Madhav C. Menon

Molecular targets for treatment of kidney fibrosis

Renal fibrosis is the culmination of processes driven by signaling pathways involving transforming growth factor-β family of cytokines, connective-tissue growth factor, nuclear factor κB, Wnt/β-catenin, Notch, and other growth factors. Many studies in experimental animal models have directly targeted these pathways and demonstrated efficacy in mitigating renal fibrosis. However, only a small fraction of these approaches have been attempted in human and even fewer have been successfully translated to clinical use for patient with kidney diseases. Drugs with proven efficacy for treatment of kidney diseases and tissue fibrosis exert some of their effects by interfering with components of these pathways. This review considers key molecular mediators of renal fibrosis and their potential as targets for treatment of renal fibrosis.

Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study

BACKGROUND Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis. METHODS This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702. FINDINGS We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve [AUC] 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972). INTERPRETATION Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis. FUNDING National Institutes of Health.

The Glomerular Filtration Barrier: Components and Crosstalk

The glomerular filtration barrier is a highly specialized blood filtration interface that displays a high conductance to small and midsized solutes in plasma but retains relative impermeability to macromolecules. Its integrity is maintained by physicochemical and signalling interplay among its three core constituents—the glomerular endothelial cell, the basement membrane and visceral epithelial cell (podocyte). Understanding the pathomechanisms of inherited and acquired human diseases as well as experimental injury models of this barrier have helped to unravel this interdependence. Key among the consequences of interference with the integrity of the glomerular filtration barrier is the appearance of significant amounts of proteins in the urine. Proteinuria correlates with kidney disease progression and cardiovascular mortality. With specific reference to proteinuria in human and animal disease phenotypes, the following review explores the roles of the endothelial cell, glomerular basement membrane, and the podocyte and attempts to highlight examples of essential crosstalk within this barrier.

Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis

Fibrosis underlies the loss of renal function in patients with chronic kidney disease (CKD) and in kidney transplant recipients with chronic allograft nephropathy (CAN). Here, we studied the effect of an intronic SNP in SHROOM3, which has previously been linked to CKD, on the development of CAN in a prospective cohort of renal allograft recipients. The presence of the rs17319721 allele at the SHROOM3 locus in the donor correlated with increased SHROOM3 expression in the allograft. In vitro, we determined that the sequence containing the risk allele at rs17319721 is a transcription factor 7-like 2-dependent (TCF7L2-dependent) enhancer element that functions to increase SHROOM3 transcription. In renal tubular cells, TGF-β1 administration upregulated SHROOM3 expression in a β-catenin/TCF7L2-mediated manner, while SHROOM3 in turn facilitated canonical TGF-β1 signaling and increased α1 collagen (COL1A1) expression. Inducible and tubular cell-specific knockdown of Shroom3 markedly abrogated interstitial fibrosis in mice with unilateral ureteric obstruction. Moreover, SHROOM3 expression in allografts at 3 months after transplant and the presence of the SHROOM3 risk allele in the donor correlated with increased allograft fibrosis and with reduced estimated glomerular filtration rate at 12 months after transplant. Our findings suggest that rs17319721 functions as a cis-acting expression quantitative trait locus of SHROOM3 that facilitates TGF-β1 signaling and contributes to allograft injury.

Dietary phosphorus, serum phosphorus, and cardiovascular disease

Recent epidemiologic studies have linked higher serum phosphorus concentrations to cardiovascular disease (CVD) events and mortality. This association has been identified in the general population and in those with chronic kidney disease (CKD). The risk of adverse outcomes appears to begin with phosphorus concentrations within the upper limit of the normal reference range. Multiple experimental studies have suggested pathogenetic mechanisms that involve direct and indirect effects of high phosphorus concentrations to explain these associations. Drawing from these observations, guideline‐forming agencies have recommended that serum phosphorus concentrations be maintained within the normal reference range in patients with CKD and that dietary phosphorus restriction or use of intestinal phosphate binders should be considered to achieve this goal. However, outside the dialysis population, the links between dietary phosphorus intake and serum phosphorus concentrations, and dietary phosphorus intake and CVD events, are uncertain. With specific reference to the nondialysis populations, this review discusses the available data linking dietary phosphorus intake with serum phosphorus concentrations and CVD events.

Moving Biomarkers toward Clinical Implementation in Kidney Transplantation

Long-term kidney transplant outcomes remain suboptimal, delineating an unmet medical need. Although current immunosuppressive therapy in kidney transplant recipients is effective, dosing is conventionally adjusted empirically on the basis of time after transplant or altered in response to detection of kidney dysfunction, histologic evidence of allograft damage, or infection. Such strategies tend to detect allograft rejection after significant injury has already occurred, fail to detect chronic subclinical inflammation that can negatively affect graft survival, and ignore specific risks and immune mechanisms that differentially contribute to allograft damage among transplant recipients. Assays and biomarkers that reliably quantify and/or predict the risk of allograft injury have the potential to overcome these deficits and thereby, aid clinicians in optimizing immunosuppressive regimens. Herein, we review the data on candidate biomarkers that we contend have the highest potential to become clinically useful surrogates in kidney transplant recipients, including functional T cell assays, urinary gene and protein assays, peripheral blood cell gene expression profiles, and allograft gene expression profiles. We identify barriers to clinical biomarker adoption in the transplant field and suggest strategies for moving biomarker-based individualization of transplant care from a research hypothesis to clinical implementation.

Epithelial-to-mesenchymal transition of tubular epithelial cells in renal fibrosis: a new twist on an old tale

Recent publications have questioned whether epithelial-to-mesenchymal transition of tubular epithelial cells is an important contributor to renal fibrosis. Two recent publications describe an intratubular epithelial-to-mesenchymal transition-like program of epithelial cell dedifferentiation that may contribute to the recruitment or proliferation of interstitial myofibroblasts after kidney injury.

The burden of dialysis-requiring acute kidney injury among hospitalized adults with HIV infection: a nationwide inpatient sample analysis.

Objective:The objective of this study was to describe the incidence of acute kidney injury (AKI) requiring renal replacement therapy (’dialysis-requiring AKI’) and the impact on in-hospital mortality among hospitalized adults with HIV infection. Design:A longitudinal analysis of a nationally representative administrative database. Methods:We reviewed the Healthcare Cost and Utilization Projects Nationwide Inpatient Sample Database, a large, nationally representative sample of inpatient hospital admissions, to identify all adult hospitalizations with an associated diagnosis of HIV infection from 2002 to 2010. We analysed temporal trends in the incidence of dialysis-requiring AKI and the associated odds of in-hospital mortality. We also explored potential reasons behind temporal changes. Results:Among 183 0041 hospitalizations with an associated diagnosis of HIV infection, the proportion complicated by dialysis-requiring AKI increased from 0.7% in 2002 to 1.35% in 2010. This temporal rise was completely explained by changes in demographics and an increase in concurrent comorbidities and procedure utilization. The adjusted odds of in-hospital mortality associated with dialysis-requiring AKI also increased over the study period, from 1.45 [95% confidence interval (95% CI) 0.97–2.12] in 2002 to 2.64 (95% CI 2.04–3.42) in 2010. Conclusion:These data suggest that the incidence of dialysis-requiring AKI among hospitalized adults with HIV infection continues to increase, and that severe AKI remains a significant predictor of in-hospital mortality in this population. The increased incidence of dialysis-requiring AKI was largely explained by ageing of the HIV population and increasing prevalence of chronic non-AIDS comorbidities, suggesting that these trends will continue.

The management of hyponatremia in HIV disease

Hyponatremia is reported to be the most common electrolyte abnormality encountered in clinical prac- tice. Diagnosis and principles of management of hy- ponatremia are everyday issues in patient care. Inter- est has also been generated by its association with adverse prognosis from studies in specific disease groups. Patients with human immunodeficiency virus (HIV) disease are living longer and medical diseases similar to the general population are more frequently encountered in them. Hyponatremia has been ob- served to be widely prevalent in both hospitalized and outpatient HIV patients, although population-based estimates are not known. From case series, these pa- tients appear to be at greater risk for the development of hyponatremia from pathomechanisms encountered in the non-HIV population. In addition, certain HIV- specific mechanisms from infectious etiologies, endo- crine causes, and medications are unique to them. Us- ing an illustrative case as an example, in the following review, we discuss the varied etiologies, pathogenetic mechanisms , clinical features, diagnosis, and outline the management of hyponatremia in HIV patients.

Role of Podocyte Injury in IgA Nephropathy

IgA nephropathy (IgAN) encompasses different pathological entities, all of which are characterized by the mesangial deposition of IgA. Aberrantly glycosylated IgA molecules appear to play a major role in the pathogenesis of IgAN. Both genetic and environmental factors contribute to the formation of IgG antibodies that binds to aberrantly glycosylated IgA molecules and the glomerular deposition of circulating polymeric IgA complexes. Mesangial cells serve as primary glomerular cell type injured in IgAN with a variety of pathological changes leading to progressive renal dysfunction. Recent evidence suggests that indirect podocyte injury also contributes to glomerular damage observed in IgAN. These mechanisms were demonstrated in cultured podocytes exposed to mesangial cell-conditioned medium of human IgAN. Large-scale biopsy series of human kidneys also suggest that podocyte injury plays a role in IgAN. In this review, we discuss the recent advances that have helped elucidate the mechanisms of podocyte injury in IgAN and how these mechanisms correlate with clinically important outcomes in human studies.