Lawrence Copelovitch

Streptococcus pneumoniae-associated hemolytic uremic syndrome

Streptococcus pneumonia-associated hemolytic uremic syndrome (HUS) (pneumococcal HUS) is an uncommon condition mainly observed in young children. Early recognition is critical, because of the potential to improve morbidity and mortality. In our review we summarize the pathophysiology, clinical features, diagnostic difficulties and management of this potentially under-diagnosed condition.

Streptococcus pneumoniae–Associated Hemolytic Uremic Syndrome: Classification and the Emergence of Serotype 19A

Streptococcus pneumoniae–associated hemolytic uremic syndrome (HUS) is an underrecognized condition that mainly occurs in young children. Early diagnosis is important because of the potential to improve morbidity and mortality rates. The purposes of this report are to review the clinical and laboratory features of 14 patients with pneumococcal HUS and present a modified classification to capture cases that may not have been documented with a diagnosis of pneumococcal HUS. We thereby provide a rationale for including patients with concurrent disseminated intravascular coagulopathy and/or those whose culture results were negative, and we highlight the emergence of serotype 19A subsequent to the introduction of 7-valent pneumococcal protein conjugate vaccine (Prevnar). This is the largest series of such subjects (to our knowledge) from a single center. Sixty-four percent of the patients recovered without any long-term sequelae. Three patients developed chronic kidney disease, 1 developed end-stage renal failure, and 1 died in the acute phase. The greatest risk factor for the development of chronic kidney disease is the need for acute dialysis for >20 days, and death in the acute phase is rare unless meningitis is the primary infection.

Hypothesis: Dent Disease Is an Underrecognized Cause of Focal Glomerulosclerosis

BACKGROUND AND OBJECTIVES Dent disease is a hereditary form of progressive renal failure characterized by hypercalciuria and proximal tubular dysfunction. The clinical presentation is often insidious with the majority of patients remaining asymptomatic throughout childhood. Despite the seemingly mild, early course, more than 20% of 32 asymptomatic patients in one study had biopsy evidence of focal glomerulosclerosis. Furthermore, end-stage renal disease often occurs in men in early to middle adulthood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This article describes two male patients who presented with asymptomatic proteinuria and were found to have focal glomerulosclerosis. Despite the absence of nephrocalcinosis on renal ultrasound, the diagnosis of Dent disease was considered because of unexplained proteinuria. Subsequent history revealed renal calculi in each maternal family. RESULTS The clinical diagnosis of Dent disease was established by intermittent hypercalciuria and low molecular weight proteinuria and confirmed through mutational analysis. CONCLUSIONS It is hypothesized that a diagnosis of Dent disease may be unrecognized in patients with unexplained proteinuria and idiopathic focal glomerulosclerosis.

Urolithiasis in Children: Medical Approach

Childhood urolithiasis is an evolving condition with an increasing incidence and prevalence over the last 2 decades. Over that time the underlying cause has shifted from predominantly infectious to metabolic in nature. This review describes the pathophysiology, underlying metabolic abnormalities, clinical presentation, evaluation, and management of childhood urolithiasis. A comprehensive metabolic evaluation is essential for all children with renal calculi, given the high rate of recurrence and the importance of excluding inherited progressive conditions.

Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America.

Background: To better characterize Streptococcus pneumoniae-associated hemolytic-uremic syndrome (SP-HUS), we report the largest series of SP-HUS among children in North America. Methods: We surveyed pediatric members of the Emerging Infections Network to identify SP-HUS cases. Respondents contributed clinical and laboratory features of these pediatric cases. Results: A total of 37 cases occurring between 1997 and 2009 were submitted. Of them, 33 cases (89%) were culture-confirmed and 4 (11%) were diagnosed clinically. The median patient age was 2 years, and 28 (76%) patients had completed their heptavalent pneumococcal conjugate vaccination (PCV7) series. Most patients presented with pneumonia (84%) and bacteremia (78%), whereas other clinical manifestations such as pericardial effusion (14%) and meningitis (11%) were less common. Of 29 patients, with bacteremia 6 (21%) had S. pneumoniae concurrently isolated from cerebrospinal fluid or pleural fluid. Severe illness was common with 35 (95%) patients requiring admission to the intensive care unit, over half requiring mechanical ventilation and chest tube placement or video-assisted thoracoscopic surgery, and 27 (73%) requiring dialysis during hospitalization. Among 30 patients with follow-up of 6 months, 7 (23%) remained dialysis dependent, 3 (10%) had undergone renal transplantation, 4 (13%) had neurologic sequelae, and 1 (3%) died. Among 24 serotyped isolates, 96% were non-PCV7 serotypes, most commonly 19A (50%), 92% are included in PCV13, and 10% were penicillin nonsusceptible (minimal inhibitory concentration >2 &mgr;g/mL). Conclusions: North American children with SP-HUS had severe clinical manifestations and significant morbidity. In this series, nearly all cases were caused by serotypes that are not in PCV7 but are included in PCV13.

Annual Incidence of Nephrolithiasis among Children and Adults in South Carolina from 1997 to 2012

BACKGROUND AND OBJECTIVES The prevalence of nephrolithiasis in the United States has increased substantially, but recent changes in incidence with respect to age, sex, and race are not well characterized. This study examined temporal trends in the annual incidence and cumulative risk of nephrolithiasis among children and adults living in South Carolina over a 16-year period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a population-based, repeated cross-sectional study using the US Census and South Carolina Medical Encounter data, which capture all emergency department visits, surgeries, and admissions in the state. The annual incidence of nephrolithiasis in South Carolina from 1997 to 2012 was estimated, and linear mixed models were used to estimate incidence rate ratios for age, sex, and racial groups. The cumulative risk of nephrolithiasis during childhood and over the lifetime was estimated for males and females in 1997 and 2012. RESULTS Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for nephrolithiasis. Between 1997 and 2012, the mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons. Among age groups, the greatest increase was observed among 15-19 year olds, in whom incidence increased 26% per 5 years (incidence rate ratio, 1.26; 95% confidence interval, 1.22 to 1.29). Adjusting for age and race, incidence increased 15% per 5 years among females (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.16) but remained stable for males. The incidence among blacks increased 15% more per 5 years compared with whites (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.17). These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period. CONCLUSIONS The incidence of kidney stones has increased among young patients, particularly women, and blacks.

Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.

Purpose of review Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient with a S. pneumoniae infection. We review the pathophysiology, clinical course, treatment and prognosis for SpHUS. We also describe an expanded classification system that uses additional diagnostic criteria to identify more patients with a high likelihood of having SpHUS. Recent findings SpHUS often may be underdiagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology has changed with the emergence of different pneumococcal serotypes as newer pneumococcal vaccines have been introduced. Summary SpHUS accounts for 5–15% of all HUS cases. The majority of SpHUS patients have pneumonia and a low mortality rate in contrast to those with meningitis, who have a more severe clinical course. Although the pathogenesis of SpHUS remains unknown, the Thomsen–Friedenreich antigen seems to play a central role. S. pneumoniae produces neuraminidase, thereby exposing the Thomsen–Friedenreich antigen on the surface of cell membranes. Thomsen–Friedenreich antigen exposure can result in hemolysis and direct endothelial injury leading to HUS phenotype. Early identification of these patients is critical so that fresh frozen plasma may be avoided.

Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease.

Congenital Anomalies of the Kidney and Urinary Tract can be associated with Hirschsprung disease. We report on three children with a similar 16p11.2 microdeletion with a spectrum of clinical anomalies consisting of congenital anomalies of the kidney and urinary tract in two patients (Patients 1 and 2) and Hirschsprung disease in two patients (Patients 1 and 3), leading us to hypothesize that a gene in this region is associated with these phenotypes. Patient 1 presented with left renal agenesis, grade‐IV vesicoureteral reflux, and Hirschsprung disease, Patient 2 with left renal agenesis, chronic kidney disease, chronic constipation, seizures, and developmental delay, and Patient 3 with Hirschsprung disease and normal kidneys. Genome‐wide microarray analysis demonstrated overlapping microdeletions within 16p11.2. The shortest region of overlap in the three patients contained only eight genes, including the SH2 domain‐containing binding protein 1 (SH2B1), an adaptor protein which has been implicated in enhancement of the tyrosine kinase activity of RET, whose role in developmental disease of the kidney and enteric enervation is well established. Our findings suggest that 16p11.2 deletions are associated with abnormalities of renal and enteric development and we hypothesize that deletion of SH2B1 may account for the observed phenotype.

Insights from the Chronic Kidney Disease in Children (CKiD) Study

Over the last 5 years, the Chronic Kidney Disease in Children (CKiD) prospective cohort study has enrolled close to 600 children ages 1 to 16 years with mild to moderate chronic kidney disease (CKD). The main purpose of this interim report is to review the initial cross-sectional data and conclusions derived from the clinical studies conducted within CKiD in the context of findings from other pediatric CKD and end-stage renal disease (ESRD) registry and cohort studies. In particular, special emphasis was placed on studying four aspects of chronic kidney disease in children, including the identification of risk factors related to disease progression, the impact of CKD on neurocognition and quality of life (QoL), the cardiovascular morbidity associated with CKD, and identifying the causes and effects of growth failure in the context of mild to moderate kidney failure.

Risk of Fracture in Urolithiasis: A Population-Based Cohort Study Using the Health Improvement Network

BACKGROUND AND OBJECTIVES Studies have shown decreased bone mineral density in individuals with urolithiasis, but their burden of fracture remains unclear. This study sought to determine whether urolithiasis is associated with increased fracture risk across the lifespan and to delineate sex effects. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A population-based retrospective cohort study using The Health Improvement Network was performed. The median calendar year for the start of the observation period was 2004 (1994-2012). This study identified 51,785 participants with ≥1 of 87 diagnostic codes for urolithiasis and 517,267 randomly selected age-, sex-, and practice-matched participants. Cox regression was used to estimate the hazard ratio (HR) for first fracture. Fractures identified using diagnostic codes were classified by anatomic site. RESULTS Median age was 53 years, and 67% of participants were men, confirming their greater urolithiasis burden. Median time from urolithiasis diagnosis to fracture was 10 years. The HR for fracture associated with urolithiasis differed by sex and age (P for interactions, P≤0.003). In men, the adjusted HR was greatest in adolescence (1.55; 95% confidence interval [95% CI], 1.07 to 2.25) with an overall HR of 1.10 (95% CI, 1.05 to 1.16). Urolithiasis was associated with higher fracture risk in women aged 30-79 years (HR, 1.17-1.52), and was highest in women aged 30-39 years (HR, 1.52; 95% CI, 1.23 to 1.87). Peak background fracture rates were highest in boys aged 10-19 years and in women aged 70-79 years. The incidence per 10,000 person-years in participants with versus without urolithiasis was 392 versus 258 in male participants aged 10-19 years, and 263 versus 218 in women aged 70-79 years. Distribution of fracture site within sex did not differ between participants with versus without urolithiasis. CONCLUSIONS Urolithiasis was associated with higher incident fracture risk. The significantly higher risk at times of peak background fracture incidence in adolescent boys and elderly women has profound public health implications.