Heme Oxygenase-1 as a Target for TGF-β in Kidney Disease

Transforming growth factor-β (TGF-β) is a multifunctional regulatory cytokine that is implicated in a variety of kidney diseases, including diabetic nephropathy and chronic transplant rejection, where it promotes stimulation of the extracellular matrix deposition, cell proliferation, and migration. TGF-β exerts its biological functions largely via its downstream complex signaling molecules, Smad proteins. Paradoxically, TGF-β also is essential for normal homeostasis and suppression of inflammation through mechanisms that are yet to be fully elucidated. One feasible mechanism by which TGF-β may exert its beneficial properties is through induction of heme oxygenase-1 (HO-1). Induction of this redox-sensitive enzyme is known to be cytoprotective through its potent antioxidant, anti-inflammatory, and anti-apoptotic properties in different conditions including several kidney diseases. In this overview, recent advances in our understanding of the role of TGF-β in kidney disease, its molecular regulation of HO-1 expression, and the potential role of HO-1 induction as a therapeutic modality in TGF-β-mediated kidney diseases are highlighted.     

Decreased Hypoxia-Inducible Factor-1α in Gastrocnemius Muscle in Rats with Chronic Kidney Disease

Background/Aims: Hypoxia-inducible factor (HIF)-1α is responsible for increased expression of genes engaged in angiogenesis. Our previous study indicated capillary rarefaction and atrophy of glycolytic fibers, mainly in locomotor muscles of uremic animals. Perhaps these changes are secondary to disturbances of HIF-1α in skeletal muscles. Methods: Expression of HIF-1α at mRNA and protein levels, as well as mRNA of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), in gastrocnemius muscle (MG) and longissimus thoracic muscle (ML) were measured by RT-PCR and Western blot. Rats were randomized to subtotal nephrectomy (CKD5/6), uninephrectomy (CKD1/2) or sham operation (controls). Results: For CKD5/6 versus controls, mRNA levels for HIF-1α, VEGF-A, VEGFR-1 and VEGFR-2 were significantly reduced only in MG, while eNOS was significantly decreased and iNOS was significantly increased only in ML. Western blot analysis indicated significantly increased HIF-1α protein levels in MG and ML from CKD1/2 animals versus controls, whereas in the CKD5/6 group, the level of HIF-1α protein decreased significantly in MG and increased significantly in ML versus controls and CKD1/2. Conclusion: The reduced expression of HIF-1α mRNA and protein in locomotor muscle from CKD5/6 animals may be involved in the pathogenesis of uremic myopathy. Increased expression of iNOS in the postural muscles may act as a protective factor through HIF-1α stabilization.     

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease–Mineral Bone Disorder

The Cy/+ rat has been characterized as a progressive model of chronic kidney disease–mineral bone disorder (CKD-MBD). We aimed to determine the effect of kidney disease progression on intestinal phosphorus absorption and whole-body phosphorus balance in this model. A total of 48 Cy/+ (CKD) and 48 normal littermates (NL) rats were studied at two ages: 20 weeks and 30 weeks, to model progressive kidney function decline at approximately 50% and 20% of normal kidney function. Sodium-dependent and sodium-independent intestinal phosphorus absorption efficiency were measured by the in situ jejunal ligated loop method using ³³P radioisotope. Our results show that CKD rats had slightly higher sodium-dependent phosphorus absorption compared to NL rats, and absorption decreased from 20 to 30 weeks. These results are in contrast to plasma 1,25OH₂D, which was lower in CKD rats. Gene expression of the major intestinal phosphorus transporter, NaPi-2b, was not different between CKD and NL rats in the jejunum but was lower in CKD rats versus NL rats in the duodenum. Jejunal ligated loop phosphorus absorption results are consistent with percent net phosphorus absorption results obtained from metabolic balance: higher net percent phosphorus absorption values in CKD rats compared with NL, and lower values in 30-week-olds compared with 20-week-olds. Phosphorus balance was negative (below zero) in CKD rats, significantly lower in 30-week-old rats compared with 20-week-old rats, and lower in CKD rats compared with NL rats at both ages. These results demonstrate no reduction in intestinal phosphorus absorption with progression of CKD despite lower 1,25OH₂D status when assessed by an in situ ligated loop test, which is in contrast to the majority of in vitro studies, and if confirmed in further studies, could challenge the physiological relevance of in vitro findings. © 2019 American Society for Bone and Mineral Research.     

Why Is Your Patient Still Short of Breath? Understanding the Complex Pathophysiology of Dyspnea in Chronic Kidney Disease

Dyspnea is one of the most common symptoms associated with CKD. It has a profound influence on the quality of life of CKD patients, and its underlying causes are often associated with a negative prognosis. However, its pathophysiology is poorly understood. While hemodialysis may address fluid overload, it often does not significantly improve breathlessness, suggesting multiple and co‐existing alternative issues exist. The aim of this article is to discuss the main pathophysiologic mechanisms and the most important putative etiologies underlying dyspnea in CKD patients. Congestive heart failure, unrecognized chronic lung disease, pulmonary hypertension, lung fibrosis, air microembolism, dialyzer bio‐incompatibility, anemia, sodium, and fluid overload are potential frequent causes of breathing disorders in this population. However, the relative contributions in any one given patient are poorly understood. Systemic inflammation is a common theme and contributes to the development of endothelial dysfunction, lung fibrosis, anemia, malnutrition, and muscle wasting. The introduction of novel multimodal imaging techniques, including pulmonary functional magnetic resonance imaging with inhaled contrast agents, could provide new insights into the pathophysiology of dyspnea in CKD patients and ultimately contribute to improving our clinical management of this symptom.     

Should Hemoglobin be Normalized in Patients with Chronic Kidney Disease?

In the last decade the nephrology community has learned much about the impact of anemia on patients with kidney disease. Therapy of anemia can correct many of the symptoms which seriously compromise patient function. Despite the obvious benefits, controversy continues regarding the optimal target hemoglobin concentration both in patients prior to dialysis and in dialysis populations. In this editorial we review the clinical data that contribute to this controversy and the physiologic concepts underlying the treatment of anemia. Furthermore, we discuss the need to individualize hemoglobin targets for specific patient populations and the importance of early identification and treatment of anemia in patients with kidney disease. The economic impact of normalizing hemoglobin with the use of erythropoietin and intravenous or oral iron has affected clinical practice over the last decade. Current guidelines published by Kidney Disease Outcomes and Quality Initiative (KDOQI), the European Working Group on Anemia Management, and the Canadian Society of Nephrology all recommend target hemoglobin concentrations and thresholds for initiation of therapy and also suggest the need for reevaluation of current targets in light of new evidence. This editorial supports those guidelines and challenges the reader to critically evaluate current practice in the context of the accumulating data and the physiologic principles discussed herein. The therapy of anemia in patients with chronic kidney disease (CKD) is becoming increasingly sophisticated and is an essential component of care in patients with CKD. However, the effects of therapy will be most impressive when accompanied by the optimal care of all hemodynamic and metabolic abnormalities that are associated with CKD.     

Is There a Role for Bisphosphonates in Chronic Kidney Disease?

Patients with stage 5 chronic kidney disease (CKD) including those on dialysis can and do develop osteoporosis. They also develop a wide range of other metabolic bone diseases that may look like osteoporosis when it is defined by either the World Health Organization bone mineral density (BMD) criteria or by the development of fragility fractures. Those dialysis patients with osteoporosis that is due to gonadal hormone deficiency such as postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, or male osteoporosis may benefit from the administration of bisphosphonates (BPs). The challenges lie in the diagnosis of osteoporosis in this population where adynamic, osteomalacic, hyperparathyroid, or aluminum bone disease are also prevalent, with concommitant low BMD and low trauma fractures, but where BPs may be contraindicated. The only secure means to diagnose osteoporosis in this patient population is by quantitative bone histomorphometry demonstrating low trabecular bone volume and disrupted microarchitecture. Once the diagnosis of osteoporosis is established, BPs should be considered for a well-defined brief period of time (e.g., 2-3 years), even though there is no evidence for a fracture reduction benefit in this population. If a BP is chosen there may be a need for dose adjustment or slower infusion rates (for the intravenous formulations), as a greater bone retention may occur for these renally cleared agents. While it is unknown what consequences could develop from increased bone retention in patients with little renal function, data are needed if more bone retention of BP might lead to a greater risk of the development of adynamic bone disease and lower bone strength. More data are needed to define the risks and benefits of BPs in patients with stage 5 CKD.     

Treatment of Anemia With Erythropoietin-Stimulating Agents in Kidney Transplant Recipients and Chronic Kidney Disease—Another Drawback of Immunosuppression?

Anemia is more prevalent in allograft recipients compared with glomerular filtration rate (GFR) matched patients with chronic kidney diseases. There is a paucity of data concerning the correction of anemia in the posttransplant period with erythropoietin-stimulating agents (ESA). The aim of this study was to compare the iron status, kidney function, inflammatory state, use of drugs affecting erythropoiesis (immunosuppressants ACEi/ARB) and correction of anemia using ESA in a chronic kidney disease (CKD) population versus kidney transplant recipients. We included 67 patients treated with ESA including 17 after kidney transplantation. CKD Patients with native kidneys were significantly older than allograft recipients (mean age 69 versus 51 years; P < .001, and despite similar serum creatinine and iron parameters showed an estimated lower GFR (19 mL/min versus 23 mL/min; P < .05). Median time of ESA therapy was similar among patients with native kidney CKD versus kidney recipients, but they achieved a significantly higher hemoglobin (11.04 versus 10.36 g/dL; P < .05). There was no difference between patients administered or not a mammalian target of rapamycin antagonist. None of the patients with native kidney CKD received immunosuppressive therapy, but they were prescribed ACEi more often than kidney recipients. The higher degree of anemia in kidney allograft recipient is the most probably attributed to the use of immunosuppressive drugs, despite their better kidney function and comparable iron status. This study suggested that higher doses of ESA should be employed to anemia in kidney transplant recipients.     

Chronic kidney disease prevention—a challenge for Asian countries: report of the Third Asian Forum of Chronic Kidney Disease Initiatives

As an independent meeting, the third Asian Forum of Chronic Kidney Disease Initiatives was held on April 18–19, 2009, in Kaohsiung, Taiwan. Nearly 700 participants from 17 countries attended and 78 posters were presented. To begin with, status quo in Asia and in Taiwan was briefed, followed by Theme 1A “Special Epidemiology and Risk Factors”, during which the interrelations between chronic kidney disease (CKD) and use of herbs, low birth weight, infections, and immunoglobulin A (IgA) nephropathy were discussed. Theme 1B dealt with both cardiovascular and renal outcomes of CKD patients. In Theme 2, five presenters from different countries shared their experiences on “Cost-effectiveness of Community-based or Nationwide CKD Prevention Programs”. In between the conference themes, three international and integrative works—Kidney Disease Improving Global Outcomes, the World Kidney Day, and Kidney Early Evaluation Program—were presented and possible implications for Asia were suggested. Theme 3 was initiated with a thorough discussion on “Equation of the Estimated Glomerular Filtration Rate for Asians” and the preliminary results of a cross-country study were presented. In Theme 4, the care plan, strategies, and outcomes of timely initiation of dialysis in different countries were discussed. The final session started with a concise summary of all speeches and ended with a position statement.     

Inactivation of Integrin-β1 Prevents the Development of Polycystic Kidney Disease after the Loss of Polycystin-1

Dysregulation of polycystin-1 (PC1) leads to autosomal dominant polycystic kidney disease (ADPKD), a disorder characterized by the formation of multiple bilateral renal cysts, the progressive accumulation of extracellular matrix (ECM), and the development of tubulointerstitial fibrosis. Correspondingly, cystic epithelia express higher levels of integrins (ECM receptors that control various cellular responses, such as cell proliferation, migration, and survival) that are characteristically altered in cystic cells. To determine whether the altered expression of ECM and integrins could establish a pathologic autostimulatory loop, we tested the role of integrin-β1 in vitro and on the cystic development of ADPKD in vivo. Compared with wild-type cells, PC1-depleted immortalized renal collecting duct cells had higher levels of integrin-β1 and fibronectin and displayed increased integrin-mediated signaling in the presence of Mn²⁺. In mice, conditional inactivation of integrin-β1 in collecting ducts resulted in a dramatic inhibition of Pkd1-dependent cystogenesis with a concomitant suppression of fibrosis and preservation of normal renal function. Our data provide genetic evidence that a functional integrin-β1 is required for the early events leading to renal cystogenesis in ADPKD and suggest that the integrin signaling pathway may be an effective therapeutic target for slowing disease progression.