Light Chain Cast Nephropathy in Multiple Myeloma: Prevalence, Impact and Management Challenges

"Cast nephropathy" (CN) is a pathological feature of myeloma kidney, also seen to a lesser extent in the context of severe nephrotic syndrome from non-haematological diseases. The name relates to obstruction of distal tubules by "casts" of luminal proteins concentrated by intensive water reabsorption resulting from dehydration or high-dose diuretics. Filtered proteins form complexes with endogenous tubular Tamm-Horsfall glycoprotein. The resulting gel further slows or stops luminal flow upon complete obstruction of distal convoluted tubules and collecting ducts. Thus, a tubular obstructive form of acute kidney injury (AKI) is a common consequence of CN. The pathogenesis of CN will be reviewed in light of recent advances in the understanding of monoclonal disorders of B lymphocytes, leading to the release of immunoglobulin components (free light chains, FLC) into the bloodstream and their filtration across the glomerular basement membrane. Treatment aiming at reduction of the circulating burden of FLC may help recovery of renal function in a fraction of these patients, besides filling the void between the onset of AKI, histopathological diagnosis, and full response to pharmacologic treatment

Serum Free Light Chains Removal by HFR Hemodiafiltration in Patients with Multiple Myeloma and Acute Kidney Injury. a Case Series

Background/Aims: Multiple myeloma (MM) represents 10% of all haematologic malignancies. Renal involvement occurs in 50% of MM patients; of them, 12-20% have acute kidney injury (AKI), with 10% needing dialysis at presentation. While hemodialysis (HD) has no effect upon circulating and tissue levels of monoclonal proteins, novel apheretic techniques aim at removing the paraproteins responsible for glomerular / tubular deposition disease. High cut-off HD (HCO-HD) combined with chemotherapy affords a sustained reduction of serum free light chains (FLC) levels. One alternative technology is haemodiafiltration with ultrafiltrate regeneration by adsorption on resin (HFR–SUPRA), employing a “super high-flux” membrane (polyphenylene S-HF, with a nominal cut-off of 42 kD). Aim of our pilot study was to analyze the effectiveness of HFR-SUPRA in reducing the burden of FLC, while minimizing albumin loss and hastening recovery of renal function in 6 subjects with MM complicated by AKI. Methods: Six HD-dependent patients with MM were treated with 5 consecutive sessions of HFR-SUPRA on a Bellco® monitor, while simultaneously initiating chemotherapy. Levels of albumin and FLC were assessed, calculating the rates of reduction. Renal outcome, HD withdrawal and clinical follow-up or death were recorded. Results: All patients showed a significant reduction of FLC, whereas serum albumin concentration remained unchanged. In three, HD was withdrawn, switching to a chemotherapy alone regimen. The other patients remained HD-dependent and died shortly thereafter for cardiovascular complications. Conclusion: Our study suggests that HFR-SUPRA provides a rapid and effective reduction in serum FLC in patients with MM and AKI

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities

Transient receptor potential channels in the kidney: calcium signalling, transport and beyond.

Multiple cationic channels with variable selectivity for Ca(2+) , K(+) and Na(+) have been identified in smooth muscle cells (SMC) as well as non-excitable cells. They control Ca(2+) store refilling and depletion, G-protein-mediated receptor activation, apoptosis and cell growth, membrane potential, intracellular pH, oxidative stress, phospholipid signaling, and other critical cell functions. A novel superfamily of divalent cation channels has been recently characterized as highly conserved heterotetramer homologues of Drosophila transient receptor potential (TRP). At least 50 members of seven major TRP channel families have been identified to date. The involvement of TRP in store-operated Ca(2+) - gating has been demonstrated in various tissues, along with intestinal and renal epithelial cell Ca(2+) and Mg(2+) transport, indicating a role in total body homeostasis of divalent cations. TRPV5-null mice display phenotypic defects including hypercalciuria and impaired bone mineral density. TRPP2 or polycystin 2 (PC2), encoded by the PKD2 gene, is an integral protein of epithelial cilia whose mutation is associated with autosomal dominant polycystic kidney disease (ADPKD). A TRPP1 (polycystin 1)-PC2 channel complex is actually implicated in the transduction of environmental signals (i.e. luminal tubular fluid flow and composition) into cellular events, such as epithelial cell growth. TRP channels can eventually play a role in the pathogenesis of arterial hypertension via direct effects on vascular smooth muscle contraction, renal blood flow, glomerular hemodynamics and the tubular handling of Ca2+ and electrolytes

Transient receptor potential channels, the kidney and hypertension

Smooth muscle cells as well as non-excitable cells express multiple cationic channels with significant permeability to calcium, potassium and sodium. Several of these channels are sensors of calcium store depletion, G-protein coupled receptor activation, membrane stretch, intracellular Ca2+, pH, oxidative stress, phospholipid signals and other factors. A novel family of such channels is encoded by genes homologues of Drosophila TRP (transient receptor potential). Direct evidence exists for roles of TRPC1, TRPC4/5, TRPC6, TRPV2, TRPP1 and TRPP2 in store-operated Ca2+- gating and epithelial cell Ca2+ transport, thus controlling smooth muscle reactivity and at the same time renal homeostasis of divalent cations. Mice deficient in TRPV5 express phenotypic defects amongst which hypercalciuria and impaired bone mineral density. Polycystin 2 (PC2), encoded by the PKD2 gene, is an epithelial transmembrane protein whose mutation is associated to autosomal dominant polycystic kidney disease (ADPKD). PC2 behaves as a TRP-type Ca2+-permeable nonselective cation channel. It is implicated in the transient increase in cytosolic Ca2+ in renal epithelial cells, and may be linked to the activation of subsequent signaling pathways. Recent studies indicate that a PC1-PC2 channel complex is an obligatory novel signaling pathway implicated in the transduction of environmental signals into cellular events. TRP-related ion channels may thus play a role in the pathogenesis of hypertension through direct effects on vascular smooth muscle contraction, renal perfusion/hemodynamics, and the total body balance of divalent cations

Recent perspectives in the mechanisms and therapy of renal sclerosis

Chronic renal failure results from progressive sclerosis of injured kidney structures and overload of remnant functioning nephrons in an attempt to compensate for the lost excretory and fluid/solute regulatory capabilities. Key to delaying--or even reversing--the decay of renal function would be a therapy capable of blocking re-nal sclerosis. Therefore, a number of recent studies deal with this issue with a wealth of novel approaches. Considerable success has been achieved in experimental models by applying gene therapy, cell therapy, novel pharmacologic inhibitors of growth factors and matrigenic molecules. While the final step forward to human therapy is not an immediate option, it is likely that the next few years will witness initial trials of novel pharmacologic agents. Along with the already available new drugs suitable to prevent or delay renal transplant rejection or immunologic renal injury, the therapeutic scenario of contemporary nephrology is rapidly evolving. Some major novel findings in the area will be summarized, along with potential implications for human therapy