[Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD]. / Gli inibitori del trasportatore Sodio-Glucosio di tipo 2 (SGLT2) nell'insufficienza renale cronica.

Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD.

Renal transplantation parenchymal complications: what Doppler ultrasound can and cannot do.

Kidney transplantation is the treatment of choice in end-stage renal disease, given the better quality of life of transplanted patients when compared with patients on maintenance dialysis. In spite of surgical improvements and new immunosuppressive regimens, parts of transplanted grafts still develop chronic dysfunction. Ultrasonography, both in B-mode and with Doppler ultrasound, is an important diagnostic tool in case of clinical conditions which might impair kidney function. Even though ultrasonography is considered fundamental in the diagnosis of vascular and surgical complications of the transplanted kidney, its role is not fully understood in case of parenchymal complications of the graft. The specificity of Doppler is low both in case of acute complications, such as acute tubular necrosis, drugs toxicity and acute rejection, and in case of chronic conditions, such as chronic allograft nephropathy. Single determinations of resistance indices present low diagnostic accuracy, which is higher in case of successive measurements performed during the follow-up of the graft. Modern techniques such as tissue pulsatility index, maximal fractional area and contrast-enhanced ultrasound increase ultrasonography diagnostic power in case of parenchymal complications of the transplanted kidney.

Contrast-enhanced ultrasound (CEUS) in nephrology: Has the time come for its widespread use?

Grey-scale ultrasound has an important diagnostic role in nephrology. The absence of ionizing radiations and nephrotoxicity, rapidity of execution, excellent repeatability, the possibility to perform the test at the patient's bed and the low cost represent important advantages of this technique. Paired with real-time sonography and colour-power-Doppler contrast-enhanced ultrasound (CEUS) reduces the diagnostic gap with computed tomography (CT) and magnetic resonance (MR) and represents a major step in the evolution of clinical ultrasound. Although there are several situations in which contrast-enhanced CT and MR are indicated (i.e. evaluation of cystic or ischemic lesions, traumatisms and ablative therapies of the native and transplanted kidney), the use of CT contrast media presents a high risk of contrast-induced nephropathy (i.e. in elderly people, subjects with comorbidities and those with renal dysfunction), while gadolinium-based RM contrast agents are contraindicated for the risk of nephrogenic systemic fibrosis (i.e. in patients with severe renal dysfunction). In these situations, CEUS may be a viable alternative, however, as any technique associated with the infusion of pharmacological substances, the potential advantages and risks of CEUS should be critically evaluated. In this regard, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) has published the guidelines for the use of CEUS for the kidney imaging and the International Contrast Ultrasound Society (ICUS) has been recently founded. The aim of this review is to offer an updated overview of the potential applications of CEUS in nephrology, reporting some indications and possible risks associated to its use.

[Use of rituximab in primary and secondary glomerulonephritis]. / Il rituximab nella terapia delle glomerulonefriti primitive e secondarie.

Primary and secondary glomerulonephritis are a heterogeneous group of disorders characterized by "glomerular inflammation" with an immune-mediated pathogenesis. Considering the severe side effects of the immunosuppressive drugs, the therapeutic approach remains a challenge for the nephrologists. Corticosteroids, cytotoxic agents such as cyclophosphamide, or calcineurin inhibitors such as cyclosporine and tacrolimus, azathioprine and mycophenolate mofetil can all be used for the treatment of glomerulonephritis. Several studies has been published to better understand the pathogenesis of these diseases and to identify the drugs with lower toxicity. Different mechanisms involve, directly or indirectly, the B cells in the pathogenesis of glomerulonephritis. For this reason, the attention of the nephrologists has been focused on the identification of drugs that act at this level, such as chimeric monoclonal antibodies. Rituximab, binding to the CD20 receptor expressed on the surface of B cells, induces their apoptosis and persistent depletion for 6-9 months. B cells contribute to the immune response by the maturation into plasma cells with consequent antibody production, the processing and presentation of the antigen to T cells and the production of various cytokines. For these reasons, the potential role of these drugs in the treatment of primitives and secondary glomerulonephritis is clear. In this review, we aimed to evaluate the use of rituximab in the treatment of these diseases, by focusing on the results of the most recent clinical trials.

[Oral hypoglycemic drugs in chronic kidney disease: which limitations in the clinical setting]. / Ipoglicemizzanti orali nella malattia renale cronica: quali limiti nell'uso clinico.

A large amount of recent epidemiological studies have shown the worldwide growth on the incidence and prevalence of diabetes mellitus type II (DM2), especially in industrialized countries where DM2 is the most frequent cause of chronic kidney disease. Diabetic nephropathy progression to ESRD (End Stage Renal Disease) may be slowed down only with a tight glycemic control, since no hypoglycemic drugs have been shown to possess renoprotective effects. Treatment with oral hypoglycemic agents should be closely and regularly monitored in patients with diabetic nephropathy since the decline of renal function below 60 ml/min of glomerular filtration rate (GFR) could cause multiple pharmacokinetic alterations. It may expose the patient to serious side effects if cautious dose reduction or even withdrawal of these drugs is not considered. Pharmacological approaches to the treatment of diabetes type 2 include the traditional oral hypoglycemic drugs (insulin sensitizers, insulin secretagogues and drugs inhibiting the absorption of glucose), incretin system drugs (orally or intravenously administered) and insulin therapy, if these drugs are insufficient or are contraindicated. The objective of this review is to evaluate the evidence regarding the use of oral hypoglycemic agents (with particular attention to the DPP-4 inhibitors) in diabetes type 2 with chronic kidney disease stage III- IV and ESRD, while in case of eGFR > 60 ml / min no dosage adjustment is usually required.

[Index resistance in renal ultrasound: what is the clinical significance?]. / Gli indici di resistenza ecografici in nefrologia: quale significato clinico?

In the area of renal diagnosis, B-mode ultrasound allows for the study of renal morphology, while power color Doppler is of strategic importance not only for the qualitative and quantitative information it provides on renal vasculature, but also because it allows for the measurement of 'Index Resistance'. This is the ratio between the peak systolic speed [VPS] minus the telediastolic speed [VTD] and the VPS: [VPS-VTD/VTD]), now one of the most sensitive parameters in the study of renal pathologies through the quantification of changes in renal plasma flow. The reliability of the measurement of IR is dependent on accurate methodology, such as sampling at the level of the interlobar or arcuate arteries of 3 to 5 waves of similar dimensions in three different areas of the kidney, etc. Reliability also depends on careful analysis of the value obtained, owing to the confounding influence of peripheral resistance in addition to many other factors, including tachy-brady-arrhythmias, severe hypotension, and perirenal or subcapsular fluid collections. In adults an average IR of < 0.70 is considered normal, although this figure varies with age, giving higher values in children in the first years of life and in the elderly. The color Doppler measurement of IR at the level of the interlobar artery has been proposed as an indicator for differential diagnosis of acute or chronic nephropathies: for example, the ratio was higher in acute pathologies with vascular and tubulo-interstitial involvement, but not in those with glomerular involvement. This review aims to highlight clinical situations in which the study of intrarenal IR can provide useful information on the physiopathology of renal disease in both the native and in the transplanted kidney, as illustrated by the alterations of the morphology of the Doppler wave that are caused by variations in vascular resistance, hydrostatic capillary pressure and pressure inside the urinary tract.

[The future of the ultrasonography techniques in nephrology]. / Il futuro delle tecniche ultrasonografiche in nefrologia.

Thanks to the wide geographical diffusion, low cost and lack of ionizing radiation, ultrasound is now the most widely used imaging technique in clinical practice, second only to chest radiography. Recent technological innovations and introduction of ultrasound contrast agents, further expanded the fields of application of ultrasound, guarantying for the future to this technique an important role in imaging of the urinary tract. The nephrologist must be able to exploit the potential offered by technological innovations in ultrasound imaging for the study of the kidney. The proper management of equipment, in fact, allows to obtain ultrasound images in gray scale of the highest quality, to optimize the diagnostic accuracy of Doppler techniques and take full advantage of the tools offered by means of ultrasound contrast agents.

[Contrast enhanced ultrasound in renal diseases]. / L'imaging ecocontrastografico nella patologia renale.

Contrast-enhanced ultrasound (CEUS) is one of the most interesting and promising clinical applications of imaging and ultrasound. Thanks to the absence of ionizing radiation, the lack of nephrotoxicity and low cost it has the potential to become a reference in imaging of the kidney. This review, besides providing a brief description of the proper methodology, presents possible applications of CEUS in nephrology and urology, including renal ischemia, the differential diagnosis of cystic and solid lesions, follow-up of ablative therapies, kidney trauma, kidney transplant, inflammatory diseases, ischemic nephropathy and vesicoureteral reflux.

[Ultrasound assessment in renal infections]. / L'ecografia nelle infezioni del rene.

Urinary tract infections (UTIs) are a common clinical problem, especially among women. Ultrasound assessment is indicated in case of complicated UTIs, in particular in children, pregnant women and patients with chronic kidney disease. Even though B-mode imaging alone is rarely diagnostic in case of particular kidney infections such as focal and multifocal acute pyelonephritis, Doppler and power-Doppler (PD) techniques are able to increase its sensitivity. Contrast-enhanced ultrasound (CEUS) further improves the signal-to-noise ratio, thus increasing the diagnostic accuracy of ultrasound in case of renal infectious disease. Recent studies performed on kidney transplant recipients have indeed demonstrated the high sensitivity and specificity of CEUS in diagnosing acute pyelonephritis. Moreover, ultrasonography is a useful diagnostic tool in case of kidney abscesses, emphysematous pyelonephritis, early phases of pyonephrosis, and in the evaluation and monitoring of echinococcal cysts. Ultrasound imaging is less specific in diagnosing xanthogranulomatous pyelonephritis, malacoplakia and renal tuberculosis. Finally, several authors recommend routine ultrasound assessment in HIV patients, given the high incidence of renal complications in this population of patients.

[Parenchymal complications of the transplanted kidney: the role of color-Doppler imaging]. / Le complicanze parenchimali del rene trapiantato: il ruolo dell'eco-color-Doppler.

Kidney transplantation is the treatment of choice for end-stage renal disease, given the better quality of life of transplanted patients when compared to patients on maintenance dialysis. In spite of surgical improvements and new immunosuppressive regimens, part of the transplanted grafts still develop chronic dysfunction. Ultrasonography, both in B-mode and with Doppler ultrasound, is an important diagnostic tool in case of clinical conditions which might impair kidney function. Even though ultrasonography is considered fundamental in the diagnosis of vascular and surgical complications of the transplanted kidney, its role is not fully understood in case of parenchymal complications of the graft. The specificity of Doppler ultrasound is low both in case of acute complications such as acute tubular necrosis, drug toxicity and acute rejection, and in case of chronic conditions such as chronic allograft nephropathy. Single determinations of resistance indices present low diagnostic accuracy, which is higher in case of successive measurements performed during the follow-up of the graft. Modern techniques including tissue pulsatility index, maximal fractional area and contrast-enhanced ultrasound increase the diagnostic power of ultrasonography in case of parenchymal complications of the transplanted kidney.

Indication to renal biopsy in DM2 patients: potential role of intrarenal resistive index.

Diagnosis of diabetic nephropathy is generally based, rather than on histological confirmation, on clinical criteria (long history of diabetes, presence of proteinuria, diabetic retinopathy or peripheral neuropathy). This clinical approach has perhaps limited utility in DM2 patients, because only 50% of them show microvascular complications in presence of nephropathy. Eco-colour-Doppler sampling of interlobular renal arteries and determination of their resistance indices (RI), was proposed in the differential diagnosis of numerous nephropathies. Aim of this study was to evaluate whether RI can be useful in discerning non-diabetic renal disease (NDRD), in order to better define indications to perform renal biopsy among proteinuric DM2 patients. All patients were submitted to: echo-colour-Doppler study of renal vessels; systematic screening for diabetic retinopathy; needle renal biopsy. RI resulted to be significantly higher in diabetic glomerulosclerosis (GSD) group as compared with NDRD group, while no significant difference was found with respect to NDRDs overlapping GSD (overlapping group). The last one showed however median RI significantly higher than isolated NDRD group. Normalized chi square Pearson for the hypothesis that RI can predict GSD resulted 0.73, while it resulted 0.43 for the hypothesis that diabetic retinopathy can predict GSD. Echo-colour-Doppler can significantly contribute, more than the other parameters proposed (nephritic or nephrotic syndrome, hematuria, diabetic retinopathy), to the identification of underlying nephropathy in DM2 subjects. In the light of our experience, it seems that the detection of RI values > 0.72 suggests the diagnosis of GSD or mixed forms, reducing the indications to renal biopsy only in presence of values < 0.72.

Tacrolimus versus cyclosporine for early steroid withdrawal after renal transplantation.

INTRODUCTION: This study compares cyclosporine (CsA) with tacrolimus (Tac) in preventing acute rejection (AR) after steroid withdrawal (SW) 5 days after renal transplantation (Tx). METHODS: The data were collected from 2 prospective sequential studies carried out from February 2002 to May 2006. Forty-nine patients received CsA, 56 patients Tac. Rapamycin (Rapa) was added to both calcineurin inhibitors (CNIs). The studies were homogeneous regarding both clinical procedures and patient demographics. RESULTS: Three years after SW, Tac was more effective than CsA in reducing the risk both of AR (35% vs. 53%; p<0.06) and mainly of relapses (9% vs. 33%; p<0.007). In addition, Tac enabled more patients to go onto a steroid-free regime (88% vs. 65%; p<0.01). No difference arose concerning the timing of AR, graft function, CNI withdrawal, incidence of side effects or patient and graft survival rates. In both groups, rejection after SW was associated with a worse graft function. CONCLUSIONS: Tac was more effective than CsA in preventing AR after early SW, and increased significantly patient probability of maintaining a steroid-free regime. In this setting, Tac and CsA had the same safety profile. However, a follow-up longer than 3 years might be needed to estimate the consequences of the higher rate of AR encountered under CsA therapy.

[Kidney transplantation and lymphomas]. / Linfomi nel trapianto renale.

Post-transplant lymphoproliferative disease (PTLD) accounts for 30% of nonskin cancers after kidney transplants. Diffuse large B-cell lymphoma is the most frequent form of PTLD. The incidence of PTLD increases over time: from 1.2% at 5 years to 6.8% at 20 years. Its late occurrence is therefore not unusual. Moreover, not only is it more frequent but also more serious than the early type because of the lower responsiveness to therapy. Epstein-Barr virus (EVB) infection is one of the most important risk factors for this disease, along with the use of antilymphocyte agents, which should be avoided in EVB-negative patients. During the first year after transplant, EBV-PCR monitoring can be helpful for the early diagnosis of EBV-associated PTLD, especially in children. No effective strategy has yet been reported for the prevention of late PTLD. Interruption of immunosuppression is the first step of therapy, but it is rarely effective by itself. Rituximab (4-8 doses) is widely used and is successful in about 50% of cases. Chemotherapy becomes essential in relapsed or refractory disease, but it significantly increases the risk of life-threatening infections. The mortality rate is around 50% 12 months after diagnosis, often due to the side effects of chemotherapy.