Clinical features, therapeutic interventions and long-term aspects of hemolytic-uremic syndrome in Norwegian children: a nationwide retrospective study from 1999-2008.

BACKGROUND: Hemolytic-uremic syndrome (HUS) is a clinical triad of microangiopathic hemolytic anemia, impaired renal function and thrombocytopenia, primarily affecting pre-school-aged children. HUS can be classified into diarrhea-associated HUS (D(+)HUS), usually caused by Shiga toxin-producing Escherichia coli (STEC), and non-diarrhea-associated HUS (D(-)HUS), both with potentially serious acute and long-term complications. Few data exists on the clinical features and long-term outcome of HUS in Norway. The aim of this paper was to describe these aspects of HUS in children over a 10-year period. METHODS: We retrospectively collected data on clinical features, therapeutic interventions and long-term aspects directly from medical records of all identified HUS cases <16 years of age admitted to Norwegian pediatric departments from 1999 to 2008. Cases of D(+)HUS and D(-)HUS are described separately, but no comparative analyses were possible due to small numbers. Descriptive statistics are presented in proportions and median values with ranges, and/or summarized in text. RESULTS: Forty seven HUS cases were identified; 38 D(+)HUS and nine D(-)HUS. Renal complications were common; in the D(+)HUS and D(-)HUS group, 29/38 and 5/9 developed oligoanuria, 22/38 and 3/9 needed dialysis, with hemodialysis used most often in both groups, and plasma infusion(s) were utilized in 6/38 and 4/9 patients, respectively. Of extra-renal complications, neurological complications occurred in 9/38 and 2/9, serious gastrointestinal complications in 6/38 and 1/9, respiratory complications in 10/38 and 2/9, and sepsis in 11/38 and 3/9 cases, respectively. Cardiac complications were seen in two D(+)HUS cases. In patients where data on follow up ≥1 year after admittance were available, 8/21 and 4/7 had persistent proteinuria and 5/19 and 4/5 had persistent hypertension in the D(+)HUS and D(-)HUS group, respectively. Two D(+)HUS and one D(-)HUS patient were diagnosed with chronic kidney disease and one D(+)HUS patient required a renal transplantation. Two D(+)HUS patients died in the acute phase (death rate; 5 %). CONCLUSIONS: The HUS cases had a high rate of complications and sequelae, including renal, CNS-related, cardiac, respiratory, serious gastrointestinal complications and sepsis, consistent with other studies. This underlines the importance of attention to extra-renal manifestations in the acute phase and in renal long-term follow-up of HUS patients.

Incidence and etiology of hemolytic-uremic syndrome in children in Norway, 1999-2008--a retrospective study of hospital records to assess the sensitivity of surveillance.

BACKGROUND: Public awareness of hemolytic-uremic syndrome (HUS), especially related to Shiga toxin-producing Escherichia coli (STEC), has increased in Europe in recent years; accentuated in Norway by a national outbreak in 2006 and in a European context especially by the 2011 outbreak originating in Germany. As STEC surveillance is difficult due to diagnostic challenges in detecting non-O157 infections, surveillance of HUS can be used to indicate the burden of STEC infection. Until 2006, notification of HUS to the Norwegian Communicable Disease Surveillance System (MSIS) was based on microbiologically confirmed infection with enterohemorrhagic Escherichia coli (EHEC), humanpathogenic STEC. In 2006, diarrhea-associated HUS (D(+)HUS) was made notifiable based on clinical criteria alone. The incidence and etiology of HUS in children in Norway has not previously been described. METHODS: In order to assess the sensitivity of STEC and D+HUS surveillance and describe the incidence and etiology of HUS in children in Norway, we conducted a nationwide retrospective study collecting data from medical records from pediatric departments for the period 1999-2008 and compared them with data from MSIS. Descriptive statistics are presented as proportions, median, average and mean values with ranges and as incidence rates, calculated using population numbers provided by official registries. RESULTS: Forty-seven HUS cases were identified, corresponding to an average annual incidence rate of 0.5 cases per 100,000 children. Diarrhea-associated HUS was identified in 38 (81%) cases, of which the median age was 29 months, 79% were <5 years of age and 68% were girls. From 1999 to 2006, thirteen more diarrhea-associated HUS cases were identified than had been notified to MSIS. From the change in notification criteria to 2008, those identified corresponded to those notified. STEC infection was verified in 23 (49%) of the HUS cases, in which O157 was the most frequently isolated sporadic serogroup. CONCLUSIONS: Our results show that the incidence of HUS in children in Norway is low and suggest that D+HUS cases may be underreported when notification requires microbiological confirmation. This may also indicate underreporting of STEC infections.

The incidence and aetiology of acute kidney injury in children in Norway between 1999 and 2008.

AIM: Primary acute kidney injury (AKI) is a direct cause of hospitalisation in children, but can also result from other conditions. There is limited information on the epidemiology of this condition. Our aim was to describe the national incidence rate and aetiology of acute kidney injury in children under the age of 16 in Norway from 1999 to 2008. METHODS: We carried out a retrospective study of medical records provided by all 18 of the paediatric hospital departments that specialise in treating paediatric patients with AKI. RESULTS: We identified 315 cases of AKI (53% male), with an estimated average annual incidence rate of 3.3 cases per 100 000 children and a median annual occurrence of 33 cases. Most cases (43%) were in children under five. We identified 53 aetiologies and classified these into 30 aetiological groups: 24% of the cases were prerenal (n = 75), 74% were intrinsic/renal (n = 234) and 2% were postrenal (n = 5). Nephritic syndromes was the major cause (44%) of AKI, followed by haemolytic-uraemic syndrome (HUS) (15%). CONCLUSION: Nephritic syndromes and HUS are the most common aetiologies of AKI in Norway. Although our results could indicate a low incidence of paediatric AKI in Norway, the lack of other national studies makes comparisons difficult.

Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes.

OBJECTIVE: Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro-inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes. MATERIAL AND METHODS: In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumour necrosis factor-alpha, interleukin-6, interleukin-8 and highly sensitive C-reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI-1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years. RESULTS: PAI-1 activity at baseline was a significant independent variable of the 8-year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L-arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed. CONCLUSIONS: Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI-1 activity may have a predictive role in the development of the tubulointerstitial expansion.

Matrix metalloproteinases in subjects with type 1 diabetes.

BACKGROUND: Nephropathy is serious complication of diabetes. We have previously shown that level of the proteoglycan syndecan-1 in blood is associated with ultrastructural kidney changes in young persons with type 1 diabetes. Dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) may contribute to the development of nephropathy. The aim of this study was to investigate if the levels of MMPs in blood samples are potential markers of early nephropathy in type 1 diabetes. METHODS: Blood samples were collected from type 1 diabetes patients after 11 years of diabetes (n = 15) and healthy volunteers (n = 12) and stored at /80 degrees C until measurement. Levels and activities of serum MMP-2, MMP-9, TIMP-1 and TIMP- 2 were analyzed and compared to those of control individuals using ELISA, SDS-PAGE gelatin zymography, and Western blot analysis. RESULTS: The serum levels of both MMP-9 and MMP-2 were significantly higher in subjects with type 1 diabetes, compared to controls (p = 0.016 and p = 0.008 respectively). Western blotting revealed no differences between the two groups in the levels of TIMP-1 or TIMP-2, respectively. CONCLUSION: Our MMP analysis of serum from a limited number of patients with type 1 diabetes suggest that such analysis is potentially useful as markers in studies of people at risk of progression to chronic kidney disease.

Aberrant heparan sulfate profile in the human diabetic kidney offers new clues for therapeutic glycomimetics.

BACKGROUND: Diabetic nephropathy poses an increasing health problem in the Western world, and research to new leads for diagnosis and therapy therefore is warranted. In this respect, heparan sulfates (HSs) offer new possibilities because crude mixtures of these polysaccharides are capable of ameliorating proteinuria. The aim of this study is to immuno(histo)chemically profile HSs from microalbuminuric kidneys from patients with type 1 diabetes and identify specific structural HS alterations associated with early diabetic nephropathy. METHODS: Renal cryosections of control subjects and patients with type 1 diabetes were analyzed immunohistochemically by using a set of 10 unique phage display-derived anti-HS antibodies. HS structures defined by relevant antibodies were characterized chemically by means of enzyme-linked immunosorbent assay and probed for growth factor binding and presence in HS/heparin-containing drugs. RESULTS: In all patients, HS structure defined by the antibody LKIV69 consistently increased in basement membranes of proximal tubules. This structure contained N- and 2-O-sulfates and was involved in fibroblast growth factor 2 binding. It was present in HS/heparin-containing drugs shown to decrease albuminuria in patients with diabetes. The HS structure defined by the antibody HS4C3 increased in the renal mesangium of some patients, especially those who developed macroalbuminuria within 8 to 10 years. This structure contained N- and 6-O-sulfates. For 8 other antibodies, no major differences were observed. CONCLUSION: Specific structural alterations in HSs are associated with early diabetic nephropathy and may offer new leads for early diagnosis and the rational design of therapeutic glycomimetics.

[Advanced glycation end products and hyperglycaemia]. / Avanserte glykerte endeprodukter og hyperglykemi.

Hyperglycaemia leads to increased formation and accumulation of advanced glycation end products, and these molecules play an important role in the development of micro- and macrovascular complications in diabetes. The formation of advanced glycation end products are complex reactions that take place both intra- and extracellularly. Advanced glycation end products affect gene regulation by binding to receptors, but can also modify proteins, DNA and lipids directly. The amount in serum and tissues depends upon several factors. The extent of hyperglycaemia is the main determining factor for levels of glycation products in the body, but the ability to break down and excrete these products in the urine is also important. The most effective way of preventing late complications in diabetes caused by glycation products is strict regulation of blood sugar levels. Drugs that inhibit advanced glycation end products could potentially be important in the prevention of late complications in diabetes, but this needs further investigation.

Development of renal structural lesions in type-1 diabetic patients with microalbuminuria. Observations by light microscopy in 8-year follow-up biopsies.

Kidney biopsies were obtained in 18 type-1 diabetic patients with microalbuminuria and again 8 years later. Over the first 30 months, a treatment protocol (conventional versus intensified treatment) was followed. The biopsies were embedded into plastic and sectioned serially. The volume of individual glomeruli and the vascular pole area was determined. The number of glomeruli showing capsular drops, fibrinoid lesions, adhesions, extra efferent arterioles and corpuscles totally occluded were counted and expressed as a percentage of the total number of corpuscles. Cortical interstitium and degenerated tubules were estimated by point counting. From baseline to the 8-year biopsy, the group of patients showed significant increase in interstitial volume fraction, mean glomerular volume and vascular pole area. The frequency of glomerular occlusion, fibrinoid lesions, adherences and extra efferent arterioles increased, whereas the frequency of capsular drops did not change, and degenerated tubular profiles showed a non-significant increase. No correlation was seen between these light microscopic observations and the concomitant development of diabetic glomerulopathy. Increase in albumin excretion rate was associated with increase in glomerular volume and vascular pole area. No correlation was seen with the glomerular filtration rate, blood pressure or metabolic control. The increase in structural parameters illustrates the slowly ongoing alteration of renal structures in type-1 diabetic patients with microalbuminuria.

Clinical aspects of a nationwide epidemic of severe haemolytic uremic syndrome (HUS) in children.

BACKGROUND: Report a nationwide epidemic of Shiga toxin-producing E. coli (STEC) O103:H25 causing hemolytic uremic syndrome (D+HUS) in children. METHODS: Description of clinical presentation, complications and outcome in a nationwide outbreak. RESULTS: Ten children (median age 4.3 years) developed HUS during the outbreak. One of these was presumed to be a part of the outbreak without microbiological proof. Eight of the patients were oligoanuric and in need of dialysis. Median need for dialysis was 15 days; one girl did not regain renal function and received a kidney transplant. Four patients had seizures and/or reduced consciousness. Cerebral oedema and herniation caused the death of a 4-year-old boy. Two patients developed necrosis of colon with perforation and one of them developed non-autoimmune diabetes. CONCLUSION: This outbreak of STEC was characterized by a high incidence of HUS among the infected children, and many developed severe renal disease and extrarenal complications. A likely explanation is that the O103:H25 (eae and stx2-positive) strain was highly pathogen, and we suggest that this serotype should be looked for in patients with HUS caused by STEC, especially in severe forms or outbreaks.

Low risk of overt nephropathy after 24 yr of childhood-onset type 1 diabetes mellitus (T1DM) in Norway.

AIM: To estimate the risk of diabetic nephropathy and associated risk factors in a nationwide cohort of childhood-onset type 1 diabetes mellitus (T1DM) and 19-30 yr of diabetes duration. METHODS: Patients diagnosed with childhood-onset T1DM (<15 yr) from 1973 through 1982, who previously (1989-1990) participated in a clinical examination to assess diabetic complications, were invited for a new examination in 2002-2003. Of 355 eligible patients, 299 participated (84.2%), and complete urine samples for evaluation of albuminuria were obtained from 295 patients, with a mean age of 33 yr (range 20.9-44.0) and mean diabetes duration of 24 yr (range 19.3-29.9). Persistent microalbuminuria and overt nephropathy [albumin excretion rate (AER) 15-200 microg/min and AER > 200 microg/min, respectively] in at least two out of three consecutive overnight urine samples were defined as diabetic nephropathy. RESULTS: Overt nephropathy was found in 7.8% [95% confidence interval (CI) 4.7-10.9] and persistent microalbuminuria in 14.9% (95% CI 10.8-19.0) of the subjects. Hemoglobin A1c (HbA1c) (p = 0.001), systolic blood pressure (BP) (p = 0.002), total cholesterol (p = 0.019), and C-reactive protein (CRP) (p = 0.019) were associated with diabetic nephropathy. Significant predictors in 1989-1990 for the development of diabetic nephropathy in 2002-2003 were HbA1c (p < 0.001), AER (p = 0.007), and cholesterol (p = 0.022). CONCLUSIONS: In a subgroup of patients diagnosed with childhood-onset T1DM in 1973-1982, 7.8% had overt nephropathy after 19-30 yr of diabetes duration, which is low compared with studies from other countries. HbA1c, systolic BP, total cholesterol, and CRP were each independently associated with diabetic nephropathy.

[Measurement of fever in children--is infrared tympanic thermometry reliable?]. / Måling av feber hos barn--er metoden infrarød tympanisk øremåling god nok?

BACKGROUND: Our objective was to determine whether infrared tympanic thermometry is as reliable as the rectal digital thermometer. Earlier reports have given conflicting results on the issue. MATERIAL AND METHODS: 199 children aged 1 month to 12 years were included in the study. Rectal temperature and the temperature in at least one ear were obtained from all of the children. Children with perforated otitis media, intracranial tumours or treated with immunosuppressive medication were excluded from the study. RESULTS: The mean temperature in the rectum was 0.4 degree C higher than in the ear. The tympanic and the rectal readings were strongly correlated (r = 0.83, p = 0.01). With a definition of fever as rectal temperature > or = 38 degrees C the sensitivity of the tympanic thermometry was 71%, the specificity 95%, the positive predictive value 93%, and the negative predictive value 78%. INTERPRETATION: Infrared tympanic thermometry has obvious advantages compared to rectal measurements: It is more hygienic, faster and less painful for the child. However, its sensitivity is rather low when used in an emergency department. This means that a number of children with fever will not be diagnosed as such.