Belinda Jim

Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study.

Background Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy. Methodology/Principal Findings Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = −0.48, p<0.0001) and eGFR (rho = −0.33, p = 0.005). Conclusions/Significance These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets.

Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus.

The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes.

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines

Preeclampsia is becoming an increasingly common diagnosis in the developed world and remains a high cause of maternal and fetal morbidity and mortality in the developing world. Delay in childbearing in the developed world feeds into the risk factors associated with preeclampsia, which include older maternal age, obesity, and/or vascular diseases. Inadequate prenatal care partially explains the persistent high prevalence in the developing world. In this review, we begin by presenting the most recent concepts in the pathogenesis of preeclampsia. Upstream triggers of the well described angiogenic pathways, such as the heme oxygenase and hydrogen sulfide pathways, as well as the roles of autoantibodies, misfolded proteins, nitric oxide, and oxidative stress will be described. We also detail updated definitions, classification schema, and treatment targets of hypertensive disorders of pregnancy put forth by obstetric and hypertensive societies throughout the world. The shift has been made to view preeclampsia as a systemic disease with widespread endothelial damage and the potential to affect future cardiovascular diseases rather than a self-limited occurrence. At the very least, we now know that preeclampsia does not end with delivery of the placenta. We conclude by summarizing the latest strategies for prevention and treatment of preeclampsia. A better understanding of this entity will help in the care of at-risk women before delivery and for decades after.

Hypertension in Pregnancy: A Comprehensive Update

Hypertensive disorders of pregnancies remain a central public health concern throughout the world, and are a major cause of maternal mortality in the developing world. Although treatment options have not significantly changed in recent years, insight on the pathogenesis of preeclampsia/eclampsia has been remarkable. With improved animal models of preeclampsia and large-scale human trials, we have embarked upon a new era where angiogenic biomarkers based on mechanism of disease can be designed to assist in early diagnosis and treatment. There is also a growing recognition of how elusive the diagnosis of eclampsia can be, especially in the postpartum period. Proper treatment of these patients depends heavily on the correct diagnosis, especially by the emergency physician. Finally, large epidemiologic studies have revealed that preeclampsia, once thought to be a self-limited entity, now appears to portend real damage to the cardiovascular and other organ systems in the long term. This review will present the latest update on our understanding of the various hypertensive disorders of pregnancies and their treatment options.

Emerging New Biomarkers of Preeclampsia

Preeclampsia continues to plague some of the most vulnerable women and fetuses. It is surprisingly prevalent in developing and developed nations. According to the World Health Organization, hypertension during pregnancy is a leading cause of maternal mortality in industrialized countries at 16% and up to 25% in developing countries. As the pathogenesis of this disease is being unraveled, we are afforded new opportunities to develop novel biomarkers for early identification and prevention of disease. The angiogenic markers including soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin have demonstrated to be the most promising, perhaps in conjunction with traditional markers such as plasma protein-13 and uterine artery Doppler studies. There is also increasing evidence that the podocyte is shed during the course of preeclampsia, which may be useful for diagnosis. Systems biology approaches to biomarker discovery such as proteomics and metabolomics are also gaining more attention and will most certainly open new avenues of research. In this review, we present the best studied biomarkers of preeclampsia to date.

RTN1 mediates progression of kidney disease by inducing ER stress

Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress.

Podocyturia as a Diagnostic Marker for Preeclampsia amongst High-Risk Pregnant Patients

Urinary podocyte (podocyturia) has been studied as a diagnostic marker for preeclampsia. We sought to validate its use in preeclampsia and in differentiating it from other high risk pregnancy states. We studied an obstetric population at high risk to develop preeclampsia (study group) and uncomplicated pregnancies (control group) by analyzing their urine sediment for podocytes within 24 hours of delivery. Podocytes were identified by immunohistochemistry using the podocyte-specific protein synaptopodin. Of the 56 patients who were enrolled, 29 patients were diagnosed with preeclampsia, 9 patients had hypertensive conditions such as chronic and gestational hypertension, 6 patients had Type I/II and gestational diabetes mellitus, 3 patients were classified as others, and 9 patients exhibited uncomplicated pregnancies. Podocyturia was identified in 11 out of 29 (38%) of patients with preeclampsia/eclampsia, 3 out of 9 (33%) with gestational and chronic hypertension, and 3 out of 6 (50%) with Type I/II and gestational diabetes mellitus. None of the 9 patients (0%) with uncomplicated pregnancies demonstrated podocyturia. The sensitivity and specificity of podocyturia for preeclampsia were found to be 38% and 70%. Our study showed that podocyturia does not appear to be a sensitive nor a specific marker to diagnose preeclampsia.

Biomarkers of diabetic nephropathy, the present and the future.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Searching for the perfect biomarker of DN has become the holy grail of nephrology since the burden of this disease is untenable. The only feasible way to tackle this health care crisis is by prevention and treatment in a mechanistically rational approach. Therefore, the discovery of a specific, reliable diagnostic and prognostic biomarker for DN is imperative. Part of the difficulty in finding such a marker is the complex pathogenesis of DN; it is clearly multifactorial and involves multiple genes, proteins, metabolic pathways, and environmental factors. In this review, we will discuss the latest findings in the use of genetic, protein, and metabolic markers of DN. Particular attention will be paid to the urinary biomarker as a noninvasive method to detect either morphological or biochemical changes in DN. Urinary protein and mRNA studies have focused on either the glomerular (podocyte-specific) or tubular components (matrix or injury-related) of the nephron. The virtues and pitfalls of using the podocyte as a biomarker will be discussed. The systems biology approach of biomarker discovery in the studies of genomics, transcriptomics, proteomics, and metabolomics will be explored. Despite significant numbers of new biomarkers described, most studies are limited by either their small sample size or their cross-sectional nature, so that the ability to predict future and severity of DN is lacking. In order to successfully search for the ideal, validated biomarker, we need to conduct large, prospective, multi-center trials enlisting both Type 1 and Type II diabetic patients with and without nephropathy for at least two decades.

A Comparison of Podocyturia, Albuminuria and Nephrinuria in Predicting the Development of Preeclampsia: A Prospective Study

Preeclampsia, a hypertensive multisystem disease that complicates 5–8% of all pregnancy, is a major cause for maternal and fetal mortality and morbidity. The disease is associated with increased spontaneous and evoked preterm birth and remote cardio-renal disorders in the mother and offspring. Thus the ability to predict the disease should lead to earlier care and decreased morbidity. This has led to fervent attempts to identify early predictive biomarkers and research endeavors that have expanded as we learn more regarding possible causes of the disease. As preeclampsia is associated with specific renal pathology including podocyte injury, early urinary podocyte (podocyturia), or the podocyte specific proteinuria nephrin in the urine (nephrinuria), as well as the more easily measured urinary albumin (albuminuria), have all been suggested as predictive markers. We performed a prospective study recruiting 91 pregnant women (78 of whom were high risk) and studied the predictive ability of these three urinary biomarkers. The subjects were recruited between 15–38 weeks of gestation. Fourteen patients, all in the high-risk obstetric group, developed preeclampsia. The levels of podocyturia, nephrinuria, and albuminuria were variably higher in the high-risk pregnant patients who developed preeclampsia. The sensitivities and specificities for podocyturia were 70% and 43%, for albuminuria were 36% and 96%, and for nephrinuria were 57% and 58%, respectively. Also, abnormal nephrinuria (69%) and podocyturia (38%) were detected in low risk women who had uncomplicated gestations; none of these women exhibited albuminuria. In our study, none of the three urinary markers achieved the minimum predictive values required for clinical testing. The lack of excessive albuminuria, however, may indicate a preeclampsia-free gestation. Given a discrepant literature, further studies with larger sample size should be considered.

Acute Kidney Injury in Pregnancy

Pregnancy-related acute kidney injury (AKI) has declined in incidence in the last three decades, although it remains an important cause of maternal and fetal morbidity and mortality. Pregnancy-related causes of AKI such as preeclampsia, acute fatty liver of pregnancy, HELLP (Hemolysis, Elevated Liver function tests, Low Platelets) syndrome, and the thrombotic microangiopathies (thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome [HUS]) exhibit overlapping features and often present as diagnostic dilemmas. Differentiating among these conditions may be difficult or impossible based on clinical criteria only. In difficult and rare cases, a renal biopsy may need to be considered for the exact diagnosis and to facilitate appropriate treatment, but the risks and benefits need to be carefully weighed. The use of eculizumab for the treatment of atypical HUS has demonstrated efficacy in early case reports. Non-pregnancy related causes such as volume depletion and pyelonephritis require early and aggressive resuscitative as well as antibiotic measures respectively. We will discuss in this review the various etiologies of AKI in pregnancy, current diagnostic approaches, and the latest treatment strategies. Given the recent trends of increasing maternal age at the time of pregnancy, and the availability of modern reproductive methods increase the risks of AKI in pregnancy in the coming years.