Altitude and arteriolar hyalinosis after kidney transplantation.

The kidney is very susceptible to hypoxic injury. Calcineurin inhibitors (CNIs) induce vasoconstriction and might reduce renal tissue oxygenation. We aimed to investigate if the synergistic deleterious effects of CNI-treatment and hypoxia of high altitude living might accelerate the development of arteriolar hyalinosis in kidney allografts. We stratified all patients who received a kidney graft from 2000 to 2010 in our centre (n = 477) in three groups according to the residential elevation (below 400, between 400 to 600 and above 600 m above sea level) and we retrospectively re-evaluated all transplant biopsies performed during follow-up, specifically looking at the degree of arteriolar hyalinosis, the hallmark of chronic CNI nephrotoxicity. Living at high altitude was markedly associated with a higher degree of arteriolar hyalinosis (P < 0.001). Haemoglobin levels confirmed the functional relevance of different arterial oxygenation among the groups (P = 0.01). Thus, patients living at high altitude seem to be more susceptible to the development of arteriolar hyalinosis after kidney transplantation.

Prediction of kidney graft failure using clinical scoring tools.

BACKGROUND: Donor organ quality is a key determinant of graft function, and considerable efforts have been made to identify donor and transplant factors predicting inferior outcomes. This has resulted in the development of various scoring tools to aid in allocation of kidneys. METHODS: The performance of four donor quality scoring systems in predicting delayed graft function, and death-censored graft failure was examined in a single-center cohort of 730 consecutive deceased donor kidneys transplanted between 1990 and 2004. The predictive accuracy of the variables was analyzed with receiver operating characteristic curves and graft survival distribution. RESULTS: The three outcome tools, that is, deceased donor score (DDS; Am J Transplant, 3, 2003, 715), donor risk score (DRS; Am J Transplant, 5, 2005, 757) and kidney donor risk index (KDRI; Transplantation, 88, 2009, 231) provided a significant and equivalent prediction of graft failure by using variables available at time of transplantation (p < 0.01). The risk of delayed graft function was predicted by the (DGF) nomogram (J Am Soc Nephrol, 14, 2003, 2967; Am J Transplant 10, 2010, 2279) with a high degree of discrimination (concordance index of 0.69, p < 0.01). CONCLUSIONS: Our findings validate four pre-operative clinical scoring tools to predict early and late graft outcome in an independent, single-center set of kidney transplants.

Post-transplant nuclear renal scans correlate with renal injury biomarkers and early allograft outcomes.

BACKGROUND: Clinical- and histopathology-based scores are limited predictors of allograft outcome. In addition, more objective markers of early transplant function are needed to identify and validate biomarkers and predictive scores. We evaluated existing scores and transcriptome biomarkers of kidney injury as predictors of early transplant function measured by renal scan. METHODS: Clinical, histopathologic and transcriptome data were collected in 143 consecutive kidney transplant recipients. A post-operative renal scan was performed within 48 h. Prediction scores for early outcomes were calculated. RESULTS: Patients were stratified into three groups by renal scan: normal, mild-to-moderate or severe dysfunction. Kidneys with severe dysfunction were more often from deceased donors (P < 0.001), had greater HLA antigen mismatches (P < 0.001), were transplanted into older recipients (P = 0.040), had lower urine output during the first 8 h (P < 0.001), higher Day 7 serum creatinine (P < 0.001) and higher incidence of delayed graft function (P < 0.001). Clinical- and pathology-based scores did not discriminate between scan groups. In contrast, the overall transcriptome (P < 0.001) and transcripts of preselected acute kidney injury (AKI) genes were significantly different between the groups, with kidney injury molecule 1 (P = 0.001) and neutrophil gelatinase-associated lipocalin (P = 0.002) being most highly expressed and genes associated with glutathione metabolism (GSTA1, 3 and 4) most down-regulated in kidneys with subsequent severe dysfunction. CONCLUSIONS: Renal scans reflect early transplant function and allow for a more objective assessment of scores predicting early outcome and for identification of biomarkers. The study shows that transcript levels of AKI genes correlate better with renal scans than clinical- or histopathology-based scores.

Macrophage activation is associated with poorer long-term outcomes in renal transplant patients.

Long-term graft and patient survival after renal transplantation are largely determined by progression of chronic allograft dysfunction and cardiovascular disease. Inflammation plays a crucial role in both disease processes. We prospectively analyzed the association of early peri-transplant inflammatory burden on long-term outcomes in 144 consecutive deceased donor renal allograft recipients. Single time point and cumulative levels of markers of acute phase response (serum amyloid A [SAA] and C-reactive protein [SCRP]) and macrophage activation (serum and urine neopterin) were measured daily during the immediate post-operative period. Mean patient follow-up was 16 yr. Graft and patient survival rates at one-, five-, and 10-yr were 90%, 70%, and 51%, and 97%, 77%, and 59%, respectively. Graft loss occurred in 90 patients, of whom 71 died with a functioning graft and 19 returned to dialysis. CRP, SAA and neopterin (NEOP) levels were all elevated post-operatively. High levels of NEOP, in contrast to SAA or SCRP, were associated with poorer graft and patient survival (p < 0.05), specifically with death from cardiovascular events and cytomegalovirus IgG positivity. These findings strongly suggest that early post-transplant macrophage activation, as reflected by NEOP levels, is associated with poorer long-term graft and patient survival.

Chronic inflammation and accelerated atherosclerosis as important cofactors in nephrogenic systemic fibrosis following intravenous gadolinium exposure.

Nephrogenic systemic fibrosis (NSF) is a rare disorder in patients with chronic kidney disease characterized by an increased tissue deposition of collagen. Its pathogenesis remains unclear. Prior studies indirectly suggested a possible impact of chronic inflammation and accelerated atherosclerosis--a common feature in kidney diseased patients--whereas recent data focused almost exclusively on gadolinium (Gd)-based MR contrast agents. Usually NSF develops a maximum of 2-3 months after Gd. Longer intervals have not yet been described. Therefore, we present the first case with an extraordinary long time course in terms of chronic inflammation. A 52-year-old Caucasian woman with end-stage renal disease was admitted to our hospital with progressive muscle weakness and skin induration resulting in growing immobility. Her past medical history revealed a secondary HPT, multiple vascular complications, a seronegative rheumatoid arthritis, and a pituitary gland adenoma. The latter conditions led to multiple MR examinations with Gd-based contrast agents, the last one more than 4 years ago. Numerous laboratory tests were performed including ESR, CRP, intact parathyroid hormone (iPTH), serum ferritin, cyclic-citrullinated peptide antibodies (CCP), ANA, ANCA, immunoelectrophoresis, and serology for hepatitis as well as human immunodeficiency virus. Eventually a skin biopsy of her left thigh was obtained. The laboratory investigation showed persistently elevated levels of CRP, ESR, serum ferritin, and iPTH, whereas all other parameters were inconspicuous. The hisology displayed typical signs of nephrogenic systemic fibrosis. NSF can occur at any time after Gd exposure in the long term. Gd is a necessary, but not the sole cause of NSF. Certain other cofactors such as chronic inflammation and accelerated atherosclerosis seem to be involved.