Long-term outcome of renal transplantation in light-chain deposition disease.

BACKGROUND: Light-chain deposition disease (LCDD) is a monoclonal gammopathy characterized by nonamyloid deposition of light chain in various organs. A small number of kidney transplantations have been performed on LCDD patients in whom end-stage renal disease (ESRD) developed. METHODS: The authors retrospectively reviewed the clinical and histologic findings and outcome of 7 patients with LCDD who underwent kidney transplantation at our institution. RESULTS: Renal insufficiency, hypertension, and proteinuria were present in all 7 patients. Proteinuria level was greater than 3.5 g/24 h in 3 patients. Three patients had microscopic hematuria. Monoclonal protein was detected in the serum in 3 patients, urine in 5, and was undetectable in 2. Median age at presentation was 42.7 (range, 33 to 58) years. The most common renal biopsy findings were mesangial expansion, mesangial nodules, tubular basement membrane thickening, and tubular atrophy. Kappa light chain was detected in all 7 renal biopsy results. Five patients were on dialysis before transplantation. LCDD recurred after a median of 33.3 (range, 2 to 45) months in 5 of the 7 patients. One patient remains on dialysis, whereas the other 4 have died. One patient died of progression of multiple myeloma 3 months after kidney transplantation without evidence of recurrence. Only 1 patient remains recurrence free after 13 years with normal renal allograft function. CONCLUSION: Although long-term benefits are occasionally seen, renal allograft survival is reduced significantly in LCDD patients. Kidney transplantation should not be an option for LCDD patients unless measures have been taken to reduce light chain production.

Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat.

We hypothesized that the venous limb of an arteriovenous (AV) fistula would evince up-regulation of genes relevant to vascular remodeling along with neointimal hyperplasia and relevant histological changes. Using the aorto-caval model of an AV fistula model in the rat, we demonstrate marked up-regulation in such proinflammatory genes as monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and endothelin-1, 2 weeks after the creation of the fistula. Neointimal hyperplasia occurred in variable degrees by 5 weeks after establishing the fistula, and by 16 weeks, such neointimal hyperplasia was progressive and pronounced; at this time point, abundant extracellular matrix was also observed. Smooth muscle cells were present in the hyperplastic neointima as evidenced by staining for alpha-smooth muscle actin; ultrastructurally, smooth muscle cells with a synthetic as well as a contractile phenotype were readily observed. Accumulation of extracellular matrix in the model at 16 weeks was accompanied by increased expression of transforming growth factor-beta1 mRNA, the latter finding contrasting with the suppression of transforming growth factor-beta1 mRNA observed in this model at 2 weeks. In summary, we describe marked up-regulation in proinflammatory genes and progressive neointimal formation in the venous vasculature in an AV fistula model in the rat. We suggest that such alteration in gene expression and histological injury, in conjunction with the relative simplicity of this model, offer a new approach in the study of such timely biological and clinically relevant phenomena as differential gene expression in response to hemodynamic forces, processes involved in vascular remodeling, mechanisms of injury in venous bypass grafts, and mechanisms of dysfunction of AV fistulae used in hemodialysis.

Iodine toxicity treated with hemodialysis and continuous venovenous hemodiafiltration.

Continuous mediastinal irrigation with povidone-iodine is used commonly for treating severe postoperative mediastinitis. However, concurrent iodine toxicity has been reported, particularly in patients with renal dysfunction (likely because absorbed iodine is renally excreted). The authors were consulted on a 45-year-old patient with mediastinitis who had renal and hepatic dysfunction while being treated with mediastinal irrigation of povidone-iodine. The povidone-iodine irrigation was discontinued because he had toxic plasma iodine levels. Despite this, his condition worsened, and the iodine levels remained elevated. Thus, hemodialysis (HD) was initiated using high-flux membranes followed by continuous venovenous hemodiafiltration (CVVHDF; 2 L/h of hemofiltration and 2 L/h of HD). Plasma and effluent iodine levels were measured repeatedly to determine iodine clearance by these 2 modalities (HD, 120 mL/min; CVVHDF, 37 mL and 44 mL/min on days 1 and 2, respectively). Hepatic and renal functions improved with decreasing plasma iodine levels. Based on this experience and after reviewing the literature the authors conclude that: (1) iodine irrigation can increase blood iodine levels significantly, especially in the setting of renal failure, and lead to increased morbidity and mortality; (2) plasma iodine levels should be monitored in patients with renal insufficiency; and (3) HD and CVVHDF are effective at clearing iodine. The authors suggest that patients that are at high risk or already developing signs of iodine toxicity should have the iodine irrigation discontinued and may benefit from renal replacement therapy (RRT). Alternatively, concomitant RRT during iodine irrigation may be attempted to maintain the systemic iodine levels at nontoxic levels.

Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms.

This study examined the effect of hemin on the expression of heme oxygenase-1 (HO-1) and monocyte chemoattractant protein-1 (MCP-1) in immortalized rat proximal tubular epithelial cells (IRPTCs). Hemin elicited a dose- and time-dependent induction of HO-1 and MCP-1 mRNA. HO activity contributed to MCP-1 mRNA expression at early time points (4-6 h) because inhibition of HO activity by zinc protoporphyrin (ZnPP) prevented hemin-induced expression of MCP-1 mRNA. Catalytically active intracellular iron was markedly increased in hemin-treated IRPTCs and contributed to the induction of HO-1 and MCP-1 mRNA because an iron chelator blocked hemin-induced upregulation of both genes, whereas a cell-permeant form of iron directly induced these genes. N-acetylcysteine completely blocked hemin-induced expression of HO-1 and MCP-1 mRNA, thereby providing added evidence for redox regulation of expression of these genes. The redox-sensitive transcription factor NF-kappaB was recruited in hemin-induced upregulation of MCP-1 because two different compounds that abrogate the activation of NF-kappaB (TPCK and BAY 11-7082) completely blocked hemin-induced upregulation of MCP-1 mRNA. In contrast to this HO-mediated induction of MCP-1 through redox-sensitive, iron-dependent, and NF-kappaB-involved pathways observed after 4-6 h, hemin also elicited a delayed induction of MCP-1 at 18 h through HO-independent pathways. We conclude that hemin is a potent inducer of MCP-1 in IRPTCs: HO-dependent, heme-degrading pathways lead to an early, robust, and self-remitting induction of MCP-1, whereas HO-independent mechanisms lead to a delayed expression of MCP-1.