Chronic kidney disease-associated pruritus (CKD-aP) is associated with worse quality of life and increased healthcare utilization among dialysis patients.

PURPOSE: Chronic pruritus significantly impairs hemodialysis patients' health status and quality of life (QOL) and it is associated with higher mortality rate, more frequent hospitalizations, poorer dialysis and medication adherence, and deteriorated mental status. However, pruritus is still underestimated, underdiagnosed, and undertreated in the real-life clinical scenario. We investigated prevalence, clinical characteristics, clinical correlates, severity as well as physical and psychological burden of chronic pruritus among adult hemodialysis patients in a large international real-world cohort. METHODS: We conducted a retrospective cross-sectional study of patients registered in 152 Fresenius Medical Care (FMC) NephroCare clinics located in Italy, France, Ireland, United Kingdom, and Spain. Demographic and medical data were retrieved from the EuCliD® (European Clinical) database, while information on pruritus and QoL were abstracted from KDQOL™-36 and 5-D Itch questionnaire scores. RESULTS: A total of 6221 patients were included, of which 1238 were from France, 163 Ireland, 1469 Italy, 2633 Spain, and 718 UK. The prevalence of mild-to-severe pruritus was 47.9% (n = 2977 patients). Increased pruritus severity was associated with increased use of antidepressants, antihistamines, and gabapentin. Patients with severe pruritus more likely suffered from diabetes, more frequently missed dialysis sessions, and underwent more hospitalizations due to infections. Both mental and physical QOL scores were progressively lower as the severity of pruritus increased; this association was robust to adjustment for potential confounders. CONCLUSION: This international real-world analysis confirms that chronic pruritus is a highly prevalent condition among dialysis patients and highlights its considerable burden on several dimensions of patients' life.

Secretion of IL-1ß From Monocytes in Gout Is Redox Independent.

The pro-inflammatory cytokine interleukin-1ß (IL-1ß) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1ß secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1ß secretion. Gout is a disease driven solely by IL-1ß secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1ß secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation.

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 uraemic 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 cells and complement activation, haemolysis, adsorption of electrolytes and plasma proteins. The small monoliths were tested in a naive 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 uraemic toxins IS, PCS and high molecular weight cytokines TNF-α and IL-6 over 240 min using a flow rate of 300 ml min-1 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.

Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury.

OBJECTIVES: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function. METHODS: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined. RESULTS: Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8-93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months. CONCLUSION: In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to myeloma cast nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function.

Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease.

OBJECTIVE: To determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD). PATIENTS AND METHODS: From January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels. The cohort was prospectively followed up for a median of 63 months (interquartile range, 0-93 months). Cox regression analysis was performed to determine variables predictive of mortality. RESULTS: High cFLC levels were an independent risk factor for death (hazard ratio [HR], 2.71; 95% CI, 1.98-3.70; P<.001). Other independent risk factors were age (HR, 1.79; 95% CI, 1.52-2.10; P<.001), South Asian ethnicity (HR, 0.33; 95% CI, 0.14-0.64; P=.02), preexisting cardiovascular disease (HR, 1.59; 95% CI, 1.09-2.31; P=.02), and high-sensitivity C-reactive protein (HR, 1.13; 95% CI, 1.00-1.28; P=.04). Neither estimated glomerular filtration rate nor albuminuria was an independent risk factor for death. CONCLUSION: High cFLC levels independently predict mortality in people with CKD.

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.

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.

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 nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism.

One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase-dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKß and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase-dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.

Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney.

BACKGROUND: Most cases of dialysis-dependent acute kidney injury due to myeloma cast nephropathy do not recover renal function. Renal biopsy typically shows cast formation, direct tubular injury and interstitial inflammation caused by nephrotoxic monoclonal free light chains (FLC). Established scarring at presentation is rarely severe. There is little data on in situ evolution of renal injury. AIMS: To conduct a detailed histological study of four patients with cast nephropathy. METHODS: Cast nephropathy was confirmed by renal biopsy. Treatment consisted of chemotherapy and high cut-off dialysis to maximise extracorporeal removal of FLC and reduce renal toxicity. All four patients remained dialysis dependent at 6 weeks, at which time they underwent a further biopsy. RESULTS: Three patients achieved independence from dialysis. Six-week biopsies showed differential changes in chronic damage from no progression, to accelerated progression of scarring from 10% to 42%, despite a rapid and sustained fall in FLC in all patients. In three patients there was a major reduction in intratubular cast numbers; these patients subsequently recovered renal function. In one patient who continued to have high cast formation at 6 weeks there was no subsequent renal recovery. CONCLUSIONS: Some FLC clones can promote rapid renal scarring. Significant reductions in cast formation on repeat biopsy may identify the potential for late renal recovery. Early diagnosis and treatment may prove crucial in determining renal recovery. Patients who have not recovered renal function after a period of treatment may be usefully reassessed by repeat biopsy for quantitative analysis of chronic damage and cast numbers.

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 H(2)O(2) 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 H(2)O(2) 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 H(2)O(2), indicating that production of H(2)O(2) 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 H(2)O(2) induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1.

Serum free light chain assessment in monoclonal gammopathy and kidney disease.

Abnormalities of immunoglobulin free light chains (FLCs) are frequently present in patients with monoclonal gammopathies and can cause kidney disease. The recent introduction of highly sensitive immunoassays that measure FLCs to levels below those present in normal individuals has provided a new tool for diagnosis and management in this setting. Here, we review the biology of FLC production in health and disease, and the utility of FLC immunoassays in the assessment of monoclonal gammopathies in kidney disease.

Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis.

BACKGROUND AND OBJECTIVES: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD. RESULTS: There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012). CONCLUSION: In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function.

Resolution of cast nephropathy following free light chain removal by haemodialysis in a patient with multiple myeloma: a case report.

INTRODUCTION: Acute renal failure in multiple myeloma is most frequently caused by cast nephropathy, when excess monoclonal free light chains co-precipitate with Tamm-Horsfall protein in the distal nephron, causing tubular obstruction. The natural history of cast nephropathy after diagnosis is unknown. This report provides supporting histological evidence that, as serum free light chain concentrations fall, intratubular casts may resolve within weeks. CASE PRESENTATION: We report the case of a 61-year-old Caucasian woman who presented with multiple myeloma and dialysis-dependent acute renal failure, with serum kappa free light chain concentrations of 15,700 mg/litre (normal range 3.3 to 19.4 mg/litre). Renal biopsy demonstrated cast nephropathy with waxy casts in distal tubules and collecting ducts. There was an interstitial inflammatory cell infiltrate with diffuse fibrosis and tubular atrophy. Following rehydration, chemotherapy and free light chain removal using high cut-off haemodialysis, free light chain concentrations fell to less than 5% of the starting level (500 mg/litre). A repeat renal biopsy 6 weeks after the first showed resolution of cast nephropathy. CONCLUSION: These observations indicate that cast nephropathy can quickly resolve on rapid reduction of monoclonal serum free light chains. This has important implications for the development of treatment strategies aimed at improving renal recovery rates for patients in this setting.

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

BACKGROUND: 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 kappa to lambda 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. METHODS: 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. RESULTS: 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. CONCLUSION: Measurement of serum FLC concentrations and calculation of the serum kappa/lambda 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.