Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

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.

Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.

Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.

Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.

The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA. We assessed agreement between tests and correlated antibody titer with clinical baseline parameters and outcome. In this cohort, aPLA(2)R antibodies were positive in 74% and 72% of patients using IIFT and ELISA, respectively. Concordance between both tests was excellent (94% agreement, κ=0.85). Among 82 aPLA(2)R-positive patients, antibody titer significantly correlated with baseline proteinuria (P=0.02). Spontaneous remissions occurred significantly less frequently among patients with high antibody titers (38% versus 4% in the lowest and highest tertiles, respectively; P<0.01). IgG4 was the dominant subclass in the majority of patients. Titers of IgG4, but not IgG1 or IgG3, significantly correlated with the occurrence of spontaneous remission (P=0.03). In summary, these data show high agreement between IIFT and ELISA assessments of aPLA(2)R antibody titer and highlight the pathogenetic role of these antibodies, especially the IgG4 subclass, given the observed relationships between aPLA(2)R titer, baseline proteinuria, and outcome.

Prevalence and management of anaemia in renal transplant recipients: data from ten European centres.

BACKGROUND: Although it is a known predictor of mortality, there is a relative lack of recent information about anaemia in kidney transplant recipients. Thus, we now report data about the prevalence and management of post-transplant anaemia (PTA) in Europe 5 years after the TRansplant European Survey on Anemia Management (TRESAM) study. METHODS: In a cross-sectional study enrolling the largest number of patients to date, data were obtained from 5,834 patients followed at 10 outpatient transplant clinics in four European countries using the American Society of Transplantation anaemia guideline. RESULTS: More than one third (42%) of the patients were anaemic. The haemoglobin (Hb) concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (r = 0.4, p < 0.001). In multivariate analysis, eGFR, serum ferritin, age, gender, time since transplantation and centres were independently and significantly associated with Hb. Only 24% of the patients who had a Hb concentration <110 g/l were treated with an erythropoiesis-stimulating agent. The prevalence of anaemia and also the use of erythropoiesis-stimulating agents were significantly different across the different centres, suggesting substantial practice variations. CONCLUSIONS: PTA is still common and under-treated. The prevalence and management of PTA have not changed substantially since the TRESAM survey.

Oligosaccharide composition is similar in drusen and dense deposits in membranoproliferative glomerulonephritis type II.

Drusen are a feature of age-related macular degeneration (AMD). Lesions similar in appearance to drusen are also found in the fundi of patients with membranoproliferative glomerulonephritis type II (dense deposit disease, DDD). The lamina densa of the glomerular basement membrane, in DDD, is transformed into an electron-dense structure by deposition of microscopically homogeneous material. Our study sought to compare the saccharide composition of drusen and dense deposits in the formalin-fixed, paraffin-embedded tissue from the eye and kidney. Six eye specimens were obtained from patients diagnosed with AMD but another eye was obtained from a patient with partial lipodystrophy, who died after renal failure presumably because of DDD. The kidney specimens were from three biopsy-proven cases of DDD. Glycosylation patterns were measured by the binding of 19 biotinylated lectins before and after neuraminidase pre-treatment. High mannose, bi/tri-antennary non-bisected and bisected complex N-glycan, N-acetyl glucosamine, galactose, and sialic acid residues were found in both drusen and dense deposits. Treatment with neuraminidase exposed subterminal galactose in both sites and sparse N-acetyl galactosamine residues in drusen alone. Our study found similar pathologic oligosaccharide structures in the eye and kidney, suggesting that drusen may be a common end result of retinal and glomerular disease.

TGF-beta1 in chronic allograft nephropathy following renal transplantation.

BACKGROUND: Evidence from experimental models and clinical studies supports a major role for transforming growth factor-beta1 (TGF-beta1) in renal fibrosis. The aim of this study was to use repeated measurement of plasma TGF-beta1 as an indicator of persistent expression in a cohort of patients during the first 2 years post-renal transplantation and to correlate the findings with the development of chronic allograft nephropathy (CAN). METHODS: Active plasma TGF-beta1 was quantified in 100 consecutive renal allograft recipients (samples/patient = 35.6 +/- 12.9) under standard clinical management for a mean of 23 months (range 3.4-45 months). All patients were followed up for a minimum of 5 years. RESULTS: By 5 years, 23 patients had developed biopsy-proven CAN (CAN+), all of whom had been positive for plasma TGF-beta1. Demographic data were compared between patients who were CAN+ and CAN-negative (CAN-) and were not significantly different. TGF-beta1 exposure expressed as area under the curve / day (AUC/day) was correlated with the incidence of CAN. A Cox regression model was used to investigate the interrelationship of CAN, acute cellular rejection (ACR) and TGF-beta1 levels. ACR episodes were predictive of the development of CAN (log-rank test, p=0.003). After allowing for the effect of ACR (hazard ratio [HR]=3.6; 95% confidence ratio [95% CI], 1.5-8.7) between patients with and without ACR episodes, p=0.003), the independent effect of TGF-beta1 was confirmed (HR=1.7; 95% CI, 1.1-2.6; per quartile; p=0.008). CONCLUSION: The results demonstrate that episodes of ACR are highly predictive of chronic damage in the graft. Cumulative exposure to TGF-beta1 is identified as an independent predictor of CAN in the first 2 years posttransplantation.

Paraoxonase gene polymorphism and serum activity in progressive IgA nephropathy.

BACKGROUND: HDL-associated paraoxonase (PON1) reduces oxidation of lipids in LDL, and activity is inversely related to coronary heart disease risk with a beneficial effect on the development of atherosclerosis. Risk factors associated with atherosclerosis, such as hypertension, dyslipidemia and smoking, also promote the progression of chronic glomerulonephritides which may therefore be associated with perturbations in PON1 activity. METHODS: We performed a genetic association study in patients with IgA nephropathy (IgAN) (n=115) compared with control subjects (n=118). The aim was to test whether polymorphisms in the PON1 coding region (Q192R and L55M) and its promoter (-108C/T and -162A/G) are associated with either IgAN or with the progression. We measured serum paraoxonase activity in 60 out of 115 patients. All patients had been followed up for more than 4 years. RESULTS: There were no differences in the genotype frequency at 3 of the polymorphic sites (Q192R, L55M and -108C/T) between the patients and controls. However, the frequency distribution at -162 position (A/G) was significantly diffe-rent in IgAN (p=0.028, chi-square test) with a higher frequency of the heterozygote (0.017, Fisher exact test [FE]; odds ratio [OR] = 1.99; 95% confidence interval [95% CI], 1.14-3.47). Although there were no differences in the genotype frequency at 3 of the polymorphic sites (Q192R, L55M and -162C/T) between the patients with progressive IgA and the nonprogressive patients, we found that the frequency of the C allele for the -108C/T polymorphism was elevated in those patients with nonprogressive disease (n=85) compared with those with progressive disease (n=30) (61% vs. 47%; p=0.070, FE; OR=1.75, 95% CI, 0.97-3.18). Furthermore, PON1 activity was significantly higher in nonprogressive patients compared with progressors (206 +/- 71 vs. 136 +/- 48; p<0.001), and activity significantly correlated with 1/serum creatinine (SCr) (p<0.001; r=0.38). CONCLUSIONS: The results of this study suggest that in IgAN, lower PON1 activity may be associated with the deterioration of kidney function. This could be due to variable expression of the PON1 gene, or a functional effect of the gene product.

VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5.

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-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 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 < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 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 +405 (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-beta1 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 = 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 = 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 = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease. CONCLUSION: In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.

Heparanase activity is dysregulated in children with steroid-sensitive nephrotic syndrome.

BACKGROUND: Immune cells express heparanase, an endoglycosidase, able to degrade heparan sulfate glycosaminoglycan (HSGAG) in the glomerular capillary wall (GCW) and potentially induce proteinuria. The aim of this study was to determine whether dysregulated heparanase expression is associated with the heavy proteinuria of childhood steroid-sensitive nephrotic syndrome (SSNS). METHODS: Plasma and urinary heparanase activity and peripheral blood mononuclear cell (PBMC) mRNA heparanase levels [real-time polymerase chain reaction (PCR)] were measured in children with SSNS in relapse and remission. Plasma and urinary heparanase activity was determined in adult patients with nephrotic syndrome and in age- and gender-matched controls. RESULTS: Plasma heparanase activity was reduced in SSNS with relapse (811.2 units) compared to remission (1147.96 units) (P= 0.003) and control subjects (1390.51 units) (P < 0.001). In adult nephrotic syndrome, plasma heparanase activity was significantly lower in patients compared to controls. However, there was no difference between remission and relapse states. In children, urinary heparanase activity/urinary creatinine ratio was highest in SSNS relapse (14.26 units/mg) compared with remission (7.43 units/mg) (P= 0.016) and controls (2.29) (P < 0.001). However, PBMC heparanase mRNA expression was not different between these three groups. In adult nephrotic syndrome, urinary heparanase activity/urinary creatinine levels were lower in both remission and relapse compared to controls and there was no difference between remission and relapse states. CONCLUSION: In childhood SSNS, there is a qualitative and quantitative difference in urinary heparanase activity expression that is not paralleled in adult nephrotic syndrome. These data suggest that dysregulated heparanase expression may play a significant role in the pathogenesis of SSNS, possibly through an abnormality in post-translational control of latent heparanase activation.

Madura foot in the U.K.: fungal osteomyelitis after renal transplantation.

We report the case of an ethnic Asian patient who attended the renal transplant follow-up clinic complaining of pain in the right great toe. He had undergone transplantation nine months earlier and was maintained on triple immunosuppression. Initially, a clinical diagnosis of gout was made and the patient treated with analgesia. Two weeks later he remained symptomatic and developed a discharging sinus on his toe. A plain X-ray revealed a lytic lesion with minimal periosteal reaction. Aspiration of his first right metatarsal phalangeal joint was performed and fungal hyphae were observed in the fluid. Subsequently, despite surgical debridement and treatment with Itraconozaole amputation of the toe was required. Microbiological analysis revealed the organism to be Madurella grisea,which was resistant to both Itraconazole and Amphotericin B. He has remained well since amputation. We believe this to be the first case of Madurella infection to be described in a transplant patient.