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Background and Aims Membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults worldwide. Despite this, there is currently no robust data on the epidemiology of MN in the UK population. The Health Improvement Network (THIN) is an electronic medical record database that holds longitudinal anonymised patient records for over 17 million patients and has shown to be generalisable to the UK regarding demographics and crude prevalence’s of major conditions. To our knowledge, accuracy of the read codes for glomerular disease is yet to be validated. This will be the first study into MN validating the diagnostic accuracy using the THIN database. Method THIN database was interrogated for patients with MN using read codes. Two cohorts were considered: Definite cohort, defined as read codes expected to correspond to a diagnosis of MN, and Probable cohort, defined as read codes that could correspond to a diagnosis of MN. In order to confirm the diagnosis of MN, a short questionnaire was sent to the GP practice of a randomly selected cohort of patients asking if the diagnosis of MN was correct, and that the diagnosis had been confirmed by a specialist renal centre, with or without a renal biopsy. Results 267 patients with a record of MN were identified from the THIN database. 235 of the patients had Definite cohort read codes, with a mean age at diagnosis of 57 years. There were 155 (66.2%) male and 79 (33.8%) female patients. 32 patients were identified in the Probable cohort. GP questionnaires were sent to 71 randomly selected patients with 61 responses (85.9% response rate). This represented 23% (n=53) of the total Definite cohort and 25% (n=8) of the total Probable cohort. Of the 61 returned questionnaires, an MN diagnosis was confirmed in 96% (n=51) of patients with a definite read code and 25% (n=2) with a probable read code. Amongst the confirmed MN diagnoses in the Definite cohort, 88% (n=45) of the patients had primary MN. Conclusion The THIN database is a valid data resource for studying MN in patients with a read code from the Definite cohort list. Read codes from the Probable cohort list cannot be used unless confirmed on a case by case basis such as through the GP. The results of this study will feed into a larger project with an aim to describe accurately the epidemiology of MN in the UK population, and report the incidence and prevalence of specific secondary associations of MN. Once these factors are fully understood, diagnostic and care pathways for MN can be developed.

Background: Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems.Methods: We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime.Results: At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of -£5251.03 but with a reduced quality of life (incremental QALY of -0.512) giving an ICER of £10 246.09.Conclusions: Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care.

Idiopathic membranous nephropathy (IMN) remains the most common cause of the nephrotic syndrome in adults and one of the leading identifiable causes of end-stage kidney disease. Prior to considering the best approach to treatment, three important components need to be considered. First, the natural history of the typical membranous patient today; second, the importance of identifying the causative factors; and third, the integration of the current data on the known autoantibody/antigen systems involved in IMN into the diagnosis and management of the patient. Combining this with information on the known indicators associated with a poor prognosis plus new data on surrogate markers that provide important clues that the treatment plan is correct has provided us with a more secure platform for choosing the right treatment for each patient. This already provides a more rational and precise approach to the use of our current therapeutic options. Even today, we can slow disease progression and in the future new approaches and new therapies are likely to lead to prevention of progression or even reversal of the injury in IMN, thereby leading to improved quality of life of our patients.

BACKGROUND Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.

BackgroundEncapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis. The etiology is unclear, but genetic predisposition may be a contributing factor. We used adenovirus-mediated gene transfer of transforming growth factor (TGF) ?1 to the peritoneum in four genetically distinct laboratory mouse strains to assess differences in fibrogenic response.MethodsMice from four genetic backgrounds (C57BL/6J, DBA/2J, C3H/HeJ and SJL/J) received an intraperitoneal injection of an adenovirus expressing TGF?1 (AdTGF?1) or control adenovirus (AdDL) and were assessed 4 and 10 days after infection. Submesothelial thickening, angiogenesis and gene expression were quantified from peritoneal tissue. Protein was extracted from omental tissue and assessed for collagen, E-cadherin and TGF? signaling pathway proteins.ResultsThere was a graded response among the mouse strains to the peritoneal overexpression of TGF?1. TGF?1 induced a significant fibrogenic response in the C57BL/6J mice, whereas the SJL/J mice were resistant. The DBA/2J and the C3H/HeJ mice had intermediate responses. A similar graded response was seen in collagen protein levels in the omental tissue and in fibrosis-associated gene expression. TGF? type 1 receptor and SMAD signaling pathways appeared to be intact in all the mouse strains.ConclusionsThere were significant differences in mouse strain susceptibility to peritoneal fibrosis, suggesting that genetic factors may play a role in the development of peritoneal fibrosis and possibly EPS. As early TGF?1 signaling mechanisms appear to be intact, we hypothesize that fibrosis resistance in the SJL/J mice lies further down the wound-healing cascade or in an alternate, non-SMAD pathway.

Background. Prolonged peritoneal dialysis (PD) therapy can result in the development of encapsulating peritoneal sclerosis (EPS), characterized by extensive sclerosis of the peritoneum with bowel adhesions often causing obstruction. Methods. As a proof-of-principle study, holistic profiling of endogenous metabolites has been applied in a prospective collection of PD effluent collected in multiple UK renal centres over 6 years in order to investigate metabolic differences in PD effluent between PD therapy patients who later developed clinically defined EPS (n ¼ 11) and controls, who were matched for PD vintage, age and gender (n ¼ 11). Results. ‘Fit-for-purpose’ analytical methods employing gas chromatography–mass spectrometry (MS), direct injection MS and quality control samples were developed and validated. These methods were applied in a proof-of-principle study to define metabolic differences in PD effluent related to subsequent development of EPS. Changes in amino acids, amines and derivatives, short-chain fatty acids and derivatives and sugars were observed prior to EPS developing, and changes in the metabolomic profiles could be detected. Conclusion. There is potential for applying metabolic profiles to identify patients at risk of developing EPS although long-term prospective studies with larger patient cohorts are required.

Background. Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-b1 (TGF-b1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-b1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2). Methods. Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or � 30% increase over 5 years, n ¼ 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n ¼ 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions � 460 (C/T) and þ405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-b1 polymorphisms at positions � 800, � 509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). Results. In cohort 1, there was a significant increase in frequency of the � 460 VEGF CC genotype 30.8 vs 5.1%, P ¼ 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94–58.72 and C allele 56.7 vs 37.2%, P ¼ 0.009; OR 2.22, 95% CI, 1.21–4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF � 460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P ¼ 0.011; OR CC vs TT 1.59, 95% CI, 0.72–3.51. The � 460 and þ405 polymorphisms were in LD P

The concept that some forms of proteinuria may be induced by the action of circulating systemic permeability factors on the glomerular capillary wall is intriguing. First proposed in the 1970s in the context of steroid-sensitive nephrotic syndrome, the immune system was proposed as a source of such a vascular permeability factor (VPF). More recently, some forms of focal segmental glomerular sclerosis appear to be associated with another type of systemic factor. This paper reviews the evidence for such factors and compares the properties of a number of candidate VPFs.

An understanding of the molecular basis of angiogenesis is key to the appreciation of many of the advances made in the field of neovascularization over the past two decades. The sequence of events involved in angiogenesis includes: (i) increased vascular permeability and leakage; (ii) degradation of basement membrane; (iii) endothelial cell proliferation and migration through the surrounding extracellular matrix; and (iv) maturation and stabilization of the newly formed vessel bed. This review provides an update on the molecular basis of such pathways in the skin, with particular emphasis on the endothelial cell-specific vascular endothelial growth factor and angiopoietins as modulators of angiogenesis that can be targeted in therapy of cutaneous disease.

The success of unravelling the human genome in 2001 [1] has provided clinical researchers with an estimate of the number of genes, their relative position on chromosomes and access to the entire nucleotide sequence. Despite the promises of the daily press/ news that this achievement heralds the introduction of genetically tailored treatment and the answer to every known disease, the reality of the situation is very different. Six years later, nephrologists may justifiably ask how this knowledge of the human genome has had impact on their clinical practices and may correctly conclude that it has made, as yet, a little impact. While encouraging advances have been made in relation to single-gene disorders for a large majority of the renal patient population, renal damage and its complications should be considered as complex traits with contributions of multiple genetic and environmental factors. So, facing this complexity, what is required to translate novel genetic knowledge into improved clinical practice? The answer, we suggest, lies in three areas

We have previously reported that urinary excretion of the complement activation products C3dg and C5b-9 in human membranous nephropathy (MN) correlated with clinical outcome in a cross-sectional analysis. We report here the results of a retrospective longitudinal study of the temporal relationship between urinary C3dg and C5b-9 excretion and clinical parameters. A group of 23 adult patients with biopsy-proven MN were studied over a mean time period per patient of 3.5 years. Freshly voided urine samples were collected regularly; C3dg and C5b-9 were measured by ELISA (mean number of samples per patient = 13). During the period of the study, nine patients with declining renal function (group A) were treated with a standard steroid regimen. Serum creatinine had improved or stabilized in seven of these patients at the end of treatment. All nine patients were excreting C3dg and C5b-9 before treatment. Six other patients with declining renal function (group B) were not treated with steroids because of clinical contraindications. Serum creatinine continued to increase during the study in four of these six patients. C3dg and C5b-9 were present in the urine samples of these six patients on the majority of dates tested. Eight patients maintained stable renal function during the study (group C), either normal (6 patients) or impaired (2 patients). Of these patients, six were consistently negative for urinary C3dg and C5b-9 despite persistent proteinuria, and one patient who was initially positive became negative within 15 months, and remained negative for the rest of the study period. One patient was positive on one of 12 occasions tested. These results suggest that urinary complement activation products indicate ongoing active glomerular damage and may prove to be important determinants for the introduction and monitoring of therapy.