Shubhada N. Ahya

Outcomes and Native Renal Recovery Following Simultaneous Liver-Kidney Transplantation

With the increase in patients having impaired renal function at liver transplant due to MELD, accurate predictors of posttransplant native renal recovery are needed to select candidates for simultaneous liver–kidney transplantation (SLK). Current UNOS guidelines rely on specific clinical criteria for SLK allocation. To examine these guidelines and other variables predicting nonrecovery, we analyzed 155 SLK recipients, focusing on a subset (n = 78) that had post‐SLK native GFR (nGFR) determined by radionuclide renal scans. The 77 patients not having renal scans received a higher number of extended criteria donor organs and had worse posttransplant survival. Of the 78 renal scan patients, 31 met and 47 did not meet pre‐SLK UNOS criteria. The UNOS criteria were more predictive than our institutional criteria for all nGFR recovery thresholds (20–40 mL/min), although at the most conservative cut‐off (nGFR ≤ 20) it had low sensitivity (55.3%), specificity (75%), PPV (67.6%) and NPV (63.8%) for predicting post‐SLK nonrecovery. On multivariate analysis, the only predictor of native renal nonrecovery (nGFR ≤ 20) was abnormal pre‐SLK renal imaging (OR 3.85, CI 1.22–12.5). Our data support the need to refine SLK selection utilizing more definitive biomarkers and predictors of native renal recovery than current clinical criteria.

Clinical Performance and Skill Retention after Simulation-based Education for Nephrology Fellows

We previously demonstrated that simulation‐based education (SBE) improved temporary hemodialysis catheter (THDC) insertion skills by nephrology fellows. SBE, featuring deliberate practice and rigorous achievement standards, was a powerful method to enhance THDC insertion skills in nephrology fellows. However, experts have called for further research to evaluate skill transfer from the simulated environment to actual clinical care and skill retention. This is a prospective observational cohort study of THDC insertion skills. Twelve nephrology fellows from three academic centers in Chicago were evaluated using a skills checklist from July 2008 to June 2009. Simulator‐trained fellows were tested after the SBE intervention and expected to meet or exceed a minimum passing score (MPS) set by an expert panel. To assess transfer of skill to clinical care, three simulator‐trained fellows were assessed at 6 months on actual patient THDC insertions using the checklist. To assess retention of skill, 11 of 12 simulator‐trained fellows were reassessed at 1 year using the checklist and central venous catheter simulator. Outcomes were determined by THDC insertion skill performance. Simulator‐trained fellows scored similarly during 6‐month THDC insertions on actual patients and immediate posttest (M = 86.2%, SD = 22.3% vs. M = 93.5%, SD = 5.3%, p = 0.32). However, 1 year after SBE, simulated THDC insertion scores were significantly lower than at immediate posttest (M = 73.4%, SD = 22.2% vs. M = 93.5%, SD = 5.3%, p = 0.01). Our results show that nephrology fellows who completed SBE displayed high levels of performance during THDC insertions on actual patients 6 months later. At 1 year, there was statistically significant skills decay. We recommend booster training at 6 months.

Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients.

BACKGROUND Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D(3)) to suppress parathyroid hormone (PTH), but dosing of 1,25D(3) is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1alpha-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca x P, while still suppressing PTH. METHODS We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h. RESULTS Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 +/- 0.11 mmol/l) than paricalcitol (1.85 +/- 0.07 mmol/l; p = 0.025). Ca x P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 +/- 0.26 vs. 4.54 +/- 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol). CONCLUSION Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca x P.

Outcomes of patients with hepatitis C undergoing simultaneous liver–kidney transplantation

BACKGROUND/AIMS The number of simultaneous liver-kidney transplants (SLK) has increased since the MELD era. Data on short- and long-term outcomes of hepatitis C virus positive (HCV+) SLK compared to HCV+ liver transplant alone (LTA) recipients are limited. METHODS A case-control study comparing outcomes of HCV+SLK versus transplant year-matched HCV+ LTA (1:1) was performed. RESULTS 38/142 (26.7%) SLK recipients were HCV+. LTA controls had lower MELD (17.4+/-8.6) at transplant than SLK (34.5+/-6.6) (p=0.001). There were increased early post-transplant infection episodes in SLK (56.3%) versus LTA (21.6%) (p=0.001) and a trend towards increased early mortality in the SLK group (p=0.08). However, there was no difference in long-term patient and graft survival, time to HCV recurrence, % >or=stage 2 fibrosis, renal function, and graft function between the groups. Ten SLK recipients were treated for HCV recurrence with pegylated interferon+ribavirin: two had sustained virologic response, five stopped due to side effects, and three had no response. None had liver or kidney rejection on treatment. CONCLUSION Our data represent the largest analysis of HCV+ SLK outcomes to date. We demonstrate increased early complications in SLK versus LTA recipients, likely due to being more critically ill at transplant (higher MELD) and complications unrelated to HCV within the first year. However, long-term outcomes, i.e. HCV recurrence, graft/renal dysfunction, are similar to LTA. In addition, while data are limited, treatment of HCV recurrence with interferon appeared safe in our SLK recipients.

Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation

Biomarkers predictive of recovery from acute kidney injury (AKI) after liver transplantation (LT) could enhance decision algorithms regarding the need for liver‐kidney transplantation or renal sparing regimens. Multianalyte plasma/urine kidney injury protein panels were performed immediately before and 1 month post‐LT in an initial test group divided by reversible pre‐LT AKI (rAKI = post‐LT renal recovery) versus no AKI (nAKI). This was followed by a larger validation set that included an additional group: irreversible pre‐LT AKI (iAKI = no post‐LT renal recovery). In the test group (n = 16), six pre‐LT plasma (not urine) kidney injury proteins (osteopontin [OPN], neutrophil gelatinase‐associated lipocalin, cystatin C, trefoil factor 3, tissue inhibitor of metalloproteinase [TIMP]‐1, and β‐2‐microglobulin) were higher in rAKI versus nAKI (P < 0.05) and returned to normal values with renal recovery post‐LT. In the validation set (n = 46), a number of proteins were significantly higher in both rAKI and iAKI versus nAKI. However, only pre‐LT plasma OPN (P = 0.009) and TIMP‐1 (P = 0.019) levels were significantly higher in rAKI versus iAKI. Logistic regression modeling was used to correlate the probability of post‐LT rAKI, factoring in both pre‐LT protein markers and clinical variables. A combined model including elevated OPN and TIMP‐1 levels, age <57, and absence of diabetes had the highest area under the curve of 0.82, compared to protein‐only and clinical variable–only models. Conclusion: These data suggest that plasma protein profiles might improve the prediction of pre‐LT kidney injury recovery after LT. However, multicenter, prospective studies are needed to validate these findings and ultimately test the value of such protein panels in perioperative management and decision making. (Hepatology 2014;60:2016–2025)

Interventions to Reduce Late Referrals to Nephrologists

Background: Despite the adverse health outcomes with late nephrology referral for patients with chronic kidney disease (CKD), little is known about the underlying mechanisms and reasons for late referral patterns. Methods: We conducted a Medline search for peer-reviewed articles focused on nephrology referral among adults with CKD. We critically reviewed this literature in regard to late nephrology referral, highlighted its shortcomings, and provided a theoretically based framework for future research. Results: Late referral has been attributed to three key types of factors: primary care provider (PCP), patient, and healthcare system factors. Limited empirical research has pointed to knowledge deficits, perceptions, and preferences by PCPs as well as to knowledge deficits, psychological concerns, and economic concerns by patients. The existing literature is severely limited by retrospective designs, closed-ended surveys, and the absence of a theoretically driven conceptual framework to fully evaluate root causes of this ongoing problem. Social Cognitive Theory may be a particularly well-suited conceptual model for late nephrology referral because important PCP and patient factors correspond to key constructs of this theory. Conclusion: Future research is needed to delineate pathways underlying reasons for PCPs’ late referral patterns and CKD patients’ referral nonadherence. Interventions are urgently needed to reduce late referrals and improve the health of patients with CKD.

Early Onset of Tenofovir-Induced Renal Failure: Case Report and Review of the Literature

Tenofovir is an acyclic nucleotide analogue reverse transcriptase inhibitor that is commonly prescribed as part of a highly active antiretroviral therapy (HAART) regimen in HIV-infected patients. Although it is generally well tolerated, renal insufficiency has been associated with its use. We report a biopsy-proven case of acute renal failure that developed within weeks of initiating a HAART regimen containing tenofovir, and review the literature with specific attention to cases of renal failure occurring within 8 weeks of tenofovir initiation. Our patient developed renal insufficiency within 3 weeks of initiating tenofovir-containing HAART and overt renal failure was noted within 5 weeks. Renal biopsy demonstrated histopathologic changes suggestive of HIV nephropathy, despite normal baseline serum creatinine values. Thirty additional cases of tenofovir-associated renal failure have been reported. In the majority (n = 22, 73%), renal failure occurred months after initiating therapy (range: 5–26 months). However, in a significant subset (n = 8, 27%), renal failure occurred within 8 weeks of treatment initiation. Our data suggest that some patients are at risk for developing renal failure within weeks of tenofovir initiation. Thorough evaluation of renal function should be undertaken before prescription of tenofovir-containing HAART. For those in whom subclinical renal disease is discerned, added vigilance when monitoring renal function may be warranted.

Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation

BACKGROUND Calciphylaxis and calcinosis can both cause severe morbidity and mortality in patients with systemic lupus erythematosus (SLE). Haematopoietic stem cell transplantation (HSCT) has been successfully used to treat patients with refractory SLE. It was hypothesized that in calciphylaxis and calcinosis, ongoing inflammatory activity contributes to the calcium deposition in the media of small arteries, as well as perivascular and periarticular tissues. We report three patients whose soft-tissue calcification syndromes dramatically resolved after undergoing HSCT. METHODS Three patients referred for refractory SLE underwent HSCT at a tertiary care medical center. SLE serologies and clinical features before and after HSCT were recorded. RESULTS Despite receiving >6 months of intravenous cyclophosphamide (CYC), three SLE patients showed signs of persistent lupus activity, including severe soft-tissue calcification. The first patient was on haemodialysis and developed severe calciphylaxis with large ulcers and tissue necrosis. The second patient had calcinosis, with palpable crystals extruding from ulcers. The third patient had calcinosis characterized by subcutaneous nodules and plaques. Because prior conventional therapies had failed, the three were treated with high-dose CYC, anti-thymocyte globulin and HSCT. They have been followed post-HSCT for 26-38 months, with excellent clinical responses, including sustained resolution of skin abnormalities. CONCLUSIONS The successful treatment of advanced calcium deposition by aggressive immune ablation underscores the contribution of SLE-mediated inflammation to soft-tissue calcification syndromes.

A Case of Simultaneous, Biopsy-Proven, Classic, ANCA-Positive Wegener's Granulomatosis and Anti-GBM Disease, but without Detectible Circulating Anti-GBM Antibodies

Wegeners granulomatosis (WG) is a systemic, necrotizing, granulomatous vasculitis of unknown etiology. Approximately 75% of cases present as classic WG with both pulmonary and renal involvement, while the remaining 25% of patients present with a limited form with either predominantly upper or lower respiratory tract symptoms. Ninety percent of WG patients have circulating anti–neutrophil cytoplasmic antibodies (ANCA), and approximately 10% have both circulating ANCA antibodies and concomitant anti–glomerular basement membrane (anti-GBM) disease on renal biopsy. Virtually all of these patients also have circulating anti-GBM antibodies. While it has been reported that some patients with ANCA vasculitis have circulating anti-GBM antibodies, and patients with anti-GBM disease may have positive ANCA, review of the literature does not demonstrate other cases of biopsy-proven, simultaneous, ANCA-associated vasculitis and anti-GBM disease. We report a case of simultaneous, biopsy-proven, classic, ANCA-positive WG and anti-GBM disease, but without detectible circulating anti-GBM antibodies. We present findings characteristic of both WG and linear IgG deposition along the GBM suggesting concurrent anti-GBM disease, in the absence of detectable circulating anti-GBM antibodies. Possible theories to explain the absence of these antibodies are discussed.

The Unpredictability of Idiopathic Membranous Nephropathy: An Illustrative Case Report

The case of a female patient with primary membranous nephropathy is presented. She was treated with corticosteroids and chlorambucil after conservative therapy had failed and went into remission for 5 years. Her nephrotic syndrome recurred but did not respond to the same regimen. She had another complete remission after treatment with corticosteroids and cyclosporine, but the nephrosis recurred after 7 years. Again, she failed to respond with retreatment of steroids plus cyclosporine. She was treated with alternate-day steroid plus mycophenolate and, once again, had a complete remission. She was maintained on low-dose mycophenolate for 7 more years. The mycophenolate had to be discontinued because of cytomegalovirus colitis. Treatment with ganciclovir abolished the colitis. She is still in remission 10 years later. The case is discussed with regard to current knowledge of the immune pathogenesis of membranous nephropathy as well as the unknowns of the immunogenesis of the disease.