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Background: Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury demonstrated by renal biopsy that can arise from a diverse range of causes and mechanisms. It has an estimated incidence of 7 per 1 million and is the most common primary glomerular disorder leading to end-stage renal disease in the United States. This review focuses on damage to the podocyte and the consequences of this injury in patients with FSGS, the genetics of FSGS, and approaches to treatment with a focus on the effects on podocytes. Summary: The podocyte is central to the glomerular filtration barrier and is particularly vulnerable because of its highly differentiated post-mitotic phenotype. The progressive structural changes involved in the pathology of FSGS include podocyte foot process effacement, death of podocytes and exposure of the glomerular basement membrane, filtration of nonspecific plasma proteins, expansion of capillaries, misdirected filtration at points of synechiae, and mesangial matrix proliferation. Although damage to and death of podocytes can result from single-gene disorders, evidence also suggests a role for soluble factors, such as soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine-1, and anti-CD40 antibodies, that promote FSGS recurrence post transplant. Several classes of medications, including corticosteroids, calcineurin inhibitors, endothelin receptor antagonists, adrenocorticotropic hormone, and rituximab, have been shown to be effective for the treatment of FSGS and have been demonstrated to have significant protective effects on podocytes. Key Messages: Greater understanding of podocyte biology is essential to the identification of new treatment targets and medications for the management of patients with FSGS.

Conventional treatment of acute and chronic renal diseases has focused on solute removal. Novel strategies aim to treat the multifactorial disease states of acute kidney injury and chronic kidney disease by mitigating inflammation. Cell-based technologies for the treatment of kidney dysfunction fall under two broad categories: cell therapy and cell processing. Cell therapy utilizes cells that are isolated, cultured outside of the body, and reintroduced as therapy, leveraging beneficial metabolic and synthetic functions. For example, renal tubule cells have been used to provide gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation to treat renal dysfunction. Cell processing focuses on altering the characteristics of cell populations inside the body to provide therapy. The selective cytopheretic device is an example of this novel therapeutic strategy that aims to modulate the innate immune response during organ dysfunction, additional organ injury, by binding and deactivating leukocytes. In this review, both cell therapy and cell processing approaches will be discussed in the context of acute kidney injury and chronic renal disease.

Preface: McCullough, P.A. et al. Acute Dialysis Quality Initiative (ADQ): Ronco, C. et al. Implementation of Novel Biomarkers in the Diagnosis, Prognosis, and Management of Acute Kidney Injury: Executive Summary from the Tenth Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): McCullough, P.A. et al, for the Acute Dialysis Quality Initiative (ADQI) Consensus Group Diagnosis of Acute Kidney Injury Using Functional and Injury Biomarkers: Workgroup Statements from the Tenth Acute Dialysis Quality Initiative Consensus Conference: McCullough, P.A. et al., for the ADQI 10 Workgroup Differential Diagnosis of AKI in Clinical Practice by Functional and Damage Biomarkers: Workgroup Statements from the Tenth Acute Dialysis Quality Initiative Consensus Conference: Endre, Z.H. et al., for the ADQI 10 Workgroup Use of Biomarkers to Assess Prognosis and Guide Management of Patients with Acute Kidney Injury: Cruz, D.N. et al., for the ADQI 10 Workgroup Physiological Biomarkers of Acute Kidney Injury: A Conceptual Approach to Improving Outcomes: Okusa, M.D. et al., for the ADQI 10 Workgroup Pathophysiology of the Cardiorenal Syndromes: Executive Summary from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): McCullough, P.A. et al., for the Acute Dialysis Quality Initiative (ADQI) Consensus Group Pathogenesis of Cardiorenal Syndrome Type 1 in Acute Decompensated Heart Failure: Workgroup Statements from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): Haase, M. et al., for the Acute Dialysis Quality Initiative (ADQI) Consensus Group Pathophysiology of Cardiorenal Syndrome Type 2 in Stable Chronic Heart Failure: Workgroup Statements from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): Cruz, D.N. et al., for the Acute Dialysis Quality Initiative (ADQI) Consensus Group Cardiorenal Syndrome Type 3: Pathophysiologic and Epidemiologic Considerations: Bagshaw, S.M. et al., for the Acute Dialysis Quality Initiative 11 Working Group Cardiorenal Syndrome Type 4: Insights on Clinical Presentation and Pathophysiology from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): Tumlin, J.A. et al., for the Acute Dialysis Quality Initiative (ADQI) 11 Consensus Group Cardiorenal Syndrome Type 5: Clinical Presentation, Pathophysiology and Management Strategies from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI): Mehta, R.I. et al., for the Acute Dialysis Quality Initiative (ADQI) 11 Working Group Appendix 1: 10th Acute Dialysis Quality Initiative (ADQI) Consensus Group Appendix 2: 11th Acute Dialysis Quality Initiative (ADQI) Consensus Group.

In developed countries, the continuing rise in the prevalence of hypertension, hyperlipidemia and diabetes has contributed to an overall increase in the incidence of both cardiovascular disease (CVD) and chronic kidney disease (CKD). The observation that even modest reductions in renal function correlate with increased CVD morbidity and mortality has led to the recognition that CKD is an independent risk factor for CVD. Conversely, there is a growing recognition that many pathologic conditions that contribute to CVD, including coronary artery disease, left ventricular hypertrophy and diastolic dysfunction, can accelerate the decline in renal function. In addition, physiologic mechanisms designed to compensate for reduced glomerular filtration rate including activation of the renin-angiotensin-aldosterone axis, the release of fibroblastic growth factor 23 and other mechanisms for calcium-phosphate homeostasis as well as and the pathophysiologic effects of uremic toxins can also directly contribute to CVD. The end result of the interaction between changes in pressure and volume overload and the physiologic compensation for the loss of function in both the heart and the kidney leads to accelerated decline in both organ systems. This complex physiologic and pathophysiologic interplay between the cardiovascular and renal systems is collectively referred to as the cardiorenal syndrome. The discussion which follows is aimed at outlining the pathophysiologic mechanisms linking advanced CKD (4 and 5) to the development of cardiac abnormalities which occur with unique frequency and severity in patients with severe impairment of renal function.