Background: Muscle weakness is a risk factor for mortality in haemodialysis (HD) patients; we wished to determine whether measuring the composition of the arm with bioimpedance was associated with ...arm muscle strength. Methods: We measured pinch strength (PS) and hand grip strength (HGS) in 250 adult HD patients with corresponding post-dialysis multifrequency bioelectrical assessments with segmental body analysis. Results: Mean age 64.0 ± 15.6, 66% male and 45.6% diabetic. The maximum HGS in the dominant or non-fistula arm was 18.9 ± 9.2 kg and PS 4.09 ± 1.96 kg respectively, with a correlation of r = 0.80, p < 0.001. HGS was associated with body cell mass (β 0.37, p < 0.001) and PS with appendicular muscle mass (β 0.06, p < 0.001). Both HGS and PS were independently associated with the ratio of extracellular water (ECW) to total body water (TBW); β -139.5, p = 0.024, β -44.8, p < 0.001 in the arm. The presence of an arterio-venous fistula increased the ECW/TBW ratio in the arm from 0.383 ± 0.009 to 0.390 ± 0.012, p < 0.05. Conclusion: Muscle strength measured by HGS and PS was associated with both markers of whole body and segmental body composition within the arm, particularly ECW/TBW. Bioimpedance measurements and assessment of muscle strength should be measured in the non-fistula arm.
Introduction: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly ...phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. Methods: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome. Results: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive (N = 372) compared with both the unaffected control (N = 4,929) and anti-THSD7A-positive (N = 31) groups (p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset (p = 0.009). Further, the GRS in the dual antibody-negative group (N = 355) was intermediate between controls and the PLA2R1-positive group (p < 0.0001). Conclusion: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1.
Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. MN is a clinically heterogeneous disease and it is difficult to accurately predict outcomes (including end stage ...renal failure) at presentation and whom to treat with potentially toxic therapies. We aimed to identify factors predicting outcome in MN in our cohort from two large tertiary London units by undertaking a retrospective data analysis of 148 biopsy-proven MN patients from North East and Central London between 1995 and 2015.
Review of clinical and biochemistry databases.
Surprisingly, patients that reached end stage renal failure (ESRF) had a less severe nephrosis compared to those that did not develop ESRF; serum albumin 33 g/L (3.3 g/dL) versus 24 g/L (2.4 g/dL), p = 0.002 and urinary protein creatinine ratio (uPCR) 550 mg/mmol (5500 mg/g) versus 902 mg/mmol (9020 mg/g), p = 0.0124. The correlation with ESRF was strongest with the presenting creatinine; 215 μmol/L (2.43 mg/dL) compared to 81 μmol/L (0.92 mg/dL), p < 0.0001. Patients presenting with creatinine of >120 μmol/L (1.36 mg/dL; corresponding to an eGFR of ≤60 ml/min in non-Black males) had an increased rate of ESRF and a faster decline. Other traditional risk factors for progression were not significantly associated with ESRF. Black patients presented with higher serum creatinine but no statistically significant difference in the estimated glomerular filtration rate, a higher rate of progression to ESRF and had a poorer response to treatment.
This ethnically diverse cohort does not demonstrate the traditional risk profile associated with development of ESRF. Thus, careful consideration of therapeutic options is crucial, as current risk modelling cannot accurately predict the risk of ESRF. Further studies are required to elucidate the role of antibodies and risk genes.
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male ...predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.
We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.
Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R–associated MN and were not different from controls.
Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R–associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
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Abstract
Background and Aims
Barts Health has a dedicated membranous nephropathy (MN) service with 15-20 incident cases per year. Nephrotic syndrome secondary to MN in particular is associated with ...arterial and venous thrombosis. There is little evidence to guide optimum pharmacological prophylaxis. In those considered high risk, options include warfarin, heparin or aspirin. The advent of direct oral anti-coagulants (DOACs) offers an alternative, though evidence of efficacy is isolated to case studies.
All patients with an albumin <25g/L are offered anticoagulation. We describe our use of DOACs in a large single centre MN cohort.
Method
Retrospective data MN patients between 2015-2019 was analysed. This included: demographics; frequency, type and timing of thromboembolic and bleeding events; biochemical data at initiation and cessation of agent.
Results
Total number of patients: 26
DOAC treatment courses: 30
Exposure to drug (patient days): 9899
Malignancy was excluded in all cases, with the exception of 1 case of MN secondary to cancer.
There were 3 thromboembolic events in 3 patients; all events occurred on rivaroxaban and in PLA2Rab positive MN.
Thrombotic events were all arterial, with no venous events, 2 cerebral artery infarcts and 1 lower limb arterial thrombosis. These patient’s mean initial presentation PLA2Rab titres were 164 Kunits/L (75-248) and all were nephrotic at the time of the thromboembolic event. Events were 29, 128 and 340 days post DOAC initiation. 2 of these patients had a venous thrombosis prior to DOAC initiation. Event rate: 0.11 per patient year
Safety data also demonstrated 3 bleeds in this patient cohort - all were minor as per ISTH criteria. 2 epistaxes and 1 associated with rectal prolapse, all without a haemoglobin drop.
Conclusion
Our experience is that DOACs are safe and effective in patients with MN and offer a viable anti-coagulant alternative.
Table 1:
Cohort demographics
Gender, n (%)
19 (65) Male / 7 (35) Female
Mean age (range) years
54.9 (26-76)
Mean eGFR (range) ml/min/1.73m2
63.5 (17-124)
Median albumin (interquartile range) g/L
23.5 (20-28)
Phospholipase A2 receptor antibody (PLA2Rab) positivity, n (%):
PLA2Rab seropositive
20 (76)
PLA2Rab seronegative, immunohistochemistry positive
2 (8)
PLA2Rab seronegative, immunohistochemistry negative
2 (8)
PLA2Rab seronegative, immunohistochemistry unknown
2 (8)
Median DOAC initiation PLA2Rab titre, Kunits/L (interquartile range)
141 (75-993)
DOAC %
Rivaroxaban 80%
Apixaban 20%
Mean treatment course duration, days (range)
330 (46-964)
Autoimmune membranous nephropathy (AMN) is a rare kidney disease. The genetics of AMN have been partially elucidated and confirmed the role of phospholipase A2 receptor-1 (PLA2R1) and HLA. The ...functional effect of the genetic variations is not fully understood. This thesis investigates these unexplored genetic aspects utilising a range of methodologies and unique cohorts. Analysing genomic sequencing data of PLA2R1 in 335 AMN patients identified 109 strongly associated variants; 9 with a very strong association, p-value < 10-50. In a larger cohort of 1158 European AMN patients, the findings from previous GWAS were confirmed with a strong association with HLA-DQA1, HLA-DRB1 and PLA2R1. No associations were found on a genome wide scale with clinical correlates of disease such as proteinuria, sex, and age. HLA typing by imputation in 372 anti-PLA2R1 antibody positive and uniquely 32 antithrombospondin type-1 domain-containing 7A (THSD7A) antibody positive AMN confirmed the dominant HLA type in European AMN as HLA-DRB1*03:01 and HLADQA1*05:01; replicating previous studies. No statistically significant HLA type was identified for anti-THSD7A AMN. Anti-PLA2R1 AMN has a different genetic risk than anti-THSD7A and anti-contactin AMN as determined by the genetic risk score (GRS), and this can help differentiate between them. Interestingly, 33% of dual antibody negative AMN is likely to be anti-PLA2R1 AMN. AMN patients with a higher genetic risk have a younger age of onset. In a rare, undescribed cohort of 15 non-familial paediatric cases of AMN the GRS proved that these individuals did not have the same genetic risk factors as anti-PLA2R1 AMN. Finally, the genetic risk of AMN in UK Biobank Europeans is 0.8%. Even though there is a high genetic risk for AMN this does not mean this proportion of individuals will develop AMN. In conclusion, this thesis highlights important differences between antibody status groups, confirms previous GWAS findings and reports unique features about rare AMN cohorts.
This thesis develops and assesses new ways to study the conditional quantiles of a population using a sample of data that represents the population. All methods presented here build on a ...recently-proposed non-parametric approach to quantile regression that is analogous to local linear regression in the least-squares setting. A major challenge is that the raw local quantile estimates are cumbersome to interpret and gain insight from directly. Aiming to overcome this challenge, there are four main contributions herein. First, we demonstrate how a low-rank additive regression analysis can produce insight into a collection of local nonparametric quantile estimates. The low rank structure regularizes the noisy quantile estimates and facilitates interpretation of the findings. Second, we show how a multivariate dimension reduction approach provides a different type of insight into a collection of estimated conditional quantile functions. The third contribution of the thesis leverages the combination of nonparametric quantile estimation and low-rank regression in the context of mediation analysis. We show that this produces a novel quantile-based approach to mediation analysis that expresses direct and indirect effects in a concise and interpretable way. The final methodological contribution of the thesis is a framework for moment-based estimation of conditional covariance functions for stochastic processes. Throughout the thesis, we motivate our work through analyses looking at the proximal and distal factors predicting human blood pressure.
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and ...European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10
) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10
), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10
) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10
), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10
), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10
and OR = 3.39, P = 5.2 × 10
, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.
In rats, a maternal diet rich in lard is associated with reduced Na + ,K + -ATPase activity in adult offspring kidney. We have addressed the role of different fatty acids by evaluating Na + ,K + ...-ATPase activity in offspring of dams fed diets rich in saturated (SFA), monounsaturated (MUFA) or polyunsaturated (PUFA)
fatty acids. Female SpragueâDawley rats were fed, during pregnancy and suckling, a control diet (4% w/w corn oil) or a fatty
acid supplemented diet (24% w/w). Offspring were reared on chow (4% PUFA) and studied at 6 months. mRNA expression (real-time
PCR) of Na + ,K + -ATPase α subunit and protein expression of Na + ,K + -ATPase subunits (Western blot) were assessed in kidney and brain. Na + ,K + -ATPase activity was reduced in kidney ( P < 0.05 versus all groups) and brain ( P < 0.05 versus control and MUFA offspring) of the SFA group. Neither Na + ,K + -ATPase α1 subunit mRNA expression, nor protein expression of total α, α1, α2, α3 or β1 subunits were significantly altered
in kidney in any dietary group. In brains of SFA offspring α1 mRNA expression ( P < 0.05) was reduced compared with MUFA and PUFA offspring, but not controls. Also in brain, SFA offspring demonstrated reduced
( P < 0.05) α1 subunit protein and increased phosphorylation ( P < 0.05) of the Na + ,K + -ATPase modulating protein phospholemman at serine residue 63 (S63 PLM). Na + ,K + -ATPase activity was similar to controls in heart and liver. In utero and neonatal exposure to a maternal diet rich in saturated fatty acids is associated with altered activity and expression
of Na + ,K + -ATPase in adulthood, but mechanisms appear tissue specific.
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