Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Non-crystalline light chain proximal tubulopathy, a morphologically protean entity.

BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. METHODS: We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. RESULTS: The median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. CONCLUSIONS: The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.

Alport syndrome: Proteomic analysis identifies early molecular pathway alterations in Col4a3 knock out mice.

AIM: Alport syndrome (AS) is the second most common hereditary kidney disease caused by mutations in collagen IV genes. Patients present with microhaematuria that progressively leads to proteinuria and end stage renal disease. Currently, no specific treatment exists for AS. Using mass spectrometry based proteomics, we aimed to detect early alterations in molecular pathways implicated in AS before the stage of overt proteinuria, which could be amenable to therapeutic intervention. METHODS: Kidneys were harvested from male Col4a3-/- knock out and sex and age-matched Col4a3+/+ wild-type mice at 4 weeks of age. Purified peptides were separated by liquid chromatography and analysed by high resolution mass spectrometry. The Cytoscape bioinformatics tool was used for function enrichment and pathway analysis. PPARα expression levels were evaluated by immunofluorescence and immunoblotting. RESULTS: Proteomic analysis identified 415 significantly differentially expressed proteins, which were mainly involved in metabolic and cellular processes, the extracellular matrix, binding and catalytic activity. Pathway enrichment analysis revealed among others, downregulation of the proteasome and PPAR pathways. PPARα protein expression levels were observed to be downregulated in Alport mice, supporting further the results of the discovery proteomics. CONCLUSION: This study provides additional evidence that alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells are early events in the development of chronic kidney disease in AS. Of note is the dysregulation of the PPAR pathway, which is amenable to therapeutic intervention and provides a new potential target for therapy in AS.

Biomarkers of systemic lupus erythematosus identified using mass spectrometry-based proteomics: a systematic review.

Advances in mass spectrometry technologies have created new opportunities for discovering novel protein biomarkers in systemic lupus erythematosus (SLE). We performed a systematic review of published reports on proteomic biomarkers identified in SLE patients using mass spectrometry-based proteomics and highlight their potential disease association and clinical utility. Two electronic databases, MEDLINE and EMBASE, were systematically searched up to July 2015. The methodological quality of studies included in the review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Twenty-five studies were included in the review, identifying 241 SLE candidate proteomic biomarkers related to various aspects of the disease including disease diagnosis and activity or pinpointing specific organ involvement. Furthermore, 13 of the 25 studies validated their results for a selected number of biomarkers in an independent cohort, resulting in the validation of 28 candidate biomarkers. It is noteworthy that 11 candidate biomarkers were identified in more than one study. A significant number of potential proteomic biomarkers that are related to a number of aspects of SLE have been identified using mass spectrometry proteomic approaches. However, further studies are required to assess the utility of these biomarkers in routine clinical practice.

Tocilizumab (anti-IL-6) treatment for AA renal amyloidosis in a patient with advanced chronic kidney disease, a case report.

Systemic amyloid A amyloidosis is a progressive condition in which sustained elevation of serum amyloid A protein concentration leads to widespread amyloid deposition resulting in multiorgan failure without treatment. The kidney is the most commonly affected organ, and renal amyloid A amyloidosis can cause nephrotic syndrome and chronic kidney disease (CKD) leading to end stage kidney disease (ESKD). Serum Amyloid A protein is produced in the liver in response to chronic inflammation, specifically by inflammatory cytokines, especially IL-6. Tocilizumab, a monoclonal antibody that targets the interleukin-6 receptor, has increasingly been of interest in treating amyloid A amyloidosis. We present a case of a 79-year-old male with long-term seronegative polyarthritis who was referred with gradual decline in kidney function and nephrotic range proteinuria. His renal biopsy showed amyloid A amyloidosis with significant interstitial fibrosis and tubular atrophy. He was commenced on monthly tocilizumab infusions and peritoneal dialysis with good clinical response and rapid resolution of his nephrotic state. This case adds to the current literature on the benefits of tocilizumab in treating amyloid A amyloidosis in patients with advanced CKD.

Monoclonal gammopathies of renal significance.

The term monoclonal gammopathies of renal significance (MGRS) encompasses a group of renal histopathological lesions fulfilling two criteria: (a) they are caused by nephrotoxic monoclonal immunoglobulins and (b) the monoclonal immunoglobulins are produced by small B-cell or plasma cell clones which do not meet the criteria for multiple myeloma or malignant lymphoma. Here, we provide a review of the MGRS definition and related terminology and elaborate on the diagnostic approach and treatment principles from the general physician perspective.

The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies.

AIM: Fibrates have proven efficacy in cardiovascular risk reduction and are commonly used, in addition to statins, to control hypertriglyceridaemia. Their use is often limited due to reduction in glomerular filtration rate at treatment initiation. However, recent studies suggest benign changes in kidney function and improvement of proteinuria, an established early marker of microvascular disease and kidney disease progression. We summarize the evidence from existing trials and provide a summary of effects of fibrates, alone or in combination, on kidney disease progression and proteinuria. METHODS AND RESULTS: Systematic review and meta-analysis of randomized, controlled trials (PROSPERO CRD42020187764). Out of 12,243 potentially eligible studies, 29 were included in qualitative and quantitative analysis, with a total of 20,176 patients. Mean creatinine increased by 1.05 (95% CI (0.63 to 1.46)) units in patients receiving fibrates vs. comparator, and this was similar in all other subgroups. eGFR showed a bigger decrease in the fibrates arm (SMD -1.99; 95% CI (-3.49 to -0.48)) when all studies were pooled together. Notably, short-term serum creatinine and eGFR changes remained constant in the long-term. Pooled estimates show that fibrates improve albuminuria progression, RR 0.86; 95% CI (0.76 to 0.98); albuminuria regression, RR 1.19; 95% CI (1.08 to 1.310). CONCLUSIONS: Fibrates improve albuminuria in patients with and without diabetes when used to treat hyperlipidaemia. The modest creatinine increase should not be a limiting factor for fibrate initiation in people with preserved renal function or mild CKD. The long-term effects on kidney disease progression warrant further study.

Cardiovascular Risk Assessment Using Ultrasonographic Surrogate Markers of Atherosclerosis and Arterial Stiffness in Patients With Chronic Renal Impairment: A Narrative Review of the Evidence and a Critical View of Their Utility in Clinical Practice.

PURPOSE OF THE REVIEW: Validated tools to improve cardiovascular disease (CVD) risk assessment and mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) are lacking. Noninvasive measures of arteriosclerosis and subclinical atherosclerosis such as pulse wave velocity (PWV) and carotid intima-media thickness (cIMT), respectively, have emerged as promising risk stratification tools and potential modifiable biomarkers. Their wide use as surrogate markers in clinical research studies is based on the strong pathophysiological links with CVD. However, whether their effect as risk stratification or intervention targets is superior to established clinical approaches is uncertain. In this review, we examine the evidence on the utility of PWV, cIMT, and plaque assessment in routine practice and highlight unanswered questions from the clinician's perspective. SOURCES OF INFORMATION: Electronic databases PubMed and Google Scholar were searched until February 2020. METHODS: This narrative review is based on peer-reviewed meta-analyses, national and international societies' guidelines, and on focused critical review of recent original studies and landmark studies in the field. KEY FINDINGS: Although patients with CKD are considered in the high-risk CVD groups, there is still need for tools to improve risk stratification and individualized management strategies within this group of patients. Carotid intima-media thickness is associated with all-cause mortality, CVD mortality, and events in CKD and hemodialysis cohorts. However, the evidence that measurement of cIMT has a clinically meaningful role over and above existing risk scores and management strategies is limited. Plaque assessment is a better predictor than cIMT in non-CKD populations and it has been incorporated in recent nonrenal-specific guidelines. In the CKD population, one large observational study provided evidence for a potential role of plaque assessment in CKD similar to the non-CKD studies; however, whether it improves prediction and outcomes in CKD is largely understudied. Pulse wave velocity as a marker of arterial stiffness has a strong pathophysiological link with CVD in CKD and numerous observational studies demonstrated associations with increased cardiovascular risk. However, PWV did not improve CVD reclassification of dialysis patients when added to common risk factors in a reanalysis of ESRD cohorts with available PWV data. Therapeutic strategies to regress PWV, independently from blood pressure reduction, have not been studied in well-conducted randomized trials. LIMITATIONS: This study provides a comprehensive review based on extensive literature search and critical appraisal of included studies. Nevertheless, formal systematic literature review and quality assessment were not performed and the possibility of selection bias cannot be excluded. IMPLICATIONS: Larger, prospective, randomized studies with homogeneous approach, designed to answer specific clinical questions and taking into consideration special characteristics of CKD and dialysis, are needed to study the potentially beneficial role of cIMT/plaque assessment and PWV in routine practice.

JUSTIFICATION: Les outils validés pour faciliter l'évaluation des risques de maladies cardiovasculaires (MCV) et de mortalité chez les patients atteints d'insuffisance rénale terminale (IRT) sont insuffisants. Les mesures non invasives de l'artériosclérose et de l'artériosclérose infraclinique, respectivement la vitesse de l'onde de pouls (VOP) et la mesure de l'épaisseur intima-média de la carotide (EIMc), sont apparues comme des outils prometteurs de stratification des risques et des biomarqueurs potentiellement modifiables. L'usage répandu de la VOP et de l'EIMc comme marqueurs de substitution dans les études cliniques est fondé sur leurs liens physiopathologiques étroits avec les MCV. On ignore toutefois si leur effet pour la stratification des risques ou comme cibles d'intervention est supérieur aux approches cliniques établies. Cette revue examine les données probantes sur la pertinence des mesures de VOP et d'EIMc et de l'analyse plaquettaire dans les pratiques courantes et met en lumière les questions sans réponses du point de vue du clinicien. SOURCES: Les bases de données PubMed et Google Scholar ont été consultées jusqu'en février 2020. MÉTHODOLOGIE: Cette revue narrative est fondée sur des méta-analyses révisées par les pairs, sur les lignes directrices de sociétés nationales et internationales et sur un examen critique et ciblé des études originales récentes et d'études phares dans le domaine. PRINCIPAUX RÉSULTATS: Bien que les patients atteints d'IRT fassent déjà partie des groupes présentant un risque élevé de MCV, l'ajout d'outils pour améliorer la stratification des risques et de stratégies de gestion individualisées est toujours nécessaire pour ce groupe de patients. L'EIMc est associée à la mortalité toutes causes, ainsi qu'aux risques d'événements cardiovasculaires et de mortalité liée aux MCV dans les cohortes de patients atteints d'IRT et hémodialysés. Les preuves soutenant un rôle cliniquement significatif de la mesure de l'EMIc au-delà des scores de risque et des stratégies de gestion existantes sont toutefois limitées. L'analyse plaquettaire s'avère un meilleur prédicteur que l'EIMc dans les populations non atteintes d'IRT et a récemment été intégrée aux lignes directrices non liées aux maladies rénales. Dans les populations atteintes d'IRT, une vaste étude observationnelle a fourni des preuves quant à un possible rôle de l'analyse plaquettaire similaire à celui rapporté dans les études ne portant pas sur des patients atteints d'IRT. Cependant, la question de savoir si cette mesure améliore la prédiction et les résultats des patients atteints d'IRT demeure largement sous-étudiée. La VOP, à titre de marqueur de la rigidité artérielle, a un lien physiopathologique fort avec les MCV en contexte d'IRT, plusieurs études observationnelles ayant démontré des associations avec un risque accru d'événements cardiovasculaires. Par contre, la VOP n'a pas amélioré le reclassement cardiovasculaire des patients dialysés lorsqu'on l'a ajoutée aux facteurs de risques communs dans une nouvelle analyse des cohortes de patients atteints d'IRT disposant de données de VOP. Les stratégies thérapeutiques pour réduire la VOP, indépendamment de la pression artérielle, n'ont pas été étudiées dans le cadre d'essais à répartition aléatoire bien menés. LIMITES: Cette étude fournit une revue complète fondée sur une recherche documentaire approfondie et une évaluation critique des études incluses. Cependant, aucune analyse documentaire systématique formelle ou d'évaluation de la qualité n'ont été effectuées et un biais de sélection ne peut être exclu. CONCLUSION: L'étude d'un rôle potentiellement bénéfique des mesures de VOP et d'EIMc et de l'analyse plaquettaire dans la pratique courante en contexte d'IRT requiert des essais prospectifs de grande envergure avec répartition aléatoire. Ces essais devraient s'articuler autour d'une approche homogène, être conçus pour répondre à des questions cliniques spécifiques et tenir compte des caractéristiques propres aux patients atteints d'IRT et dialysés.

Association of non-invasive measures of subclinical atherosclerosis and arterial stiffness with mortality and major cardiovascular events in chronic kidney disease: systematic review and meta-analysis of cohort studies.

BACKGROUND: Non-invasive cardiovascular disease (CVD) risk prediction, in subclinical stages, aiming to stratify patients and tailor interventions remains an unmet need in chronic kidney disease (CKD). In this meta-analysis, we summarize the association of carotid intima-media thickness (cIMT), coronary artery calcium score (CACS) and pulse wave velocity (PWV) with all-cause mortality, cardiovascular (CV) mortality and CV events in non-dialysis CKD and patients on haemodialysis. METHODS: Systematic review and meta-analysis of prospective cohort studies. RESULTS: Out of 27 984 records, a total of 45 studies were eligible for quantitative synthesis; 11 for cIMT, 18 for CACS and 16 for PWV involving 2235, 4904 and 5717 patients, respectively. Meta-analysis was possible from pooled data of five cIMT studies (708 subjects), eight CACS studies (862 subjects) and nine PWV studies (1508 subjects). In dialysis patients, cIMT was associated with all-cause mortality [relative risk (RR) per unit increase: 1.08, 95% confidence interval (CI) 1.00-1.17, I 2: 68%] and CV mortality (RR: 1.29, 95% CI 1.14-1.47, I 2: 0%). High versus low CACS was associated with all-cause mortality (RR: 2.51, 95% CI 1.66-3.79, I 2: 5.7%) and CV events (RR: 3.77 95% CI 2.16-6.58, I 2: 20.2%). High versus low PWV was associated with all-cause (RR: 5.34, 95% CI 3.01-9.47, I 2: 0%) and CV mortality (RR: 8.55, 95% CI 4.37-16.73, I 2: 0%). The combined estimated for all-cause mortality per 1 m/s increment unit in PWV was 1.25 (95% CI 1.17-1.34, I 2: 0%) and for CV mortality was 1.24 (95% CI 1.16-1.34, I 2: 15.5%). In non-dialysis patients, CACS was associated with CV events (RR: 4.02, 95% CI 1.57-10.29, I 2: 63.4%). High versus low PWV was associated with all-cause mortality (RR: 2.52, 95% CI 1.40-4.55, I 2: 62.6%). CONCLUSIONS: Non-invasive measures of atherosclerosis and arterial stiffening are associated with all-cause and CV mortality as well as CV events among patients with all stages of CKD. These markers could be considered for the evaluation of CV morbidity and mortality risks. Moreover, the results of this meta-analysis support the study of interventions, with effect on these markers of vascular disease, on long-term CVD outcomes.

Proteomic analysis in lupus mice identifies Coronin-1A as a potential biomarker for lupus nephritis.

BACKGROUND: Approximately 50% of systemic lupus erythematosus (SLE) patients develop nephritis, which is among the most severe and frequent complications of the disease and a leading cause of morbidity and mortality. Despite intensive research, there are still no reliable lupus nephritis (LN) markers in clinical use that can assess renal damage and activity with a high sensitivity and specificity. To this end, the aim of this study was to identify new clinically relevant tissue-specific protein biomarkers and possible underlying molecular mechanisms associated with renal involvement in SLE, using mass spectrometry (MS)-based proteomics. METHODS: Kidneys were harvested from female triple congenic B6.NZMsle1/sle2/sle3 lupus mice model, and the respective sex- and age-matched C57BL/6 control mice at 12, 24 and 36 weeks of age, representing pre-symptomatic, established and end-stage LN, respectively. Proteins were extracted from kidneys, purified, reduced, alkylated and digested by trypsin. Purified peptides were separated by liquid chromatography and analysed by high-resolution MS. Data were processed by the Progenesis QIp software, and functional annotation analysis was performed using DAVID bioinformatics resources. Immunofluorescence and multiple reaction monitoring (MRM) MS methods were used to confirm prospective biomarkers in SLE mouse strains as well as human serum samples. RESULTS: Proteomic profiling of kidney tissues from SLE and control mice resulted in the identification of more than 3800 unique proteins. Pathway analysis revealed a number of dysregulated molecular pathways that may be mechanistically involved in renal pathology, including phagosome and proximal tubule bicarbonate reclamation pathways. Proteomic analysis supported by human transcriptomic data and pathway analysis revealed Coronin-1A, Ubiquitin-like protein ISG15, and Rho GDP-dissociation inhibitor 2, as potential LN biomarkers. These results were further validated in other SLE mouse strains using MRM-MS. Most importantly, experiments in humans showed that measurement of Coronin-1A in human sera using MRM-MS can segregate LN patients from SLE patients without nephritis with a high sensitivity (100%) and specificity (100%). CONCLUSIONS: These preliminary findings suggest that serum Coronin-1A may serve as a promising non-invasive biomarker for LN and, upon validation in larger cohorts, may be employed in the future as a screening test for renal disease in SLE patients.

Does complement Factor H-Related protein 5 Nephropathy (Troodos Nephropathy) protect from rickettsial infections?

Complement Factor H-Related protein 5 Nephropathy (CFHR5N) is an endemic hereditary renal disease in the island of Cyprus. Although only very recently recognized, it has provided insight into previously unknown genetic aspects of complement-mediated renal diseases and in fact it has contributed to the introduction of the new disease classification, 'C3 Glomerulopathy'. Herein, based on evidence from epidemiological, genetic, clinical and basic research studies, the hypothesis that CFHR5N could be protective from rickettsial infections is proposed. Confirming this hypothesis, could have significant implications for the study of Complement Factor- H Related Proteins (CFHRs) in renal diseases and rickettsial molecular microbiology.

Matrix Metalloproteinases and Subclinical Atherosclerosis in Chronic Kidney Disease: A Systematic Review.

Background. Cardiovascular disease (CVD) remains a significant problem in Chronic Kidney Disease (CKD). Subclinical atherosclerosis identified by noninvasive methods could improve CVD risk prediction in CKD but these methods are often unavailable. We therefore systematically reviewed whether circulating levels of Matrix Metalloproteinases (MMPs) and tissue inhibitors (TIMPs) are associated with subclinical atherosclerosis in CKD, as this would support their use as biomarkers or pharmacologic targets. Methods. All major electronic databases were systematically searched from inception until May 2015 using appropriate terms. Studies involving CKD patients with data on circulating MMPs levels and atherosclerosis were considered and subjected to quality assessment. Results. Overall, 16 studies were identified for qualitative synthesis and 9 studies were included in quantitative synthesis. MMP-2 and TIMP-1 were most frequently studied while most studies assessed carotid Intima-Media Thickness (cIMT) as a measure of subclinical atherosclerosis. Only MMP-2 demonstrated a consistent positive association with cIMT. Considerable variability in cIMT measurement methodology and poor plaque assessment was found. Conclusions. Although MMPs demonstrate great potential as biomarkers of subclinical atherosclerosis, they are understudied in CKD and not enough data existed for meta-analysis. Larger studies involving several MMPs, with more homogenized approaches in determining the atherosclerotic burden in CKD, are needed.