Hemolytic Uremic Syndrome Associated With Non-Shigatoxin-producing Infectious Agents: Expanding the Shigatoxin Theory.

Diarrhea-associated hemolytic uremic syndrome (HUS) is usually associated with shigatoxin-producing Escherichia coli or shigella infections. We report 2 cases of HUS, respectively, caused by salmonella and Campylobacter jejuni infections. None of these bacteria produce shigatoxins, and the underlying mechanism of HUS development remains unknown. In streptococcus pneumoniae-associated HUS, bacterial neuraminidase cleaves neuraminic acid and causes exposure of Thomsen-Friedenreich cryptantigen on the cell surface of, for example, erythrocytes, which induces an inflammatory response caused by binding of preformed IgM. Both campylobacter and salmonella bacteria also produce neuraminidase, and HUS development could be explained by a similar mechanism.

An Atypical Case of Atypical Hemolytic Uremic Syndrome.

We present the case of a 2-month-old infant presenting with pallor and laboratory results showing: hemoglobin 5.1 (10 to 1.5) g/dL, MCV 94.7 (75 to 105) fL, leukocytes 17.4 (7 to 15) ×10/µL, platelets 259 (150 to 450) ×10/µL, hyperbilirubinemia and renal dysfunction. A hemolytic anemia with tubular injury secondary to hemoglobinuria was suspected. Hyperhydration and packed cells were given but she deteriorated. Fluid overload with anuria further complicated the course necessating hemodialysis. Atypical hemolytic uremic syndrome was suspected and eculizumab was administered resulting in rapid improvement. Genetic analysis revealed a mutation in the gene encoding complement factor H and atypical hemolytic uremic syndrome was confirmed.

Is Plasma Exchange Efficacious in Shiga Toxin-Associated Hemolytic Uremic Syndrome? A Narrative Review of Current Evidence.

Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) is associated with significant mortality and morbidity. Case fatalities are often associated with severe neurological involvement in children and advanced age in adults but specific treatment is currently unavailable. Plasma exchange (PE) could theoretically enable removal of Shiga toxins, pro-inflammatory cytokines, and prothrombotic factors and has been used in deteriorating patients with STEC-HUS but the efficacy remains uncertain. In order to assess efficacy of PE in STEC-HUS, a literature review was performed. PubMed, Web of Science, Embase, and LiLACS were searched for reports describing the outcomes of patients with STEC-HUS treated with PE and 16 reports were included. Reports ranged from case reports to cohort studies and one case-control study with the largest study population coming from the 2011 German STEC-HUS outbreak. Outcomes were variable but seemed to point towards lower case fatality rates in the elderly and improved outcomes in children with STEC-HUS, treated with PE early in the course. However studies were mostly of low quality with risk of observation bias and confounding. Currently no definitive answers concerning the efficacy of PE in STEC-HUS can be given, highlighting the need for well performed randomized controlled trials.

A case of Graves' disease associated with membranoproliferative glomerulonephritis and leukocytoclastic vasculitis.

Background The association of hyperthyroidism with renal disease is very rare and the importance of timely clinical recognition cannot be overemphasized. Case presentation An 11-year-old girl presented with gastrointestinal symptoms while hypertension, edema and abdominal pain were noticed on clinical examination. Laboratory investigation revealed: hemoglobin 9.4 (11.5-15.5) g/dL, total white cell count 16 (4.5-12)×109/L, platelets 247 (150-450)×109/L, C-reactive protein (CRP) 31.8 (<5) mg/L, blood urea nitrogen (BUN) 126 (13-43) mg/dL, creatinine 0.98 (0.53-0.79) mg/dL, albumin 25 (35-52) g/dL, complement factor C3 0.7 (0.9-1.8) g/L, complement factor C4 0.1 (0.1-0.4) g/L, tri-iodothyronine 6.5 (2.5-5.2) pg/mL, free thyroxine 2.4 (1-1.7) ng/dL, thyroid stimulating hormone (TSH) <0.02 (0.5-4.3) mU/L. Urinalysis showed nephrotic range proteinuria. Renal function deteriorated necessitating hemodialysis (HD). A renal biopsy revealed an immune complex-mediated membranoproliferative glomerulonephritis (MPGN). Elevated thyroid hormones and suppressed TSH levels with elevated thyroperoxidase antibodies and thyroid stimulating immunoglobulins confirmed the diagnosis of Graves' disease. Corticosteroids were commenced and eventually thiamazole was added with gradual improvement of renal function, cessation of HD and discharge from the hospital. Conclusions Graves' disease complicated by MPGN is extremely rare, but can cause life-threatening complications.

Audit of Hemodialysis in Children Weighing Less than 20 kg in an African Pediatric Nephrology Unit.

Peritoneal dialysis and kidney transplantation remain the preferred choices for renal replacement therapy in young children. These options, however, are not always feasible, and hemodialysis (HD) is therefore an accepted alternative. In small children presenting with end-stage renal disease, HD presents several challenges and is often unavailable in lower- and middle-income countries. To assess these challenges and outcomes of maintenance HD in young children, we performed an audit of children below 20 kg with end-stage renal disease, receiving HD for ≥4 weeks, from 1 January 2008 to 31 July 2016 at the Red Cross War Memorial Children's Hospital. We identified 15 children weighing 6.8-18.5 kg (mean 12.9 kg ±3.5 SD) and aged 11.5-105 months (mean 52.2 months±4.2 SD) at HD initiation. Mean duration of HD was 11.8 months (range 1-61.5 months ± 16.9 SD). Seven children underwent successful transplantation, two patients died, and four currently still receive HD. Two patients, while on HD, relocated to other centers. An average of 2.6 (range 1-5) different vascular accesses was required per patient. Technical difficulties were the most common cause of central-line removal (81%), while catheter-associated bacteremia was 1.1/1000 catheter days. Frequent problems were intradialytic hypotension, growth stunting, and interdialytic hypertension. HD in lower- and middle-income countries is feasible in small children but presents with certain challenges. Advocacy with lobbying for funding and development of "child-friendly" dialysis equipment and specialized centers with highly skilled personnel are the cornerstones of successful pediatric HD programs in less-resourced centers.

A 2-year-old boy with circulatory failure owing to streptococcal toxic shock syndrome: case report.

A 2-year-old boy presented with severe hypotension and acute kidney injury after a prodrome of non-bloody diarrhoea and fever in the preceding 3 days. He had a mild Ebstein cardiac anomaly but otherwise a normal past history and growth. On examination, he looked ill, his temperature was 37.5 °C, circulation was poor, and there were several purpuric lesions on the face, hands and scrotum. Haemoglobin was 7.8 g/dL (11-14), total white cell count 27 × 109/L, platelets 62 × 109/L, blood urea nitrogen 20.7 mmol/L (4.2-17.1), serum creatinine 95.4 µmol/L (21.2-36.2), CRP 154 mg/L (<5), AST 296 U/L (11-50), ALT 909 U/L (7-40) and C3 component of complement 0.8 g/L (0.9-1.8). Activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged and fibrinogen level was 1.0 g/L (2-4). He received immediate fluid resuscitation (IV 0.9% saline solution, 2 × 10 ml/kg boluses, followed by glucose 5/0.45% sodium chloride solution, 2 × 10 ml/kg) and antibiotics (ciprofloxacin and amikacin) but circulation continued to deteriorate with development of decreased consciousness. He was placed on mechanical ventilation and vasopressor agents were added. Despite improved circulation over the next 2 days, he developed oliguria, progressive fluid overload, generalised oedema and a right-sided pleural effusion. Dialysis was commenced on day 3 of admission. Differential diagnosis included sepsis, atypical haemolytic uraemic syndrome and lupus nephritis. Blood and urine cultures remained negative but an anti-streptolysin O titre of 1318 (<200) IU/mL led to the diagnosis of streptococcal toxic shock syndrome which is rare in early childhood and associated with high mortality. Haemodialysis was commenced and continued for 10 days with successful treatment of fluid overload and subsequent extubation. Renal function was completely restored over the following 6 weeks and he was discharged in good clinical condition about 2 months after intial admission. The clinical course and outcome are discussed, and the importance of timely initiation of dialysis when there is fluid overload is emphasised.

An infant presenting with failure to thrive and hyperkalaemia owing to transient pseudohypoaldosteronism: case report.

A 3-month-old boy presented with failure to thrive and a history of a prenatally detected unilateral hydroureteronephrosis which was confirmed after birth. His growth and developmental milestones had been normal during the first 2 months but in the third month his appetite was poor with reduced intake but no vomiting. At presentation, his temperature was normal, there was mild dehydration and there was weight loss (his weight had decreased by 270 g in the past month). Haemoglobin was 11.9 g/dL, total white cell count 20.2 × 109/L (7-15) [neutrophils 30% (39-75) and lymphocytes 61% (16-47)], platelets 702 × 109/L (150-450), BUN12.1 mmol/L (2.1-16.1), serum creatinine 35.4 µmol/L (15.0-37.1), sodium 126 mmol/L (135-144), potassium 6.8 mmol/L (3.6-4.8), chloride 88 mmol/L (98-106) and bicarbonate 14 mmol/L (19-24). Intravenous rehydration with sodium chloride 0.9% solution was commenced and he was transferred to the paediatric intensive care unit. A salt-wasting syndrome was suspected and a differential diagnosis included adrenal insufficiency, pseudohypoaldosteronism and congenital adrenal hyperplasia (owing to 21-hydroxylase deficiency). Urinalysis confirmed a urinary tract infection. Serum aldosterone was 3608 ng/dL (3.7-43.2), plasma renin activity > 38.9 pmol/L (<0.85), random cortisol 459 nmol/L (74-289), adrenocorticotropic hormone (ACTH) 6.01 pmol/L (1.32-6.60) and 17-hydroxyprogesterone 4.01 nmol/L (<3.2). Treatment of the urinary tract infection was followed by normalisation of serum electrolytes and other biochemical abnormalities, return of appetite and normal growth, which confirmed the diagnosis of transient pseudohypoaldosteronsim (TPHA). TPHA is discussed and insight provided to enable early recognition and adequate treatment of this rare clinical entity.

Is eculizumab efficacious in Shigatoxin-associated hemolytic uremic syndrome? A narrative review of current evidence.

Severe complications due to Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) currently present a serious challenge since no specific treatment for this condition is available. Eculizumab, a terminal complement inhibitor, has been used especially in STEC-HUS patients with severe neurological involvement, but the efficacy remains undetermined. In order to determine its efficacy, we searched the databases Pubmed, Web of Science, Embase, and LiLACS for reports describing outcomes of eculizumab administration in STEC-HUS. We retrieved 11 reports ranging from case reports to cohort studies with the largest study population emanating from the 2011 German outbreak. Outcomes were variable and difficult to interpret in light of the absence of high-quality studies but seemed to point towards potential efficacy of eculizumab if administered early in the course. CONCLUSION: The efficacy of eculizumab in STEC-HUS could not be established nor disproven based on current data, and there is a desperate need for randomized controlled trials. What is known? • Eculizumab has been used in complicated cases of Shigatoxin-associated hemolytic uremic syndrome but the efficacy remains unknown? What is new? • Eculizumab might be efficacious if given early in selected cases of Shigatoxin-associated hemolytic uremic syndrome; however, randomized trials are needed to assess this.

A devastating case of diarrhea-associated hemolytic uremic syndrome associated with extensive cerebral infarction; why we need to do better.

A 4-year-old girl with diarrhea-associated hemolytic uremic syndrome (D+HUS) was transferred to the PICU of our center due to deteriorating renal function and neurological involvement. On admission, a comatous child was seen with hypoventilation and she was placed on mechanical ventilation. Hemodialysis was commenced but plasma exchange was discontinued due to repeated hypersensitivity reactions. A trial of eculizumab was given in light of the worsening of her neurologic condition with development of a pyramidal syndrome and deepening of the coma. Hematological and renal improvement were noted but severe neurologic involvement persisted. MRI revealed extensive bilateral zones of corticocerebral infarction and neurological damage proved to be irreversible. Diarrhea-associated hemolytic uremic syndrome is a common cause of Acute Kidney Injury associated with severe short- and long-term complications. Neurologic involvement is frequent but often reversible. Currently, no effective treatment strategies are available and a paucity of data exists concerning the efficacy of potential treatment options such as early plasma exchange, eculizumab, and high dose corticosteroids. A concerted effort is needed to early identify patients at risk for poor outcome with trials aimed at evaluating the efficacy of potential treatment options for this subgroup.

Urinary potassium to urinary potassium plus sodium ratio can accurately identify hypovolemia in nephrotic syndrome: a provisional study.

There is evidence pointing to a decrease of the glomerular filtration rate (GFR) in a subgroup of nephrotic children, likely secondary to hypovolemia. The aim of this study is to validate the use of urinary potassium to the sum of potassium plus sodium ratio (UK/UK+UNa) as an indicator of hypovolemia in nephrotic syndrome, enabling detection of those patients who will benefit from albumin infusion. We prospectively studied 44 nephrotic children and compared different parameters to a control group (36 children). Renal perfusion and glomerular permeability were assessed by measuring clearance of para-aminohippurate and inulin. Vaso-active hormones and urinary sodium and potassium were also measured. Subjects were grouped into low, normal, and high GFR groups. In the low GFR group, significantly lower renal plasma flow (p = 0.01), filtration fraction (p = 0.01), and higher UK/UK+UNa (p = 0.03) ratio were noted. In addition, non-significant higher plasma renin activity (p = 0.11) and aldosteron (p = 0.09) were also seen in the low GFR group. CONCLUSION: A subgroup of patients in nephrotic syndrome has a decrease in glomerular filtration, apparently related to hypovolemia which likely can be detected by a urinary potassium to potassium plus sodium ratio > 0.5-0.6 suggesting benefit of albumin infusion in this subgroup. What is Known: • Volume status can be difficult to assess based on clinical parameters in nephrotic syndrome, and albumin infusion can be associated with development of pulmonary edema and fluid overload in these patients. What is New: • Urinary potassium to the sum of urinary potassium plus sodium ratio can accurately detect hypovolemia in nephrotic syndrome and thus identify those children who would probably respond to albumin infusion.

Epidemiology and outcome of acute kidney injury in children, a single center study.

BACKGROUND: Information on the epidemiology of Acute Kidney Injury (AKI) in children is scarce. We performed a single center retrospective cohort study to analyze the incidence of AKI, the male/female ratio, the underlying etiology, and age at presentation. We also aimed to assess outcome measured by mortality, duration of PICU stay, and development of Chronic Kidney Disease (CKD). METHODS: Records were searched for children presenting with or developing AKI between 1st January 2008 and 1st January 2015. AKI was classified according to the pediatric Rifle criteria while the cause of AKI was defined as the major underlying disease. RESULTS: Of the 28,295 children admitted, 167 episodes of AKI were identified, equaling 5.9 cases per 1000 children. Patients classified as Failure at presentation according to pRifle criteria where significantly more likely to need dialysis (27/50, 54%) compared to those presenting with Injury (12/57, 21.1%) or Risk (6/60, 10 %). Diarrhea-associated Hemolytic Uremic Syndrome (D+HUS) was the most frequent cause (20.3 %) peaking during the summer months, followed by cardiac surgery (13.7%), medication-related nephrotoxicity (13.2%), and acute Glomerulonephritis (12%). The median age of children admitted with AKI was 6.1 years (range 0.1-17) and 50.8% of cases were male. Twenty five (15%) children died while 27 (16.1%) developed CKD. CONCLUSIONS: Pediatric AKI poses a significant problem and strategies aimed at prevention, early detection, treatment, and adequate follow-up are needed. D+HUS is the most common underlying cause and effective surveillance of Enterohemorrhagic E. coli infections in association with additional measures is highly recommended.

Blood urea nitrogen to serum creatinine ratio is an accurate predictor of outcome in diarrhea-associated hemolytic uremic syndrome, a preliminary study.

Diarrhea-associated hemolytic uremic syndrome (D+HUS) is a common thrombotic microangiopathy during childhood and early identification of parameters predicting poor outcome could enable timely intervention. This study aims to establish the accuracy of BUN-to-serum creatinine ratio at admission, in addition to other parameters in predicting the clinical course and outcome. Records were searched for children between 1 January 2008 and 1 January 2015 admitted with D+HUS. A complicated course was defined as developing one or more of the following: neurological dysfunction, pancreatitis, cardiac or pulmonary involvement, hemodynamic instability, and hematologic complications while poor outcome was defined by death or development of chronic kidney disease. Thirty-four children were included from which 11 with a complicated disease course/poor outcome. Risk of a complicated course/poor outcome was strongly associated with oliguria (p = 0.000006) and hypertension (p = 0.00003) at presentation. In addition, higher serum creatinine (p = 0.000006) and sLDH (p = 0.02) with lower BUN-to-serum creatinine ratio (p = 0.000007) were significantly associated with development of complications. A BUN-to-sCreatinine ratio ≤40 at admission was a sensitive and highly specific predictor of a complicated disease course/poor outcome. CONCLUSION: A BUN-to-serum Creatinine ratio can accurately identify children with D+HUS at risk for a complicated course and poor outcome. What is Known: • Oliguria is a predictor of poor long-term outcome in D+HUS What is New: • BUN-to-serum Creatinine ratio at admission is an entirely novel and accurate predictor of poor outcome and complicated clinical outcome in D+HUS • Early detection of the high risk group in D+HUS enabling early treatment and adequate monitoring.

A 4-year-old boy presenting with persistent urinary incontinence: Questions.

A 4-year-old boy was referred to the nephrologist with daytime urinary incontinence and suspicion of an overactive bladder. At the age of 17 months he had been referred to the pediatric endocrinologist because of polyuria and polydipsia in order to exclude diabetes insipidus. Repeated water deprivation tests and a magnetic resonance imaging scan of the brain were normal. Diabetes insipidus was excluded, and primary polydipsia was thought to be most likely since diabetes mellitus also had been excluded. At the current presentation, he drank up to 3 L a day and quite often had wet diapers. He also seemed to pass stools infrequently and with difficulty. Curiously his grandmother had similar symptoms of polyuria and polydipsia since childhood and had been diagnosed with primary polydipsia. The physical examination of our pediatric patient was normal. In the differential diagnosis we included diabetes insipidus but also contemplated other possibilities, such as nephronophthisis, tubulopathies and hypercalciuria. Laboratory results including urinalysis and an ultrasound of the kidney did not show any abnormalities, making a tubulopathy or hypercalciuria unlikely. A desmopressin test by the intravenous route came back completely normal, pointing to another cause than diabetes insipidus. Genetic testing for the nephronophthisis came back negative but was positive for a missense mutation in the AVPR2 gene (p.Arg104Cys) associated with partial nephrogenic diabetes insipidus. He was started on daily desmopressin. Within 3 days the urinary incontinence resolved as did the polyuria and faecal incontinence. His grandmother was referred to the geneticist and eventually the adult nephrologist. This case highlights the importance of being thorough when confronted with a difficult diagnosis. It also emphasizes that a test result does not necessarily equate to the presence or absence of a condition since the test with 100 % sensitivity and specificity has yet to be discovered.