Pathophysiology of Physical Exercise in Kidney Patients: Unveiling New Players- The Role of Myokines.

Background Chronic kidney disease (CKD) is a progressive systemic condition characterized by numerous complications. Among these, alterations in skeletal muscle physiology, such as sarcopenia, are particularly significant, as they are associated with poor outcomes and reduced quality of life. Summary Various interventions, including pharmacological approaches and lifestyle modifications have been investigated to slow CKD progression and prevent or treat its complications. Physical exercise, in particular, has emerged as a promising intervention with multiple beneficial effects. These include improvements in physical functioning, increased muscle mass, modulation of metabolic abnormalities, and reduced cardiovascular risk. However, the pathophysiology of physical exercise in patients with kidney disease is complex and remains only partially understood. A crucial advancement in understanding this phenomenon has been the identification of myokines-molecules expressed and released by skeletal muscle in response to physical activity. These myokines can exert both paracrine and systemic effects, influencing not only skeletal muscle physiology but also other processes such as energy metabolism and lipid regulation. Key Messages The interplay among skeletal muscle, physical activity, and myokines may act as a pivotal regulator in various physiological processes, including aging, as well as in pathological conditions like cachexia and sarcopenia, frequently observed in CKD patients at different stages, including patients on dialysis. Despite the potential importance of this relationship, only a limited number of studies have explored the relationship between exercise and myokine, and the effect of this interaction on experimental models or individuals with kidney disease. In the following sections, we review and discuss this topic.

SA-ß-Gal in Kidney Tubules as a Predictor of Renal Outcome in Patients with Chronic Kidney Disease.

Cellular senescence has emerged as an important driver of aging and age-related disease in the kidney. The activity of ß-galactosidase at pH 6 (SA-ß-Gal) is a classic maker of senescence in cellular biology; however, the predictive role of kidney tissue SA-ß-Gal on eGFR loss in chronic kidney disease (CKD) is still not understood. We retrospectively studied the expression of SA-ß-Gal in kidney biopsies obtained in a cohort [n = 22] of incident patients who were followed up for 3 years as standard of care. SA-ß-Gal staining was approximately fourfold higher in the tubular compartment of patients with CKD vs. controls [26.0 ± 9 vs. 7.4 ± 6% positive tubuli in patients vs. controls; p < 0.025]. Tubular expressions of SA-ß-Gal, but not proteinuria, at the time of biopsy correlated with eGFR loss at the follow up; moreover, SA-ß-Gal expression in more than 30% of kidney tubules was associated with fast progressive kidney disease. In conclusion, our study shows that SA-ß-Gal is upregulated in the kidney tubular compartment of adult patients affected by CKD and suggests that tubular SA-ß-Gal is associated with accelerated loss of renal function.

Multifaceted relationship between diabetes and kidney diseases: Beyond diabetes.

Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.

Daratumumab in the treatment of C3 glomerulopathy with monoclonal gammopathy: a case report and literature review.

Although rare, C3 glomerulopathy (C3G) is increasingly recognized thanks to the currently available diagnostic skills. C3G is not a single disease but a group of disorders with distinct pathogenesis and progression. Thus, an essential step for its management remains an in-depth characterization of the specific form and the identification of underlying conditions, which may also impact treatment choices as well. Among these entities, an emerging condition is the association of C3G with monoclonal gammopathy, which confers poor outcomes. Overall, diagnosis of C3G remains challenging, and determining the appropriate treatment remains unclear. Conventional immunosuppressive therapy has proven ineffective in such cases, while clone-directed therapies have shown promising results in small interventional studies and case series. Here, we report a case of a patient affected by C3G with monoclonal gammopathy of renal significance who experienced rapid deterioration of kidney function requiring replacement therapy. After the failure of first-line treatment, a switch to the anti-CD38 therapy with daratumumab resulted in the progressive improvement of the patient's kidney function, leading to the discontinuation of hemodialysis after approximately 10 months. Serial renal biopsies were also performed to study the disease's evolution in response to the treatment. Based on the description of this single case, we have comprehensively reviewed available studies on daratumumab use in patients with C3G associated with monoclonal gammopathy to provide insights for the design of prospective studies which aim to enhance the management of such poor prognosis disease.

The Contribution of Muscle Innate Immunity to Uremic Cachexia.

Protein energy wasting (PEW) is a common complication both in chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Of note, PEW is one of the stronger predictors of morbidity and mortality in this patient population. The pathogenesis of PEW involves several mechanisms, including anorexia, insulin resistance, acidosis and low-grade inflammation. In addition, "sterile" muscle inflammation contributes to PEW at an advanced CKD stage. Both immune and resident muscle cells can activate innate immunity; thus, they have critical roles in triggering "sterile" tissue inflammation. Toll-like receptor 4 (TLR4) can detect endogenous danger-associated molecular patterns generated or retained in blood in uremia and induce a sterile muscle inflammatory response via NF-κB in myocytes. In addition, TLR4, though the activation of the NLRP3 inflammasome, links the sensing of metabolic uremic stress in muscle to the activation of pro-inflammatory cascades, which lead to the production of IL-1ß and IL-18. Finally, uremia-induced accelerated cell senescence is associated with a secretory phenotype that favors fibrosis in muscle. Targeting these innate immune pathways could lead to novel therapies for CKD-related PEW.

Histology for nephrology, from pre-implantation to post-transplant kidney biopsy. Lesson learned from ReBIrth (Renal BIopsy for Kidney Transplantation Therapy).

A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31st, 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management.

Homocysteine exchange across skeletal muscle in patients with chronic kidney disease.

Sites and mechanisms regulating the supply of homocysteine (Hcy) to the circulation are unexplored in humans. We studied the exchange of Hcy across the forearm in CKD patients (n = 17, eGFR 20 ± 2 ml/min), in hemodialysis (HD)-treated patients (n = 14) and controls (n = 9). Arterial Hcy was ~ 2.5 folds increased in CKD and HD patients (p < 0.05-0.03 vs. controls). Both in controls and in patients Hcy levels in the deep forearm vein were consistently greater (+~7%, p < 0.05-0.01) than the corresponding arterial levels, indicating the occurrence of Hcy release from muscle. The release of Hcy from the forearm was similar among groups. In all groups arterial Hcy varied with its release from muscle (p < 0.03-0.02), suggesting that muscle plays an important role on plasma Hcy levels. Forearm Hcy release was inversely related to folate plasma level in all study groups but neither to vitamin B12 and IL-6 levels nor to muscle protein net balance. These data indicate that the release of Hcy from peripheral tissue metabolism plays a major role in influencing its Hcy plasma levels in humans and patients with CKD, and that folate is a major determinant of Hcy release.

Myostatin: Basic biology to clinical application.

Myostatin is a member of the transforming growth factor (TGF)-ß superfamily. It is expressed by animal and human skeletal muscle cells where it limits muscle growth and promotes protein breakdown. Its effects are influenced by complex mechanisms including transcriptional and epigenetic regulation and modulation by extracellular binding proteins. Due to its actions in promoting muscle atrophy and cachexia, myostatin has been investigated as a promising therapeutic target to counteract muscle mass loss in experimental models and patients affected by different muscle-wasting conditions. Moreover, growing evidence indicates that myostatin, beyond to regulate skeletal muscle growth, may have a role in many physiologic and pathologic processes, such as obesity, insulin resistance, cardiovascular and chronic kidney disease. In this chapter, we review myostatin biology, including intracellular and extracellular regulatory pathways, and the role of myostatin in modulating physiologic processes, such as muscle growth and aging. Moreover, we discuss the most relevant experimental and clinical evidence supporting the extra-muscle effects of myostatin. Finally, we consider the main strategies developed and tested to inhibit myostatin in clinical trials and discuss the limits and future perspectives of the research on myostatin.

Deciphering the Prognostic and Predictive Value of Urinary CXCL10 in Kidney Recipients With BK Virus Reactivation.

BK virus (BKV) replication increases urinary chemokine C-X-C motif ligand 10 (uCXCL10) levels in kidney transplant recipients (KTRs). Here, we investigated uCXCL10 levels across different stages of BKV replication as a prognostic and predictive marker for functional decline in KTRs after BKV-DNAemia. uCXCL10 was assessed in a cross-sectional study (474 paired urine/blood/biopsy samples and a longitudinal study (1,184 samples from 60 KTRs with BKV-DNAemia). uCXCL10 levels gradually increased with urine (P-value < 0.0001) and blood BKV viral load (P < 0.05) but were similar in the viruria and no BKV groups (P > 0.99). In viremic patients, uCXCL10 at biopsy was associated with graft functional decline [HR = 1.65, 95% CI (1.08-2.51), P = 0.02], irrespective of baseline eGFR, blood viral load, or BKVN diagnosis. uCXL10/cr (threshold: 12.86 ng/mmol) discriminated patients with a low risk of graft function decline from high-risk patients (P = 0.01). In the longitudinal study, the uCXCL10 and BKV-DNAemia trajectories were superimposable. Stratification using the same uCXCL10/cr threshold at first viremia predicted the subsequent inflammatory response, assessed by time-adjusted uCXCL10/cr AUC (P < 0.001), and graft functional decline (P = 0.03). In KTRs, uCXCL10 increases in BKV-DNAemia but not in isolated viruria. uCXCL10/cr is a prognostic biomarker of eGFR decrease, and a 12.86 ng/ml threshold predicts higher inflammatory burdens and poor renal outcomes.

Enhanced myostatin expression and signalling promote tubulointerstitial inflammation in diabetic nephropathy.

Myostatin (MSTN), a family member of the transforming growth factor (TGF)-ß super family, has been detected in the tubuli of pig kidney, but its role in the human kidney is not known. In this study we observed upregulation of MSTN mRNA (~8 to 10-fold increase) both in the glomeruli and tubulointerstitium in diabetic nephropathy (DN). In DN, immunoreactive MSTN was mainly localized in the tubuli and interstitium (∼4-8 fold increase), where it colocalized in CD45+ cells. MSTN was also upregulated in the glomeruli and the arterial vessels. Tubulointerstitial MSTN expression was directly related to interstitial fibrosis (r = 0.54, p < 0.01). In HK-2 tubular epithelial cells, both high (30 mmol) glucose and glycated albumin upregulated MSTN mRNA and its protein (p < 0.05-0.01). MSTN-treated HK-2 cells underwent decreased proliferation, together with NF-kB activation and CCL-2 and SMAD 2,3 overexpression. In addition, MSTN induced intracellular ROS release and upregulated NADPH oxidase, effects which were mediated by ERK activation. In conclusion, our data show that MSTN is expressed in the human kidney and overexpressed in DN, mainly in the tubulointerstitial compartment. Our results also show that MSTN is a strong inducer of proximal tubule activation and suggest that MSTN overexpression contributes to kidney interstitial fibrosis in DN.

Long-term blood pressure behavior and progression to end-stage renal disease in patients with immunoglobulin A nephropathy: a single-center observational study in Italy.

BACKGROUND: Antihypertensive treatment by the use of RAAS inhibitors (RAAS-is) is of paramount importance in the management of slowly progressive IgA nephropathy (IgAN). With the aim of better understanding the relationship between BP behavior and progression, we looked at time-averaged SBP and time-averaged proteinuria and renal outcome in a single-center cohort of IgAN patients. METHODS: Among 248 consecutive patients referred to the Clinic of Nephrology of San Martino Hospital from 1996 to 2018 for native renal biopsy with a diagnosis of IgAN, we retrospectively analyzed 145 with available data at baseline and during follow-up. All patients received Supportive Care, 39% were on RAAS-is alone, 45% plus steroids, and 16% plus steroids and immunosuppressors. Renal replacing treatment (RRT) was the primary endpoint. RESULTS: During a mean follow-up of 67 ±â€Š6 months, 23% of study patients (n = 33) progressed to RRT and 6% (n = 9) died. Patients who reached the renal endpoint, had lower baseline eGFR and higher proteinuria and proteinuria indexed at baseline. Moreover, they had higher TA-SBP (139 ±â€Š17 vs. 130 ±â€Š13, P = 0.0016). The incidence of RRT was higher in IgAN patients in the highest time-averaged SBP tertile as compared with the others (32 vs. 23 vs. 9%, χ 6.8, P = 0.033). After adjusting for baseline SBP, baseline and time-averaged proteinuria indexed, MEST-C score, and treatment, the association between TA-SBP and RRT persisted. CONCLUSION: Time-averaged low BP values were independently associated to a decreased risk of renal progression in IgAN with no evidence of a J-curve relationship even at SBP levels below 125 mmHg.

Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis.

BACKGROUND: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. METHODS: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. RESULTS: Cell senescence (p16INK4A, SA-ß-galactosidase [SA-ß-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05-0.01). Tubular SA-ß-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-ß-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-ß-Gal, contributed significantly to the prediction of eGFR loss. CONCLUSIONS: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Emerging role of myostatin and its inhibition in the setting of chronic kidney disease.

The past two decades have witnessed tremendous progress in our understanding of the mechanisms underlying wasting and cachexia in chronic kidney disease (CKD) and in other chronic illnesses, such as cancer and heart failure. In all these conditions wasting is an effect of the activation of protein degradation in muscle, a response that increases the risk of morbidity and mortality. Major recent advances in our knowledge on how CKD and inflammation affect cellular signaling include the identification of the myostatin (MSTN)/activin system, and its related transcriptional program that promotes protein degradation. In addition, the identification of the role of MSTN/activin in the vascular wall shows premise that its inhibition can better control or prevent some effects of CKD on vessels, such as accelerated atherosclerosis and vascular calcifications. In this review, we summarize the expanding role of MSTN activation in promoting muscle atrophy and the recent clinical studies that investigated the efficacy of MSTN/activin pathway antagonism in sarcopenic patients. Moreover, we also review the utility of MSTN inhibition in the experimental models of CKD and its potential advantages in CKD patients. Lessons learned from clinical studies on MSTN antagonism in sarcopenic patients tell us that the anabolic intervention is likely better if we use a block of the two ActRII receptors. At the same time, however, it is becoming clear that MSTN-targeted therapies should not be seen as a substitute for physical activity and nutritional supplementation which are mandatory to successfully manage patients with wasting.

Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy.

Toll-like receptors (TLRs) are a class of receptors of the innate immune system which detect pathogen-associated and danger-associated molecular patterns in order to initiate an inflammatory response. TLR2 and TLR4 downward signaling causes the production of proinflammatory cytokines that can induce insulin resistance and cardiovascular damage in obesity and type 2 diabetes mellitus. In diabetic nephropathy, TLR4, nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and NLRP3 inflammasome are involved in the production and persistence of inflammation. The activation of TLRs stimulates the expression of several inflammatory cytokines and chemokines such as CCL2 and tumor necrosis factor (TNF)-α, which are associated with the progression of diabetic nephropathy. Different inflammatory mechanisms seem to take place in the early and late stages of diabetic kidney disease, with activation of the innate immunity response and enhanced chemiotactic effects in native kidney cells at an early stage, followed by tubulointerstitial monocyte infiltration at a more advanced disease state. Overall, available data indicate that the upregulated TLR4 response in the kidney translates the metabolic alterations of diabetes into kidney damage.