Crosstalk between bone and muscle in chronic kidney disease.

With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines via autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients.

Low muscle mass and early hospital readmission post-kidney transplantation.

PURPOSE: Patients exhibiting features of frailty and sarcopenia increasingly are presenting for kidney transplantation (KT) assessment. Sarcopenia, when ascertained by radiological measures, is associated with a higher transplant waiting list mortality; but studies on post-operative outcomes are lacking. We aimed to determine the clinical significance of low muscle mass in chronic kidney disease (CKD) patients subsequently receiving KT. METHODS: We retrospectively analyzed 63 patients with Stage 4-5 CKD who, between 2012 and 2020, had undergone abdominal computed tomography (CT) scanning up to 2 years before KT. The degree of skeletal muscle loss was assessed using the total cross-sectional skeletal muscle area at the third lumbar vertebral level (L3). Cox proportional-hazards regression and Frailty models were used to identify risk factors for early hospital readmission post KT. RESULTS: Thirty-four patients (54%) displayed low muscle mass, which was independently associated with a lower serum creatinine and phosphate, lower body mass index, lower mean muscle attenuation of the L3 cross-sectional area, and higher serum parathyroid hormone (for all p < 0.05). Deceased donor transplant recipients (n = 45) with low muscle mass demonstrated greater hospital readmissions within 30 days of KT [adjusted hazard ratio (HR) = 4.24, 95% CI 1.40-12.90, p = 0.01]. CONCLUSION: Low muscle mass is highly prevalent in the pre-transplant CKD population and is associated with increased hospital readmission in the early post-transplant period.

Sarcopenia and Frailty: Challenges in Mainstream Nephrology Practice.

Sarcopenia and frailty are prevalent in the chronic kidney disease (CKD) population. Sarcopenia is characterised by the loss of muscle mass and function, while frailty is defined as a multi-system impairment associated with increased vulnerability to stressors. There is substantial overlap between the 2 conditions, particularly with regards to physical aspects: low grip strength, gait speed and low muscle mass. Both sarcopenia and frailty have been associated with a wide range of adverse health outcomes. Although there is no recommended pharmacological treatment as yet, it is widely accepted that exercise training and nutritional supplementation are the key interventions to maintain skeletal muscle mass and strength. This review aims to present a comprehensive overview of sarcopenia and frailty in patients with CKD.

Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases.

BACKGROUND: Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging. METHODS: Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension "basis" that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging. RESULTS: We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations. CONCLUSIONS: Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.

Successful kidney transplantation normalizes platelet function.

BACKGROUND: Uraemic platelet dysfunction is not completely understood, in part due to non-physiological platelet function assays. We have developed a physiological flow-based assay that quantifies platelet function in microlitre volumes of blood under arterial shear. The aim of this study was to characterize platelet function before and after kidney transplantation. METHODS: Ten patients scheduled for living donor kidney transplant surgery and nine healthy controls were analysed using the assay. The motional parameters of platelet behaviour on von Willebrand factor (VWF) were recorded using customized platelet tracking software. The assay was repeated 3-8 weeks post-transplant in the transplant group and at an interval of >3 weeks in normal healthy volunteers. RESULTS: Platelet-VWF interactions were markedly reduced in the 10 pre-transplant patients compared with the healthy controls. In seven patients with immediate graft function, dynamic platelet function returned to normal (despite a small decrease in haemoglobin and haematocrit), but remained markedly abnormal in the three patients with delayed graft function (DGF). CONCLUSIONS: Dynamic platelet function returned to normal following transplantation in those with immediate graft function. This early improvement was not observed in those with DGF. There may be important clinical implications, as patients with DGF are more likely to undergo invasive procedures, including transplant biopsies and insertion of central venous catheters.

The impact of donor and recipient weight incompatibility on renal transplant outcomes.

BACKGROUND: Donor/recipient size mismatching and correlation to allograft outcome remains poorly defined. This study assessed the impact of donor body weight (DBW) to recipient body weight (RBW) ratio on allograft function and survival. METHODS: A total of 898 deceased donor renal transplant recipients were included in the study. Patients were divided into quartiles depending on the ratio of DBW/RBW: Q1 (≤ 0.88), Q2 (0.89-1.00), Q3 (1.01-1.22) and Q4 (> 1.22). Donor and recipient characteristics were obtained from the national kidney transplant service database. Serum creatinine and estimated glomerular filtration rate (eGFR) at 1 and 5 years after transplant were compared. RESULTS: Q4 patients had a higher eGFR 1 year post-transplant (median 59.5 ml/min, IQR 46.8-76.2) compared to Q1-Q3 which had median eGFRs of 54.3, 54.8 and 55.3 ml/min, respectively (p < 0.001). At 5 years post-transplant, there were modest differences in the eGFR across the four quartiles, Q1-4 with median eGFRs of 56.9, 61.1, 61.2 and 58.6 ml/min, respectively (p = 0.02). However, there were no significant differences in 1- and 5-year allograft survival between groups. CONCLUSIONS: In the setting of deceased donor renal transplantation, mismatching of donor to recipient weight had no impact on 5-year allograft survival, but a low DBW/RBW ratio is modestly associated with lower eGFR.

Kidney transplant outcomes in familial C3 glomerulopathy.

C3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.

Urinary Soluble CD163 in Active Renal Vasculitis.

A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.

The Irish Kidney Gene Project--Prevalence of Family History in Patients with Kidney Disease in Ireland.

BACKGROUND: The prevalence of kidney disease (KD) due to inherited genetic conditions in Ireland is unknown. The aim of this study was to characterise an adult kidney disease population in Ireland and to identify familial clusters of kidney disease within the population. METHODS: This was a multicenter cross-sectional study of patients with kidney disease in the Republic of Ireland, from January 2014 to September 2014, recruiting from dialysis units and out-patient renal departments. A survey was performed by collecting data on etiology of kidney disease and whether a family history of kidney disease exists. Medical records were cross-referenced to confirm the etiology of kidney disease. RESULTS: A total of 1,840 patients were recruited with a mean age of 55.9 years (range 17-94.5) and a male predominance (n = 1,095; 59.5%). A positive family history was reported by 629 participants (34.2%). Excluding polycystic kidney disease (n = 134, 7.3%), a positive family history was reported by 495 participants (26.9%). Kidney disease due to an unknown etiology was the commonest etiology in the non-polycystic kidney disease group with a positive family history (10.6%, n = 67). Kidney diseases that are not classically associated with familial inheritance including tubulo-interstitial kidney disease, congenital abnormalities of the kidney and urinary tract and glomerulonephritis demonstrated familial clustering. CONCLUSION: In an Irish non-polycystic kidney disease population, 26.9% reports a positive family history. The commonest etiology of kidney disease in the positive family history cohort, excluding autosomal dominant polycystic kidney disease, was kidney disease due to unknown etiology. Examining families with kidney disease provides an opportunity to better understand disease pathogenesis and potentially identify genetic predispositions to kidney disease.

Getting the balance right: adverse events of therapy in anti-neutrophil cytoplasm antibody vasculitis.

Antineutrophil cytoplasm antibody associated systemic vasculitides (AASV) have traditionally been managed with a combination of cyclophosphamide and glucocorticoids during the induction phase, followed by azathioprine in the maintenance phase. Whilst these therapies have markedly improved the prognosis in AASV, treatment related adverse events remain a major challenge and include complications such as infection, glucocorticoid related side effects, malignancy, cardiovascular disease, infertility and death. Newer biologic therapies have been shown to demonstrate equivalent efficacy as cyclophosphamide for remission but the hoped for reduction in adverse events has yet to be realised. More recent efforts have been focused on refining existing therapeutic regimens and strategies, tailoring individual treatment to disease severity, patient age and kidney function to derive maximum treatment efficacy while minimising treatment toxicity. In particular, current interventional trials are targeting a reduction in corticosteroid exposure in an effort to make induction and maintenance regimens safer.

C3 glomerulopathy: clinicopathologic features and predictors of outcome.

BACKGROUND AND OBJECTIVES: The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS: Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS: Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

Recurrence of anti-neutrophil cytoplasmic antibody-associated vasculitis in appropriately immunosuppressed renal transplant patients: a discussion of two cases.

BACKGROUND: Granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is a multisystem autoimmune disease of unknown aetiology. Renal disease manifests as a crescentic glomerulonephritis, with varying degrees of renal failure. Ten percent of patients progress to end-stage kidney disease. Relapse of GPA in renal transplant patients is rare, with a rate of 0.09 relapses per patient per year. PATIENTS AND METHODS: We describe two cases of GPA relapse in immunosuppressed renal transplant patients. RESULTS: These patients presented with new-onset graft disfunction, having previously had an uncomplicated posttransplant course. Both patients were on appropriate doses of immunosuppressive agents at the time of relapse, with therapeutic target levels of tacrolimus. We describe the background history and management of both patients. CONCLUSION: The cases described inform us that although recurrence of anti-neutrophil cytoplasmic antibody vasculitis in transplant patients is rare, it should remain on our list of differential diagnoses in allograft disfunction.

Acute renal failure secondary to tuberculosis: a diagnostic challenge.

Tuberculosis is a multiorgan disease with varied clinical presentations and is reemerging due to increasing immigration and globalization. We present the case of an immigrant female patient who developed acute renal failure with clinical and biochemical features suggestive of lupus nephritis but with a timely renal biopsy showing caseating granulomata in the renal parenchyma consistent with renal tuberculosis. Despite treatment with antituberculosis treatment and resolution of TB on repeat renal biopsy, she remained haemodialysis dependent. We discuss the diagnostic challenges faced in this presentation and also explore possible differential diagnoses. This rare presentation highlights the importance of renal biopsy in the diagnosis and treatment of acute renal failure and the atypical presentation of tuberculosis.

HER-2 positive and p53 negative breast cancers are associated with poor prognosis.

p53 and HER-2 coexpression in breast cancer has been controversial. These markers were tested using immunohistochemistry and HercepTest. HER-2 expression is related to reduced breast cancer survival (p = .02) . p53 expression relates to HER-2 expression (p = .029). Coexpression between p53 and HER-2 has no relation to prognosis. On univariate and multivariate analysis, combination of HER-2 positive and p53 negative expression was associated with a poor prognosis (p = .018 and p = .027, respectively), while the combination of HER-2 negative and p53 positive expression was associated with a favorable prognosis (p = .022 and p = .010, respectively). Therefore the expression of these markers should be considered collectively.