Antonio Guasch

Transplanting the highly sensitized patient: The emory algorithm.

Renal transplant patients sensitized to HLA antigens comprise nearly one‐third of the UNOS wait‐list and receive 14% of deceased donor (DD) transplants, a rate half that of unsensitized patients. Between 1999 and 2003, we performed 492 adult renal transplants from DD; 120 patients (∼25%) had a panel reactive antibody (PRA) of >30%, with nearly half (n = 58) having a PRA of >80%. Our approach is based upon high‐resolution solid‐phase HLA antibody analysis to identify class I/II antibodies and a ‘virtual crossmatch’ to predict compatible donor/recipient combinations. Recipients are excluded from the United Network for Organ Sharing match run if donors possess unacceptable antigens. Thus, when sensitized patients appear on the match run, they have a high probability of a negative final crossmatch. Here, we describe our 5‐year experience with this approach. Five‐year graft survival ranged from 66% to 70% among unsensitized (n = 272), moderately sensitized (PRA < 30%, n = 100) and highly sensitized (>30% PRA; n = 120) patients, equal to the average national graft survival (65.7%). The application of this approach (the Emory Algorithm) provides a logical and systematic approach to improve the access of sensitized patients to DD organs and promote more equitable allocation to a highly disadvantaged group of patients awaiting renal transplantation.

Renal Transplantation Using Belatacept Without Maintenance Steroids or Calcineurin Inhibitors

Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroids. Belatacept is a less toxic CNI alternative, but existing regimens rely on steroids and have higher rejection rates. Experimentally, donor bone marrow and sirolimus promote belatacepts efficacy. To investigate a belatacept‐based regimen without CNIs or steroids, we transplanted recipients of live donor kidneys using alemtuzumab induction, monthly belatacept and daily sirolimus. Patients were randomized 1:1 to receive unfractionated donor bone marrow. After 1 year, patients were allowed to wean from sirolimus. Patients were followed clinically and with surveillance biopsies. Twenty patients were transplanted, all successfully. Mean creatinine (estimated GFR) was 1.10 ± 0.07 mg/dL (89 ± 3.56 mL/min) and 1.13 ± 0.07 mg/dL (and 88 ± 3.48 mL/min) at 12 and 36 months, respectively. Excellent results were achieved irrespective of bone marrow infusion. Ten patients elected oral immunosuppressant weaning, seven of whom were maintained rejection‐free on monotherapy belatacept. Those failing to wean were successfully maintained on belatacept‐based regimens supplemented by oral immunosuppression. Seven patients declined immunosuppressant weaning and three patients were denied weaning for associated medical conditions; all remained rejection‐free. Belatacept and sirolimus effectively prevent kidney allograft rejection without CNIs or steroids when used following alemtuzumab induction. Selected, immunologically low‐risk patients can be maintained solely on once monthly intravenous belatacept.

Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients.

African‐American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end‐points of dose‐adjusted PK parameters AUC0–12 and Cmax of MPA using log‐transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back‐transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose‐adjusted AUC0–12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race‐by‐gender effects (p‐values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

High one year mortality in adults with sickle cell disease and end-stage renal disease

Adequate pre‐dialysis care reduces mortality among end‐stage renal disease (ESRD) patients. We tested the hypothesis that individuals with ESRD due to sickle cell disease (SCD–ESRD) receiving pre‐ESRD care have lower mortality compared to individuals without pre‐ESRD care. We examined the association between mortality and pre‐ESRD care in incident SCD–ESRD patients who started haemodialysis between 1 June, 2005 and 31 May, 2009 using data provided by the Centers for Medicare and Medicaid Services (CMS). SCD–ESRD was reported for 410 (0·1%) of 442 017 patients. One year after starting dialysis, 108 (26·3%) patients with incident ESRD attributed to SCD died; the hazard ratio (HR) for mortality among patients with SCD–ESRD compared to those without SCD as the primary cause of renal failure was 2·80 (95% confidence interval [CI] 2·31–3·38). Patients with SCD–ESRD receiving pre‐dialysis nephrology care had a lower death rate than those with SCD–ESRD who did not receive pre‐dialysis nephrology care (HR = 0·67, 95% CI 0·45–0·99). The one‐year mortality rate following an ESRD diagnosis was almost three times higher in individuals with SCD when compared to those without SCD but with ESRD and could be attenuated by pre‐dialysis nephrology care.

Chronic kidney disease and albuminuria in children with sickle cell disease.

BACKGROUND AND OBJECTIVES Sickle cell nephropathy begins in childhood and may progress to renal failure. Albuminuria is a sensitive marker of glomerular damage that may indicate early chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The aims of this study were to determine the cross-sectional prevalence and clinical correlates of albuminuria and CKD among children with sickle cell disease (SCD). Over a 10-year period (1995 to 2005) 410 pediatric SCD patients ages 2 to 21 years were enrolled: 261 with hemoglobin SS (HbSS) or HbSβ(0) thalassemia (HbSβ(0)) and 149 with HbSC or HbSβ(+) thalassemia (HbSβ(+)). The albumin/creatinine ratio (ACR) of spot-urine specimens and serum creatinine were measured; abnormal albuminuria was defined as urinary ACR ≥ 30 mg/g. RESULTS The prevalence of abnormal albuminuria was 20.7% (23.0% in HbSS/HbSβ(0), 16.8% in HbSC/HbSβ(+)). Among HbSS/HbSβ(0), abnormal albuminuria was associated with increasing age and lower baseline hemoglobin. GFR, estimated in 189 patients using the updated Schwartz formula, correlated negatively with age (r = -0.27, P = 0.0002). CKD defined according to the Kidney Disease: Improving Global Outcomes study was present in 26.5% (50 of 189) of patients: stage 1 in 27 (14.8%) and stage 2 in 22 (11.6%). In multivariate analysis, age and HbSC/HbSβ(+) genotype were associated with CKD. CONCLUSIONS This is the first study to stage CKD in children with SCD and highlights a high prevalence of albuminuria and glomerular injury early in life. Detecting CKD in childhood could allow for earlier intervention and prevention of renal failure in adulthood.

Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.

Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation‐resistant T cells. In this study, we report control of costimulation‐resistant rejection when belatacept was combined with perioperative alemtuzumab‐mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept‐resistant rejection, we studied 20 ABR‐treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third‐party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester–based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28+ naïve cells, notably diminished in belatacept‐resistant CD28− memory subsets and depleted of polyfunctional donor‐specific T cells but able to respond to third‐party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets—changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28+ T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.

Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function

Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept‐based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus‐based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low‐intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade‐based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor–free immunosuppression.

Improving renal outcomes in chronic anemia: Learning from paroxysmal nocturnal hemoglobinuria

More than 100 years have passed since the original description of William Gull (1866), further characterized by the German physician Paul Strübing in 1882, of patients with episodic hemolysis and dark discoloration of the urine in the absence of red cells on urinary microscopy. As an astute physician, Strübing noticed that the dark color in the urine was more apparent in the first voided morning specimen. He hypothesized that erythrocytes of patients with paroxysmal nocturnal hemoglobinuria were defective, and were more susceptible to effects of the accumulation of carbon dioxide and lactic acid that he thought occurred during sleep hours because of a general slowing of the circulation; this resulted in hemolysis and the typical dark red morning urine. A century later, we know that paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder that arises from a somatic mutation of the phosphotidylinositol glycan class A (PIGA) gene in hematopoietic stem cells. This gene is involved in the synthesis of certain anchoring proteins (glycosyl phosphatidylinositolanchored proteins) on the plasma membrane. Consequently, the stem cell(s) and its progeny (erythrocytes, white blood cells, and platelets) lack two surface regulatory proteins, CD55 and CD59, involved in the activation of complement, making PNH erythrocytes more susceptible to both intravascular and extravascular hemolysis. The clinical presentation of PNH is characterized by Coombs negative hemolysis, venous thrombosis, often affecting uncommon sites like hepatic or mesenteric veins, and marrow failure. Some patients may experience constitutional symptoms (fatigue, malaise), but nocturnal hemoglobinuria occurs in only 25% of cases. Still, other patients may experience dysphagia, odinophagia, abdominal pain, and, in males, impotence. Although spontaneous remissions may occur in up to 15% of individuals, the clinical course is characterized by a chronic process with episodes of hemolysis, thromboembolic complication, and cytopenias. In one study of 80 patients that were given only supportive treatment, the mean survival was 10 years [1]. Bone marrow transplantation is the only curative treatment for PNH, but is associated with significant morbidity and mortality. More recently, eculizumab, a humanized monoclonal antibody against C5 that inhibits the terminal complement activation (membrane attack complex) and other proinflammatory mediators (C5a) has been approved by the Food and Drug Administration for use in PNH. Eculizumab is highly effective in reducing intravascular hemolysis, decreases the need for transfusions, and reduces the risk of thrombosis. Since it does not restore normal erythrocytes, it must be given on a long-term basis. The kidneys are thought to be commonly affected in PNH, although the reported series have focused on selected patients and/or postmortem findings. Clark et al. conducted a long-term study of 21 PNH patients followed at Vanderbilt University between 1957 and 1980 who underwent intravenous pyelography (IVP) and renal arteriograms, urinary concentration testing, and creatinine clearance determinations. Ten of the 17 tested patients had evidence of cortical infarcts by IVP, 10 of 11 tested patients were unable to concentrate the urine above a specific gravity greater than 1.016 (normal individuals should be able to achieve a specific gravity of >1.025 after water deprivation), and 13 of 19 patients tested had reduced creatinine clearances, six of them had values of less than 60 ml/min. Intermittent proteinuria was also seen in most patients [2]. More recently, magnetic resonance imaging (MRI) studies in PNH patients have revealed hemosiderosis in the renal cortex, with a reversal of the cortico-medullary intensity ration in T1 weighted images [3]. In the current issue of this journal, Hillmen et al describe the short and long-term effects of treatment with the complement inhibitor eculizumab on renal function in patients with paroxysmal nocturnal hemoglobinuria. The authors extracted renal outcomes data from three independent studies in PNH: a pilot, Phase 2 study [4], and two Phase 3 studies (TRIUMPH [5] and SHEPHERD [6] studies), along with a subsequent extension study [7]. In total, renal functional data was available in 195 adult patients followed for up to 18 months. The primary end point of these studies was the degree of hemolysis as assessed by LDH levels, with secondary end points of functional assessment of chronic illness and certain measurements of quality of life. None of the trials measured renal outcomes as an end point. However, as part of the trials, serum creatinine and a urinalysis were measured at baseline, 6, 12, and 18 months. This provided the investigators with additional data to quantify renal function. Glomerular filtration rate (GFR) was estimated from the modification of renal disease study (MDRD) equation (input values are serum creatinine, age, gender, and ethnicity) and renal damage was assessed from the urinalysis (presence of proteinuria, or imaging when available). Patients were grouped according to the level of eGFR, using a well-accepted classification of the stages of chronic kidney disease: Stages 1–5 [8]. The major findings of the study are that significant renal disease occurs in 65% of adult individuals with PNH enrolled in the study, with advanced kidney failure (Stages 3–5 chronic kidney disease (CKD)) being present in 20% of individuals. At 6 months, treatment with eculizumab was associated with improvement in the stage of CKD in 29% of patients vs. only 17% in the placebo group, and this effect persisted up to 18 months. This effect was more pronounced in patients with lesser degrees of renal insufficiency (Stages 1–2 CKD): at 18 months, 67% of patients with Stages 1–2 had improvement in the stage of CKD, vs. 23% of patients with Stages 3–5; there were no difference in response

Losartan therapy decreases albuminuria with stable glomerular filtration and permselectivity in sickle cell anemia

Sickle cell nephropathy begins with hyperfiltration and microalbuminuria and may progress to renal failure. The aim of this study was to determine the effects of losartan on glomerular function and albumin excretion in sickle cell anemia (SCA). Individuals with SCA on hydroxyurea with persistent albuminuria were enrolled in a 1-year study of losartan. Glomerular filtration rate (GFR) measured by iohexol clearance, albumin excretion rate (AER), and fractional clearance of dextran were assessed at baseline, short-term (1-2month), and long-term (≥12month) intervals. Twelve subjects (6 microalbuminuria, 6 macroalbuminuria) completed short-term studies; 8 completed long-term studies. Baseline GFR was 112ml/min/1.73m2 (71-147ml/min/1.73m2). AER decreased significantly at the short-term (median decrease -134 mcg/min, p=0.0063). GFR was not significantly-different at short-term or long-term intervals. Dextran clearance improved for diameters smaller than albumin (<36Å) but not larger sizes. Losartan therapy for ≥1year in sickle nephropathy results in lower albumin excretion with stable GFR. Filtration of neutral molecules ≥36Å was not changed by losartan, suggesting that the effect of losartan is a mechanism other than alteration of glomerular filtration size-selectivity.