Protected: Waiting time on dialysis for active access to renal transplantation: a multicenter cross-sectional study in Lombardy

Abstract

Background: The amount of time spent in dialysis waiting for a renal transplantation significantly affects its outcome. Hence, the timely planning of patients’ transplant evaluation is crucial. According to data from the Nord Italia Transplant program (NITp), the average waiting time between the beginning of dialysis and the admission to the regional transplant waiting list in Lombardy is 20.2 months.

Methods: A multicenter cross-sectional study was conducted in order to identify the causes of these delays and find solutions. Two questionnaires were administered to the directors of 47 Nephrology Units and to 106 patients undergoing dialysis in Lombardy respectively, during their first visit for admission to the transplant waiting list.

Results: The comparative analysis of the results revealed that both patients (52%) and directors (75%) consider the time required for registering to the waiting list too long. Patients judge information about the transplant to be insufficient, especially regarding the pre-emptive option (63% of patients declare that they had not been informed about this opportunity). Patients report a significantly longer time for the completion of pre-transplantation tests (more than 1 year in 23% of the cases) compared to that indicated by the directors.

Conclusions: The study confirmed the necessity of providing better and more timely information to patients regarding the different kidney transplantation options and highlighted the importance of creating target-oriented and dedicated pathways in all hospitals.

 

Keywords: Renal transplantation, waiting list, active access to renal transplantation, questionnaire, Lombardy region

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Correction of secondary hyperparathyroidism with paricalcitol in renal transplant improves left ventricular hypertrophy

Abstract

Background – Left ventricular hypertrophy (LVH) is common in renal transplant recipients (RTRs), and persistent secondary hyperparathyroidism (SHPT) is considered to be one of the main causes of its pathogenesis. In this study we evaluated if the control of SHPT with paricalcitol is associated with a reduction of LVH in RTRs. Methods – For this purpose we selected 24 RTRs with LVH and SHPT . Secondary hyperparathyroidism was defined as PTH levels 1.5 times higher than the high normal limits, while LVH was defined as a left ventricular mass index (LVMi) >95g/m2 in females, and >115g/m2 in males. Treatment with paricalcitol started at mean dose of 1µg/day and lasted 18 months. The dose of paricalcitol was reduced to 1µg on the other day when serum calcium was >10.5mg/dl and/or fractional excretion of calcium was >0.020%; administration was temporarily stopped when serum calcium was >11 mg/dl. Results – At follow-up PTH levels decreased from 198 ± 155 to 105 ± 43pg/ml (P < .01), and LVMi decreased from 134 ± 21 to 113 ± 29g/m2 (P < .01); the presence of LVH decreased from 100% at baseline to 54% at F-U. Serum calcium levels showed a modest and not significant increase. Renal function was stable in all patients. Conclusions – Secondary hyperparathyroidism seems to play an important role in the development and maintenance of LVH and its correction with paricalcitol has a favorable impact on its progression.

Keywords: left ventricular hypertrophy; parathormone; paricalcitol; renal transplantation; secondary hyperparathyroidism

Sorry, this entry is only available in Italian.

Diagnosis of Biliary Hamartomatosis in Kidney Transplant Recipient affected by ADPKD

Abstract

Biliary hamartomas (BH) are rare benign lesions of the liver characterized by a dilation of a variable number of small biliary ducts, usually surrounded by abundant fibrotic tissue. These malformations are due to an aberrant remodelling of the ductal plate, that is the embryonic structure generating the normal biliary tree. BH are usually asymptomatic, but in rare cases they can be associated with jaundice, heartburn and fever. Evidences for a sharing of similar pathological pathways between BH and adult dominant polycystic kidney disease (ADPKD) are widely reported. These similarities induce an increased neoplastic risk transformation in both conditions. This risk is even greater in immunosuppressed patients. The diagnosis of BH by imaging is not easy, especially in the context of ADPKD. We present a clinical case of a 54-year-old kidney transplant recipient affected by ADPKD in which BH, previously undetected, was for the first time suspected on routine ultrasound scan and confirmed with MRI 4 years after renal transplantation. Demodulation of proliferative signals induced by immunosuppressive therapy, and particularly by calcineurin inhibitors, could cause an enlargement of AB and increase the risk of neoplastic transformation. Our case-report suggests a close imaging follow-up may be needed in ADPKD patients with BH, especially if transplanted. High sensitivity techniques, such as CEUS and MRI, should be preferred to conventional ultrasound.

Keywords: Biliary Hamartomatosis, Kidney Transplant, ADPKD

Sorry, this entry is only available in Italian.

Bardet-Biedl syndrome and Kidney failure: a case report

Abstract

Bardet-Biedl Syndrome (BBS) is a rare multi-systemic disease with autosomal recessive transmission. BBS was at first considered to be homogeneous as for its genetics, but subsequent studies have shown an extensive gene variability. Currently, 21 genes (BBS1-21) present on different chromosomes have been mapped: these genes are responsible for BBS phenotypes and they show a great heterogeneity of mutations.The most common genes are BBS1 (locus 11q13) and BBS10.We show here the case of a 50 year old patient with BBS. Medical History: retinitis pigmentosa at 4 years of age evolved to complete blindness, generalized epilepsy crises, poly-syndactyly, left-hand malformation. In April 1986 developed an epileptic episode: on that occasion Chronic Kidney Failure (CKF) diagnosis and starting of haemodialysis. In 1989, hospitalization for epileptic seizures. In 2009 the patient underwent kidney transplantation from deceased donor. Immunosuppressive initial protocol: Basiliximab, Azathioprine, Tacrolimus, Steroid, and Tacrolimus, Azathioprine, Steroid at hospital discharge. Post-operative care complicated by respiratory failure with mechanical ventilation assistance. During hospitalization, the neurological picture remained stable. At hospital discharge Creatinine 1.8 mg/dl. Subsequently, immunosuppressant were gradually tapered until monotherapy with Tacrolimus. At present the patient’s conditions appear to be good, renal function has remained substantially stable with Creatinine between 1.4-1.5 mg/dl and glomerular filtration rate (GFR) estimated at 39-42 mL/min/1.73 m2 according to MDRD study Equation. This case shows the possibility to successfully manage a BBS-affected uremic patient, despite the complexity of the pathology and the aggravating factor of extreme rarity in diagnostic pathway.

 

Keywords: Bardet-Biedl syndrome (BBS), renal failure, renal transplantation

Sorry, this entry is only available in Italian.

First case report of using Ofatumumab in kidney transplantation AB0 incompatible

Abstract

Modern methods for desensitization protocol rely heavily on combined apheresis therapy and Rituximab, a chimeric (murine and human) anti-CD20 antibody used in AB0 incompatible kidney transplants. Severe infusion related reactions due to the administration of Rituximab are reported in 10% of patients. These adverse reactions may hinder the completion of the desensitization protocol. Therefore, it’s useful to test alternative B cell depleting therapies. Our clinical case focuses on a 41-year-old male who developed an adverse infusion reaction following the administration of Rituximab and was given Ofatumumab as an alternative treatment.Ofatumumab is a fully humanized monoclonal anti-CD20 antibody. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions. The patient tolerated the administration of the drug showing no signs of adverse side effects and with good clinical efficacy. Our case report suggest that Ofatumumab is a valid alternative B cell depleting agent.

KEY WORDSOfatumumab, kidney transplant, AB0 incompatible

Introduction

Out of the millions of people who suffer from end stage renal failure worldwide every year, only a third are eligible for kidney transplants. The ability to perform transplants between donors and recipients with different blood types has increased the possibility of performing live donor transplants, made possible by effective new drugs being used during the desensitization process. Modern methods of desensitization are based on the application of apheretic techniques combined with immunosuppressive drugs such as Rituximab, a chimeric anti-CD20 antibody, which has a key role in B lymphocyte depletion. Severe infusion related reactions due to the administration of Rituximab are reported in approximately 10% of patients (1). Such reactions restrict the use of the drug. Therefore, it is common practice to test alternative B cell depleting therapies. We reported on the first clinical case of a patient undergoing desensitization protocol for kidney disease transplantation AB0 incompatible with Ofatumumab, a fully humanized monoclonal anti-CD20 antibody, given as an alternative B-cell depleting treatment.

 

Case report

A 41-year-old male diagnosed with end stage kidney disease due to nephroangiosclerosis was presented to our transplant center for live kidney donation accompanied by his mother: a potential, healthy, willing AB0 incompatible kidney donor. The patient was on regular, peritoneal dialysis for the last 18 months and also had ischemic heart disease treated with dual stent placement approximately one year before. Immunological tests [complement-dependent cytotoxicity lymphocytotoxicity crossmatches (CDC-LT, CDC LB), luminex DSA, Match-HLA], were performed in the recipients. Table 1 gives demographic and immunological data of the donor and recipient. After finding the donor and recipient eligible for transplantation, we proceeded with the desensitization protocol by using the Stockholm model (Tydel et al. AJ of Transplantation 2005; 5:145-148) (2) and the Johns Hopkins Hospital model (Montgomery et al. N Engl J Med 2011;365:318-326) (3) as a guideline. This protocol states that all AB0 incompatible recipients must have received the anti-CD20 antibody (Rituximab) for four weeks before the transplant. Then, two weeks before the patients must have received plasmapheresis to reduce the anti-ABO antibody. Most recipients received plasmapheresis 4 to 5 times (range, 2–9 times) until the isoagglutinin anti-ABO antibody ratio was ≤1:8.

The qualifying patient was admitted to our department and administered Rituximab (375 mg/m2 i.v.) as part of the desensitization protocol but despite the antihistamine, anti-inflammatory, and steroid i.v. premedication given prior (Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g), he displayed an adverse infusion reaction: high fever, tremors, malaise and dyspnea.

Due to the impossibility of continuing the treatment with Rituximab, we decided to complete the procedure using another anti-CD20 antibody (Ofatumumab), after a period of clinical oversight. One month after the Rituximab reaction, the patient started a new desensitization therapy which consisted of Ofatumumab (300 mg i.v. 35 days before the transplant and 2000 mg i.v. 28 days before the transplant), six sessions of apheresis and a low dose intravenous immunoglobulin (0,5 g/Kg).

The intravenous dose of Ofatumumab was administered following doses of antihistamine, anti-inflammatory, and steroid i.v. premedication (Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g). The patient tolerated the administration without reaction and it was possible to complete the cycle of desensitization without any side effects. The plasmapheresis sessions were performed on alternate days, up to the achievement of a sufficiently low antibody blood titer (≤1:8). In our clinical case six apheresis sessions (5 plasma-exchange and 1 cascade filtration) were necessary in order to achieve sufficiently low isoagglutinins levels and proceed to transplantation. The graphics 1 and 2 shows the pharmacological and apheresis procedural results: a progressive decrease in isoagglutinins levels.

The triple immunosuppressive therapy was started on the first day of the plasmapheresis through oral administration of Tacrolimus (0,15 mg/Kg/day), Mycophenolic Mophetil (1000 mg x 2/day) and Prednisone (25 mg/day). On the day of the renal transplantation Basiliximab, an anti-CD25 antibody, was administered at a dose of 20 mg i.v., and then readministered on the fourth post-operative day as induction therapy.

After the desensitization protocol the patient underwent a renal transplant from an incompatible living donor with no surgical complications. The target trough level for tacrolimus was 10-15 ng/mL during the early postoperative period, but this decreased to 6-10 ng/mL after 3 months. Trimethoprim-sulfamethoxazole was used for prophylaxis for Pneumocystis jiroveci pneumonia for 6 months. No prophylaxis for CMV was performed because the patient was CMV-IgG positive.

The clinical course was characterized by a good functional recovery with creatinine values that reached 1.6 mg/dl after 1 month. Levels of IgG isoagglutinin anti-B were rechecked periodically after transplantation, and were at 1:2. Six weeks after transplantation, the patient developed a symptomatic reactivation of the cytomegalovirus for which he is undergoing antiviral therapy.

 

Discussion

The percentage of severe infusion reactions following treatment with Rituximab is approximately 10%. Ultimately, this side effect restricts the use of the drug. Rituximab, a chimeric monoclonal antibody (murine and human), consisting of a glycosylated immunoglobulin with a constant region of human origin and a variable region sequence of murine origin (4). The study of anti CD20 alternative is important in order to find alternative treatment options. Currently, three fully humanized anti-CD20 antibodies are available: Ofatumumab, Obinutuzumab and Ocrelizumab (5). There is no experience in the use of these drugs in renal transplantation.

Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to an epitope encompassing both the small and large extracellular loops of the CD20 molecule. The binding of Ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of cells (6, 7). It was also observed that Ofatumumab can induce lysis in cells Rituximab-resistant expressing CD20. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions (8).

Today Ofatumumab is approved and used in malignant hematological disorders with encouraging results especially in those patients resistant or intolerant to treatment with Rituximab (910111213). In immune-mediated pathologies, there are sporadic clinical cases in which Ofatumumab treatment was administered. These include studies on pediatric Rituximab resistant nephrotic syndrome (14), treatment of lupus nephritis (15) and vasculitis ANCA-associated (8). In all these trials the Ofatumumab had a good clinical efficacy and is tolerated well. This is the first use of Ofatumumab in kidney transplantation protocol and our case report suggests that is a valid alternative B cell depleting agent, especially in patients who are intolerant to Rituximab due to infusion related reactions. Further studies are needed to secure and define the role of Ofatumumab and other emerging anti-B cell therapies in kidney transplantation.

 

Reference

  1. Vogel WH, et al. Infusion reactions: Diagnosis, Assessment and Management. Clinical Journal of Oncology Nursing 2010, 10.1188/10.CJON.E10-E21
  2. Tyden G, et al. Implementation of a Protocol for ABO-Incompatible Kidney Transplantation – A Three-Center Experience With 60 Consecutive Transplantations. AJ of Trasplantation 2005; 5:145-148
  3. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011; 365:318-326
  4. Pescovitz MD. Rituximab an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action Journal of Transplantation 2006; 6: 859–866
  5. Knepper TC, et al. Novel and expanded Oncology drug approvals of 2016-part 2: new options in the management of hematologic malignancies. Oncology, 2017, 15;31(2)
  6. Capuano C, Romanelli M, et al. Anti-CD20 therapy acts via Fc γRIIIA to diminish responsiveness of human natural killer cells. Cancer Reserch 2015, 75(19); 4097-108.
  7. Tomita A. Genetic and epigenetic modulation of CD20 expression in B-cell malignancies: molecular mechanisms and significance to rituximab resistance. J Clin Exp Hematop 2016, 56(2):89-99
  8. McAdoo SP, Bedi R, et al. Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre series. Rheumatology 2016, 55:1437-1442
  9. Linden MA, Bachanova V, et al. Trasformed large B-cell lymphoma in rituximab-allergic patient with chronic lymphocytic leukemia after allogenic stem cell transplant: successful treatment with ofatumumab. Leuk Lymphoma 2013 January, 54(1): 174-176.
  10. Laurenti L, Innocenti I, et al. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab. Onco Targets and Therapy 2016, 9 421-429
  11. Barth MJ, Mavis C, et al. Ofatumumab exhibits enhanced in vitro and in vivo activity compared to Rituximab in preclinical models of mantle cell lymphoma. Clinical Cancer Reserch 2015, 21(19) 4391-7
  12. Czuczman MS, Fayad L, et al. Ofatumumab monotherapy in rituximab refractory follicular lymphoma: results from a multicenter study. Blood 2012, 119(16):3698-3704
  13. Bologna L, Gotti E et al. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. The Journal of Immunology 2013, 190:231-239
  14. Biswanath Basu MD, et al. Ofatumumab for rituximab resistant nephrotic syndrome. The New England Journal of Medicine 2014, 370, 13.
  15. Loberg Haarhaus M, Svenungsson E, et al. Ofatumumab treatment in lupus nephritis patients. Clinical Kidney Journal 2016, vol.9, no. 4, 552-555

Novel antiviral agents for the treatment of HCV among renal transplant recipients

Abstract

The frequency of hepatitis C virus infection remains high in renal transplant recipients and plays a detrimental role on survival in this population. According to the latest evidence, the adjusted relative risk of mortality and graft loss for anti-HCV seropositive versus anti-HCV negative renal transplant recipients was 1.85 with a 95% confidence interval (CI) of 1.49; 2.31 (P < 0.0001) and 1.76 (95% CI, 1.46; 2.11) (P < 0.0001), respectively. Interferon-based regimens have been recommended for the treatment of hepatitis C after renal transplantation only in selected circumstances because of an increased risk of acute rejection due to the immuno-stimulatory properties of interferon. Limited data exist on the treatment of HCV with direct-acting antiviral agents among kidney transplant recipients. To date, the most important evidence comes from the European multicenter study where a large cohort (n=114) of patients with glomerular filtration rate of 40 mL/min/1.73m2 received an interferon-free, ribavirin-free combination of direct-acting antivirals (Ledipasvir/Sofosbuvir) for 12 or 24 weeks. A high efficacy [SVR12 rate, 100% (114/114)] was found even if three serious adverse were observed; all were determined to be treatment related, one patient interrupted permanently treatment. Also, single-center single-arm observational studies have reported high efficacy and safety of sofosbuvir-based combinations for the treatment of HCV after renal transplant. A decline in through levels of calcineurin inhibitors after completion of antiviral therapy has been found in many patients; an enhanced metabolism of calcineurin inhibitors associated with resolution of liver injury has been suggested. An effective and safe therapy for HCV in kidney transplant recipients might improve the current suboptimal utilization of HCV-positive kidney donors and provide many patients with end-stage renal disease access to HCV-infected donor kidneys.

Key-words Direct-acting antivirals; Hepatitis C; Renal transplantation; Sustained viral response

Sorry, this entry is only available in Italian.

Immunosuppression in kidney transplantation: a way between efficacy and toxicity

Abstract

Renal transplantation is the best treatment for patients with end-stage renal disease.

Over the last decades, the introduction of new immunosuppressive agents resulted into the reduction of the incidence of acute rejection and early graft loss. Despite this progress, there has been little improvement in the average life of the transplant.

The main reasons of late failure are patient’s death due to several complications (e.g. cancer, infectious or metabolic), and progressive deterioration of renal function caused by immunological and non-immunological factors.

The immunosuppressive therapy can be distinguished into two components: the induction therapy and the maintenance therapy. The former has the aim to implement intense and immediate immunosuppression. This therapy is mostly useful in transplant with high immunological risk, although it is correlated with an increased risk of cytopenias and viral infections.

The latter offers the rationale to prevent organ rejection and minimize drug toxicity. This is generally constituted by the association of two or three drugs with different mechanism of action.

The most common application of this scheme includes a calcineurin inhibitor in combination with an antimetabolite and a minimum dose of steroids.

Immunosuppressive therapy is also associated to an increased risk of infections and cancer development. For instance, each class of drugs is related to a different profile of toxicity.

The choice of treatment protocol should take into account the clinical characteristics of the donor and recipient. Furthermore, this treatment may change anytime when clinical conditions result into complications.

Key words: immunosuppressive protocols, immunosuppressive therapy, induction therapy, renal transplantation

Sorry, this entry is only available in Italian.