Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney)

Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains. This paper bridges recent advances in the pathogenesis and management of cast nephropathy in multiple myeloma

An adsorbent monolith device to augment the removal of uraemic toxins during haemodialysis

Adsorbents designed with porosity which allows the removal of protein bound and high molecular weight uraemic toxins may improve the effectiveness of haemodialysis treatment of chronic kidney disease (CKD). A nanoporous activated carbon monolith prototype designed for direct blood contact was first assessed for its capacity to remove albumin bound marker toxins indoxyl sulphate (IS), p-cresyl sulphate (p-CS) and high molecular weight cytokine interleukin-6 in spiked healthy donor studies. Haemodialysis patient blood samples were then used to measure the presence of these markers in pre- and post-dialysis blood and their removal by adsorbent recirculation of post-dialysis blood samples. Nanopores (20–100 nm) were necessary for marker uraemic toxin removal during in vitro studies. Limited removal of IS and p-CS occurred during haemodialysis, whereas almost complete removal occurred following perfusion through the carbon monoliths suggesting a key role for such adsorbent therapies in CKD patient care

Irregular Migration as a Potential Source of Malaria Reintroduction in Sri Lanka and Use of Malaria Rapid Diagnostic Tests at Point-of-Entry Screening

Background. We describe an irregular migrant who returned to Sri Lanka after a failed people smuggling operation from West Africa. Results. On-arrival screening by Anti-Malaria Campaign (AMC) officers using a rapid diagnostic test (RDT) (CareStart Malaria HRP2/PLDH) indicated a negative result. On day 3 after arrival, he presented with fever and chills but was managed as dengue (which is hyperendemic in Sri Lanka). Only on day 7, diagnosis of Plasmodium falciparum malaria was made by microcopy and CareStart RDT. The initially negative RDT was ascribed to a low parasite density. Irregular migration may be an unrecognized source of malaria reintroduction. Despite some limitations in detection, RDTs form an important point-of-entry assessment. As a consequence of this case, the AMC is now focused on repeat testing and close monitoring of all irregular migrants from malaria-endemic zones. Conclusion. The present case study highlights the effective collaboration and coordination between inter-governmental agencies such as IOM and the Ministry of Health towards the goals of malaria elimination in Sri Lanka

A haemocompatible and scalable nanoporous adsorbent monolith synthesised using a novel lignin binder route to augment the adsorption of poorly removed uraemic toxins in haemodialysis

Nanoporous adsorbents are promising materials to augment the efficacy of haemodialysis for the treatment of end stage renal disease where mortality rates remain unacceptably high despite improvements in membrane technology. Complications are linked in part to inefficient removal of protein bound and high molecular weight uremic toxins including key marker molecules albumin bound indoxyl sulphate (IS) and p-cresyl sulphate (PCS) and large inflammatory cytokines such as IL-6. The following study describes the assessment of a nanoporous activated carbon monolith produced using a novel binder synthesis route for scale up as an in line device to augment haemodialysis through adsorption of these toxins. Small and large monoliths were synthesised using an optimised ratio of lignin binder to porous resin of 1 in 4. Small monoliths showing combined significant IS, p-CS and IL-6 adsorption were used to measure haemocompatibility in an ex vivo healthy donor blood perfusion model, assessing coagulation, platelet, granulocyte, t cell and complement activation, haemolysis, adsorption of electrolytes and plasma proteins. The small monoliths were tested in a niave rat model and showed stable blood gas values, blood pressure, blood biochemistry and the absence of coagulopathies. These monoliths were scaled up to a clinically relevant size and were able to maintain adsorption of protein bound uremic toxins IS, PCS and high molecular weight cytokines TNF and IL-6 over 60 minutes using a flow rate of 300 mL/min without platelet activation. The nanoporous monoliths where haemocompatible and retained adsorptive efficacy on scale up with negligible pressure drop across the system indicating potential for use as an in-line device to improve haemodialysis efficacy by adsorption of otherwise poorly removed uraemic toxins

Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure

<p>Abstract</p> <p>Background</p> <p>Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal κ to λ FLC ratio (reference range 0.26–1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37–3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure.</p> <p>Methods</p> <p>Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis.</p> <p>Results</p> <p>Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed.</p> <p>Conclusion</p> <p>Measurement of serum FLC concentrations and calculation of the serum κ/λ ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.</p

The biology of immunoglobulin free light chains in kidney disease: a study of Monoclonal and Polyclonal light chains

Monoclonal immunoglobulin free light chains (FLCs) cause a range of disorders in the kidney. In multiple myeloma, FLCs can activate the proximal tubule to release MCP-1, an important cytokine in renal fibrosis. Distal tubular cast formation can also occur when FLCs co-precipitate with uromodulin. However a pathogenic role for the elevated polyclonal FLC concentrations seen in chronic kidney disease has not been assessed to date. This thesis explores the biology of monoclonal FLCs as well as polyclonal FLCs. Detailed histological analyses demonstrated that in multiple myeloma, interstitial fibrosis can progress rapidly in situ and indicated that intratubular cast numbers might be linked to potential for renal recovery. The functional basis of this fibrosis was explored by in vitro studies, which showed that upon endocytosis of FLCs, oxidative stress activated redox signalling, resulting in MCP-1 production. Further in situ analyses showed that in chronic kidney disease, polyclonal FLCs co-localised with uromodulin in distal tubular casts. Relationships between these casts and markers of progression of chronic kidney disease were demonstrated. In vitro analyses then showed that polyclonal FLCs bind to uromodulin and promote aggregation. These findings: (i) further delineate the pathways for proximal tubular injury in myeloma and (ii) indicate a potential pathogenic role for polyclonal FLCs in the distal nephron

The biology of immunoglobulin free light chains and kidney injury.

Kidney injury caused by immunoglobulin free light chains (FLCs) in the setting of plasma cell dyscrasias is common and associated with increased morbidity and mortality. All compartments of the kidney may be affected, from the glomerulus to the tubulointerstitium, in a wide variety of disease patterns. Here, we review our current knowledge of the biological effects of FLCs and the mechanisms that lead to kidney injury

Immunoglobulin Light Chains Activate Tubular Epithelial Cells through Redox Signaling

The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H2O2 production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H2O2 generated after light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different light chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the light chain–induced MCP-1 response, but had no effect on H2O2, indicating that production of H2O2 is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H2O2 induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1