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Purpose Variability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant recipients (KTRs); however, limited data on alemtuzumab induction or infection exist. We sought to determine the impact of tacrolimus variability in KTRs on dnDSAs, graft outcomes, and infections 3 years posttransplant after alemtuzumab induction. Methods Adult KTRs from January 1, 2013, to December 31, 2017, receiving alemtuzumab and tacrolimus-based immunosuppression at a single center were included. Tacrolimus variability was calculated using coefficient of variability (CV), and high CV was defined as ≥30%. Graft and infectious outcomes were assessed between high and low CV groups. Results Two hundred fourteen KTRs were included. The median tacrolimus CV from 0 to 3 months and from 3 to 12 months was 28.1% and 25.8%, respectively. Recipients with high CV had decreased glomerular filtration rate at 3 and 12 months (67.7 ± 35.48 vs 80.7 ± 29.3, P = .01 and 70.9 ± 35.4 vs 83.3 ± 30.2, P = .015). High CV was also associated with increased cytomegalovirus viremia and disease (19.6% vs 9.3%, P = .046 and 6.4% vs 17.9%, P = .015). No difference in biopsy-proven acute rejection, survival, or dnDSA development at 3 years was observed. Conclusions High tacrolimus variability was associated with significantly reduced graft function and increased cytomegalovirus viremia and disease but not biopsy-proven acute rejection, survival, or dnDSA development.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p 0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.

BACKGROUND Pulmonary hypertension (PH) is frequently reported in patients with advanced chronic kidney disease and is associated with early allograft failure and death. However, the causes of PH are heterogeneous, and patient prognosis may vary by etiologic subtype. METHODS Data from the University of North Carolina Cardiorenal Registry were examined to determine associations between PH, with or without elevated left atrial pressure (eLAP), and mortality in candidates for kidney transplantation. PH and eLAP were determined by Doppler echocardiography and by tissue Doppler imaging, respectively. RESULTS From 2006 to 2013, 778 registry patients were screened preoperatively by echocardiography. Most patients were black (64%) and men (56%); the mean age was 56 years. PH was identified in 97 (12%) patients; of these, eLAP was prevalent in half. During a median follow-up of 4.4 years, 179 (23%) received a kidney transplant, and 195 (25%) died. After adjustments for demographics, comorbidities, dialysis vintage, and kidney transplantation, PH was associated with twice the 5-year mortality (hazard ratio [HR] = 2.11; 95% confidence interval [CI]: 1.48-3.03), with stronger associations in the absence of eLAP (HR = 2.87; 95% CI: 1.83-4.49) than with eLAP (HR = 1.11; 95% CI: 0.57-2.17), P for interaction = 0.01. CONCLUSIONS The mortality risk associated with PH among patients with advanced chronic kidney disease appears to differ by etiology. Patients with PH in the absence of eLAP are at high risk of death and in need of focused attention. Future research efforts should investigate potential strategies to improve outcomes for these patients.

Degree of mechanical anisotropy in renal cortex can be assessed by evaluating the ratio of viscoelastic response (VisR) parameters achieved when the long axis of a spatially asymmetric ARF excitation PSF is aligned along versus across nephrons. In this work, intra-observer reproducibility and variability in VisR derived DoA assessment in renal cortex due to donor type, sex, race, and BMI is evaluated in healthy human kidney allografts, in vivo. Transcutaneous, in vivo VisR imaging was performed in 20 kidney allografts 2 months post-transplantation using a Siemens Acuson Antares™ imaging system and a VF7-3 linear array transducer. Ratios of VisR derived relative elasticity (RE), relative viscosity (RV), and peak displacement (PD) obtained with the ARF short-axis aligned along versus across nephrons were calculated. Patients were divided based on their sex (male: N=14 versus female: N=6), race (African American: N = 6 versus Caucasian: N=14), donor type (living: N=14 versus deceased: N =6), and BMI (BMI >30: N= 8 versus BMI 0.05) due to sex, race, donor types, or BMI. The median absolute percent difference in (PD, RE, RV) ratios were (23, 13, 23) due to sex, (5, 3, 3) due to race, (0.35, 14, 13) due to donor type, and 8.6, 6, 12) due to BMI. Ratios of PD, RE, and RV were not statistically different between 1st and 2nd imaging events with mean percent difference in (PD, RE, and RV) ratios of (-0.04, -0.11, and - 0.01). These findings suggest that VisR outcome measures are robust to potentially confounding demographic factors and reproducible by a trained practitioner.

Background and objectives Idiopathic collapsing FSGS has historically been associated with poor renal outcomes. Minimal clinical data exist on the efficacy of immunosuppressive therapy. Our study sought to provide a comprehensive description of renal survival in patients with collapsing and not otherwise specified FSGS after controlling for factors affecting renal prognosis. Design, setting, participants, & measurements We performed a retrospective analysis of an inception cohort study of patients diagnosed between 1989 and 2012. All potential patients with collapsing FSGS fulfilling the inclusion criteria were identified and compared with patients with not otherwise specified FSGS (approximately 1:2 ratio) on the basis of biopsy report and record availability. Time to ESRD was analyzed using Cox proportional hazards models. Results In total, 187 patients were studied (61 collapsing and 126 not otherwise specified), with a mean follow-up of 96 months. At baseline, patients with collapsing FSGS had higher median proteinuria (12.2 [5.6–14.8] versus 4.4 [2.3–8.1] g/d, respectively; P Conclusions Compared with not otherwise specified FSGS, idiopathic collapsing FSGS presented with more severe nephrotic syndrome and lower eGFR but had a similar renal survival after controlling for exposure to immunosuppressive treatment. These results highlight the importance of early diagnosis and institution of immunosuppressive therapy in patients with collapsing FSGS.

Introduction Animal models of chronic kidney disease demonstrate that a redundant population of therapeutically bioactive selected renal cells (SRCs) can be delivered to the kidney through intraparenchymal injection and arrest disease progression. Direct injection of SRCs has been shown to attenuate nuclear factor−κB, which is known to drive tissue inflammation, as well as the transforming growth factor−β−mediated plasminogen activator inhibitor−1 response that drives tissue fibrosis. Methods We present experience from the first-in-human clinical study with SRCs. Seven male type 2 diabetic patients (63 ± 2 years of age) with chronic kidney disease stage 3 to 4 (estimated glomerular filtration rate 25 ± 2 ml/min) were recruited. After blood and urine sampling, iohexol clearance, magnetic resonance imaging, and renal scintigraphy, patients underwent ultrasound-guided renal biopsy. Two cores of renal tissue were shipped to the manufacturing plant for cell isolation, culture, and product preparation. Formulated SRCs were transported back to study sites (range 59–87 days after biopsy) for intracortical injection using a retroperitoneoscopic technique. Results Laparoscopically assisted implantation of SRCs was uneventful in all patients. However, postoperative complications were common and suggest that other techniques of SRC delivery should be used. Kidney volume, split function, and glomerular filtration rate did not change during 12 months of follow-up. An extended 24-month follow-up in 5 of the patients showed a decline in estimated glomerular filtration rate (cystatin C). Discussion Postoperative complications following retroperitoneoscopic implantation of SRC in the kidney cortex seem to be related to the surgical procedure rather than to injection of the cell product. No changes in renal function were observed during the original 12-month protocol. Beyond the first 12 months after cell implantation, individual renal function began to deteriorate during further follow-up.

In large registries of hemodialysis patients, higher body mass index (BMI) is known to be associated with lower mortality rates, while weight loss associates with reduced survival. This so-called 'obesity paradox' includes patients categorized as overweight and obese. Transplantation in the obese patient population has been shown to improve quality of life and reduce mortality when compared with obese recipient candidates remaining on dialysis. Most transplant centers, however, restrict access to transplant based upon predetermined BMI cutoffs. This policy effectively mandates weight loss for many obese transplant candidates. However, BMI, though easily measured, is an inadequate assessment of nutritional status and lean muscle mass in obese patients. Regimens designed to prevent protein-energy wasting may include dietary recommendations and exercise programs that result in favorable changes in body composition without significantly impacting weight. The goal of weight loss is not achievable for many if not most obese dialysis patients. The consequence to the patient is reduced access to life improving transplantation. Patients are forced to pursue dietary, behavioral and possibly surgical interventions to accomplish weight loss despite limited evidence regarding the safety and utility of these interventions. The delay in transplantation also hinders the achievement of improved exercise capacity after successful transplant, a time when weight loss regimens may be safer and more effective.

BK polyomavirus nephropathy (BKN) affects 1 to 9% of renal allografts.1–5 No specific and potent antipolyomavirus therapy is available. Therapeutic attempts include reduction in overall immunosuppression often combined with some antiviral drugs (e.g., leflunomide, cidofovir).6–10 Outcome of BKN largely depends on the histologic stage at time of diagnosis. Whereas BKN early stage A fares favorably, advanced disease stage C generally results in chronic allograft failure/loss, making an early diagnosis of BKN imperative for long-term graft survival.2,7,11–15 The definitive diagnosis of BKN requires a renal biopsy. For facilitation of diagnostic workup, patient screening strategies are used for the clinical risk assessment. They are based on signs of BK virus (BKV) replication in urine/viruria and plasma/viremia: Urine cytology for polyomavirus inclusion-bearing “decoy cell” quantification and PCR assays for quantitative BKV load measurements.2,7,13,16–18 However, these screening techniques have only limited predictive value to diagnose accurately BKN; they are not “kidney disease specific” and cannot reliably distinguish between clinically insignificant polyomavirus replication and manifest intrarenal disease (BKN).7,19–24 Given the dependence on renal biopsies for accurately diagnosing BKN and the limitations of currently available screening tests, we propose a new diagnostic method. In voided urine samples from patients with biopsy-proven BKN, we observed three-dimensional cast-like polyomavirus aggregates, hereafter termed “Haufen” (after the German word for “cluster or stack”) by electron microscopy (EM). Such densely arranged viral aggregates have not been described before. We hypothesized that Haufen were morphologic biomarkers of a productive intrarenal BKV infection. The data presented here support our hypothesis and show that the detection of Haufen can be clinically used to diagnose BKN accurately and noninvasively.

Bone morphogenetic protein 7 (BMP7), a member of the tumor growth factor beta superfamily, appears to have a role in both kidney development and response to kidney injury. Signals through its pathways permit both epithelial differentiation during embryogenesis and preservation of normal kidney architecture after stress, leading to the hypothesis that BMP7 may exert its kidney-protective effects in adult animals by preventing or reversing epithelial-to-mesenchymal transformation. This review attempts to synthesize the data supporting those conclusions and suggest some future areas of research.

Albuminuria breakthrough is associated with an increase in systemic oxidative damage in well-controlled hypertensive patients under chronic raas suppression Gema Ruiz-Hurtado, Luis Condezo-Hoyos, Helena Pulido-Olmo, Isabel Aranguez, Mar ia del Carmen Gonz alez, Silvia Arribas, C esar Cerezo, Julian Segura, Manuel Praga, Marisol Fern andez-Alfonso, Luis Miguel Ruilope. Hospital Universitario 12 de Octubre, Madrid, Spain; Universidad Aut onoma de Madrid, Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain

Human immunodeficiency virus-associated nephropathy (HIVAN) is characterized by massive proteinuria with rapidly progressive renal failure. We report an adult with HIV infection who developed nephrotic-range proteinuria and acute renal failure requiring hemodialysis. Renal biopsy findings were consistent with HIVAN, exhibiting focal and segmental glomerulosclerosis with dilated microcystic tubules filled with pale eosinophilic material. Institution of corticosteroid therapy was followed by significant improvement in renal function and proteinuria. Corticosteroids were tapered, and the patient experienced worsening of his renal failure and proteinuria. A second course of corticosteroids was again associated with improved renal function. This and other reports suggest that corticosteroids may improve the clinical course of HIVAN.

Aim Recently our renal transplant (Tx) program has implemented routine HLA antibody monitoring of allograft recipients. We determined the incidence of donor specific antibody (DSA) in the 6 months – 1 year post-Tx period. Methods 155 renal allograft recipients (Tx in 2011-2012) were tested for HLA antibody prior to Tx and 6 – 12 months post-Tx. Pre and post-Tx monitoring of antibodies was determined using flow cytometry screening beads and a Luminex-based solid-phase class I and II single antigen bead assay with a positive cutoff of 1000 MFI. Crossmatches (XM) were performed using pronase treated cells and flow cytometry. Correlations between DSA development and serum creatinine were analyzed. Results Overall, 67 of 155 renal Tx recipients were sensitized at time of Tx of which 41 were tested for DSA post-transplant. Of 88 non-sensitized patients, 50 were tested post-Tx. 5 of 41 sensitized patients developed de novo DSA compared to 4 of 50 patients in the non-sensitized group. Of the 9 patients that developed DSA, 7 had DSA to HLA-II antigens while 2 had antibodies against HLA-I antigens. In patients with DSA, serum creatinine level ranged from 1.39 – 5.87. However, no correlation was observed between DSA MFI and serum creatinine level. Conclusions Institution of routine testing for DSA following renal Tx has allowed identification of patients with HLA DSA that may not have been tested in an indication based scheme. A higher percentage of sensitized patients received routine monitoring than non-sensitized patients. More monitoring in sensitized patients is consistent with sensitized patients increased susceptibility to develop DSA. Development of DSA does not correlate with a positive XM but does correlate with sensitization. Consistent with previous reports, the majority of patients developed DSA to HLA-II antigens. Routine testing for DSA will enable a better understanding of possible connections between development of DSA and clinical outcomes in our cohort.

Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Sixteen patients with renal biopsy findings of extensive focal glomerular capillary collapse, visceral epithelial cell hypertrophy and hyperplasia, and variable degrees of tubulointerstitial injury in the absence of evidence for human immunodeficiency virus (HIV) infection or intravenous drug abuse were prospectively identified by renal biopsy. The pathologic process was designated collapsing glomerulopathy to distinguish it from other patterns of focal glomerular sclerosis. The clinical and pathologic characteristics of these 16 patients were analyzed and compared to a group of 25 patients with noncollapsing focal segmental glomerulosclerosis (FSGS). Thirteen of 16 patients with collapsing glomerulopathy were black as compared with 11 of 25 with FSGS (P = 0.018). The most common findings at presentation were hypertension and manifestations of the nephrotic syndrome. Although the duration of symptoms prior to presentation was no longer in the collapsing glomerulopathy group, the presenting mean serum creatinine was higher in patients with collapsing glomerulopathy than in those with noncollapsing FSGS (3.5 ± 3.4 mg/dl vs. 1.3 0.6 mg/dl, P = 0.001). Twenty-four-hour urine protein excretion was also higher in the collapsing glomerulopathy group (13.2 ± 7.7 g/day vs. 4.6 ± 4.5 g/day FSGS, P = 0.005). The collapsing glomerulopathy patients had a mean age of 41.4 ± 19.1 (range 19 to 81), a male-to-female ratio of 11:5 and a black-to-white ratio of 13:3. Renal survival, evaluated by life-table analysis, was markedly worse in collapsing glomerulopathy patients than in FSGS patients (P = 0.0004). It is proposed that collapsing glomerulopathy is a distinct entity characterized by black racial predominance, massive proteinuria, relatively rapidly progressive renal insufficiency, and distinctive pathologic findings. The data suggest that collapsing glomerulopathy is clinically, pathologically, and epidemiologically different from noncollapsing FSGS. Although collapsing glomerulopathy resembles HIV-nephropathy both pathologically and clinically, it differs clinically by having no evidence for associated HIV infection and differs pathologically by lacking endothelial tubuloreticular inclusions.