Ioannis Boletis

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

Immunohistochemical evaluation of podocalyxin expression in glomerulopathies associated with nephrotic syndrome

It is now well established that morphological change of podocytes is closely correlated to the development of proteinuria. The aim of this study was to investigate the role of podocalyxin, a major podocyte protein, in the pathogenesis of glomerulopathies primarily associated with the nephrotic syndrome. Immunohistochemical expression of podocalyxin has been evaluated in 51 renal samples, including healthy controls, patients with podocytopathies (minimal change disease [MCD], focal segmental glomerulosclerosis [FSGS]) and membranous glomerulopathy (MG). A computerized image analysis program has been used. Statistical analysis was performed using analysis of variance and Bonferroni tests. Immunohistochemical expression of podocalyxin has been observed within the podocytes of healthy controls. In MCD, podocalyxin expression was globally reduced despite the normal appearance of the glomeruli. In FSGS, podocalyxin loss was observed in both the segmental sclerotic and the nonsclerotic areas being significantly more prominent in the former. Reduction of podocalyxin in MG was demonstrated for the first time immunohistochemically. The percentage of the stained area was statistical significantly higher in the controls than in each pathologic group. However, among pathologic groups (FSGS, MCD, MG), there was no statistically significant difference. This is one of the few studies investigating podocalyxin immunohistochemical expression in glomerulopathies associated with nephrotic syndrome. The observed reduction in podocalyxin expression suggests that it constitutes a target molecule in nephrotic syndrome pathogenesis regardless of the underlying cause.

Chronic allograft nephropathy – a clinical syndrome: early detection and the potential role of proliferation signal inhibitors

Abstract:  Chronic allograft nephropathy (CAN) leads to the majority of late graft loss following renal transplantation. Detection of CAN is often too late to permit early intervention and successful management. Most current strategies for managing CAN rely on minimizing or eliminating calcineurin inhibitors (CNIs) once CAN has become established. The proliferation signal inhibitors everolimus and sirolimus have potent immunosuppressive and antiproliferative actions, with the potential to alter the natural history of CAN by reducing CNI exposure whilst avoiding acute rejection. Whilst data will be forthcoming from a number of clinical trials investigating this potential, we discuss early detection of CAN and the rationale for a role for this class of agent.

Hematologic and renal improvement of monoclonal immunoglobulin deposition disease after treatment with bortezomib-based regimens.

Abstract Monoclonal immunoglobulin deposition disease (MIDD) is characterized by non-organized immunoglobulin-fragments along renal basement membranes with subsequent organ deterioration. Treatment is directed against the immunoglobulin-producing clone. We treated 18 MIDD patients with bortezomib-based regimens (12 received bortezomib-dexamethasone, 6 bortezomib-dexamethasone with cyclophosphamide). Eleven (61%) patients achieved a hematologic response, but only 6 (33.3%) reached to a complete (CR) or very good partial response (VGPR). Regarding renal outcomes 77.8 and 55.6% had ≥30 and ≥50% reduction of proteinuria, respectively, but 33.3% ended up in end-stage renal disease (ESRD). Among patients with CR or VGPR, median eGFR improvement was 7.7 ml/min/1.73 m2 and none progressed to ESRD, but no significant renal recovery was observed in patients achieving a partial response or less, with 50% progressing to dialysis. Pretreatment eGFR seems to influence renal prognosis. Bortezomib-based treatment is considered an effective approach in MIDD and reaching to a deep hematologic response (≥VGPR) conditionally controls further renal declining.

Impact of donor and recipient age difference on long-term allograft survival after living donor renal transplantation: analysis of 478 cases

Either deceased or living‐related renal transplantation constitutes the best therapeutic option for patients with end‐stage renal disease. In this retrospective study, an attempt to identify parameters that affect allograft survival in living donor renal transplantation was made.

Quality of sleep in renal transplant recipients and patients on hemodialysis

BACKGROUND Sleep disorders are very common in patients with chronic kidney disease and they may not always subside after kidney transplantation. AIM AND METHODS The aim of this cross-sectional study was to evaluate the self-reported quality of sleep, insomnia problems in particular, and examine the factors that disturb sleep of kidney transplant recipients (KTx: n=152) in comparison to age- and sex-matched patients on dialysis (HD: n=67) and participants with normal renal function (NOR: n=49), through the administration of the Athens Insomnia Scale (AIS) at least six months after transplantation. Clinical and laboratory data, as well as health-related quality of life, depression, anxiety, post-traumatic stress symptoms, and the presence of restless legs syndrome (RLS) and pruritus were investigated in relation to sleep problems. RESULTS The highest mean AIS score was observed in the transplant patients (KTx: 4.6±13.3 vs. HD: 3.8±8.1 vs. NOR: 2.4±10.2); both KTx and HD patients had a lower quality of sleep compared to participants with normal renal function. Multiple linear regression analysis showed that the determinants of the total AIS score were the frequency of post-traumatic stress symptoms, depression, RLS, diastolic blood pressure, and pain (all p<0.0001). CONCLUSION Although amelioration of renal function post-transplantation improves several aspects of quality of life, it does not seem to have a beneficial effect on self-reported sleep.

Update on the management of lupus nephritis

Abstract The treatment of lupus nephritis still represents a therapeutic challenge for the clinician. Besides early recognition, appropriate guiding by the histologic classification at presentation as well as at relapsing disease, is essential. The most severe proliferative and mixed forms require aggressive induction therapy. Nevertheless, recent but established by RCTs advances, as low dose iv cyclophosphamide, lower doses of cor-ticosteroids and mychophenolate acid (MPA) allow us to achieve remission induction with lower toxicity without any cost in terms of efficacy. For maintenance, azathioprine and mycophenolate acid with concomitant low dose steroids have shown both good results with a slight superiority of mycophenolate acid. Emerging therapies as B cell targeting-either by depleting agents as the anti-CD 20 mAb Rituximab, or by modulating agents as the anti-Bliss Belimumab, further contribute to the effort to minimize toxicity. This review mainly focuses on the recent efforts to treat the most aggressive form of lupus nephritis effectively with the minimal possible toxicity.