An information theoretic approach to insulin sensing by human kidney podocytes

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordPodocytes are key components of the glomerular filtration barrier (GFB). They are insulin-responsive but can become insulin-resistant, causing features of the leading global cause of kidney failure, diabetic nephropathy. Insulin acts via insulin receptors to control activities fundamental to GFB integrity, but the amount of information transferred is unknown. Here we measure this in human podocytes, using information theory-derived statistics that take into account cell-cell variability. High content imaging was used to measure insulin effects on Akt, FOXO and ERK. Mutual Information (MI) and Channel Capacity (CC) were calculated as measures of information transfer. We find that insulin acts via noisy communication channels with more information flow to Akt than to ERK. Information flow estimates were increased by consideration of joint sensing (ERK and Akt) and response trajectory (live cell imaging of FOXO1-clover translocation). Nevertheless, MI values were always <1Bit as most information was lost through signaling. Constitutive PI3K activity is a predominant feature of the system that restricts the proportion of CC engaged by insulin. Negative feedback from Akt supressed this activity and thereby improved insulin sensing, whereas sensing was robust to manipulation of feedforward signaling by inhibiting PI3K, PTEN or PTP1B. The decisions made by individual podocytes dictate GFB integrity, so we suggest that understanding the information on which the decisions are based will improve understanding of diabetic kidney disease and its treatment.Kidney Research UK Gran

Diagnosis, treatment and follow-up of 25 patients with melamine-induced kidney stones complicated by acute obstructive renal failure in Beijing Children’s Hospital

A total of 25 Chinese patients aged 6 to 36 months hospitalised at Beijing Children’s Hospital due to melamine-induced kidney stones complicated by acute obstructive renal failure in 2008 were included in a study in order to diagnose and treat these special cases more effectively. Feeding history, clinical presentation, ultrasound findings, treatments and effects were summarised. Twelve to seventeen months follow-up was reported also. Ultrasound examination showed that calculi were located at the kidney and ureters. Stones were composed of both uric acid and melamine in a molar ratio of 1.2:1 to 2.1:1. Treatments providing liquid plus alkalisation of urine proved to be effective in helping the patients pass the stones. Surgical intervention was needed in severe cases. Renal function returned to normal in all 25 patients after various durations of therapy. Sixty-eight percent of the patients expelled all of the calculi within 3 months, 90% in 6 months and 95% in 9 months, without sequelae till now. Melamine-contaminated milk formula can cause kidney stones in infants, which should be diagnosed by feeding history, clinical symptoms and ultrasound examination. Composition of the stones was not only of melamine but also uric acid. Providing liquid orally or intravenously plus alkalisation of urine proved to promote the removal of the stones. Follow-up of 12 to 17 months after discharge showed no sequelae

Ibuprofen induced acute renal failure in an infant

This portrait of two young women posed with their heads together before a backdrop was taken by traveling photographer Albert J. Ewing, ca. 1896-1912. Written on the negative is the name Lottie Edwards of Burning Springs, West Virginia. Like most of Ewing's work, it was taken in the region of southeastern Ohio and central West Virginia. Born in 1870 in Washington County, Ohio, near Marietta, Ewing most likely began his photography career in the 1890s. The 1910 US Census and a 1912-1913 directory list him as a photographer. A negative signed "Ewing Brothers" and a picture with his younger brother, Frank, indicate that Frank may have joined the business. After 1916, directories list Albert as a salesman. He died in 1934. The Ewing Collection consists of 5,055 glass plate negatives, each individually housed and numbered. Additionally, the collection includes approximately 450 modern contact prints made from the glass plate negatives. Subjects include infants and young children, elderly people, families, school and religious groups, animals and rural scenes. In 1982, the Ohio Historical Society (now the Ohio History Connection) received the collection, still housed in the original dry plate negative boxes purchased by Ewing. A selection of the original glass plate negatives were exhibited for the first time in 2013 at the Ohio History Center

Epidemiology of paediatric renal stone disease in the UK

Background: The previous epidemiological study of paediatric nephrolithiasis in Britain was conducted more than 30 years ago. Aims: To examine the presenting features, predisposing factors, and treatment strategies used in paediatric stones presenting to a British centre over the past five years. Methods: A total of 121 children presented with a urinary tract renal stone, to one adult and one paediatric centre, over a five year period (1997–2001). All children were reviewed in a dedicated stone clinic and had a full infective and metabolic stone investigative work up. Treatment was assessed by retrospective hospital note review. Results: A metabolic abnormality was found in 44% of children, 30% were classified as infective, and 26% idiopathic. Bilateral stones on presentation occurred in 26% of the metabolic group compared to 12% in the infective/idiopathic group (odds ratio 2.7, 95% CI 1.03 to 7.02). Coexisting urinary tract infection was common (49%) in the metabolic group. Surgically, minimally invasive techniques (lithotripsy, percutaneous nephrolithotomy, and endoscopy) were used in 68% of patients. Conclusions: There has been a shift in the epidemiology of paediatric renal stone disease in the UK over the past 30 years. Underlying metabolic causes are now the most common but can be masked by coexisting urinary tract infection. Treatment has progressed, especially surgically, with sophisticated minimally invasive techniques now employed. All children with renal stones should have a metabolic screen

Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, podocin, and CD2 associated protein in cultured human podocytes

Podocytes are critical in maintaining the filtration barrier of the glomerulus and are dependent on the slit diaphragm (SD) proteins nephrin, podocin, and CD2-associated protein (CD2AP) to function optimally. The effects of normal human plasma and nephrotic plasma on podocytes were tested, focusing particularly on the SD complex. With the use of a conditionally immortalized human podocyte cell line, it first was shown that exposure to normal and non-nephrotic human plasma leads to a concentration of nephrin, podocin, CD2AP, and actin at the cell surface. Next, the effects of plasma from patients with nephrotic conditions to non-nephrotic conditions were compared. When exposed to all nephrotic plasma samples (and a non-human serum control), nephrin podocin and CD2AP assumed a cytoplasmic distribution; nephrin and synaptopodin were selectively downregulated, and the relocation of nephrin induced by nephrotic plasma could be rescued back to the plasma membrane by co-incubation with non-nephrotic plasma. Furthermore, intracellular calcium signaling was altered by nephrotic plasma, which was mediated by tyrosine kinase phosphorylation. With the use of nephrin mutant human cell lines, it was shown that this signaling and translocation response to normal plasma is nephrin dependent. This work demonstrates that nephrotic plasma seems to be deficient in factors that act via the podocyte SD complex, which are essential in maintaining its physiologic function. Copyright © 2005 by the American Society of Nephrology.link_to_subscribed_fulltex

Insulin signaling to the glomerular podocyte is critical for normal kidney function

Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function. © 2010 Elsevier Inc.link_to_subscribed_fulltex