Proteinuria is a late-onset adverse event in patients treated with cabozantinib.

PURPOSE: The use of tyrosine kinase inhibitors (TKIs) in thyroid cancer patients is often limited by toxicities. Some have a long-term onset and potentially could impact patients' survival. Among them, there is the nephrotoxicity, mainly represented by proteinuria. The aim of the study was to evaluate the prevalence of proteinuria in medullary thyroid cancer patients treated with cabozantinib, to examine whether it could be a marker for treatment monitoring and to evaluate histological kidney alterations. METHODS: We collected data of 31 medullary thyroid cancer patients enrolled in the EXAM trial. Proteinuria was defined and evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events. In two symptomatic cases with high-grade proteinuria, a kidney biopsy was performed. RESULTS: Proteinuria was observed in 4/18 patients (22.2%) and occurred after a mean period of 38 months (median: 35.5 months). It was significantly associated with previous chemotherapy (p = 0.005) and/or treatment with other TKIs (p = 0.04), a prolonged use of cabozantinib (p = 0.0004), and a better radiological response at the end of follow-up (p = 0.002). The kidney biopsy showed pathognomonic features of thrombotic microangiopathy in both cases and a focal amyloid deposit in one. CONCLUSION: Proteinuria is a quite frequent adverse event during cabozantinib treatment. It is relatively well manageable with the early detection and correction of risk factors, the temporary discontinuation of cabozantinib and/or its dose reduction, and the use of anti-proteinuric and renoprotective drugs in patient with hypertension. The histological findings confirmed some typical features of the anti-VEGF inhibition injury, already described for other TKIs.

Correlation Between Renal Cortical Stiffness and Histological Determinants by Point Shear-Wave Elastography in Patients With Kidney Transplantation.

INTRODUCTION: Renal allograft biopsy is the gold standard for the detection of histological lesions of chronic allograft dysfunction. The identification of a noninvasive routine test would be desirable. Elastosonography is used to assess tissue stiffness according to viscosity, and no data are available on the use of point quantification shear-wave elastography (ElastPQ) for the evaluation of renal chronic lesions. RESEARCH QUESTION: To evaluate the feasibility of ElastPQ to assess cortical allograft stiffness and to determine the correlation of clinical, biological, and pathological factors with the diagnostic accuracy of kidney stiffness values in patients with histological lesions. DESIGN: Forty-two patients underwent kidney transplant biopsy and 10 valid measurements of ElastPQ, blindly performed by 2 operators. The interobserver reproducibility was assessed according to intraclass correlation coefficient. The ElastPQ measurements and the clinical data were compared using the Spearman correlation analysis. RESULTS: 97.6% reliable measurements were obtained using ElastPQ, with an excellent interobserver agreement. The kidney stiffness was significantly higher in the patients with a time since transplantation >12 months and was correlated with chronic lesions (interstitial fibrosis, tubular atrophy transplant glomerulopathy, and mesangial matrix), with the interstitial fibrosis/tubular atrophy, score and with the sum of the scores of the chronic lesions. Mesangial matrix increase is the only independent determinant of kidney stiffness. DISCUSSION: ElastPQ is a noninvasive, reproducible, and sensitive diagnostic tool able to detect moderate/severe chronic lesions. Its routine use during follow-up can identify patients eligible for biopsy, which remains the gold standard exam for detecting chronic allograft dysfunction.

A very early and acute renal impairment due to polyomavirus allograft nephropathy.

Polyomavirus-associated nephropathy (PVAN) has become an important cause of graft loss in the last few years. The typical course of PVAN is characterized by an asymptomatic period of viruria followed, within weeks, by the development of viremia in the context of stable renal function. The persistence of viral replication characterized by high viremia, leads to parenchymal injuries and causes the development, within months, of PVAN that could lead to deterioration in graft function and graft loss. We reported, in a patient who received a renal transplant, an unusual presentation of PVAN characterized by the development of acute renal failurte earlier than would be expected after transplantation, where the histological presentation alone could be confused with an acute rejection. We underline the importance of the association of histological findings with the viral load in urine and blood and with ancillary techniques such as immunohistochemistry and polymerase chain reaction (PCR) in situ for virus detection. We also want to emphasize that decoy cells and PCR for BK virus DNA research could be considered among the diagnostic tools for possible acute renal failure in kidney transplant.

[Clinical evaluation of living donor]. / La valutazione clinica del donatore vivente.

When possible, living donor transplantation represents the best therapeutic strategy for patients suffering from chronic renal failure. Studying the donor allows a complete and thorough clinical, laboratory and instrumental assessment that guarantees good organ function whilst protecting the health of the donor. The main parameters considered within this framework are age, renal function, nephrological complications, comorbidities (diabetes, hypertension, obesity, etc.), malignancies, and infection. Moreover, particular attention is paid to the sociopsychological aspects of the donation, particularly related to the donor, the recipient, and the entire family situation.

[Chronic allograft dysfunction: role of immunosuppressive treatment]. / Disfunzione cronica del trapianto renale (CAD): ruolo della terapia immunosoppressiva.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. In recent years a major improvement has been observed in short-term graft survival, but there has been no corresponding improvement in long-term survival. Chronic allograft dysfunction (CAD) is an anatomical and clinical alteration that can lead to the loss of the transplanted organ without any specific cause. The pathogenesis of CAD, which still remains to be fully clarified, involves both immunological factors (acute rejection, subclincial rejection, HLA mismatches between donor and recipient, noncompliance, etc) and non-immunological factors (marginal donor ischemia/reperfusion injury, infection, cardiovascular risk factors, nephrotoxicity, etc). Immunosuppressive therapy represents one of the strategies for the prevention of CAD. The introduction into clinical practice of novel immunosuppressive agents with no or lower nephrotoxicity, like mycophenolate mofetile, rapamycin and everolimus, will make therapeutic strategies aimed at decreasing the incidence of CAD feasible.

Is beta2-microglobulin-related amyloidosis of hemodialysis patients a multifactorial disease? A new pathogenetic approach.

PURPOSE: Beta2-microglobulin amyloidosis (Abeta(2)M) is one of the main long-term complications of dialysis treatment. The incidence and the onset of Abeta(2)M has been related to membrane composition and/or dialysis technique, with non-homogeneous results. This study was carried out to detect: i) the incidence of bone cysts and CTS from Abeta(2)M; ii) the difference in Abeta(2)M onset between cellulosic and synthetic membranes; iii) other risk factors besides the membrane. METHODS: 480 HD patients were selected between 1986 to 2005 and grouped according to the 4 types of membranes used (cellulose, synthetically modified cellulose, synthetic low-flux, synthetic high-flux). The patients were analyzed before and after 1995, when the reverse osmosis treatment for dialysis water was started at our center, and the incidence of Abeta(2)M was compared between the two periods. Routine plain radiography, computer tomography (CT) and nuclear magnetic resonance imaging (MRI) as well as electromyography were used to investigate the clinical symptoms. RESULTS: Bone cysts occurred in 29.2% of patients before 1995 vs. 12.2% after 1995 (p<0.0001). CTS occurred in 24% of patients before 1995 vs. 7.1% after 1995 (p<0.0001). Bone cysts and CTS occurred in older patients, who began dialysis at a late age, with high CRP, low albumin, low residual GFR, and low Hb. Cox regression analysis showed that the risk factor for bone cysts was high CRP (RR 1.3, p<0.01), while albumin (RR 0.14, p<0.0001) and residual GFR (RR 0.81, p<0.0001) were revealed to be protective factors. Cox analysis for CTS confirmed CRP as a risk factor (RR 1.2, p<0.01), and albumin (RR 0.59, p<0.0001) and residual GFR (RR 0.75, p<0.0001) as protective factors. The comparison obtained between membranes did not suggest any protective effect on Abeta(2)M. CONCLUSIONS: The findings that the inflammatory status as well as low albumin and the residual GFR of the uremic patient are predictive of Abeta(2)M lesions suggests that Abeta(2)M has a multifactorial origin rather than being solely a membrane- or technique-related side effect.

[Protonic pump inhibitors in kidney transplant patients: efficacy and safety]. / Inibitori di pompa protonica nel paziente trapiantato di rene: efficacia e sicurezza.

Kidney transplant patients show a significantly elevated incidence of gastrointestinal disorders. Protonic pump inhibitors (PPI) are considered to be the correct therapy in the treatment of peptic ulcers, as they have proven to be safe and efficient. The metabolization of the PPIs mainly occurs on a hepatic level; therefore, there is no need to change the therapy accordingly, as there is with the inhibitors of the histamine receptors (anti-H2). The PPIs currently available are omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole which present different pharmacokinetic characteristics and different metabolic routes which are responsible both for differences in terms of efficacy between the different molecules, and for the possible side-effects they may have. All the PPIs, apart from rabeprazole, are metabolized through an oxidization and sulphurization processes which involves the enzymatic system of the P450 cytochrome. The rabeprazole metabolism is different from the other molecules of the same category in that it only moderately involves the CYP450 (CYP3A4 and CYP2C19) from the moment its metabolization begins through nonenzymatic routes and 80% is involved in a thioether non enzymatic reduction mechanism. Consequently, rabeprazole represents: a) a potentially low pharmacological interaction with immunosuppressive drugs; b) a pharmacokinetic aspect much less subject to interindividual differences between one patient and another, due to genetically determined polymorphisms of the CYP2C19 and of the CYP3A4. Moreover, rabeprazole may be administered safely in standard doses with no need to change the dosage of the other pharmaceutical drugs taken simultaneously in nephropathic patients, patients undergoing dialysis and transplanted patients.

[Low-toxicity immunosuppressive therapy in renal transplant]. / Il successo del trapianto di rene dipende anche da una terapia efficace a bassa tossicità.

INTRODUCTION: Renal allograft loss in the long term may be due to the death of a patient with a functioning graft or to chronic allograft nephropathy. One of the most important factors in the development of chronic allograft nephropathy is drug nephrotoxicity. The term nephrotoxicity comprises two distinct forms of renal injury: acute and chronic. Immunosuppressive drugs, and in particular calcineurin inhibitors, have a variety of side effects including nephrotoxicity. The nephrotoxicity associated with calcineurin inhibitors is well known; this association has also been described for the newer agents. METHODS: We reviewed a large number of recent studies that attempted to reduce the toxicity of immunosuppressive regimens. RESULTS: A number of low-toxicity protocols have been developed. Encouraging results have been obtained with regimens that reduce or eliminate nephrotoxicity-inducing calcineurin inhibitors and with regimens that reduce or eliminate steroids, which are responsible for many diseases that may lead to the death of the patient, even with a functioning graft. CONCLUSION: All immunosuppressive drugs may be nephrotoxic, even if they act through different mechanisms. Combining different drugs at low dosage would therefore seem the best solution. It is not yet clear which regimens will be the most effective from the point of view of maximizing patient and graft survival, minimizing rejection, and minimizing adverse events.

Jugular vein-mammary artery fistula after catheterism for hemodialysis: case report.

The demographic characteristics of hemodialysis (HD) patients increase the need for the tunneled cuffed permanent catheter (TCC) as a definitive vascular access (VA) for HD. The internal jugular vein is increasingly being used as a route for TCC or temporary catheter placement and can be associated with serious complications. Among them other authors have described arteriovenous fistula (AVF) creation between the common carotid artery and the right jugular vein. We describe a case of an AVF between the right internal jugular vein and the right internal mammary artery. The fistula was detected during the TCC placement in a patient who underwent several jugular and subclavian catheterisms for HD in her clinical history.

Nephrological indications in combined liver-kidney transplantation.

In isolated liver transplantation pretransplant renal failure is a major mortality risk, there are no guidelines at the moment to establish the indications for a combined liver-kidney transplantation (LKT). In irreversible chronic renal failure (CRF) not on dialysis, nephrological evaluation is required to assess the need for a simultaneous kidney transplantation. There are no experiences about the functional contribution of native kidneys post-LKT. Herein we have reported the case of two patients who underwent LKT in 2004 due to CRF, not yet on dialysis. At the moment of LKT, the first patient (polycystic kidney disease) had a glomerular filtration rate (GFR) = 29 mL/min, and the second recipient (vascular nephropathy and diabetes), a GFR = 33 mL/min. In both cases we did not observe delayed graft function. At discharge the serum creatinine was 1.1 and 1.0 mg/dL, respectively, which was maintained during follow-up. In both cases renal scintigraphy with Tc-99 DMSA was performed to evaluate the functional contributions of transplanted versus native kidneys. In the first case scintigraphy at 9 months after LKT demonstrated an 81% contribution from the transplanted kidney, 9% from the right and 10% from the left native kidneys. In the second case, at 3 months after LKT, the functional contributions were 76%, 10%, and 14%, respectively. The transplanted kidney nephron mass may avoid the need for hemodialysis in the early posttransplant period; in the midterm it may help to maintain residual renal function. As in other combined transplant programs (heart-kidney, kidney-pancreas) with irreversible CRF, a GFR < or = 30 to 35 mL/min may be an indication for LKT, but we need more experience.

Anticoagulation therapy for the prevention of hemodialysis tunneled cuffed catheters (TCC) thrombosis.

BACKGROUND: Chronic oral anticoagulation is currently used to avoid thrombosis and the malfunction of tunneled cuffed catheters (TCCs) for hemodialysis (HD). The aim of the study was to assess the efficacy of early warfarin administration, after TCC placement, in comparison to its administration after the first thrombosis or malfunction event of the TCC. PATIENTS AND METHODS: One hundred and forty-four chronic dialysis patients, who underwent TCC placement between June 2001 and June 2005, were randomized into two groups: 81 patients, group A, started oral anticoagulation 12 hr after the TCC placement (target international normalized ratio (INR) 1.8-2.5), in association with ticlopidine 250 mg/die; 63 patients, group B, started warfarin after the first thrombosis/malfunction episode (target INR 1.8-2.5) in association with ticlopidine 250 mg/die. The efficacy of oral anticoagulation therapy in preventing TCC thrombotic complications was evaluated in a 12-month follow-up period, after TCC placement, in terms of: a) the number of patients with thrombotic-malfunction events; b) the number of thrombotic-malfunction events with urokinase infusion (events/patient/year); c) intradialytic blood flow rate (BFR, ml/min); d) negative blood pressure (BP) from the arterial line of the TCC (AP, mmHg); e) positive BP, in the extracorporeal circuit from the venous line (VP, mmHg); and f) bleeding complications. RESULTS: Ten patients (12%) in group A showed TCC thrombosis/malfunction vs. 33 patients (52%) in group B (p < 0.01). In group A, 0.16 events of thrombosis/malfunction per patient/year vs. 1.65 in group B (p < 0.001) were ob-served. BFR was respectively 305 +/- 34 vs. 246 +/- 42 ml/min (p < 0.001). AP was -124 +/- 13 in group A vs. -174 +/- 21 mmHg in group B (p < 0.05). VP was 112 +/- 28 in group A vs. 168 +/- 41 mmHg in group B (p < 0.05). No patient showed any bleeding events. CONCLUSIONS: Early warfarin therapy allows a significant reduction in TCC thrombotic complications and an improvement in both arterial and venous fluxes in comparison with the same therapy administered after the first TCC thrombotic/malfunction event. This therapy did not induce any bleeding complications in the patients included in the study.

Predictive factors in chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is characterized by progressive renal dysfunction leading in many cases to graft loss. The pathogenesis of CAN involves both immune and nonimmune factors. Concerning immune factors, one of the most remarkable predictors of CAN is acute rejection, which is associated with a worse prognosis if there are multiple episodes or when late onset occurs. Delayed graft function is also a major risk factor for CAN because of a correlation between late restoration of renal function after transplantation and long-term decreased graft survival. High creatinine levels at 6 months and 1 year after transplantation, proteinuria, viral infections, and cardiovascular risk factors are additional significant parameters for the development of CAN. Recent findings suggest that a high renal segmental arterial resistance index measured by Doppler ultrasonography in intrarenal vessels is associated with poor allograft function. Moreover, the study of patient genetic profile represents a new approach to identify predictive factors for CAN.

[Therapy strategies in the prevention of chronic allograft nephropathy]. / Strategie terapeutiche nella prevenzione della nefropatia cronica da trapianto.

Chronic allograft nephropathy (CAN) is an anatomical and clinical alteration, characterized by proteinuria, hypertension and a progressive decline in kidney function, which begins at variable times (months, years) and can lead to the loss of the transplanted organ. CAN pathogenesis, which remains to be fully clarified, involves both immunological (early acute rejection, hyperimmunization, HLA-mismatches between donor and recipient, suboptimal immunosuppression, etc) and non-immunological factors (ischemia/reperfusion injury, reduced nephron mass, age differences between donor and recipient, dialysis time, hypertension, dislipidemia, proteinuria, etc). The possible prevention strategies for CAN consist of procedures aimed at the reduction of some potential risk factors: optimization of the conditions for organ explantation, diminution of ischemia/reperfusion injury, aggressive pharmacological treatment of acute rejection episodes, routine utilization of anti-hypertensive and hypolipidemic agents, and appropriate and rational immunosuppressive regimen. Moreover, some categories of immunosuppressive drugs, such as calcineurin inhibitors, can have a nephrotoxic effect, often regardless of therapeutic dosage. The introduction in clinical practice of novel immunosuppressive drugs with no nephrotoxicity, like mycophenolate mofetil and rapamycin, makes therapeutical strategies able to reduce the incidence of CAN feasible.

On-line estimation and prediction of urea kinetics during hemodialysis: a simulation approach.

A new method for the on-line estimation of urea kinetic parameters from blood urea concentration (BUN) continuously measured during a dialysis session is proposed. The method, based on the variable-volume double-pool model, is evaluated through a simulation approach in order to easily consider a large set of well-controlled test conditions. The model is characterized by six parameters, knowledge of which enables early prediction of the end dialysis urea concentration and the dose of dialysis. The sensitivity of the model predicted BUN with respect to the parameters was first analyzed to investigate which can be reliably estimated from blood urea measurements taken at a suitable rate. This analysis showed that the model predicted BUN is highly sensitive to the initial blood urea concentration and to the dialyzer clearance, normalized with respect to the total initial distribution volume, while it is scarcely influenced by the normalized ultrafiltration and urea generation rates. The new on-line estimation technique keeps these two last parameters constant and takes advantage of an original analytic solution of the second order urea kinetics. The results of the estimation process on realistic simulated data showed that the proposed method provides early and reliable estimates of the normalized clearance and of the end dialysis concentration. The transcellular mass transfer coefficient and the intra-extra cellular volume ratio can also be estimated, although with less accuracy. Moreover, it was shown that the use of the single-pool model, instead of the double-pool one, provides systematic errors on the estimates.

Induction therapy with alemtuzumab (campath) in combined liver-kidney transplantation: University of Bologna experience.

BACKGROUND: Combined liver-kidney transplantation (LKT) is considered to be a safe procedure, but the appropriate immunosuppressive regimen is unclear. PATIENTS AND METHODS: Between January 1997 and October 2011, 55 patients were listed for LKT: 45 (82%) were effectively transplanted, 5 (9.2%) died whereon here the waiting list, 3 (5.5%) temporarily out of waiting list, 1 (1.8%) was on waiting list and 1 (1.8%) refused LKT. Five LKTs treated with cyclosporine (CyA) were excluded from the analysis. Mean recipient age was 50.32 ± 10.32 years (14-65), MELD score at time of LKT was 19.22 ± 4.69 (8-29), mean waiting list time was 8.14 ± 9.50 months (0.1-35.76), and follow-up, 4.09 ± 3.02 years (0.01-10.41). Main indications for LKT were policystic disease (n = 15; 37%), hepatitis virus C (HCV)-related cirrhosis (n = 9; 22%) metabolic disease (n = 5; 13%), hepatitis virus B (HBV) cirrhosis (n = 4; 10%), alcoholic cirrhosis (n = 4; 10%), and cholestatic disease (n = 3; 8%). Immunosuppressive regimen was based on tacrolimus and steroids in 40 cases with induction therapy with alemtuzumab (Campath; 0.3 mg/kg) in 13 of 40 instances cases administered on day 0 and day 7. RESULTS: Postoperative mortality was 2.5%. Acute cellular rejection episodes were biopsy-proven in 2 (5%) cases, post-LKT infections developed in 17 cases (42.5%), and de novo cancer developed in 3 (7.5%) cases. Similar 5-year overall survivals were obtained irrespective of the LKT indication: 100% in cholestatic and alcoholic cirrhosis patients, 86% in policystic disease, 75% in metabolic disease and HBV patients, and 66% in HCV cirrhosis. Overall survivals for the alemtuzumab vs without-induction therapy groups at 1, 3, and 5-years were 100%, 85.7%, and 85.7% vs 76%, 76%, and 70%, respectively (P = .04). CONCLUSION: An immunosuppressive regimen based on tacrolimus and steroids with induction therapy with alemtuzumab was safe, with excellent long-term results for combined LKT.

A simulation study for the design of a control system for the blood concentration process in autotransfusion.

Autotransfusion is the process in which a patient serves as his or her own blood donor; its most important application is the intraoperative blood salvage, in which the blood collected during a surgical operation is filtered, concentrated, washed, and then reinfused. In an automatic autotransfusion device, such as the DIDECO Compact Advanced, red blood cells (RBCs) are separated from the other unwanted components and concentrated by using a rotating bowl and the effect of centrifugal force. An important characteristic of concentrated RBCs is their hematocrit (Hct), i.e., percent RBC volume divided by total blood volume. The aim of this study is to assess the feasibility of a controller, based on the artificial neural network approach, which is able to provide a closed loop control of the hematocrit of the blood in the bowl at the end of the concentration phase. A simulation approach was adopted both for training the network and for assessing its performances. The results obtained are quite satisfactory, since the target Hct was typically reached within a 3% error, and always within 6% in highly challenging situations.