Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome.

BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.

Acute renal failure SNAPPE and mortality.

BACKGROUND: The aim of the present study was to determine, using the score for neonatal acute physiology and perinatal extension II (SNAPPE-II), whether there is an association with acute renal failure (ARF) and whether it is possible to identify newborns at risk for ARF prior to a rise in creatinine in newborns. METHODS: Information on postnatal risk factors and SNAPPE-II on the first day of life (non-ARF group, n= 475; ARF group, n= 78) were collected. Renal failure was defined as serum creatinine level >1 mg/dL and >1.3 mg/dL (for ≥ 33 weeks and < 33 weeks, respectively) after 48 h of life. RESULTS: In newborns with ARF (n= 78), the median (range) of SNAPPE-II and mortality rate were significantly higher than those of the control group. Patent ductus arteriosus (PDA), disseminated intravascular coagulation (DIC), SNAPPE-II, and resuscitation were identified as independent predictors of ARF in infants on forward stepwise logistic regression. Sepsis, respiratory distress syndrome, ARF, DIC, and SNAPPE-II were identified as independent predictors of mortality in infants on the same analysis. CONCLUSIONS: SNAPPE-II on the first day of life was significantly higher among babies with ARF, suggesting a positive association between higher scores and the development of ARF and mortality, but based on receiver operating characteristic curve results, SNAPPE-II at admission did not enhance the assessment of risk for ARF prior to a rise in creatinine.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation.

OBJECTIVES: To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria. METHODS: The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis

Etiology and outcome of acute kidney injury in children.

The aim of this prospective, multicenter study was to define the etiology and clinical features of acute kidney injury (AKI) in a pediatric patient cohort and to determine prognostic factors. Pediatric-modified RIFLE (pRIFLE) criteria were used to classify AKI. The patient cohort comprised 472 pediatric patients (264 males, 208 females), of whom 32.6% were newborns (median age 3 days, range 1-24 days), and 67.4% were children aged >1 month (median 2.99 years, range 1 month-18 years). The most common medical conditions were prematurity (42.2%) and congenital heart disease (CHD, 11.7%) in newborns, and malignancy (12.9%) and CHD (12.3%) in children aged >1 month. Hypoxic/ischemic injury and sepsis were the leading causes of AKI in both age groups. Dialysis was performed in 30.3% of newborns and 33.6% of children aged >1 month. Mortality was higher in the newborns (42.6 vs. 27.9%; p < 0.005). Stepwise multiple regression analysis revealed the major independent risk factors to be mechanical ventilation [relative risk (RR) 17.31, 95% confidence interval (95% CI) 4.88-61.42], hypervolemia (RR 12.90, 95% CI 1.97-84.37), CHD (RR 9.85, 95% CI 2.08-46.60), and metabolic acidosis (RR 7.64, 95% CI 2.90-20.15) in newborns and mechanical ventilation (RR 8.73, 95% CI 3.95-19.29), hypoxia (RR 5.35, 95% CI 2.26-12.67), and intrinsic AKI (RR 4.91, 95% CI 2.04-11.78) in children aged >1 month.

Predictors of left ventricular hypertrophy in children on chronic peritoneal dialysis.

Conflicting results have been reported in small non-homogenous groups of children with chronic renal failure in terms of casual blood pressure and ambulatory blood pressure monitoring (ABPM) parameters and left ventricular hypertrophy (LVH). The aim of our study was to assess the value of ABPM and hematological and biochemical parameters in predicting LVH in children on chronic peritoneal dialysis (CPD). Echocardiography and 24-h ABPM were performed in addition to routine biochemical and hematological evaluations in 47 children on CPD (26 male, 21 female; mean age 14.74 +/- 3.52 years). Mean daytime systolic blood pressure (SBP) and mean daytime diastolic blood pressure (DBP) values were found to be higher than the mean casual SBP and DBP (p = 0.001) values. Thirty-three (70.2%) children had LVH. The correlations between the left ventricular mass index and ABPM variables were good. Stepwise multiple regression analysis revealed daytime SBP load (beta = 0.652; p < 0.01) and hematocrit (beta = -0.282; p < 0.01) to be independent predictors of LVH. The sensitivity, specificity, positive predictive value, and negative predictive values for the combination of the SBP load >15% and hematocrit value <31% for predicting LVH were 95 [95% confidence interval (CI) 76-99], 78 (95%CI 45-94), 91 (95%CI 73-98), and 88% (95%CI 69-96%), respectively. We conclude that: (1) LVH is prevalent in children on CPD, and (2) a target hematocrit level >31% and daytime SBP load <15% may be preventive for the progression of LVH in the follow-up of children on CPD.

Renal artery aneurysm in a hypertensive child treated by percutaneous coil embolization.

A 16-year-old boy was admitted to our hospital with uncontrolled hypertension. A left renal artery aneurysm was detected on colour Doppler US and CT. Renal arteriography demonstrated the aneurysm and focal renal parenchymal areas of decreased perfusion. The renal artery aneurysm was successfully treated by transcatheter coil embolization.

Protracted febrile myalgia mimicking polyarteritis nodosa.

An insidious onset of unexplained fever, weight loss, skin lesions, abdominal pain, and musculoskeletal pain should suggest the diagnosis of polyarteritis nodosa (PAN). However, familial Mediterranean fever (FMF) with protracted febrile myalgia (PFM) should be kept in mind in the differential diagnosis. In this report, 6 cases of PFM mimicking PAN are described. Patients presented with severe muscle and abdominal pain lasting longer than 4 weeks. Their common medical history included recurrent febrile abdominal pain or arthritis. Physical examination revealed hypertension together with severe muscle tenderness. Laboratory examination revealed high acute phase reactants, negative p-ANCA, normal creatine kinase, and complement levels. Duplex abdominal ultrasonography was normal. Four of 6 patients were hospitalized with initial diagnoses of PAN. Renal and mesenteric angiography performed in 1 patient was normal. Steroid therapy controlled all the severe symptoms including hypertension in all of the cases.FMF with PFM is important in the differential diagnosis of patients with suspected vasculitis especially when myalgia is present. Hypertension may be present as a result of sympathetic discharge because of severe myalgia. Because PFM rapidly responds to a short course of corticosteroids, a rapid diagnosis of PFM in FMF patients can reduce unnecessary workup and decrease the time patients have to suffer.

Differential diagnosis of hereditary nephrogenic diabetes insipidus with desmopressin infusion test.

PURPOSE: The causes of hereditary nephrogenic diabetes insipidus (HNDI) are the mutations in the arginine vasopressin V2 receptor gene (AVPR2) (90%) and aquaporin 2 gene (AQP2) (10%). Although it is possible to perform mutation analysis where available, differentional diagnosis at clinical bases remains valuable. METHODS: In this report we present two cases of HNDI diagnosed at clinical bases with a desmopressin infusion test as AQP2 gene mutations. The results were verified by genetic analysis to stress that a desmopressin infusion test is valuable for differential diagnosis of HNDI. RESULTS: With a desmopressin infusion test, factor VIII levels were increased up to 219% and 214% respectively, establishing the presence of V2 receptor. With direct sequencing of the AQP2 gene, a previously described splicing mutation in a new codon (380) and a new frameshift mutation were determined in case 1 and case 2 respectively. CONCLUSION: It is concluded that the desmopressin infusion test is a simple and reliable method for the diagnosis and differential diagnosis of HNDI in early childhood.

Deletion of exons 2-4 in the BSND gene causes severe antenatal Bartter syndrome.

BSND gene mutations usually cause severe forms of antenatal Bartter syndrome and sensorineural deafness (SND). Chronic renal failure and transient hypercalciuria are reported as controversial symptoms of this syndrome. All twelve reported BSND mutations cause SND, whereas only two of the mutations give rise to normal glomerular filtration rate (GFR) and two other mutations cause hypercalciuria. The case we report here, where the patient presented with severe clinical symptoms and deletion on exons 2-4 of the BSND gene, has not been reported previously. Decreased GFR, along with hypercalciuria and difficulties in managing fluid and electrolyte requirements, are the reasons why this patient was brought to attention.

A case of aquaporin 2 R85X mutation in a boy with congenital nephrogenic diabetes insipidus.

Autosomal recessive nephrogenic diabetes insipidus (ARNDI) is a rare disease usually seen in patients with consanguineous parents. We report on a case of ARNDI in a patient with non-consanguineous parents who presented with recurrent febrile attacks. The differential diagnosis of ARNDI was made by desmopressin infusion test. A homozygous mutation, R85X, was detected in the aquaporin 2 gene (AQP2) of our patient, which has been described only once previously. This case is presented to stress that even male patients with non-consanguineous parents could have ARNDI with a AQP2 gene defect, and the desmopressin infusion test is useful for differential diagnosis.

Takayasu arteritis in children.

OBJECTIVE: To retrospectively evaluate the clinical features, angiographic findings, and outcomes of children with Takayasu arteritis (TA) in Turkey. METHODS: Clinical, laboratory, and angiographic findings and outcomes of 19 children with TA were evaluated with a retrospective chart review. The criteria for inclusion were those proposed by the American College of Rheumatology. RESULTS: Mean followup period was 35.89 +/- 40.75 months (range 1-168, median 30). There were 14 girls and 5 boys. The mean age at diagnosis was 12.84 +/- 2.69 years (range 8-17, median 13). The most common complaints on admission were headache (84%), abdominal pain (37%), claudication of extremities (32%), fever (26%), and weight loss (10%). One patient presented with visual loss. Examination on admission revealed hypertension (89%), absent pulses (58%), and bruits (42%). Angiography revealed type I in 13 patients (aortic arch, descending thoracic, and abdominal aorta), type II in 4 (descending thoracic aorta and abdominal aorta), and type IV in 2 (diffuse aortic and pulmonary artery). The most commonly involved vessels were the renal, subclavian, and carotid arteries. All patients received corticosteroid therapy, and further immunosuppressive therapy was added in 15 patients. Fourteen of the 17 hypertensive patients had renal artery stenosis and 9 underwent surgery or interventional therapy. Thoraco-abdominal bypass graft was performed in 2 patients who had abdominal aortic stenosis. CONCLUSION: Hypertension is the most common clinical feature at presentation. Corticosteroid and immunosuppressive therapy was effective in the control of disease activity. Angioplasty or bypass grafting was successfully performed when needed.

Protracted familial mediterranean fever arthritis presenting as septic arthritis.

In Familial Mediterranean Fever (FMF), arthritis is the initial symptom in 25% of patients. Although FMF arthritis is acute and self-limited, in 5% of cases protracted arthritis usually affecting large joints such as knee may occur. In this report, two cases are presented who were initially diagnosed as septic arthritis, first of which had four and the second had two synovectomy operations with the diagnosis of septic arthritis. Later on they were diagnosed as FMF with detailed history. We aimed to emphasize the importance of diagnosis of FMF, which is based mainly on history and clinical features in order to prevent unnecessary operations and suffering of the patient.

Reno-vascular hypertension in childhood: a nationwide survey.

Renovascular disease accounts for 8-10% of all cases of paediatric hypertension, whereas, in adults, its incidence is approximately 1%. The Turkish Paediatric Hypertension Group aimed to create the first registry database for childhood renovascular hypertension in Turkey. Twenty of the 28 paediatric nephrology centres in Turkey responded to the survey and reported 45 patients (27 girls, 18 boys) with renovascular hypertension between 1990 and 2005. The age at presentation ranged from 20 days to 17 years. The mean blood pressure at the diagnosis was 169/110 mmHg. Chief complaints of symptomatic patients were headache (38%), seizure (18%), epistaxis (4%), growth retardation (4%), cognitive dysfunction (4%), polyuria (2%), palpitation (2%), and hemiplegia (2%). Renovascular hypertension was found incidentally in 11 children. The diagnosis of renovascular hypertension was established with conventional angiography in 39 patients, MR angiography in three, CT angiography in two, and captopril diethylene triamine penta-acetic acid (DTPA) scintigraphy in one patient. Twenty-one children had bilateral renal artery stenosis and 24 had unilateral renal artery stenosis. Of these, 14 (31%) had fibromuscular dysplasia; 12 (27%) Takayasu's arteritis; six (13%) neurofibromatosis; two (5%) Williams syndrome; one (2%) Kawasaki disease; one (2%) mid-aortic syndrome; one (2%) extrinsic compression to the renal artery, and eight (18%) unspecified bilateral renal artery stenosis. Hypertension was controlled with antihypertensive drugs in 17 patients. Percutaneous transluminal angioplasty (PTRA) or surgery had to be performed in 28 patients: PTRA in 16 patients, PTRA + surgery in one patient and surgery in 11 patients (four nephrectomies). The importance of vasculitic disease, especially Takayasu's arteritis, should not be underestimated in children with renovascular hypertension.

Acute effects of gentamicin on glomerular and tubular functions in preterm neonates.

It has been reported that gentamicin causes natriuresis, magnesuria and calciuria in neonates. The aim of this study was to determine the acute effects of trough and peak levels of gentamicin on the values of serum creatinine (SCr), urine albumin/urine creatinine (UA/UCr), fractional excretion of sodium and potassium (FENa, FEK) and urine calcium/urine creatinine (UCa/UCr) in preterm neonates treated with gentamicin for suspected infection. Baseline levels of serum and urine Cr, Na and K and urine albumin and Ca levels together with trough and peak gentamicin levels were measured in 61 preterm neonates at the start of the therapy, on the day of the third gentamicin dose and 48-72 h after the cessation of the gentamicin therapy. Therapeutic trough and peak levels were recorded in 56 (91.8%) and 39 (63.9%) of the preterm neonates, respectively, whereas high trough (>2 mg/dl) and peak (>9.99 mg/dl) levels were recorded in five (8.1%) and 11 (18%) of the 61 preterm neonates, respectively. Trough and peak levels of gentamicin were positively correlated with SCr, UA/UCr, FENa, FEK and UCa/UCr values. The UA/UCr, FENa and UCa/UCr values recorded during treatment were statistically significantly different from sub-therapeutic, therapeutic and high peak gentamicin levels. Gentamicin was found to have a serum peak level-dependent microalbuminuric, natriuric and calciuric effect in preterm neonates. Based on these results, we suggest that when the monitoring of serum gentamicin levels is not possible, the monitoring of UA/UCr, FENa and UCa/UCr can be useful as a noninvasive alternative.

Intravenous cyclophosphamide is the drug of choice for steroid dependent nephrotic syndrome.

BACKGROUND: Steroid dependency is a major problem seen after therapy for idiopathic nephrotic syndrome in childhood. Although there is consensus about the usage of cyclophosphamide (CYC) in frequent relapsers, there is still a controversy concerning its usage in steroid-dependent nephrotic syndrome (SDNS). METHODS: In the present study, nineteen children with SDNS were treated with CYC: ten via the intravenous (i.v.) route, and nine via the oral route. Remission was then maintained with prednisolone. Oral CYC therapy consisted of CYC at a dose of 2 mg/kg per day for 12 weeks. Intravenous (i.v.) CYC therapy consisted of CYC 500 mg/m2 per month (with intravenous 3500 cc/m2 per 24 h one-third saline hydration) for 6 months. RESULTS: The cumulative dose of CYC was 168 mg/kg in the oral group and 132 mg/kg in the IV group. Daily oral CYC dose was 1.96~0.31 mg/kg, whereas i.v. CYC dose was 0.73~0.03 mg/kg. Long-term complications and side-effects such as alopecia, infection and hemorrhagic cystitis were not observed in the i.v. CYC treated group. In the long term, the dosage of prednisolone that held remission after CYC, the annualized relapse rates and the subsequent relapse time were significantly better in the i.v. CYC group, and the number of patients in remission for 2 years was significantly higher in the i.v. treated group (P<0.05). CONCLUSIONS: In SDNS, i.v. CYC has a long lasting effect with lower annualized relapse rates and longer subsequent relapse time with a lower steroid dosage required to maintain remission than oral CYC. The results of the present study showed the safety of the i.v. route, and it is the preferable treatment in noncompliant patients for its long lasting remission and simple and inexpensive follow up.

Childhood idiopathic nephrotic syndrome in Turkey.

BACKGROUND: It has been reported that there are racial and regional differences in peak incidence age, histopathological features and response to steroid therapy in childhood idiopathic nephrotic syndrome. METHODS: One hundred and thirty-eight patients with a diagnosis of idiopathic nephrotic syndrome, followed up in 1994-2000, were assessed retrospectively. The aim of this study was to assess the patients' response pattern to steroid therapy, to determine whether the duration of the initial steroid therapy alters the steroid response pattern of the disease and to assess renal biopsy results. RESULTS: One hundred and fourteen patients who initially received only steroid therapy and were followed up regularly were classified according to response pattern. Of the 114 patients, 30 children had an initial response, 25 children had infrequent relapse, 19 had frequent relapse, 25 had steroid dependence and 15 children had steroid resistance. The 99 patients with steroid responsive nephrotic syndrome were divided into two groups with respect to duration of the initial steroid therapy. There was no statistically significant difference between standard and short therapy groups with respect to the steroid response patterns. Percutaneous renal biopsy was performed in 43 of the 138 patients. Mesengioproliferative glomerulonephritis was the most common histopathological lesion, followed by membranoproliferative glomerulonephritis. The proportions of membranous glomerulonephritis, focal segmental glomerulosclerosis and minimal change nephrotic syndrome were low in our group. CONCLUSIONS: Our study group is similar to one reported from Saudi Arabia with respect to the steroid response pattern and to Saudi Arabian and Nigerian reports with respect to the histopathology. Although it has been reported that short initial steroid therapy was followed by a higher rate of relapses, there was no statistically significant difference between standard and short therapy groups with respect to the relapse rate in our study group.