Kidney International. Supplement

Besides locomotion, organ protection, and calcium-phosphorus homeostasis, the three classical functions of the skeleton, bone remodeling affects energy metabolism through uncarboxylated osteocalcin, a recently discovered hormone secreted by osteoblasts. This review traces how energy metabolism affects osteoblasts through the central control of bone mass involving leptin, serotoninergic neurons, the hypothalamus, and the sympathetic nervous system. Next, the role of osteocalcin (insulin secretion, insulin sensitivity, and pancreas β-cell proliferation) in the regulation of energy metabolism is described...

Fibroblast growth factor (FGF)-23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)₂D₃) levels. It is secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased serum 1,25(OH)₂D₃ levels. In human chronic kidney disease (CKD), plasma FGF-23 appears to be a sensitive biomarker of abnormal renal phosphate handling, as FGF-23 levels increase during early stages of kidney malfunction. In humans and animals with CKD, elevated FGF-23 levels increase fractional phosphate excretion, reduce serum phosphate levels, and reduce 1α-hydroxylase activity, which reduces 1,25(OH)₂D₃ formation thereby increasing parathyroid hormone (PTH) secretion...

Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone-kidney-parathyroid control of phosphate and calcium. Klotho⁻/⁻ mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor, or NaPi cotransporter)...

Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the 'intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that 'as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca²+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism...

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Risk factors for disease states are rigorously defined. This analysis considers the definition of a risk factor as applied to the question of whether the serum phosphorus level is a risk factor for cardiovascular disease. Observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. A plausible mechanism of action has been discovered demonstrating that phosphorus stimulates osteoblastic transition of cells in the neointima of atherosclerotic plaques, which, if prevented, blocks vascular calcification...

Reabsorption of glucose in the proximal renal tubule involves the Na(+)-coupled glucose cotransporter (SGLT) and the facilitative glucose transport (GLUT) multigene glucose transport families. Mutations in SLC5A2, the SGLT2 coding gene, are responsible for familial renal glucosuria (FRG), a genetic disorder characterized by glucosuria in the absence of both hyperglycemia and generalized proximal tubular dysfunction. In this paper we focus on FRG and describe other inherited and acquired clinical conditions associated with glucosuria...

Diabetic nephropathy has become a worldwide epidemic accounting for approximately one-third of all cases of end-stage renal disease. The problem is expected to grow, as the prevalence of diabetes is expected to increase from 285 million patients at present to 438 million patients in the year 2030, with increasing prevalence of diabetes particularly in Asia, and a global prevalence of microalbuminuria of ∼ 40%. This will have a major societal impact because of the enormous financial burden of renal replacement therapy and the invalidating character of this disease...

Glucose is freely filtered in the glomeruli before being almost entirely reabsorbed into circulation from the proximal renal tubules. The sodium-glucose cotransporter 2 (SGLT2), present in the S1 segment of the proximal tubule, is responsible for the majority of glucose reabsorption. SGLT2 inhibitors reduce glucose reabsorption and increase urinary glucose excretion. In animal models and humans with type 2 diabetes, this effect is associated with reduced fasting and postprandial blood glucose levels, and reduced hemoglobin A1c...

The physiological and pathological handling of glucose via sodium-glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies...

The kidney contributes to glucose homeostasis through processes of gluconeogenesis, glucose filtration, glucose reabsorption, and glucose consumption. Each of these processes can be altered in patients with type-2 diabetes (T2DM), providing potential targets for novel therapies. Recent studies have indicated that the kidney is responsible for up to 20% of all glucose production via gluconeogenesis. In patients with T2DM, overall glucose production increases by as much as 300%, with equal contributions from hepatic and renal sources...

Chronic rejection, the primary cause of late renal allograft loss, results from a complex interplay between immunological and non-immunological factors. During the past few decades, transplant research has focused almost exclusively on identifying more powerful and minimally toxic immunosuppressive strategies to prevent acute rejection and alloimmune response toward the graft, whereas poor attention has been paid to non-immunological factors. However, the discrepancy between remarkable improvements in the prevention of acute rejection and failure to ameliorate long-term graft outcomes suggests that non-immunological injuries may have an important role in the progressive loss of graft function...

Prevention of chronic allograft dysfunction is currently one of the main goals in renal transplantation for the improvement of kidney graft survival. For this purpose, refinements in immunosuppressive regimens, both controlling alloimmune responses and avoiding calcineurin inhibitor (CNI)-derived nephrotoxicity, are mandatory. The majority of trials aiming to avoid CNI-related nephrotoxicity have only reported short-term data, with different rates of acute rejection depending on the strategy performed. First attempts of CNI-free strategies in micophenolate mofetil-based regimens showed unsatisfactory results in terms of increased acute rejection events...

Late failure of a kidney transplant continues to be a major problem after transplantation, in spite of more potent immunosuppressive strategies and the focus of clinical management shifting toward prolonging long-term graft survival. It is now recognized that graft failure occurs because of two major complications: death with a functioning graft and intrinsic allograft failure. Recent studies of late kidney graft loss have indicated a complexity of findings, including etiologies that are both immune and non-immune...

Using kidneys from expanded-criteria donors to alleviate organ shortage has raised concern on reduced transplant outcomes. In this paper, we review how critical donor-related factors such as donor age, brain death, and consequences of ischemia-reperfusion injury (IRI) determine graft quality and impact chronic allograft nephropathy. We propose that combinatorial effects of organ-intrinsic features associated with increasing age and unspecific injuries related to brain death and IRI will impact innate and adaptive immune responses...

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract)...

Metabolic syndrome (MS) is a cluster of cardiovascular (CV) risk factors (hypertension, dyslipidemia, obesity, and glucose homeostasis alterations), and insulin resistance (IR) is suggested to be a common pathogenic background. In the general population, MS and IR have been proven to be risk factors for diabetes, CV disease, and chronic kidney disease. In the renal transplant setting, few studies have analyzed the relevance of MS and IR. According to the few data available, the prevalence of MS in renal transplant patients has been described as 22...

Despite the impressive reduction in early acute rejection rates over the past decades, chronic allograft dysfunction remains a key issue after renal transplantation. A number of factors, such as the quality of the original organ, ischemia/reperfusion injury, and/or (treated) acute rejection, will adversely affect renal structure, causing early (but often mild) tubular atrophy and interstitial fibrosis. It remains, however, controversial whether subclinical acute rejection or borderline changes imply a different functional prognosis with longer times of follow-up, if cases with late clinical acute rejection, inadequate dosing, and/or incompliance with drug prescription are excluded...

Chronic allograft injury (CAI) is common after kidney transplantation in which immunological (e.g., acute and chronic cellular and antibody-mediated rejection) and nonimmunological factors (e.g., donor-related factors, ischemia-reperfusion injury, polyoma virus, hypertension, and calcineurin inhibitor nephrotoxicity) have a role. Despite the new Banff pathological classification, histopathological diagnosis is still far from being the 'gold standard' to understand the exact mechanisms in the development of CAI, which may lead to appropriate treatment...

Chronic allograft dysfunction is associated with a variety of fibrosing/sclerosing changes in the allograft. Fibrosis is multifactorial, a final pathway following varying types of injury. Using a range of diagnostic criteria, the pathologist can and should define specific lesions enabling identification of pathogenic processes affecting the allograft. Although some cases remain 'interstitial fibrosis and tubular atrophy, no specific cause', specific diagnoses can be made in most cases. Drug toxicity, bacterial or viral infection, hypertension, obstruction, recurrent or de novo renal diseases, and acute and chronic cell- and/or antibody-mediated rejection can be diagnosed in this setting...