Supportive treatment for cast nephropathy in patients with multiple myeloma; a pilot study

Introduction: Cast nephropathy is a prevalent cause of acute kidney injury (AKI) in patients with myeloma. Objectives: The aim of this study is to define the outcome of a standardized supportive therapy for cast nephropathy. Patients and Methods: Retrospective analysis of the outcome of cast nephropathy in a University hospital for a period of five years. Data analysed; serum creatinine, estimated glomerular filtration rate (eGFR; mL/min/1.73 m2 BSA) and need for dialysis. Standardized therapy with the aim of preventing/removing tubular casts; fluid administration and mannitol to increase urine flow, sodium bicarbonate to alkalize the urine and low dose steroid to reduce peritubular inflammation. Statistical analysis: Student's t-test or the Mann-Whitney test according to data distribution. A two-tailed P value <0.05 was considered statistically significant. Survival curve was drawn according to Kaplan and Meier. Results: Twenty-seven cases were reviewed. Upon admission, mean serum creatinine was 7.1±4.9 mg/dL and mean eGFR 6±4 mL/min/1.73 m2 BSA; 30% of patients had oligo-anuria. Diagnosis of cast nephropathy was presumptive in 23 patients, and renal biopsy proven in four. Hemodialysis was required by 10 (37%) patients, two of whom continued dialysis after discharge. At discharge, serum creatinine was 3.7±2.5 mg/dL and eGFR 20±13 mL/min/1.73 m2 BSA (P=0.002), and after a median of 3.4 months, the values were 2.9±2.1 mg/dL and 35±32 mL/min/1.73 m2 BSA, respectively. Patient survival was 60% after 24 months. Conclusion: Administration of fluid, mannitol, sodium bicarbonate and low-dose steroid may improve the outcome of cast nephropathy. Despite the fact that the study has many limitations, its findings could be the base for prospective controlled trials on cast nephropathy and could be useful in those countries where the expensive extracorporeal treatments are not available

Outcomes of pregnancies after kidney transplantation: lessons learned from CKD. A comparison of transplanted, nontransplanted chronic kidney disease patients and low-risk pregnancies: a multicenter nationwide analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in CKD. The reasons why materno-foetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of non-transplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD and 1418 low-risk controls recruited in 2 large Italian Units, in the same period (2000-2014). The following outcomes were considered: maternal and foetal death; malformations; preterm delivery; small for gestational age baby (SGA); need for the neonatal intensive care unit (NICU); doubling of serum creatinine or increase in CKD stage. Data were analysed according to kidney diseases, renal function (staging according to CKD-EPI), hypertension, maternal age, partity, ethnicity. RESULTS: Materno-foetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. KT patients with e-GFR >90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ('progressive CKD') are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 versus 1: RR 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The materno-foetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney diseas

Diabetic retinopathy, a vascular and inflammatory disease: therapeutic implications

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in the working-age population in the Western world. Diabetic macular oedema (DME) is one of the major complications of DR. Therapy with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs has become the gold standard treatment for DR and its complications. However, these drugs have no effect on the pathogenesis of DR and must be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. Indeed, an increasing volume of data supports the role of the inflammatory process in the pathogenesis of DR itself and its complications, including both increased retinal vascular permeability and neovascularization. Inflammation may also contribute to retinal neurodegeneration. Evidence that low-grade inflammation plays a critical role in the pathogenesis of DME has opened up new pathways and targets for the development of improved treatments. Anti-inflammatory compounds such as intravitreal glucocorticoids, topical non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants, inflammatory molecule inhibitors, renin-angiotensin system (RAS) blockers and natural anti-inflammatory therapies may all be considered to reduce the rate of administration of antineovascularization agents in the treatment of DR. This report describes the current state of knowledge of the potential role of anti-inflammatory drugs in controlling the onset and evolution of DR and DME

Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection

Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration

Trace elements and diabetes: assessment of levels in tears and serum

Tear film is critical for the well-being and homeostasis of the ocular surface. Although the composition of the tear film is well known, the composition of metallic elements have yet to be analysed. Despite trace elements metabolism has been reported to play a role in the pathogenesis of diabetes mellitus, a metabolic disease that affects several aspects of homeostasis, little is known in the literature regarding concentration and possible variation of metallic elements in tear film. We studied the concentrations of several essential and non-essential metallic elements in the tear fluid and serum of patients with type II diabetes mellitus and a group of non-diabetic controls. Serum and tear fluid were collected from 97 patients: 47 type II diabetic patients and 50 non-diabetic controls. Regarding tear film, there were statistically significant differences in Zinc, Chrome, Cobalt, Manganese, Barium, and Lead between groups; the values of all metallic elements were found to be statistically significant higher in patients with mellitus type II diabetes. Regarding serum values there was a statistically significant difference in Chrome, Cobalt, and Selenium values; the concentrations of Chrome and Cobalt were higher in the control group, while Selenium concentration was higher in diabetic patients. In patients with type II diabetes, metal elements with higher concentrations in tears compared to serum were: Lead, Barium, Manganese, Cobalt, and Chrome. In the control group, the metal elements with the highest concentration in tear film compared to serum were Chrome, Manganese, Barium, and Lead. In this study, we attempted to evaluate the possible effect of a disease, such as diabetes, on the metabolism of metallic elements. Although our evidence was very interesting, it is probably limited in its accuracy due to the fact that individuals in the control group harboured ocular pathologies. This work lays the foundation for future studies

Erythropoietin and Diabetic Retinopathy

Diabetic retinopathy (DR) is the main cause of visual impairment in industrialized countries. Great efforts are in place to search for new therapies able to prevent the development of DR and the onset of its complications. At present, therapy consists of anti-VEGF intra vitreal injections and is aimed at preventing the main causes of visual impairment, that is, macular oedema and retinal proliferation. However, the current knowledge has led us to hypothesize about the roles of other factors implicated in the pathogenesis of macular oedema and retinal proliferation; erythropoietin (EPO) is one such compound. The aim of the work was to review the recent literature on the applications of EPO within the context of DR etiopathogenicit

Comparison of visual and anatomical outcomes of half-dose photodynamic therapy and 689 nm laser treatment (pseudo-PDT) in eyes with chronic central serous chorioretinopathy

Purpose : Acute central serous chorioretinopathy (CSC) is a common disorder in middle-aged patients, characterized by serous retinal detachment in the macular region. We evaluated half-dose verteporfin photodynamic therapy (hd-PDT) versus 689 nm laser treatment in chronic CSC. Methods : This was a pilot study of eyes with chronic CSC. A total of 20 patients were enrolled consecutively and randomized in a 1:1 ratio to receive hd-PDT (group 1) or 689 nm laser treatment delivering 95 J/cm2 by application of an intensity of 805 mW/cm2 over 118 seconds, using a spot size with a 3000 μm diameter (group 2). Best-corrected visual acuity (BCVA) and central macular thickness (CMT) findings were compared between groups. Results : The baseline characteristics were similar, and no significant differences between the groups were found. Both groups had significant BCVA improvements (7.3 ± 1.3 vs 7.6 ± 1.5 ETRDS letters in group 1 and 2, respectively; P = 0.64), as well as CMT reductions (-102.5 ± 13.6 vs -96.1 ± 20.5 µm in group 1 and 2, respectively; P = 0.42) at 16 weeks. Measured parameters were not significantly different between groups at any time point examined. Complete photoreceptor recovery, defined as a continuous ellipsoid zone with a discernible interdigitation zone, was observed at 16 weeks in 7 and 6 patients in group 1 and 2, respectively. Conclusions : Both hd-PDT and 689 nm laser treatment were effective in treating chronic CSC. No significant differences in visual or anatomical outcomes were observed. Additional larger studies are warranted to corroborate our results

FOVEA-SPARING VERSUS COMPLETE INTERNAL LIMITING MEMBRANE PEELING IN VITRECTOMY FOR THE TREATMENT OF MACULAR HOLES

7noPURPOSE: To compare the anatomical and functional outcomes of vitrectomy involving complete internal limiting membrane peeling (CP) with those of vitrectomy involving fovea-sparing internal limiting membrane peeling (FSP) for the treatment of macular holes measuring >250 µm. METHODS: This prospective, randomized, comparative study included 46 eyes with a medium or large macular hole that was randomized to undergo complete (CP group) or fovea-sparing (FSP group) internal limiting membrane peeling during vitrectomy. The main outcome measures included the foveal retinal sensitivity, visual acuity, and central retinal thickness. RESULTS: Both groups showed significantly improved foveal retinal sensitivity after surgery; the mean foveal retinal sensitivity change at 12 months after surgery was +2.8 ± 2.1 dB in the CP group and +7.2 ± 2.3 dB in the FSP group. The visual acuity also showed a significant improvement in both groups, with no significant differences in values at any time point. Regarding central retinal thickness, there was a significant decrease in the CP group and no change in the FSP group. Nicks or dimples in the inner retinal layers were visible in the fovea and perifovea of nine eyes in the CP group. CONCLUSION: Our findings suggest that both CP and FSP are safe and effective treatments leading to functional and anatomical improvements in patients with all size macular holes. However, the fovea-sparing technique may provide better functional outcomes because of a greater improvement in foveal retinal sensitivity.reservedmixedMorescalchi, Francesco; Russo, Andrea; Bahja, Hassan; Gambicorti, Elena; Cancarini, Anna; Costagliola, Ciro; Semeraro, FrancescoMorescalchi, Francesco; Russo, Andrea; Bahja, Hassan; Gambicorti, Elena; Cancarini, Anna; Costagliola, Ciro; Semeraro, Francesc

3D endothelial cell spheroid/human vitreous humor assay for the characterization of anti-angiogenic inhibitors for the treatment of proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) represents a main cause of acquired blindness. Despite the recognition of the key role exerted by vascular endothelial growth factor (VEGF) in the pathogenesis of PDR, limitations to anti-VEGF therapies do exist. Thus, rapid and cost-effective angiogenesis assays are crucial for the screening of anti-angiogenic drug candidates for PDR therapy. In this context, evaluation of the angiogenic potential of PDR vitreous fluid may represent a valuable tool for preclinical assessment of angiostatic molecules. Here, vitreous fluid obtained from PDR patients after pars plana vitrectomy was used as a pro-angiogenic stimulus in a 3D endothelial cell spheroid/human vitreous assay. The results show that PDR vitreous is able to stimulate the sprouting of fibrin-embedded HUVEC spheroids in a time- and dose-dependent manner. A remarkable variability was observed among 40 individual vitreous fluid samples in terms of sprouting-inducing activity that was related, at least in part, to defined clinical features of the PDR patient. This activity was hampered by various extracellular and intracellular signaling pathway inhibitors, including the VEGF antagonist ranibizumab. When tested on 20 individual vitreous fluid samples, the inhibitory activity of ranibizumab ranged between 0 and 100% of the activity measured in the absence of the drug, reflecting a variable contribution of angiogenic mediators distinct from VEGF. In conclusion, the 3D endothelial cell spheroid/human vitreous assay represents a rapid and cost-effective experimental procedure suitable for the evaluation of the anti-angiogenic activity of novel extracellular and intracellular drug candidates, with possible implications for the therapy of PD