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Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin‐2 (AQP2) from collecting duct principal cells, explaining the associated polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium‐induced NDI, unilateral ureteral obstruction, endotoxin‐induced NDI) or proteomics (hypokalaemia‐associated NDI, hypercalcaemia‐associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress‐sensor proteins, namely death receptors and stress‐sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. Key points: Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin‐2 (AQP2) protein is a common feature.Investigations of acquired NDI using transcriptomics (RNA‐seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss.Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling.These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression. [ABSTRACT FROM AUTHOR]

Background Two common mutations of the solute carrier family 4 member 1 (SLC4A1) gene, namely, Southeast Asian ovalocytosis (SAO) and band 3 Bangkok 1 (G701D), cause autosomal recessive distal renal tubular acidosis (AR dRTA) in ethnic Southeast Asian populations. In this study, we applied the high-resolution melting (HRM) method for screening of AR dRTA associated with SLC4A1 mutations in 10 new patients with unknown cause(s) of AR dRTA. Methods We analyzed SAO and G701D mutations in the patients and their family members using HRM. The results were confirmed by polymerase chain reaction–restriction fragment-length polymorphism (PCR-RFLP) and DNA sequencing techniques. Results All patients carried homozygous G701D mutation, whereas their family members had heterozygous G701D or homozygous wild-type. Conclusions Homozygous G701D is a common cause of AR dRTA in ethnic Thai pediatric populations. HRM can be used as a rapid screening method for common SLC4A1 mutations that cause AR dRTA in Southeast Asian and other populations. [ABSTRACT FROM AUTHOR]

We used a systems biology-based approach to investigate the basis of cell-specific expression of the water channel aquaporin-2 (AQP2) in the renal collecting duct. Computational analysis of the 5'-flanking region of the AQP2 gene (Genomatix) revealed 2 conserved clusters of putative transcriptional regulator (TR) binding elements (BEs) centered at -513 bp (corresponding to the SF1, NFAT, and FKHD TR families) and -224 bp (corresponding to the AP2, SRF, CREB, GATA. and HOX TR families). Three other conserved motifs corresponded to the ETS, EBOX, and RXR TR families. To identify TRs that potentially bind to these BEs, we carried out mRNA profiling (Affymetrix) in mouse mpkCCDc14 collecting duct cells, revealing expression of 25 IRs that are also expressed in native inner medullary collecting duct. One showed a significant positive correlation with AQP2 mRNA abundance among mpkCCD subclones (Ets1), and 2 showed a significant negative correlation (Elf1 and an orphan nuclear receptor Nr1h2). Transcriptomic profiling in native proximal tubules (PT), medullary thick ascending limbs (MTAL), and IMCDs from kidney identified 14 TRs (including Ets1 and HoxD3) expressed in the IMCD but not PT or MTAL (candidate AQP2 enhancer roles), and 5 TRs (including HoxA5, HoxA9 and HoxA10) expressed in PT and MTAL but not in IMCD (candidate AQP2 repressor roles). In luciferase reporter assays, overexpression of 3 ETS family TRs transactivated the mouse proximal AQP2 promoter. The results implicate ETS family TRs in cell-specific expression of AQP2 and point to HOX, RXR, CREB and GATA family TRs as playing likely additional roles. [ABSTRACT FROM AUTHOR]

After the release of bilateral ureteral obstruction (BUO), postobstructive diuresis from an impaired urine concentration mechanism is associated with reduced aquaporin 2 (AQP2) abundance in the inner medullary collecting duct (IMCD). However, the underlying molecular mechanism of this AQP2 reduction is incompletely understood. To elucidate the mechanisms responsible for this phenomenon, we studied molecular changes in IMCDs isolated from rats with 4-h BUO or sham operation at the early onset of AQP2 downregulation using mass spectrometry-based proteomic analysis. Two-hundred fifteen proteins had significant changes in abundances, with 65% of them downregulated in the IMCD of 4-h BUO rats compared with sham rats. Bioinformatic analysis revealed that significantly changed proteins were associated with functional Gene Ontology terms, including "cell-cell adhesion," "cell-cell adherens junction," "mitochondrial inner membrane," "endoplasmic reticulum chaperone complex," and the KEGG pathway of glycolysis/gluconeogenesis. Targeted liquid chromatography-tandem mass spectrometry or immunoblot analysis confirmed the changes in 19 proteins representative of each predominant cluster, including AQP2. Electron microscopy demonstrated disrupted tight junctions, disorganized adherens junctions, swollen mitochondria, enlargement of the endoplasmic reticulum lumen, and numerous autophagosomes/lysosomes in the IMCD of rats with 4-h BUO. AQP2 and seven proteins chosen as representative of the significantly altered clusters had a significant increase in immunofluorescence-based colocalization with autophagosomes/lysosomes. Immunogold electron microscopy confirmed colocalization of AQP2 with the autophagosome marker microtubule-associated protein 1A/1B-light chain 3 and the lysosomal marker cathepsin D in IMCD cells of rats with 4-h BUO. We conclude that enhanced autophagic degradation of AQP2 and other critical proteins, as well as endoplasmic reticulum stress in the IMCD, are initiated shortly after BUO.

Distal renal tubular acidosis is a clinical syndrome characterized by inability to acidify urine in the presence of metabolic acidosis. Classic dRTA patients exhibit failure to thrive, polyuria, metabolic acidosis and hypokalemia. Hyperkalemic dRTA without underlying disease is very rare. Transient bicarbonate wasting accompanied with hypokalemic dRTA was reported in infants. Herein, a transient hyperkalemic dRTA with bicarbonate wasting was reported in a young child.

Henoch Schonlein Purpura (HSP) is the most common vasculitis in childhood. It is a self-limited disease. Recurrent HSP is not uncommon. Colchicine, an anti-inflammatory drug, has been used in prolonged HSP in only a few patients with good response. The present study described pediatric HSP patients in a single center, Thailand. To determine the epidemiology, clinical manifestations, treatments, and outcomes of HSP patients, the authors retrospectively studied 26 patients (age < 15 years) diagnosed with HSP at Thammasat University Hospital, from January 01, 2004 through December 31, 2010. The mean age was 7.2 +/- 3.8 years; median (range) follow-up was 2 (0.5-39) months. Fifteen (57.7%) patients were female. Clinical manifestations were skin (100%), joint (69.2%), gastrointestinal symptoms (50%) and renal involvement (19.2%). Symptoms lasted within 8 weeks in 21 (80%) patients. Recurrences identified in 5 (19%) patients with a mean of 4.8 +/- 2.4 times. The clinical outcome was excellent without major complication. Colchicine induced remission of severe and recurrent petechiae in one patient who developed methemoglobinemia after dapsone therapy. Colchicine may be an effective drug for prolonged HSP without renal involvement. The controlled studies to establish benefit effect and optimal regimen of colchicine in HSP is required.

Osmotic demyelination syndrome (ODS) is an uncommon acute demyelinating process which involves the central nervous system. Rapid correction of chronic hyponatremia with increasing serum osmolality is the most common cause of ODS. We report the first case of an infant with moderate dehydration and initially normal serum Na who developed ODS associated with a fluctuation of serum osmolality. We present the lowest decreasing rate of serum Na level ever reported causing ODS. The fluctuation of serum osmolality in this case expands the list of precipitating causes of ODS in children. The case also highlights the appropriate intravenous fluid for initial rehydration in infant.

Background: Acute renal failure (ARF) in a newborn is a common problem. Fractional excretion of sodium (FENa) has been used to distinguish between the two main causes of ARF, prerenal failure and acute tubular necrosis (ATN). However, the clinical usefulness of FENa could be limited by furosemide diuretic that are commonly prescribed inARF patients. In contrast, urea is not reabsorbed significantly in the distal nephron, thus the fractional excretion of urea (FE UN) should not be affected by furosemide., Objective: To test the hypothesis that FE UN is not effected by furosemide and useful in differentiating between prerenal failure and ATN., Material and Method: Neonates admitted to the Department of Pediatrics, Thammasat University Hospital from August 2007-May 2009 were studies prospectively for ARF which is defined as urine output < 0.5 ml/kg/hr after the 1st day and serum creatinine > 1.5 mg/dl with normal maternal renal function. FENa and FEUN were performed on the initial time of diagnosis and were repeated on two consecutive days., Results: Neonates with ARF were classified as prerenal failure (n=38) and ATN (n=5). The prerenal failure neonates were divided into two groups: those prerenal failure without furosemide (n=27), those prerenal failure with furosemide (n=11). The FENa at the initial time of diagnosis and the two consecutive days in prerenal failure neonates (0.33 +/- 0.57, 10.1 +/- 2.73, 0.8 +/- 1.32%, respectively) were lower than ATN neonates (4.74 +/- 6.12, 5.05 +/- 4.03, 3.98 +/- 2.47%, respectively) significantly. Both FENa and FE UN were no statistical difference between the two prerenal failure groups and ATN neonates., Conclusion: A FE Na in prerenal failure is significantly lower than ATN. A FE UN has no benefit in distinguishing between prerenal failure and ATN. Furosemide has no effect on both FENa and FE UN.

Systemic lupus erythematosus (SLE) is a common autoimmune disease in children. Current standard therapies carry high adverse effects. Refractory SLE to conventional therapies is not uncommon. Rituximab, anti-CD20 monoclonal antibody, has been used as an adjunctive therapy in children with refractory SLE with limited reports. This study described pediatric SLE patients in a single center, Thailand. To determine the clinical manifestations, treatments, and outcome of SLE patients, the authors retrospectively studied 19 patients (age <15 years) diagnosed with SLE at Thammasat University hospital, from January 01, 2002 through March 31, 2010. The mean age was 12.9 +/- 1.6 years; mean follow-up 3.3 +/- 2.6 years. Seventeen (89.5%) patients were female. Clinical manifestations were hematological (89.5%), dermatologic (73.7%), and renal involvement (68.4%). SLE was diagnosed 1 year after systemic onset juvenile rheumatoid arthiris in one patient. Lupus nephritis (LN) class II was observed in 30.8%, class III (15.4%), and class IV (53.8%) of patients with LN. Overall, mean SLEDAI score at presentation was 14.9 +/- 2.2 and significantly decreased to 6.8 +/- 1.6 (p < 0.0001) at 1 month after treatment. Complete remission at 1 year demonstrated in 11 (68.7%) patients. Infection was the most common complication followed by ophthalmological complications. All patients survived during follow-up period. Rituximab induced remission of SLE after refractory diffuse alveolar hemorrhage in one patient, and rapidly progressive glomerulonephirits leading to end stage renal failure in one patient. Clinical outcome of pediatric SLE was favorable in the present study. Complications from corticosteroid and anti-inflammatory therapy were high. Rituximab may be a good adjunctive therapy for refractory SLE in children. Large controlled trials to establish safety profile and optimal regimen of rituximab in childhood SLE are required.

Hypertension in children is the major risk for cardiovascular disease in adult. Limited data are available for hypertension in children in Southeast Asia. To determine the cause, treatment, and long-term outcome of hypertension in Thai Children, the authors retrospectively studied 62 patients (age <15 years) diagnosed with hypertension at Thammasat University hospital, from December 01, 2004 through November 30, 2009. The mean age was 9.2 +/- 4.2 years; median follow-up 8 months. Fifty five (88.7%) patients had secondary hypertension. Patients presented with stage 2 hypertension (67.7%), and hypertensive emergency (9.7%). Renal parenchymal disease caused 67.3% of secondary hypertension. End organ damage included left ventricular hypertrophy (11.3%) and hypertensive retinopathy (6.4%). Hypertensive emergency was caused mostly by acute poststreptococcal glmoerulnephritis (APSGN, 66.7%). Intravenous diuretic coupled with oral antihypertensive drugs gave uncontrolled blood pressure in APSGN with hypertensive emergency. Seventy percents of patients with essential hypertension had obesity. Majority of the patients had controlled hypertension without medication. Acute poststreptococcal glomerulonephritis remained the common cause of transient hypertension and hypertensive emergency in Thai children. The high incidence of obesity among essential hypertension in children demonstrated in the present study should alert Thai pediatrician to measure blood pressure in every obese child. Treatment of childhood hypertension was associated with good long-term outcome.

Background: One striking feature observed during renal ischemia reperfusion injury (IRI) is the increase in interstitial fluid and infiltration, which reflects an increase in vascular permeability. Angiopoietin-1 (Ang-1) prevents vascular leakage and inflammation. Hyaluronic acid (HA) has a high capacity to bind and retain water and is pro-inflammatory factor., Material and Method: The authors evaluated the expression of Ang-1 and HA during renal IRI bilaterally for 30 minutes. Renal tissue was sent for pathologic study, proteins expression, and mRNA in renal IRI at 24 and 48 hr., Results: At 24 hr post-injury, histopathology studies revealed severe tubular epithelial cell (TEC) necrosis, peritubular capillary (PTC) congestion, mild interstitial infiltration, and edema. Histopathology at 48 hr post-injury showed a progressive increased degree of PTC congestion, interstitial infiltration and edema. In normal kidney, Ang-1 was abundant in glomerulus and PTC patterns, while HA is absent in the cortex but present in the medulla. At 24 and 48 h rpost-IRI, kidney cortex and medulla showed a reduced Ang-1 staining but with an increase in HA staining. Western blot analysis showed that levels of Ang-1 expression decreased to 44% of normal levels at 24 hr post-IRI and further declined to 31% at 48 hr post-IRI. Using real time RT-PCR, Ang-1 expression declined to 15% of normal levels at 24 hr post-IRI and sustained at 48 hr post-IRI., Conclusion: These results suggest that lowered Ang-1 expression levels and increased HA may contribute to an increased permeability and inflammation of microcirculation in renal IRI.