Kidney Transplantation in HIV-Infected Recipients: Therapeutic Strategy and Outcomes in Monocentric Experience.

BACKGROUND: In Human immunodeficiency virus (HIV)-positive patients undergoing kidney transplantation, outcomes and immunosuppression (IS) protocol are not yet established due to infectious and neoplastic risks as well as to pharmacokinetic interactions with antiretroviral therapy (TARV). METHODS: We report a retrospective, 1-center study on 18 HIV+ patients undergoing, between October 2007 and September 2015, kidney transplantation (13 cases) or combined kidney-liver transplant (5 cases). Inclusion criteria for transplant were based on the Italian National Transplant Center protocol. IS regimen was based on quick tapering of steroids and the use of mTOR inhibitors (mTORi) with low dose of calcineurin inhibitors (CNI). In the early post-transplant period, TARV was based on enfuvirtide, raltegravir, plus 1 or more nucleoside analogues. RESULTS: In a mean follow-up of 3.1 years, patient survival rate at 1 and 3 years was, respectively, 86.6% and 84.6%, whereas graft survival was 81.2% and 78.6%. Cumulative rejection rate was 20.0% and 26.6% (1- and 3-year results). Median eGFR (MDRD) was 58.8 mL/min and 51.9 mL/min at 1 and 3 years. We had 9 cases of clinically relevant infections (2 Pneumocystis jirovecii pneumonia, 1 pulmonary aspergillosis, 2 severe sepsis, and 4 HCV reactivation) as well as 1 case (5.5%) of HIV reactivation. CONCLUSIONS: IS therapy based on mTORi and low CNI dose ensures good graft survival, low rate of acute rejection, limited drug toxicity, and control of HIV disease. TARV has no significant interaction with IS therapy.

Interstitial Lung Disease After Kidney Transplantation and the Role of Everolimus.

BACKGROUND: Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause. METHODS: Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry). RESULTS: We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVL(TLC)) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD- (EVL(TLC) [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVL(TLC) + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVL(TLC) or the combination formula with both drugs. CONCLUSIONS: In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVL(TLC) is >9.03 ng/mL or >11.41 when a formula with summation of EVL(TLC) and CyA(C2) is used.

Everolimus, cyclosporine, and thrombotic microangiopathy: clinical role and preventive tools in renal transplantation.

INTRODUCTION: Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation. OBJECTIVE: The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy. PATIENTS AND METHODS: From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC+(cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC+(C2/100) was performed for patients exposed to mTORi. RESULTS: Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n=19) and drug-related TMA (n=17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P=.006). CONCLUSIONS: Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)]>12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

A favorable 3-year outcome of kidney transplantation in atypical hemolytic uremic syndrome associated with a factor H mutation: case report.

Complement factor H (CFH)-associated hemolytic uremic syndrome (HUS) is a genetic form of atypical HUS characterized by deficient CFH levels or activity, which cause a disorder of the regulation of the alternative pathway, leading to uncontrolled complement activation. This genetic disorder, which frequently leads to end-stage renal failure, often recurs in kidney transplants, resulting in the poorest graft outcomes among all atypical HUS forms, due to a mutation in genes encoding complement components and regulatory proteins. Herein we have report our experience with a 40-year-old woman, suffering from a clearly defined sporadic form of genetic atypical HUS, consisting of a heterozygous missense mutation in factor H gene. She underwent cadaveric kidney transplantation. At the moment of surgery she displayed positive hemolysis indices and C3 consumption. A calcineurin inhibitor (CNI)-free immunosuppressive regimen was based on sirolimus, mycophenolic acid and steroids after basiliximab induction. An early and intense prophylactic course of plasma exchange (PE), and fresh frozen plasma (40 mL/kg) was prescribed, starting before surgery and continuing daily for the first week. The frequency of PE slowly reduced over the following 2 weeks. After that, just plasma infusion at the same dose was performed once a week until 12 weeks after transplantation. There was prompt graft function and in third week there were no signs of hemolysis or of C3 consumption. More than 3 years after transplantation, the graft is still functioning well and there was no recurrence. In our opinion, this case indicates that, although evidence is lacking, avoidance of CNI and intensive prophylactic plasma therapy are essential to achieve good results in this peculiar type of kidney transplantation. Nevertheless, controlled, prospective studies are necessary to establish the actual role of these two therapeutic procedures in renal transplantation of patients with CFH-associated HUS.

Donor affected by hemosiderosis: is kidney transplantation possible? A case report.

Marginal donors (advanced age, comorbidities, and so on) provide an increasing contribution to the kidneys used to alleviate the relative organ shortage. We describe the evaluation process and clinical outcome of two kidneys with hemosiderosis used as a double graft. The donor was a 59-year-old hypertensive man, known to have a mechanical mitral valve, who died from a cerebral hemorrhage, with a normal serum creatinine (SCr) and kidneys with normal appearances at sonography. A protocol donor biopsy showed a Karpinsky score of 5 for both kidneys. A double graft was therefore scheduled. The recipient was a 59-year-old man, on dialysis because of chronic glomerulonephritis. HLA match was incompatibility 4/6; immunosuppression was based on steroids, cyclosporine, and mycophenolate mofetil with basiliximab as induction therapy. The grafts showed delayed function with dialysis treatments performed from postoperative day (POD) 1. On POD 2, a magnetic resonance imaging (MRI) study showed the typical appearance of siderosis. Pearl's staining performed on a protocol biopsy confirmed the presence of widespread iron deposits. On POD 5, a recipient renal biopsy showed a superimposed severe acute tubular necrosis. Renal function recovered slowly; SCr at discharge on POD 22 was still 4.2 mg/dL. Two months later, the SCr was 2.2 mg/dL. A second MRI performed at 3 years and 6 months after transplantation confirmed a progressive removal of iron overload while the patient had stable renal function (glomerular filtration rate) of 33 mL/min and SCr: 2.3 mg/dL. We concluded that donors with hemosiderosis should be treated as marginal donors and may be grafted based on a pretransplant biopsy.

Pancreas transplantation inside Emilia-Romagna, Italy: referral pattern, demand forecasting, and organ availability.

In Italy, referral of diabetic patients for pancreas transplantation (PT) is an unstructured process, resulting in a low rate of activity and late referrals, often when the patient has already undergone dialysis. In addition, the continuous improvement in pancreas transplant alone, offering the opportunity to reduce cardiovascular risk due to proteinuria and reduced glomerular filtration rate (GFR), is rarely appreciated. We therefore analyzed (1) referral activity to PT during the time frame 2001-2005 in Emilia-Romagna, Italy (four million inhabitants), by collecting ICD 9 CM codes (55.69 + 52.80; 52.86 and 52.80 alone) by residence of the patient; (2) demand for PT among a sample population of 1670 diabetes patients, whose charts were reviewed for the type of diabetes and presence of overt diabetic nephropathy (DN: proteinuria >300 mg/24 h and/or GFR <60 mL/min); (3) potential pancreas availability as the ratio between pancreas and hearts utilized (UP/HR) in different areas of our country. As a results, (1) referral activity reached 8.4 PT per million people in 5 years in the whole region, ranging from 2.6 in the province where a PT program is active, to a maximum value of 20.7 in the province where a devoted outpatient clinic is operated by nephrologists. (2) Prevalence of overt DN was 6% in our cohort, corresponding to 510 D1 patients worthy of evaluation for PT inside Emilia-Romagna region. (3) During 2006, UP/HR was 0.58 in Associazione Inter-Regionale Trapianti agency, 1.16 in Tuscany, 0.30 in Piedmont, and 0.26 in our region. Taken together, our data showed that (1) the referral of D1 to PT has to be empowered, keeping in touch with all patients suffering from diabetic nephropathy; (2) the outpatient clinic devoted to evaluation and recruitment of D1 with nephropathy plays the key role in this program of timely and widespread referral; (3) the availability of pancreata can be increased by utilizing broader criteria for harvesting, increased consent rate to donation and increased the demand for PT (recipient pool). Pancreas grafts need to increase, since the current low demand produces underutilization of the pancreas resource, due to the frequent lack of a suitable recipient.

["Terzo fuoco", lead poisoning and chronic renal failure]. / "Terzo fuoco", intossicazione da piombo e insufficienza renale cronica.

BACKGROUND: In ceramics, "Terzo fuoco" (Third fire) means a third firing of clay to fix colors on tiles or pottery. The low firing temperatures (800-900 degrees C) and the use of a spray gun are risk factors for lead poisoning. Because of their small size, handicraft companies often fail to implement the preventive measures that are utilized efficiently in large tile factories. We report a case of chronic lead poisoning with special emphasis on diagnostic tools and treatment goals. CASE REPORT: A 38-year-old woman was hospitalized in 2005 because of grade 3 chronic renal failure (serum creatinine 1.69 mg%, Cockroft-Gault glomerular filtration rate [GFR] 45 mL/min), hypertension and elevated serum uric acid (13.4 mg%) without gout. She had been previously hospitalized elsewhere and diagnosed as suffering from hypertensive nephropathy. Her occupational history included acute lead poisoning 12 years before, which was treated with a short leave from work. She subsequently continued her job, using a spray gun for decorative drawing in a small tile company until 2004. Because of a low GFR she underwent a 3-day chelation test with 750 mg CaNaEDTA i.v., and excreted 1056 microg Pb (n.v < 600 microg) -- (PbU/EDTA ratio 1.41; n.v < 0.6). A renal biopsy showed chronic interstitial nephropathy with severe arteriolosclerosis. The patient was treated with 5 courses of EDTA, resulting in a final Pb excretion of 517 microg/72 h (PbU/EDTA 0.69). Her serum creatinine fell to 1.32 mg% (CFR 58 mL/min). A further course of chelation therapy is planned. DISCUSSION AND CONCLUSIONS: The EDTA chelation test allows to determine the lead body burden (PbBB) and to titrate subsequent chelation therapy. Recent papers have shown that PbBB is a major factor in the progression of chronic renal failure besides pressure control, and have indicated a PbBB safety level of less than 100 microg/test (PbU/EDTA < 0.1). In order to prevent the development of chronic renal failure, it is important that not only occupational but also environmental lead exposure be identified and adequately treated.

[Early kidney-pancreas transplantation in type 1 diabetics prevents hemodialysis]. / Il trapianto precoce di rene-pancreas previene l'ingresso in dialisi dei diabetici tipo 1.

BACKGROUND: The life-expectancy of type 1 diabetics (T1D) on dialysis is still shorter than that of non-diabetics. Pancreas transplantation (PT) in its different modalities should be considered as a life-saving procedure. METHODS: We analyzed our referral activity of T1D to PT from 1992. Since 2002, we have created a kidney and diabetes out-patient clinic devoted to the prevention of diabetic nephropathy and to the early referral of suitable T1D to combined kidney- pancreas transplantation (KPT) and isolated pancreas (PTA). RESULTS: In the last 14 yrs, 25 T1D underwent KP in our district (620000 inhabitants). At the beginning, KPT was performed abroad, but then the borders were closed. After stopping in the mid 1990s, KP activity restarted addressing preemptive KPT and PTA. Currently, only one patient is on dialysis while awaiting KPT. Four T1D were evaluated and excluded from the list on medical grounds; two patients are on the list and a further two patients are currently under evaluation. CONCLUSIONS: The implementation of a cooperative network among dialysis and transplant centers, supported by devoted out-patient clinics allowed the effective prevention of the dialysis requirement in T1D. Out-patient clinics devoted to diabetic nephropathy should play a pro-active role in preemptive KP, including the 'new' option of islet transplantation according to the Edmonton protocol.

Evaluation of dialysis access care by means of process quality indicators.

Improvement of dialysis access management depends on technical skill but also on effective choice, construction, monitoring and revision of the access. Surgical procedure is only one step of a complex course, beginning with the referral of patients to nephrologists. Using two process quality indicators, we describe the evolution of access management at our centre, where access surgery and access-related activities are performed by nephrologist. The first process indicator is based on the prevalence of temporary access at first dialysis (TA1st) in end stage renal disease ESRD patients, the second one measures the prevalence of permanent central venous catheters (%CVC) in dialysis population. TA1st increased to 27.1% in 1999, more than twofold compared to the previous year. There was also an increase in %CVC from 20.6 to 26.3%. Native access remained the most utilised, well above 70% of dialysis patients. Our process monitoring suggests a rapid worsening of late referral, as indicated by the increasing use of temporary catheters at the beginning of chronic dialysis. Increasing surgical activity and diagnostic procedures were only partly effective in containing the rise in CVC. Venous sparing, early referral, Continuous Quality Improvement and a multiprofessional access-team co-ordinated by a nephrologist could be the key-elements in facing the never-ending-story of dialysis vascular access.

Which level of cytokine production is critical in haemodialysis?

Monocyte activation with cytokine production is a well known event in the course of dialysis treatment but its relation to symptoms of haemodialysis or long-term pathological changes in chronic dialysis patients is still under discussion. Cytokine production depends on the balance between inducers and inhibitors while effects rely on the peculiar uraemic environment and cell metabolism. 'Foot-prints' for monocyte activation have been found, but no marker for clinical symptoms has been demonstrated clearly. In this scenario it is almost impossible to link a specific symptom to a definite stimulus such as dialysate microbial contamination or membrane complement generation. The topics discussed in this paper include cytokines synthesis modulation factors, levels in haemodialysis patients, and results of finding markers of clinical relevance. Special attention is paid to microbial contamination of dialysis fluid with analysis of cytokine inducing substances in commercial sterile solutions. Data on cytokine synthesis and activity in the aged are also discussed, with special regard to the haemodialysis setting.

Vascular access for haemodialysis: from surgical procedure to an integrated therapeutic approach.

During the past 10 years the type of vascular access for haemodialysis procedures have changed markedly in our centre: more elbow AV fistulae and more central venous catheters are now used. Nevertheless, early referral to nephrologists and availability of central venous catheters and peritoneal dialysis allow elderly people to be admitted for dialysis treatment. Since vascular access for haemodialysis plays a key role in patient well-being, it is mandatory to apply quality assurance criteria to vascular access for haemodialysis surgery. Based on the results of a national survey, in Italy this policy is still in its early stages: monitoring of vascular access differs amongst centres, interventional radiology is used in a differing way, planning of vascular access for haemodialysis in pre-dialysis patients often remains an unsolved problem. According to our initial experience, we propose the use and validation of a quality-index [(minimum success rate) in elective vascular access for haemodialysis surgery], allowing accreditation of a department and a single surgeon for access management. Prevalence of central venous catheters at first dialysis of chronic renal failure patients is also proposed to evaluate the efficiency in access planning. Better knowledge of vascular access management by different teams could eventually lead to definition of guidelines for this 'Cinderella of dialysis'.

[Quality assurance and control of dialysis access]. / VRQ e chirurgia degli accessi dialitici.

Preliminary experience on total quality program in access surgery for dialysis is described; this kind of "border-line" surgery requires peculiar standards, documents and quality indexes. The use of a quality index based on a minimum success rate of 90% in elective access surgery is proposed. In addition, a "cross-index", suitable for quality evaluation of different dialysis sectors at the same time, is expressed. First interventions aimed at the optimal use of resources are described.

[Treatment of post-transplant erythrocytosis: comparison of lisinopril and theophylline]. / Trattamento dell'eritrocitosi post-trapianto: confronto tra lisinopril e teofillina.

OBJECTIVE: The proposal of this study is to compare the efficacy of lisinopril and theophylline, alone or in association, on erythrocytosis in renal-transplanted patients. DESIGN: Prospectic, case-control study. PATIENTS/ENVIRONMENT: 15 inpatients meeting 3 main criteria: 1) ACE therapy for past erythrocytosis, 2) actual erythrocytosis, 3) symptomatic increase of haematocrit (Hct). INTERVENTION: The treatment has been divided into 3 consecutive phases of 30 days each: 1) lisinopril (5 mg/die), 2) theophylline (4 mg/kg/die), 3) association of 2 drugs. MEASUREMENTS: The evaluations were scheduled at the beginning and every month and consisted of renal function control, haemochromocytometric exam, serum level of folates, B12 vitamin and erythropoietin (EPO), iron level, cyclosporinemia, as well as clinic control and adverse events detection. RESULTS: A significative decrease of Hct values and a decrease of serum erythropoietin values was observed in patients treated with lisinopril. Patients treated with theophylline showed a significant reduction of Hct values causing a reduction of erythropoietin serum level in 8/13 patients. Lisinopril and theophylline administered in combination presented a significant decrease of Hct values, while EPO values diminished compared to basal values. CONCLUSIONS: These data showed that lisinopril is a valid therapy for the treatment of posttransplanted patients affected by erythrocytosis and, moreover, has the benefit of antihypertensive action. Theophylline remains an alternative therapy when ACEi are contraindicated. The combination of the 2 drugs doesn't produce additional benefits.

Influence of urinary calcium concentration on erythrocyte morphology.

The effect of the urinary calcium concentration (CaU) on erythrocyte morphology was studied by incubating erythrocytes in urine with prefixed CaUs of 5, 10, 20 and 40 mmol/l by addition of CaCl2. The same experiment was carried out on erythrocytes preincubated with levo-verapamil (l-V) at 10, 100 and 200 mumol/l. Phase contrast microscopy observations were performed at 0, 30, 60, 120, and 240 min by 2 experienced investigators. At 0 min the erythrocytes showed a clear extraglomerular pattern. At 60 min marked morphological and volumetric alterations were evident when the CaU was > or = 10 mmol/l. On the contrary, no change was found when red cells were treated with > or = 100 mumol/l l-V, independent of the CaU. Dysmorphic erythrocyturia has been related to transglomerular passage even if it was sporadically observed in hypercalciuric or lithiasic patients. This work suggests a role for a high CaU in causing the formation of microcytic and warped erythrocytes. In our opinion, in hypercalciuric urine the appearance of dysmorphic or mixed hematuria does not necessarily indicate transglomerular passage.