William McKane

Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation

Background. Data from matched historical cohort studies suggest that autosomal-dominant polycystic kidney disease (ADPKD) may be a risk factor for new-onset diabetes after transplantation (NODAT). Method. A retrospective study of 429 renal allografts transplanted from 1990 through 2004 in nondiabetic patients was performed. A multivariate analysis of risk factors for NODAT was performed with focus on ADPKD. Results. A total of 6.5% of all patients developed NODAT and a further 11% developed impaired glucose tolerance. NODAT developed in 13.4% of patients with ADPKD compared with 5.2% of non-ADPKD patients (P=0.01). There were significant univariate associations between NODAT and recipient age (P=0.001) and weight (P<0.0001). There was no association between NODAT and recipient gender, human leukocyte antigen mismatch, acute rejection, or cumulative methylprednisolone dose. In a multivariate analysis, ADPKD was a strong risk factor for the development of NODAT (odds ratio [OR]=2.41, P=0.035) after correction for recipient age, weight, gender, ethnicity, and tacrolimus use. Age (OR=1.06), weight (OR=1.04), and nonwhite race (OR=5.04) were the other significant variables. Conclusion. We conclude that ADPKD is a significant risk factor for the development of NODAT. This may influence the follow up and management choices of these patients in the future.

Transplant Glomerulopathy: Morphology, Associations and Mechanism

Transplant glomerulopathy (TG) is a lesion with specific morphology and strong evidence of an immune mechanism. The incidence of TG is approximately 20% by 5 years after transplantation. TG is characterized by proteinuria, hypertension and declining graft function. Appearances on light microscopy include thickened capillary walls and double contours, with reduplication or lamination of the glomerular basement membrane on electron microscopy. TG is associated with acute rejection, the antibody status before transplantation and de novo HLA antibodies. HLA class II and/or donor-specific antibodies incur additional risks. Desensitization protocols do not always prevent the development of TG in highly sensitized individuals. Associations between TG, past or current C4d and the presence of alloantibodies are recognised, however, C4d in the peri-tubular capillaries or glomeruli is not a prerequisite at the time of diagnosis. Clinical observation and animal models suggest that TG arises as a consequence of chronic endothelial cell (EC) injury by the humoral arm of the immune system. In some cases, this follows a period of EC accommodation after an episode of acute injury. Proposed treatments include augmentation of background immunosuppression, and trials of monoclonal therapies targeted at CD20-positive B cells are underway.

Polymorphism in the human anti-pig natural antibody repertoire: Implications for antigen-specific immunoadsorption

BACKGROUND Anti-Galalpha1-3Gal antibodies cause hyperacute rejection (HAR) in pig-to-primate xenotransplantation. Long-term graft survival has not been achieved despite abrogation of HAR using transgenic pigs. IgG and IgM anti-Galalpha1-3Gal also play a role in the events following abrogation of HAR. Characterizing these antibodies and developing a system for their removal is therefore crucial to future success in xenotransplantation. METHODS AND RESULTS We have developed a neoglycoprotein enzyme-linked immunosorbent assay to probe the precise antigenic requirements for the binding of anti-Galalpha1-3Gal and have analyzed 77 normal sera. Sixty-six percent of individuals have IgG that recognizes the Galalpha1-3Gal di-, tri-, and pentasaccharides (D, T, and P, respectively), termed DTP phenotype. The frequency of other phenotypes was - -P, 13%; -TP, 12%; D-P, 8%; and DT-, 1%. The IgG subclasses found were IgG2 (95%), IgG3 (34%), IgG1 (31%), and IgG4 (17%). IgM in 91% of individuals recognized all three antigens. Further antibody heterogeneity was demonstrated when immunoadsorbents derived from Galalpha1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc (PENTA) were tested. Galalpha1-3Galbeta1-4Glc (TRI 6) or PENTA agarose were effective for IgG removal in all individuals. For IgM removal, two deoxy derivatives were completely successful in 73% of individuals. Combining the Galalpha1-3Gal (DI) and TRI 6 agarose produced an adsorbent that completely removed anti-Galalpha1-3Gal IgG and IgM in all individuals tested. CONCLUSIONS Although the polymorphism in the anti-Galalpha1-3Gal repertoire, which we have demonstrated, represents a major obstacle to the development of an effective immunoadsorbent, the combination of DI and TRI 6 agarose appears sufficient for pig-to-human xenotransplantation.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Natural history of proteinuria in renal transplant recipients developing de novo human leukocyte antigen antibodies.

Background. The relationship between humoral rejection and human leukocyte antigen (HLA) antibodies is established. Proteinuria is the hallmark of glomerular injury. The relationship between HLA antibody and proteinuria was explored in renal transplant recipients developing de novo donor-specific antibodies (DSA) and nondonor-specific antibodies (NDSA). Methods. Seventy-two patients with de novo HLA antibody (38 DSA and 34 NDSA) were identified from 475 prevalent renal transplant recipients (15.2%). Antibody surveillance occurred every 6 months, with specificity characterized by a combination of enzyme-linked immunosorbent assay, flow-bead cytometry, and Luminex bead analysis. Pooled analysis of every glomerular filtration rate (GFR) and urinary protein estimation in a 48-month window around the date of antibody detection was performed (4004 and 2084 measurements, respectively). Results. GFR slope (−5.85 vs. −3.21 mL/min/1.73 m2 per year) and graft failure rate (29% vs. 9%, P=0.039) were worse in patients with DSA. Three-year graft survival after antibody detection was worse in patients with DSA (69.5% vs. 91.1%, P=0.035). Patients with DSA had significantly more proteinuria than those with NDSA and 205 control patients with no alloantibodies, from 6 months before antibody detection (0.91 vs. 0.39 g/L, P=0.015). Graft failure was more likely in patients with DSA with excess of 0.2 g/L at antibody detection (42% vs. 0%, P=0.008). Conclusions. Proteinuria is associated with DSA detection and is likely to be an important factor that determines rapid GFR decline and earlier graft failure in patients developing de novo HLA antibodies.

Demonstration of IgM antibodies of high affinity within the anti-Galalpha1-3Gal antibody repertoire.

BACKGROUND Human anti-Galalpha1-3Gal IgG and IgM xenoantibodies can distinguish between very similar epitopes with a high degree of selectivity. METHODS Anti-Galalpha1-3Gal antibodies were affinity isolated using two separate Galalpha1-3Gal-based immunoadsorbents, Galalpha1-3Gal itself and Galalpha1-3Galbeta1-4Glc. IgG and IgM were separated using a protein G column. Antibody purity was achieved by serial adsorption/elutions from the columns. By this means, different antibody fractions were prepared that contained either IgG or IgM, reactive with either Galalpha1-3Gal, Galalpha1-3Galbeta1-4Glc, or both. The dissociation equilibrium constants (Kd) of these antibodies were then measured using an IAsys biosensor. RESULTS AND CONCLUSIONS Sera from two individuals were used and Kd values for one IgG (fraction 1A) and two IgM (fractions 1B and 2A) fractions were obtained. The Kd for the IgG was 4.85 x 10(-7) M (fraction 1A). For IgM, the Kd values were higher at 7.8x10(-10) M (fraction 1B) and 1.07x10(-10) M (fraction 2A). Natural anti-pig antibodies include high affinity IgM that continue to be produced without class switch. The B cell mechanism behind this is not known. It may be possible to exploit this mechanism in future xenotransplantation strategies.

Catheter access for hemodialysis defines higher mortality in late-presenting dialysis patients.

Background: This study explores the relationship between mortality and late presentation for dialysis, focusing on the role of catheter access for hemodialysis (HD). Methods: We analyzed data from a cohort of 286 patients commencing dialysis in 2000–2001. Survival and factors associated with death were analyzed by univariate and multivariate analysis. Dialysis access was considered in three groups: HD-AVF, HD-Catheter, and peritoneal dialysis (PD). Late referral (LR) was defined as first review by a nephrologist less than 90 days before dialysis. Results: One-year mortality was low at 10.1%. HD-Catheter patients were older (p < 0.001), more hypoalbuminemic (p < 0.001), more anemic (p = 0.005), and more likely to be LR (p < 0.001). HD-Catheter patients did not have significantly higher comorbidity (p = 0.128). HD-Catheter was strongly associated with late presentation (75% LR vs. 28% early referral, p < 0.001). Factors associated with death by univariate analysis included age (p < 0.0001), comorbidity (p < 0.0001), HD-Catheter (p < 0.0001), LR (p = 0.0001), hypoalbuminemia (p = 0.0011), and diabetes (p = 0.02). When corrected for these factors, HD-Catheter was associated with death (HR 2.226, 95% CI 1.314–3.772, p = 0.003) but LR was not (p = 0.38). Conclusions: A predominant feature of LR that predicts mortality is the use of catheter access for HD. This may be modifiable in those LR patients who do not present as uremic emergencies.

Modification of the Relationship Between Blood Pressure and Renal Albumin Permeability by Impaired Excretory Function and DiabetesNovelty and Significance

In animal models, reduced nephron mass impairs renal arteriolar autoregulation, increasing vulnerability of the remaining nephrons to elevated systemic blood pressure (BP). A feature of the resulting glomerular capillary hypertension is an increase in glomerular permeability. We sought evidence of a similar remnant nephron effect in human chronic kidney disease. In participants from the United States National Health and Nutrition Examination Surveys 1999 to 2010 (N=23 710), we examined the effect of reduced estimated glomerular filtration rate (eGFR) on the relationship between brachial artery BP and albumin permeability. Renal albumin permeability increased exponentially with systolic BP >110 mm Hg, and this association was modified by independent interactions with both excretory impairment and diabetes mellitus. Each 10 mm Hg increase in systolic BP was accompanied by an increase in fractional albumin excretion of 1.10-, 1.11-, 1.17-, 1.22-, and 1.38-fold for participants with eGFR≥90, 90>eGFR≥60, 60>eGFR≥45, 45>eGFR≥30, and eGFR<30 mL/min/1.73 m2, respectively, adjusted for age, sex, race, antihypertensive use, eGFR category, diabetes mellitus, smoking, history of cardiovascular disease, body mass index, and C-reactive protein. A 10 mm Hg systolic BP increment was associated with increases in fractional albumin excretion of 1.10- and 1.21-fold in nondiabetic and diabetic participants, respectively. Using urine albumin creatinine ratio as an alternative measure of albumin leak in eGFR-adjusted analyses gave the same conclusions. Our findings are consistent with the presence of a remnant nephron effect in human kidney disease. Future trials should consider the nephroprotective benefits of systolic BP lowering in kidney disease populations stratified by eGFR.

Defining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias.

Plasma cell dyscrasias (PCD) are due to an abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to secretion of immunoglobulin (Ig) or an Ig fragment, causing the dysfunction of multiple organs. Median survival of these patients has significantly improved over the last decade due to availability of treatment options such as high-dose melphalan with autologous stem cell transplantation and novel anti-myeloma agents. Renal transplantation has not traditionally been considered in these patients due to the previously limited prognosis, along with concerns relating to disease recurrence affecting the renal allograft and increased infection susceptibility following renal transplant due to immunosuppression and the PCD itself. However, with the increasing range of effective treatment options, renal transplantation could now be considered, especially in young patients with good performance status. It is therefore timely to reappraise the potential role of renal transplantation in end-stage renal disease due to multiple myeloma and other PCD. This review summarizes the literature relating to renal transplantation in PCD, including multiple myeloma, monoclonal Ig deposition disease and systemic AL amyloidosis, to attempt to identify patients who may benefit most from this approach and to explore areas for further development.

Long‐ and short‐term outcomes in renal allografts with deceased donors: A large recipient and donor genome‐wide association study

Improvements in immunosuppression have modified short‐term survival of deceased‐donor allografts, but not their rate of long‐term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short‐ and long‐term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large‐scale genome‐wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant‐pairs with replication in 5866 complete pairs. We studied deceased‐donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long‐ or short‐term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.