Beniamina Gallelli

The long-term outcome of renal transplantation of IgA nephropathy and the impact of recurrence on graft survival

BACKGROUND Few data are available on allograft survival at 15 years, the impact and the predictors of recurrence of the original disease in renal transplanted patients with IgA nephropathy (IgAN). METHODS In this retrospective study, we compared the long-term outcome of renal transplant in 190 patients with IgAN with that of 380 non-diabetic controls and evaluated the impact of recurrence of IgAN on the graft outcome. RESULTS At 15 years, the patient survival was 88.3% in IgAN patients and 82.6% in controls (P = 0.12), while the death-censored graft survival was 62.6 and 72.4%, respectively (P = 0.038). IgAN had a higher cumulative incidence of graft failures in comparison with controls even considering death as a competing risk (P = 0.025). At multivariate analysis, IgAN [relative risk (RR) = 1.468, P = 0.026], delayed graft function recovery (RR = 2.394, P = 0.000) and acute rejection (RR = 2.51, P = 0.000) were predictive of graft loss. IgAN recurred in 42 grafts (22.1%), of them, 12 were lost for recurrence and in another 6 recurrence was considered a concomitant cause of graft loss. The 15-year death censored graft survival was 68.3% in non-recurrent and 51.2% in recurrent patients (P = 0.069). Pure graft survival of non-recurrent IgAN patients was similar to that of controls (P = 0.406). At Cox analysis, the recurrence of IgAN significantly reduced from 1981 to 2010 (P = 0.0065, RR = 0.936). CONCLUSIONS IgAN emerged as an independent predictor of worse graft outcome in the long-term. Recurrence of IgAN seems to progressively reduce in transplants performed from 1981 to 2010.

Anti‐C1q Autoantibodies in Lupus Nephritis

Anti‐C1q antibodies are found in a variety of diseases, in addition to systemic lupus erythematosus (SLE), and in 3–5% of normal individuals. In particular, anti‐C1q antibodies are detected at a high titer in 100% of patients with hypocomplementemic urticarial vasculitis and in 30–48% of SLE patients. Their titer correlates with active renal disease with a sensitivity of 44–100% and a specificity of 70–92%. An increase in anti‐C1q antibody titer has been suggested to be able to predict renal flares in lupus nephritis so that monitoring anti‐C1q might be valuable for the clinical management of SLE patients as a noninvasive biological marker. Recently our group studied 228 patients affected by lupus nephritis and found that the association of anti‐C1q, C3, and C4, in a multivariate analysis, provided the best prediction of renal flares, particularly in patients with focal and diffuse proliferative lupus nephritis and in the absence of antiphospholipid antibodies.

Progressive improvement of patient and renal survival and reduction of morbidity over time in patients with lupus nephritis (LN) followed for 20 years.

Whether the long-term patient and renal survival of those diagnosed with lupus nephritis (LN) has improved over the decades is still debated. Eighty-nine patients diagnosed between 1968 and 1990 entered this study and their outcome was evaluated after 20 years. At presentation 54% of patients had class IV LN, 39.3% had renal insufficiency and 59.5% had nephrotic syndrome. Patients were divided into two groups: Group 1 consisted of 30 patients diagnosed between 1968 and 1980; Group 2 consisted of 59 patients diagnosed between 1981 and 1990. In Group 1 patient survival at 20 years was 84% versus 95% in Group 2 (p = 0.05). Survivals without end-stage renal failure were respectively 75% and 84% at 20 years (p = 0.05). Survivals without severe infection at 20 years were 44% in Group 1 and 66.5% in Group 2 (p = 0.02). Survivals without cardiovascular events at 20 years were: 53% in Group 1 and 90% in Group 2 (p = 0.005). At presentation, patients in Group 1 had higher serum creatinine (1.96 vs 1.15 mg/dl, p = 0.01), higher activity index (8 vs 5.5, p = 0.01), lower hematocrit (31% v s6%, p = 0.008) and lower serum C4 levels (p = 0.04) than Group 2 patients. Patients in Group 1 also received less frequent methylprednisolone pulses (43% v s81%, p = 0.0006). In Italian patients with LN, long-term life expectancy and renal survival progressively improved over the decades, while morbidity progressively declined. An earlier referral and refinement of therapy achieved this goal.

Long-term outcome of renal transplantation in patients with idiopathic membranous glomerulonephritis (MN)

BACKGROUND Little information is available about the long-term outcome of renal transplanted patients with idiopathic membranous nephropathy (MN). METHODS The outcomes of 35 first renal transplants performed between 1975 and 2008 in patients with MN were compared with those of 70 controls transplanted in the same period and matched for sex, age and source of donors. RESULTS The mean post-transplant follow-up was 117 ± 86 months for MN patients and 123 ± 83 months for controls. At 15 years, patient survival was 96% in patients with MN and 88% in the controls (P = ns), while graft survival rates were respectively 40% and 69% (P = 0.06). MN recurred in 12 patients (34%), namely in 4/8 (50%) patients who received the kidney from related living donors and in 8/27 (29.6%) who received the kidney from a deceased donor. Recurrence led to graft failure in six patients, all deceased donor kidney recipients, within 54 ± 33 months. The other six grafts are functioning 134 ± 73 months after transplantation. Patients with recurrence were more frequently females (42% vs 4.3%, P = 0.02). The recurrence occurred earlier (4.8 ± 3.0 vs 45.6 ± 46.9 months, P = 0.05), and there was a trend to develop a higher proteinuria (7.1 ± 5.5 vs 3.67 ± 2.6 g/24 h, P = 0.1) in grafts eventually lost because of recurrence. CONCLUSIONS The long-term patient survival was similar in renal transplant recipients with MN and in controls. The graft survival was lower in MN patients than in controls, although the difference was at borderline significance. Recurrence occurred in one-third of the patients and caused graft loss in half of them.

Renal transplantation in adults with Henoch-Schönlein purpura: long-term outcome

BACKGROUND Little information is available about the long-term outcome of renal transplantation in adults with Henoch-Schonlein purpura (HSP). METHODS We compared the outcomes of 17 patients with HSP who received 19 renal transplants with those of 38 controls matched for time of transplantation, age, gender and source of donor. The mean post-transplant follow-up was 109 +/- 99 months for HSP patients and 110 +/- 78 months for controls. RESULTS The actuarial 15-year patient survival was 80% in HSP patients and 82% in controls, and the death-censored graft survival was 64% in HSP patients and in controls. The risks of acute rejection, chronic graft dysfunction, arterial hypertension and infection were not different between the two groups. In eight grafts (42%) recurrence of HSP nephritis was found (0.05/patient/year). In spite of therapy, one patient died and four eventually restarted dialysis respectively 10, 32, 35 and 143 months after renal transplant. Seventy-one percent of grafts transplanted in patients with necrotizing/crescentic glomerulonephritis of the native kidney had HSP recurrence in comparison to 12% of recurrences in patients with mesangial nephritis (P = 0.05) CONCLUSIONS Long-term patient and allograft survival of HSP patients was good. However, 42% of HSP patients, particularly those with necrotizing/crescentic glomerulonephritis of the native kidneys, developed a recurrence of HSP nephritis that eventually caused the loss of the graft function in half of them.

Long-term outcome of renal transplantation in adults with focal segmental glomerulosclerosis

Little information is available about the long‐term results of kidney transplantation in adults with focal segmental glomerulosclerosis (FSGS). The outcomes of 52 renal transplants performed between 1988 and 2008 in 47 adults with FSGS were compared with those of 104 matched controls  (median follow‐up 93.4 vs. 109.4 months respectively). At 15 years, patient survival was 100% and graft survival 56% in FSGS patients vs. 88.3% and 64% respectively in controls (P = NS).  FSGS recurred in 12 out of 52 grafts (23%) and led to graft failure in seven within 10 months (median). In the other five cases, proteinuria remitted and grafts are functioning 106 months (median) after transplantation. A second recurrence developed in five out of eight re‐transplanted patients (62.5%) who lost their first graft because of recurrence; only one graft was lost. Patients with recurrence were more frequently male subjects (83% vs. 40%, P = 0.02), younger at diagnosis of FSGS (16.3 ± 6.8 vs. 24.1 ± 11.5 years, P = 0.03) and of younger age at transplantation (28.4 ± 7.8 vs. 35.8 ± 12.2 years, P = 0.05). Treatment with plasmapheresis plus ACE inhibitors achieved either complete or partial remission in 80% of the cases. Long‐term patient and renal allograft survivals of adults with FSGS were comparable to those of controls. Recurrence was more frequent in young patients and in patients who lost a previous graft from recurrence. Graft loss resulting from a second recurrence is lower than expected.

CC chemokine receptor 5 polymorphism in chronic periaortitis

OBJECTIVE Chronic periaortitis (CP) is a rare disease characterized by a fibro-inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Δ32 polymorphism confers susceptibility to CP. METHODS One hundred CP patients and 180 healthy controls were genotyped for CCR5Δ32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). RESULTS The distribution of the CCR5Δ32 genotype differed between CP patients and controls (P = 0.01). The CCR5Δ32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Δ32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Δ32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Δ32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Δ32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. CONCLUSIONS The CCR5Δ32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP.

Low-dose rituximab is poorly effective in patients with primary membranous nephropathy

Background The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. Methods Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). Results At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ∼6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. Conclusion Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce and maintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage.

OP0180 TLR4 and VEGF polymorphisms in chronic periaortitis

Background Chronic periaortitis (CP) is a rare disease characterised by a fibro-inflammatory reaction that arises from the adventitia of the abdominal aorta and common iliac arteries in the retro-peritoneum.It often entrapsadjacent structures, such as ureters and the inferior vena cava. CP includes non-aneurysmal (idiopathic retroperitoneal fibrosis, IRF) and aneurysmal forms (inflammatory abdominal aortic aneurysm, IAAA) [1]. These have common clinical and histopathological features, which suggests that they represent different manifestations of the same disease. It has been reported that variants in Toll-like receptor 4 (TLR4) are associated with inflammatory diseases, and also that VEGF polymorphisms are associated with various productions and clinical expressions of VEGF in autoimmune disease [2,3]. Objectives To investigate whether TLR4 and VEGF polymorphisms are associated with a susceptibility to, and the clinical features of, CP or its subsets, IRF and IAAA. Methods Using polymerase chain reaction and allele-specific oligonucleotide techniques, 102 CP patients and 200 healthy controls were genotyped for the TLR4 Asp299Gly (+896 A/G; rs4986790), for 936 C/T and 634 C/G mutations and for an 18 bp insertion/deletion (I/D) polymorphism in the VEGF promoter region polymorphisms. The patients were sub-grouped according to their type of CP (IRF/IAAA) and to the presence of established atherosclerotic disease (ischemic heart disease, cerebrovascular disease, peripheral arterial disease). Results There was no significant difference in allele frequency or genotype of TLR4 (+896 A/G) between CP patients and controls (P=1.00). No differences in carriage rates of the alleles I, –634C and +936T of VEGF polymorphisms were found between patients with CP and healthy controls [P=0.108, OR 1.51 (95% CI 0.92–2.48) and P=0.304, OR 1.33 (95% CI 0.79–2.23), respectively].The frequency of carriage rate T of 936 VEGF polymorphism was significantly lower in patients with CP with IAAA than in those with IRF (5.3% vs 26.5%, p=0.046, OR 6.49, 95% CI 0.82–51.54). Carrying the I allele (II+ID) was significantly associated with ureteral obstruction in comparison with non-carrying patients (74% vs. 44%; P=0.006). Moreover, those patients homozygous for the inserted version (II) had a significantly increased frequency of thrombosis compared to those without (43% vs. 19.00 P=0.031). Conclusions Our findings demonstrate that, amongst Italian patients, carrying (II +ID) polymorphism in the VEGF is associated with an increased susceptibility to the development of ureteral obstruction, and those patients homozygous for the inserted version (II) had an increased risk of thrombosis. References Vaglio A, Pipitone N, Salvarani C. Chronic periaortitis: a large-vessel vasculitis? Curr Opin Rheumatol. 2011;23(1):1-6. Boiardi L, Casali B, Nicoli D, et al. Vascular endothelial growth factor gene polymorphisms in giant cell arteritis. J Rheumatol. 2003;30:2160-4. Boiardi L, Atzeni F, Casali B, et al. -like receptor 4 (TLR4) gene polymorphisms in Italian patients with Behçet’s disease. Clin Exp Rheumatol. 2009;27(2 Suppl 53):S43-7 Disclosure of Interest None Declared