studies have established an association between quantitative or qualitative abnormalities in complement factor H and aHUS. Although plasma infusion and exchange are often advocated, guidelines have yet to be established. Long-term outcome for patients under treatment is still unknown. We describe a patient who, at 7 months of age, presented with aHUS associated with combined de novo complement factor H mutations (S1191L and V1197A) on the same allele. Laboratory investigations showed normal levels of complements C4, C3 and factor H. Plasma exchanges and large-dose infusion therapy resulted in a resolution of hemolysis and recovery of renal function. Three recurrences were successfully treated by intensification of the plasma infusion treatment to intervals of 2 or 3 days. This patient showed good response to large doses of plasma infusions and her condition remained stable for 30 months with weekly plasma infusions (30 ml/kg). Long-term tolerance and efficacy of such intensive plasma therapy are still unknown. Reported secondary failure of plasma therapy in factor H deficiency warrants the search for alternative therapeutic approaches.