Hyponatremia and cyst growth in neonatal polycystic kidney disease: a case for aquaretics?

Hyponatremia is a common complication in neonatal polycystic kidney disease and is thought to be due to water retention. Aquaretics are drugs that promote free water excretion by blocking the arginine vasopressin receptor type 2 (AVPR2) in the collecting duct and thus impair urinary concentration. AVPR2 is also a key stimulant for cyclic AMP production in the collecting duct and in this way promotes cyst proliferation and pathologic kidney growth in autosomal dominant polycystic kidney disease (ADPKD). Consequently, the aquaretic tolvaptan is now used to slow down progression of ADPKD in adult patients. Whether this beneficial effect on retarding cystic disease progression also extends to recessive forms of polycystic kidney disease (PKD) is currently not known. A recent case report in Pediatric Nephrology touches on the intersecting indications for tolvaptan for both hyponatremia and cyst retardation in neonatal PKD and suggests that use for one indication may have beneficial effects on the other.

Meckel-Gruber syndrome (dysencephalia splanchnocystica).

Meckel-Gruber syndrome is a rare lethal autosomal recessive condition which was first described by Johann Friedrich Meckel in 1822 and GB Gruber in 1934. More than 200 cases have been reported worldwide with an incidence ranging from 1:13,250 to 1:140,000 live births. A 21-year-old female with G3 A2 L0, presented with twin pregnancy with history of previous two anencephalic pregnancies. The present pregnancy was a preterm vaginal delivery of female twins by face presentation at 35 weeks of gestation (diamniotic dichorionic twin gestation). Neonatal autopsy revealed classical triad of occipital encephalocele, polycystic kidneys and lungs with postaxial polydactyly. This case is presented for its rarity and its documented occurrence in Gujarati Indians.

Malformaciones urinarias del recién nacido: estudio ECLAMC 1998-2010 / Urinary malformations among newborns: ECLAMC registry, 1998-2010

Introduction: Congenital abnormalities of the Urinary Tract are frequent and prevalence has increased since the introduction of routine prenatal sonogram. Objectives: To determine the prevalence rate of congenital urinary malformations at birth at Hospital Clínico de la Universidad de Chile. These data will be compared to other Chilean hospitals participating in ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas - Latin American Collaborative Study of Congenital Malformations). A longitudinal study will serve to evaluate if significant variation has occurred, and risk factors will be investigated. Patients and Methods: All births occurring between January, 1998 and December, 2010 were included. Prevalence rate of urinary malformations were calculated, and compared to those obtained in previous years. Statistical analysis of proportions was calculated through mean and average comparison was made through Student t test. Results: Urinary anomalies appeared at a rate of 64.5 per 10.000 births. This represents a significant increase from previous studies. Highest risk factor seemed to be "other family members with disease". Most frequent anomaly was Hydroureteronphrosis (24,2 percent) followed by Hypospadias (17 percent). The rate of these malformations in ECLAMC participating Chilean hospitales was 23.37/10.000 births. Conclusion: A significant increase in the diagnosis of these anomalies was shown, being the most important risk factor the presence of family members with similar congenital disorders.

Introducción: Las anomalías congénitas del Aparato Urinario son frecuentes y ha aumentado su prevalencia al nacimiento con la introducción rutinaria del estudio prenatal por ultrasonografía. Objetivos: Determinar la Tasa de prevalencia al nacimiento de las malformaciones urinarias en el Hospital Clínico de la Universidad de Chile. Compararlas con las del resto de los hospitales chilenos que participan en el ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas). Estudiarlas a lo largo del tiempo para ver si han tenido variaciones significativas. Investigar factores de riesgo que pueden influir en la aparición de ellas. Pacientes y Método: Se estudió todos los nacimientos ocurridos entre Enero de 1998 y Diciembre de 2010 en el Hospital Clínico de la Universidad de Chile. Se calculó las tasas de prevalencia al nacimiento de las malformaciones urinarias y se las comparó con las obtenidas en períodos anteriores. El análisis estadístico de comparación de proporciones se realizó mediante la prueba de c² y las comparaciones entre promedios se hicieron mediante prueba t de Student. Resultados: La tasa de Anomalías urinarias fue 64,5 por 10 000 nacimientos. Ellas aumentaron significativamente al compararlas con los períodos estudiados anteriormente. El factor de riesgo más influyente fue "otros malformados en la familia". La anomalía más frecuente fue Hidroureteronefrosis (24,2 por ciento) seguida por Hipospadias (17 por ciento). La tasa de estas malformaciones en los hospitales chilenos participantes del ECLAMC fue 23,37/10 000 nacimientos. Conclusión: Se demuestra un incremento significativo del diagnóstico de estas anomalías, siendo el factor de riesgo más importante el antecedente de otros malformados en la familia.

Descriptive epidemiology of selected heritable birth defects in Texas.

BACKGROUND: Few population-based studies exist on descriptive epidemiologic characteristics of rare heritable birth defects. The number of birth defect cases in the Texas Birth Defects Registry (one of the largest active birth defects surveillance systems in the world) enabled us to examine six different heritable disorders (aqueductal stenosis, infantile polycystic kidney disease, achondroplasia, thanatophoric dwarfism, chondrodysplasia/dwarfism not otherwise specified (NOS), and osteogenesis imperfecta) for a variety of descriptive demographic variables. METHODS: The Texas Birth Defects Registry was used to identify infants or fetuses with heritable birth defects. Crude prevalence rates were calculated and Poisson regression was used to test the association of each demographic variable (e.g., maternal age) with each of the selected genetic birth defects. RESULTS: White non-Hispanics exhibited higher rates of achondroplasia and osteogenesis imperfecta than other race/ethnic groups. Lower maternal education level and to a lesser extent, paternal education level, was associated with higher rates of several disorders. The birth prevalence rate for achondroplasia decreased from 1999 through 2006. CONCLUSION: The use of a large birth defects registry provides a sufficient count of cases to perform some basic epidemiologic analysis on selected rare heritable birth defects.

Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.

A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis.

UNLABELLED: Ductal plate malformations (DPMs) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling, the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. Here, we report this process is conserved in human fetal liver. These findings prompted us to evaluate how DPMs develop in three mouse models, namely mice with livers deficient in hepatocyte nuclear factor 6 (HNF6), HNF1ß, or cystin-1 (cpk [congenital polycystic kidney] mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with autosomal recessive polycystic kidney disease (ARPKD) were also analyzed. Despite the epistatic relationship between HNF6, HNF1ß, and cystin-1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apicobasal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1ß-deficient liver, maturation of the primitive ductal structures was impaired. Normal differentiation and maturation but abnormal duct expansion was apparent in cpk mouse livers and in human fetal ARPKD. CONCLUSION: DPM is the common endpoint of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM.

[Rare case of congenital cystic adenomatoid malformation associated with polycystic kidney disease]. / Rzadki przypadek wspolwystepowania wrodzonej torbielowatosci gruczolakowatej pluca z wielotorbielowatoscia nerek.

Congenital cystic adenomatoid malformation (CCAM) is a rare pulmonary abnormality that results from aberrant fetal lung development. It about 4-26% of cases it can be associated with other congenital abnormalities. We describe a case of congenital cystic adenomatoid malformation 2 associated with polycystic kidney disease. The association of these two congenital malformations is exceptional. Only four similar cases have been reported in the literature. A 2-year-old girl was referred to the Department of Paediatric Surgery and Oncology Medical University of Lodz with pneumonia and left pneumothorax. For three weeks prior to referral the patient was treated with antibiotics. Chest x-ray revealed hyperinflation of left upper lobe with mediastinal shift to right. Computer tomographic scan of the lung revealed multiple cyst in the left upper lobe, left-site pneumothorax and mediastinal shift to the right. The patient underwent thoracotomy. Intraoperatively, multiple cysts in the left upper lobe were found and left upper lobectomy was performed. Histologic study was compatible with type 2 congenital cystic adenomatoid malformation. Ultrasound examination showed multilocular cysts in both kidneys. The dimensions of the cysts were: MWR4. 54x45x45 mm and 25x21x24 mm on the left and right sides, respectively. Significant increase in cyst size on the left side was observed. Ten months after first hospitalization resection of the cystic lower pole of the left kidney was performed. The presence of even a single renal cyst in a child with CCAM is an indication for further follow up examinations.

Postnatal investigation of fetal renal disease.

Following the introduction of routine prenatal scanning, and more recently detailed anomaly scans, antenatal ultrasound (US) diagnosis of fetal renal tract abnormalities has become well established. Prenatal detection has resulted in a group of asymptomatic infants becoming patients in the last two decades. These infants are referred for paediatric (general, urological and nephrological) consultations, radiological imaging and monitoring. The urgency with which to undertake imaging depends on the suspected antenatal diagnosis and clinical scenario, with bilateral hydronephrosis, posterior urethral valves and complicated duplex systems taking a high priority. Treatment is mainly preventive and relies on close follow-up and timely intervention. US remains the main imaging modality of choice postnatally; together with nuclear medicine, it gives a powerful combination of both anatomy and function. However, magnetic resonance urography may have increasing importance in becoming the investigation of choice of the future for more complex cases.

[Dialysis treatment of infants with end stage failure]. / Dialysebehandling av spedbarn med terminal nyresvikt.

BACKGROUND: End stage renal failure in infants is rare, and was until recently regarded as untreatable. Advancements in dialysis techniques and other renal replacement therapy, have now made lifesaving treatment possible. MATERIAL AND METHODS: Three infants who developed end stage renal failure shortly after birth and were subsequently treated with long-term dialysis (as a bridge to transplantation) are presented and their results are compared with those from other dialysis centres. RESULTS AND INTERPRETATION: All three patients were successfully dialysed until transplantation, two with peritoneal dialysis and one with haemodialysis. Complications were rare and manageable. The results are in accordance with findings from previous studies. Long-term dialysis in infants with chronic renal failure should no longer be considered experimental and is now a real alternative until the child is big enough to have a transplantation. Treatment outcome is affected by co-morbidity. The treatment requires a multidisciplinary approach with specialists from many fields including paediatrics, paediatric surgery, nephrology, nutrition and dialysis. In addition it is essential to cooperate with the parents, as the treatment is demanding for the family as well as for the medical personnel.

Continuous hemofiltration dose calculation in a newborn patient with congenital heart disease and preoperative renal failure.

OBJECTIVE: To report a case of a newborn patient with renal failure due to polycystic kidneys requiring renal replacement therapy, and total anomalous pulmonary venous return requiring major cardiosurgical intervention. SETTING: Pediatric cardiosurgery operatory room and pediatric cardiologic intensive care. PATIENT: A 6-day-old newborn child weighing 3.1 kg. RESULTS: Renal function (creatinine value and urine output) was monitored during the course of the operation and intraoperative renal replacement therapy was not initiated. Serum creatinine concentration decreased from 4.4 to 3 mg/dL at cardiopulmonary bypass (CPB) start and to 1.5 at the end of surgery: the creatinine decrease was provided by the dilutional effect of CPB priming and the infusion of fresh blood from transfusions together with an adequate filtration rate (800 m/L in about 120 minutes). After the operation, extracorporeal membrane oxygenation (ECMO) for ventricular dysfunction and continuous hemofiltration for anuria refractory to medical therapy were prescribed. The hemofiltration machine was set in parallel with the ECMO machine at a blood flow rate of 60 ml/min and a predilution replacement solution infusion of 600 ml/h (4.5 ml/min of creatinine clearance once adjusted on extracorporeal circuits; 3000 mL/m2 hemofiltration): after a single hemofiltration session lasting 96 hours, serum creatinine reached optimal steady state levels around 0.5 mg/dL on postoperative day 2 and 3. CONCLUSION: Administration of intraoperative continuous hemofiltration is not mandatory in the case of a 3-kg newborn patient with established renal failure needing major cardiosurgery: hemodilution secondary to CPB, transfusion of hemoderivates, and optimal UF rate appear to be effective methods for achieving solute removal. If postoperative continuous hemofiltration is started, however, a "dialytic dose" of 4.5 ml/min allows an adequate creatinine clearance, quick achievement of a steady state of serum creatinine concentration and an eventual acceptable rate of inflammatory mediator removal.

Nesiritide therapy in a term neonate with renal disease.

A term (39-wk-old) male neonate exhibited respiratory distress and anuria within 2 days of birth. The patient was diagnosed with pulmonary hypertension, polycystic kidney disease, and heart failure; his initial B-type natriuretic peptide concentration was 2460 pg/ml. After minimal response to loop diuretics, the patient was given an infusion of nesiritide 0.01 microg/kg/minute, with no loading dose. Urine output increased over 400%, and cardiac function improved. Nesiritide was titrated to 0.03 microg/kg/minute with no hypotension, decreased renal function, or adverse cardiac sequelae over the next 6 days. No subsequent changes in cardiac function occurred during the infant's stay in a progressive care unit, but he died at age 5.5 months due to sepsis. This case report demonstrates the successful first use of nesiritide therapy in a neonate with renal disease. Further studies are warranted to evaluate the safety and administration of this agent in the neonatal patient population.

Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation.

We report on the association of absent patellae, genital and renal anomalies, dysmorphic features, and mental retardation in seven children (six boys and one girl) belonging to five unrelated families. Flexion deformities of the knees and hips with club feet and absent patellae were consistently observed and scrotal hypoplasia and cryptorchidism were present in all boys (6/6). Dysmorphic features included a coarse face, a large nose with a high nasal bridge, and microcephaly. Other features included renal anomalies (multicystic kidneys or hydronephrosis, 7/7), agenesis of the corpus callosum (4/7), swallowing difficulties, micrognathia (4/7), and pulmonary hypoplasia (3/7). Bilateral hypoplasia of the ischia and brachydactyly were also consistently observed (5/5). In two out of seven cases, prenatal ultrasound detection of microcephaly and renal anomalies led to termination of the pregnancy at 27 weeks. Three children died during the first years of life and the remaining two who survived exhibit severe developmental delay. High resolution cytogenetic studies performed on lymphocytes or fibroblasts or both were normal in all cases. Recurrence in two families suggests an autosomal recessive mode of inheritance. We propose that this unusual association, similar to that observed in a 4 year old boy by Goldblatt et al, represents a new syndrome distinct from previously reported hypoplastic patella syndromes.