Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade.

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.

Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-ß1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-ß1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-ß1-dependent effects on T cells.

Hypoalbuminemia is a risk factor for invasive fungal infections and poor outcomes in infected kidney transplant recipients.

INTRODUCTION: Invasive fungal infections (IFI), are estimated to occur in 2%-14% of kidney transplant recipients (KTRs) in the current era of immune suppression and are associated with high mortality rates. We hypothesized that hypoalbuminemia in KTRs is a risk factor for IFI and would be associated with poor outcomes. METHODS: In this study, using data from a prospective cohort registry, we describe the frequency of IFI due to Blastomycosis, Coccidioidomycosis, Histoplasmosis, Aspergillosis, and Cryptococcus in KTRs with serum albumin levels measured 3-6 months before diagnosis. Controls were selected based on incidence density sampling. KTRs were divided into three groups based on the pre-IFI serum albumin level: normal (≥4 g/dL), mild (3-4 g/dL), or severe (<3 g/dL) hypoalbuminemia. Outcomes of interest were uncensored graft failure after IFI and overall mortality. RESULTS: A total of 113 KTRs with IFI were compared with 348 controls. The incidence rate of IFI among individuals with normal, mild, and severe hypoalbuminemia was 3.6, 8.7, and 29.3 per 100 person-years, respectively. After adjustment for multiple variables, the trend for risk of uncensored graft failure following IFI was greater in KTRS with mild (HR = 2.1; 95% CI, .75-6.1) and severe (HR = 4.47; 95% CI, 1.56-12.8) hypoalbuminemia (P-trend < .001) compared to those with normal serum albumin. Similarly, mortality was higher in severe hypoalbuminemia (HR = 1.9; 95% CI, .67-5.6) compared to normal serum albumin (P-trend < .001). CONCLUSION: Hypoalbuminemia precedes the diagnosis of IFI in KTRs, and is associated with poor outcomes following IFI. Hypoalbuminemia may be a useful predictor of IFI in KTRs and could be incorporated into screening algorithms.

An automated histological classification system for precision diagnostics of kidney allografts.

For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795 .

What lies in-between: C3 glomerulopathy with non-hemolytic renal microangiopathy and an ultra-rare C3 variant.

We report a 36-year-old female with mixed nephritic-nephrotic syndrome and recurrent pancreatitis. Kidney biopsy showed a crescentic membranoproliferative glomerulonephritis with dominant C3 staining on immunofluorescence (IF) but only scant deposits on electron microscopy (EM) and instead, evidence of severe acute and chronic microangiopathy - endothelial swelling, sub-endothelial fluff, and segmental basement membrane remodeling. Her serum C3 was normal, Factor Ba, and serum Membrane attack complex (sMAC) levels were elevated, and Properdin was low. Genetic testing revealed a heterozygous ultra rare C3 variant of unknown significance (c.4838G>T, p.Gly1613Val) as well as a heterozygous deletion of CFHR3-CFHR1. She showed an initial response to terminal complement blockade with eculizumab, but her renal disease progressed in the next year. Notably, our patient never demonstrated microangiopathic hemolysis, yet pancreatitis of unclear etiology recurred periodically. Our case suggests the existence of a "C3G/aHUS overlap" clinicopathologic syndrome and highlights the challenges of treating complement-mediated kidney disease.

The Association Between Remote Work During the First Wave of the Pandemic and Faculty Perceptions of Their Productivity and Career Trajectory: A Cross Sectional Survey.

INTRODUCTION: Early in the pandemic, studies documented that there are gendered differences in many factors related to working during the pandemic, especially for caregivers. This study aimed to focus on the effects of remote work, rather than the pandemic in general, on perceptions of productivity and career trajectory in research and education faculty at an academic health center. METHODS: A questionnaire was developed and distributed to all faculty in the Department of Medicine. We obtained demographic information and asked respondents to report the effect that remote work had on their research or teaching productivity. Those who reported a decrease in productivity were asked to choose a degree of impact. We also asked about the level of concern for the effect remote work would have on their career trajectory in research and teaching and about the impact of remote work on academic wellness. RESULTS: We received responses from 51.4% of 479 faculty. A little less than half were females, and most were subspecialists. More than half (60.6%) were responsible for providing care to children, parents, or others. Nearly one-quarter of respondents (22.8%) reported a negative effect of remote work on teaching productivity, which was more pronounced in senior faculty versus junior faculty (28.6% vs 16.5%, P = 0.03). Few faculty (7.4%) were concerned about their career trajectory in teaching; however, those who provided care at home were significantly more likely to be concerned (10.7% vs 2.1%, P = 0.01). Over half of respondents (56.6%) reported a negative effect of remote work on research productivity; this was significantly higher for tenure faculty than clinician educators (71.9% vs 50.7%, P = 0.01). Almost half of respondents (39.6%) were concerned about their career trajectory in research, and this concern was significantly higher in specialists than in generalists (42.9% vs 15.8%, P = 0.02) and in clinician educators versus clinicians (39.7% vs 0.0%, P = 0.007). A small number of faculty (11.5%) reported a negative impact of remote work on their academic wellness; this impact was higher in specialists than in generalists (13.2% vs 3.7%, P = 0.05). There were no significant differences in any areas of concern for males versus females or in those with or without leadership roles. CONCLUSIONS: In this single-center study during the first wave of the pandemic, faculty perceived reduced productivity in teaching, research, and academic wellness. Our study found that remote work concerns were overall more evenly distributed across gender and those responsible for caregiving than had been reported previously; however, caregivers were more concerned about their career trajectory in teaching than noncaregivers. The lack of significant differences may have been due to several factors: remote work allowed flexibility when caregiving arrangements were disrupted; remote work was required of all faculty, mitigating concerns that caregivers were singled out; and institutional support offset some of the challenges. Further studies are needed to determine whether social or operational interventions in academic health centers can reduce the negative perception of remote working on academic productivity.

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design.

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

APRIL/BLyS deficient rats prevent donor specific antibody (DSA) production and cell proliferation in rodent kidney transplant model.

APRIL (A proliferation inducing ligand) and BLyS (B Lymphocyte Stimulator) are two critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody. We sought to characterize the specific effects of these cytokines in a kidney transplant model of antibody mediated rejection (AMR). We engineered APRIL-/- and BLyS-/- Lewis rats using CRISPR/Cas9. APRIL-/- and BLyS-/- rats were sensitized with Brown Norway (BN) blood (complete MHC mismatch). Twenty-one days following sensitization, animals were harvested and collected tissues were analyzed using flow cytometry, ELISPOT, and immunohistochemistry. Flow cross match and a 3 day mixed lymphocyte reaction (MLR) was performed to assess donor specific antibody (DSA) production and T-cell proliferation, respectively. Sensitized dual knock out Lewis rats (APRIL-/-/BLyS-/-) underwent kidney transplantation and were sacrificed on day 7 post-transplant. Sensitized BLyS-/- had significant decreases in DSA and cell proliferation compared to WT and APRIL-/- (p<0.02). Additionally, BLyS-/- rats had a significant reduction in IgG secreting cells in splenic marginal zone B lymphocytes, and in cell proliferation when challenged with alloantigen compared to WT and APRIL-/-. Transplanted APRIL-/-/BLyS-/- rodents had significantly less DSA and antibody secreting cells compared to WT (p<0.05); however, this did not translate into a significant difference in AMR seen between groups. In summary, our studies suggest that APRIL and BLyS play a greater role in DSA generation rather than AMR, highlighting the role of cellular pathways that regulate AMR.

Chronic Active Antibody-mediated Rejection in Kidney Transplant Recipients: Treatment Response Rates and Value of Early Surveillance Biopsies.

There is limited information on the value of short-term invasive and noninvasive monitoring in kidney transplant recipients (KTR) undergoing therapy for chronic active antibody-mediated rejection (cAMR). Methods: We describe response rates in patients with cAMR receiving pulse steroids/IVIG ± rituximab 3-mo after index biopsy. Results: The study included 82 consecutive KTR. Mean time from transplant to cAMR was 10 y. Mean peritubular capillaritis (ptc), glomerulitis (g), microvascular inflammation (MVI), C4d, and cg Banff scores were 1.1, 2.1, 3.2, 0.2, and 2, respectively. Mean estimated glomerular filtration rate (eGFR) and urine protein creatinine (UPC) ratio were 38 mL/min and 1.6 g/g, respectively. Thirty (37%) patients lost their allograft during the mean follow-up of 2.4 y. In patients treated with pulse steroids/IVIG (n = 41), response rates for eGFR, UPC, donor-specific antibodies (DSAs), and MVI were 27%, 49%, 7%, and 19%, respectively. In the pulse steroids/IVIG/rituximab group, response rates were 66%, 61%, 20%, and 69%, respectively. Univariate analysis identified response in eGFR (HR = 0.03; P = 0.001; 95% CI, 0.004-0.26), UPC (HR = 0.38; P = 0.01; 95% CI, 0.18-0.82), and DSA (HR = 0.11; P = 0.004; 95% CI, 0.02-0.49) as predictors of graft survival. Multivariate analysis only retained eGFR response (HR = 0.12; P = 0.01; 95% CI, 0.02-0.64). Conclusions: In cAMR, short-term response to treatment for kidney function and DSA was associated with graft survival, but the role of early surveillance biopsies needs further evaluation.

In kidney recipients from the same deceased donor, discordance in delayed graft function is associated with the worst outcomes.

INTRODUCTION: Delayed graft function (DGF) is a common complication among deceased donor kidney transplant recipients (DDKTs) and is associated with worse outcomes. The effect on outcomes of concordance versus discordance in DGF between two different recipients of kidneys from the same donor is largely unknown. METHODS: We reviewed all adult DDKTs for which both kidneys were transplanted to two different recipients at our center between 2014-2019. DDKTs were divided into four groups based on the DGF status: concordance no DGF (cc-no-DGF); discordance no DGF(dd-no-DGF); discordance DGF (dd-DGF) and concordance in DGF (cc-DGF). Acute rejection (AR) and death censored graft failure (DCGF) were outcomes of interest. RESULTS: A total of 578 DDKTs fulfilled our selection criteria, 280were in cc-no-DGF, 83 in dd-no-DGF, 83 in dd-DGF, and 132 in cc-DGF. Compared to cc-no-DGF, in univariate analysis, dd-DGF was associated with an increased risk of AR (HR: 1.60; 95% CI: 1.0-2.56) but cc-DGF was not (HR: 1.01; 95% CI: 0.63-1.62). dd-DGF was not associated with an increased risk of AR in multivariate analysis. In multivariate analysis, dd-DGF was associated with an increased risk of DCGF (HR: 2.70; 95% CI: 1.05-6.93) but cc-DGFwas not (HR: 2.36; 95% CI: 0.97-5.70). CONCLUSION: Discordance in DGF is associated with worse outcomes and may need closefollow-up and monitoring to improve the outcomes.

The Presence of Donor-specific Antibodies Around the Time of Pancreas Graft Biopsy With Rejection Is Associated With an Increased Risk of Graft Failure.

BACKGROUND: Donor-specific antibodies (DSA) against HLA are an important biomarker predicting graft injury, rejection (Rej), and failure in various solid-organ transplant recipients. However, the impact of DSA with or without histopathological evidence of rejection among pancreas transplant recipients (PTRs) is unknown. METHODS: In this study, we included all PTRs at our center between 2005 and 2020, with pancreas allograft biopsy before March 31, 2021, and with DSA checked within 15 d of the biopsy. PTRs were divided into 4 groups based on the biopsy findings on the index biopsy and DSA status as Rej-/DSA-, Rej+/DSA-, Rej-/DSA+, and Rej+/DSA+. RESULTS: Two hundred two PTRs had a pancreas allograft biopsy during the study period. Thirty-nine were in Rej-/DSA-, 84 Rej+/DSA-, 24 Rej-/DSA+, and 55 Rej+/DSA+. The mean interval from transplant to index biopsy was not statistically different between the 4 groups. The most common type of rejection was T cell-mediated rejection; however, antibody-mediated rejection was more prevalent in the Rej+/DSA+ group. At 5 y postbiopsy, the rate of death-censored graft failure (DCGF) for Rej-/DSA- was 18%, 24% in Rej+/DSA-; 17% in Rej-/DSA+ and 36% in Rej+/DSA+ (P = 0.14). In univariate analysis, mixed rejection (hazard ratio [HR], 3.0; 95% confidence intervals [CI], 1.22-7.39; P = 0.02) along with solitary pancreas transplantation and Rej+/DSA+ were associated with DCGF. In multivariate analysis, compared with Rej-/DSA-, Rej+/DSA+ was significantly associated with DCGF (HR, 2.32; 95% CI, 1.03-5.20; P = 0.04); however, Rej+/DSA- was not (HR, 1.06; 95% CI, 0.32-3.56; P = 0.92). CONCLUSIONS: PTRs with pancreas allograft rejection and concomitant DSA have an increased risk of DCGF.

How Should Acute T-cell Mediated Rejection of Kidney Transplants Be Treated: Importance of Follow-up Biopsy.

Background: Limited published data exist to guide patient monitoring after the treatment of T-cell mediated rejection (TCMR) of kidney allografts. Methods: We reviewed the kidney function and histological outcomes after treatment of 163 first episodes of biopsy-proven TCMR between January 1' 2015' and July 31' 2020. Results: Of the 146 patients treated with steroid pulse alone, complete histological response was seen in 83% of patients with borderline rejection, 82.5% with grade 1A, 67% with grade 1B, and 50% with grade IIA. Of the 17 patients treated with steroids plus antithymocyte globulin, the complete histological response rate was 100% with grade 1A, 75% with grade 1B, 100% with grade IIA, and 57% with grade IIB. Among the patients with complete response as assessed by kidney function, 14% only had a partial or no response histologically. Among patients with no kidney function response, 68% had a complete response histologically. Conclusion: We thus find that responses based on kidney function alone do not correlate well with histological responses. If further treatment had been based solely on changes in estimated glomerular filtration rate, a significant number of patients would have been subsequently undertreated or overtreated. These results support the use of protocol follow-up biopsies after the treatment of TCMR.

Early Increases in Posttransplant Pancreatic Enzymes Are Associated With Surgical Complications But Not Graft Failure Among Pancreas Transplant Recipients.

OBJECTIVES: This study aimed to find the association between immediate postoperative increases in pancreatic enzymes and posttransplant complications among pancreas transplant recipients (PTRs). METHODS: We analyzed all PTRs transplanted at the University of Wisconsin between June 2009 and September 2018. Enzyme levels were presented as a ratio of absolute numbers to the upper limit of normal value, with value >1 considered as abnormal. We specifically evaluated bleeding, fluid collections, and thrombosis complications based on the amylase or lipase ratios on day 1 (Amylase1, Lipase1) and maximum ratios within 5 days of transplant (Amylasemax, Lipasemax). For early complications, we focused on technical complications that occurred within 90 days of transplant. For long-term outcomes, we assessed patient and graft survival, and rejections. RESULTS: There were a total of 443 PTRs, 287 were simultaneous pancreas and kidney recipients, and 156 were solitary pancreas recipients. Higher Amylase1, Liplase1, Amylasemax, and Lipasemax were associated with an increase in early complications, mainly need for pancreatectomy, fluid collections, bleeding complications, or graft thrombosis, particularly in the solitary pancreas group. CONCLUSIONS: Our finding suggests that cases of early perioperative enzyme increase merit consideration for early imaging investigation to mitigate detrimental outcomes.

Dysregulation of the sensory and regulatory pathways controlling cellular iron metabolism in unilateral obstructive nephropathy.

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1+/+ and Irp1-/- mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associates with a loss of the iron uptake protein transferrin receptor 1 (TfR1), increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP dependent. In contrast, the reduction in the Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1, suggesting disruption of normal hypoxia-inducible factor (HIF)-2α regulation. Furthermore, reduced expression of some HIF-α target genes in UUO occurred in the face of increased expression of HIF-α proteins and prolyl hydroxylases 2 and 1, the latter of which is not known to be HIF-α mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRPs on EPO production is overridden by disrupted hypoxia signaling.NEW & NOTEWORTHY This study demonstrates that iron metabolism and hypoxia signaling are dysregulated in unilateral obstructive nephropathy. Expression of iron regulatory proteins (IRPs), central regulators of cellular iron metabolism, and the iron uptake (transferrin receptor 1) and storage (ferritins) proteins they target is strongly altered. This suggests a role of IRPs in previously observed changes in iron metabolism in progressive renal disease. Hypoxia signaling is disrupted and appeared to dominate the action of IRP1 in controlling erythropoietin expression.

Kidney transplant outcomes among recipients with post-transplant hip or knee joint replacement surgery.

INTRODUCTION: Patients with end-stage renal disease (ESRD) are at a higher risk of needing hip or knee replacement (joint replacement) surgery due to the high prevalence of degenerative joint disease and other conditions. However, there remains a large debate about the timing of joint replacement surgery and whether it should be pre- vs post-transplant. METHODS: We conducted a retrospective study analyzing all adult kidney transplant recipients (KTRs) at our university hospital who had undergone subsequent joint replacement between 2001 and 2017. Transplant-specific outcomes of acute rejection, death censored graft failure (DCGF), and patient death post-joint replacement surgery were outcomes of interest. Controls were selected at a 1:3 ratio based on the incidence density sampling of post-transplant interval. RESULTS: There were 101 KTRs in the joint replacement group and were compared with 281 controls. In the multivariate analysis, the need for joint replacement was not associated with acute rejection (HR: 1.59; 95% CI: 0.77-3.29; P = 0.21); DCGF (HR: 0.89; 95% CI: 0.49-1.60; P = 0.70) or patient death (HR: 0.84, 95% CI: 0.55-1.38, P = 0.42). CONCLUSION: In selected KTRs, joint replacement surgery was not associated with detrimental transplant-specific outcomes.