The role of Tamm-Horsfall protein in the pathogenesis of reflux nephropathy and chronic pyelonephritis

Recurrent bacterial infection of the kidney was previously thought to be responsible for the renal scarring typical of chronic pyelonephritis until recent studies suggested that recurrent bacteriuria rarely produces chronic pyelonephritis in the absence of obstructive uropathy. In contrast, the association between vesicoureteral reflux (VUR) and chronic pyelonephritis has been observed frequently in the absence of urinary infection. Although the mechanism by which VUR injures the kidney has not been defined, recent observations have suggested that some component of urine might serve as an antigenic determinant involved in the immunopathogenesis of renal scarring in VUR. Therefore, the present studies investigated the immunopathogenic role of Tamm-Horsfall protein (THP) in (1) a rabbit model of tubulointerstitial nephritis; (2) a swine model of reflux nephropathy; and (3) patients with recurrent nephrolithiasis. The antigenic similarities between THP and uropathic bacteria were also studied. Our observations indicate that autoimmune responses to THP may occur after exposure to THP by intravenous challenge in rabbits, by urinary reflux in pigs, and in recurrent nephrolithiasis in man. Also, extracts of uropathic coliforms competitively inhibit the binding of human THP to its antibody. These studies suggest that autoimmune responses to THP may be the pathogenetic mechanism by which these factors, including bacteriuria, contribute to "chronic pyelonephritis."     

Costochondritis: pathogenesis, diagnosis, and management considerations

The management of costochondritis of the chest wall is reviewed and four illustrative cases presented. Adequate debridement is the single most important factor to ensure eradication of this disease. Well-vascularized tissue coverage reduces ischemic factors, resists secondary infection by contamination, and promotes rapid healing. The pectoralis major, latissimus dorsi, and rectus abdominis muscle flaps are the primary choices for pedicle-flap coverage. Antibiotic coverage was not extended beyond 3 weeks in these cases, and no recurrences have been noted over a 1- to 3-year follow-up.     

Nonalcoholic fatty liver disease: Update on pathogenesis,diagnosis, treatment and the role of S-adenosylmethionine

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH.     

Gastroesophageal reflux: clinical presentations,diagnosis and management.

Symptomatic gastroesophageal reflux occurs daily in an estimated 7% of adults and weekly or monthly in 29%. Untreated it can lead to esophageal erosions, ulceration and stricture formation. The pathogenesis is often multifactorial: defects in the function of the lower esophageal sphincter, esophageal clearance mechanisms and gastric emptying combine to produce frequent lengthy periods during which the lower esophagus is bathed in regurgitated acid. In most patients reflux disease is easily recognized as recurrent heartburn, regurgitation or dysphagia, or a combination. When acute chest pain or respiratory illness is the primary presenting complaint the patient needs particularly careful investigation to determine whether the symptoms are due to a primary cardiac or respiratory condition, are secondary to gastroesophageal reflux alone or represent a combination of disorders. Endoscopy with biopsy and long-term pH monitoring are the most reliable ways of determining whether reflux disease is present. Additional investigations, such as exercise testing, cardiac catheterization or inhalation challenge, may be needed in patients with cardiac or respiratory symptoms. Treatment should follow a stepped-care approach and in most patients should begin with changes in lifestyle, including dietary manipulation, reducing alcohol and cigarette consumption, and raising the head of the bed, together with appropriate use of antacids or alginate-antacid combinations. H2-receptor antagonists and agents to improve both gastric emptying and the tone of the lower esophageal sphincter may be added in sequence. Most patients will respond well to this regimen. Surgery should be considered only for those with intractable symptoms or with complications (e.g., stricture formation, bleeding, development of dysplastic epithelium in those with Barrett''s esophagus, or secondary pulmonary disease that does not respond to medical management). It is successful in 85% of well-selected patients and has few complications.     

Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting approximately 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.     

Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1

Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults. There is a 30-50-fold increased incidence of VUR in first-degree relatives of probands, compared with the general population. We report the results of the first genomewide search of VUR and RN; we studied seven European families whose members exhibit apparently dominant inheritance. We initially typed 387 polymorphic markers spaced, on average, at 10 cM throughout the genome; we used the GENEHUNTER program to provide parametric and nonparametric linkage analyses of affected individuals. The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16. Saturation with markers at 1-cM intervals increased the NPL to 5.94 (P=.00009). Hence, VUR maps to a locus on chromosome 1. There was evidence of genetic heterogeneity at the chromosome 1 locus, and 12 additional loci were identified genomewide, with P<.05. No significant linkage was found to 6p, where a renal and ureteric malformation locus has been reported, or to PAX2, mutations of which cause VUR in renal-coloboma syndrome. Our results support the hypothesis that VUR is a genetic disorder.     

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.     

Prediction of high-grade vesicoureteral reflux after pediatric urinary tract infection: external validation study of procalcitonin-based decision rule

Background

Predicting vesico-ureteral reflux (VUR) ≥3 at the time of the first urinary tract infection (UTI) would make it possible to restrict cystography to high-risk children. We previously derived the following clinical decision rule for that purpose: cystography should be performed in cases with ureteral dilation and a serum procalcitonin level ≥0.17 ng/mL, or without ureteral dilatation when the serum procalcitonin level ≥0.63 ng/mL. The rule yielded a 86% sensitivity with a 46% specificity. We aimed to test its reproducibility.

Study Design

A secondary analysis of prospective series of children with a first UTI. The rule was applied, and predictive ability was calculated.

Results

The study included 413 patients (157 boys, VUR ≥3 in 11%) from eight centers in five countries. The rule offered a 46% specificity (95% CI, 41–52), not different from the one in the derivation study. However, the sensitivity significantly decreased to 64% (95%CI, 50–76), leading to a difference of 20% (95%CI, 17–36). In all, 16 (34%) patients among the 47 with VUR ≥3 were misdiagnosed by the rule. This lack of reproducibility might result primarily from a difference between derivation and validation populations regarding inflammatory parameters (CRP, PCT); the validation set samples may have been collected earlier than for the derivation one.

Conclusions

The rule built to predict VUR ≥3 had a stable specificity (ie. 46%), but a decreased sensitivity (ie. 64%) because of the time variability of PCT measurement. Some refinement may be warranted.     

Update on Sturge-Weber syndrome: diagnosis, treatment, quantitative measures, and controversies

Sturge-Weber syndrome (SWS) is defined by the association of a facial capillary malformation (port-wine stain), with a vascular malformation of the eye, and/or vascular malformation of the brain (leptomeningeal angioma). Variants exist where only one of these three structures is involved with the vascular malformation. SWS occurs sporadically and is congenital. Port-wine stains occur in 3 per 1000 live births. No good population-based data exist for how many people have Sturge-Weber syndrome, however, estimates range between one in 20-50,000 live births. This review summarizes literature regarding the main features and pathophysiology of Sturge-Weber syndrome, however the cause of this syndrome remains obscure. Recent advances in neuroimaging have provided important insights into the progression of neurologic injury that occurs as a result of impaired blood flow. Important limitations exist, however, as currently the early diagnosis and exclusion of Sturge-Weber syndrome is impaired by the poor sensitivity of imaging in the newborn period and early infancy. Several important controversies complicate our ability to care for these patients and include the questions of ideal timing of surgery, whether seizures themselves contribute to the neurologic injury, and what the role of low-dose aspirin should be. This review will summarize several recent advances in our understanding of the mechanisms of brain injury in SWS, new measures for quantifying the neurologic involvement and new approaches and controversies in the management of the neurologic complications.     

Bone diseases associated with human immunodeficiency virus infection: pathogenesis, risk factors and clinical management

Bone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both na?ve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects.     

The role of the nutrition in the pathogenesis of gastroesophageal reflux disease, Barrett's oesophagus and oesophageal adenocarcinoma

This paper aims at evaluating the role of improper nutrition in the pathogenesis of gastroesophageal reflux disease (GERD), Barrett's oesophagus (BE), and oesophageal adenocarcinoma (EADC). It also tries to examine the influence of the alcohol, nicotine and coffee consumption in the development of the mentioned diseases. There were 180 subjects included in the trial, 109 males and 71 females, which were divided in the four groups (70 patients with GERD, 20 patients with BE, 20 patients with EADC, and 70 healthy examinees composing a control group). Their dietary habits were investigated by the usage of the dietary questionnaires. The results show that the fast eating and the insufficient mastication were present in 64.3-85.0% patients with GERD, BE, and EADC in comparison with only 15% of the examinees from the control group. Furthermore, very hot was preferred by 25.0-42.9% of the mentioned patients in comparison with only 12.9% from the control group. Similarly, 60.0-75.0% of them preferred strongly spiced food on contrary with 17.1% of the healthy examinees. Moreover, strong alcoholic beverages were consumed three or more times per week by 55.0-75.0% of the mentioned patients in comparison with only 15.7% from the control group. Finally, there were 15.7-55.0% heavy smokers among the patients with GERD, BE, and EADC contrary to 1.4% in the control group.     

Cryptosporidiosis: biology,pathogenesis and disease

Ninety-five years after discovery and after more than two decades of intense investigations, cryptosporidiosis, in many ways, remains enigmatic. Cryptosporidium infects all four classes of vertebrates and most likely all mammalian species. The speciation of the genus continues to be a challenge to taxonomists, compounded by many factors, including current technical difficulties and the apparent lack of host specificity by most, but not all, isolates and species.     

An IRKO in the Podo: impaired insulin signaling in podocytes and the pathogenesis of diabetic nephropathy

Despite its high prevalence, the mechanisms causing diabetic kidney disease remain poorly understood. In this issue of Cell Metabolism, Welsh et al. (2010) show that elimination of insulin receptors from the glomerular podocyte, a cell that is central to the pathogenesis of proteinuric renal diseases, recapitulates many features of human diabetic nephropathy.