Swasti Chaturvedi

Slit2 Prevents Neutrophil Recruitment and Renal Ischemia-Reperfusion Injury

Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response.

Slit2-Robo signaling in inflammation and kidney injury

Acute kidney injury is an increasingly common global health problem and is associated with severe morbidity and mortality. In addition to facing high mortality rates, the survivors of acute kidney injury are at increased risk of developing chronic kidney disease and end-stage renal disease. Renal ischemia-reperfusion injury (IRI) is the most common cause of acute kidney injury, and results from impaired delivery of oxygen and nutrients to the kidney. Massive leukocyte influx into the post-ischemic kidney is one of the hallmarks of IRI. The recruited leukocytes exacerbate tissue damage and, if uncontrolled, initiate the progressive changes that lead to renal fibrosis and chronic kidney disease. Early on, recruitment and activation of platelets promotes microthrombosis in the injured kidney, further exacerbating kidney damage. The diversity, complexity, and multiplicity of pathways involved in leukocyte recruitment and platelet activation make it extremely challenging to control these processes, and past efforts have met with limited success in human trials. A generalized strategy to inhibit infiltration of inflammatory leukocytes and platelets, thereby reducing inflammation and injury, may prove to be more beneficial. In this review, we summarize recent findings demonstrating that the neuronal guidance cues, Slit and Roundabout (Robo), prevent the migration of multiple leukocyte subsets towards diverse inflammatory chemoattractants, and have potent anti-platelet functions in vitro and in vivo. These properties uniquely position Slit2 as a novel therapeutic that could be used to prevent acute kidney injury associated with IRI.

Renal manifestations of tuberous sclerosis among children: an Indian experience and review of the literature

Objective The objective of this study was to describe the renal manifestations in children 0–18 years of age diagnosed with tuberous sclerosis complex (TSC) at a tertiary hospital in South India. Methods Data of children with TSC, who presented to Christian Medical College Vellore Hospital from January 2008 to January 2013, were analysed by a retrospective chart review. The cases were identified from outpatient records and underwent ultrasonography, urine analysis and examination of serum creatinine to recognize renal involvement. Results Twenty-five children with TSC were identified. Two children did not have imaging studies available and were excluded from the analysis. The age of the included children ranged from 5 days to 15 years with a median age of 8 years. Seventy-four per cent (17/23) were males. Ten of the 23 children had evidence of renal involvement (43.5%). Of the 10 children with renal involvement, 6 had angiomyolipoma (60%), 5 had renal cysts (50%) and 1 had suspected renal cell carcinoma. In two children both angiomyolipoma (AML) and cysts were noted. One child was found to have proteinuria. The rest of the children had no evidence of proteinuria and had normal creatinine clearance. Conclusion We conclude that all children with TSC should be screened for renal involvement and regular follow-up should be arranged.

An unusual cause of severe rickets: Answers

Given the history of failure to thrive and finding of severe rickets with normal anion gap metabolic acidosis with glucosuria, phosphaturia and aminoaciduria, the diagnosis of Fanconi syndrome was made. In the presence of hepatosplenomegaly and abnormal liver function test results, the differential diagnosis of tyrosinemia type 1, cystinosis, glycogen storage disease, Fanconi–Bickel syndrome was considered.

An unusual cause of severe rickets: Questions

A two-and-half-year-old girl presented with a history of failure to thrive, increasing abdominal distension, bowing of legs, and excessive tiredness for the past 1 year. There was history of polyuria and polydipsia since birth. She had a history of fracture of the left femur following trivial trauma 6 months previously, following which she was unable to walk. Her parents were nonconsanguineous but there was a history of one male sibling death at 4 years of age with high-grade fever. He was also reported to have severe bowing of legs, pallor, and weakness. Upon examination, the child’s weight was 8.2 kg and height was 70 cm (both < third centile for age). She had clinical features of rickets, including a wide open anterior fontanel, widened wrists, rachitic rosary, and genu valgum. There was massive hepatosplenomegaly; liver 8 cm below costal margin, and spleen 6 cm below costal margin with ascites. Her eye examination was normal. Lab investigations revealed normal vitamin D levels (28 ng/ml), elevated serum alkaline phosphatase (2,458 IU/l), normal anion gap metabolic acidosis (pH 7.01, serum sodium 133 mmol/l, serum potassium 3.8 mmol/l, bicarbonate 17 mmol/l, chloride 106 mmol/l, anion gap-10) and severe hypophosphatemia (serum phosphate 0.7 mg%). Urine analysis revealed glucosuria, aminoaciduria, phosphaturia (elevated fractional excretion of phosphate: 63 %), and hypercalciuria. She had low platelet count (60,000/mm) and deranged clotting studies (prothrombin time: 17.7 s; INR: 1.62; activated partial thromboplastin time 40.9 s). The rest of the liver function was within normal limits. X-ray of the lower limbs showed pathological fracture of left femur shaft and severe osteopenia (Fig. 1). Ultrasound of abdomen showed hepatosplenomegaly with coarse echo-texture and multiple hypodense lesions in the liver. The kidneys were normalsized and there was no nephrocalcinosis.

A 12-year-old boy with renal failure and haemoptysis

A 12-year-old boy, previously well, presented with increasing pallor, lethargy and intermittent gross haematuria for 1 month. He also had a history of haemoptysis for the previous 5 days. His blood pressure was normal and he had pedal oedema. There was no hepatosplenomegaly, joint swelling or skin rash. Laboratory investigations (Table 1) revealed anaemia, hypoalbuminaemia and elevated serum creatinine (estimated glomerular filtration rate by Schwartz formula: 13 mL/min/1.73 m). His white cell count, platelet count and clotting profile were normal. His urine analysis showed 2+ protein, 3+ blood and coarse granular casts. He had nephrotic-range proteinuria. His chest X-ray showed bilateral nodular infiltrates (Figure 1A) and a CT of the chest revealed bilateral diffuse ground glass opacities consistent with alveolar haemorrhage (Figure 1B). A kidney biopsy was performed for further evaluation.