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

Effetti dell'acido urico sulle cellule glomerulari mesangiali: meccanismi intracellulari di trasduzione del segnale e possibili implicazioni nella progressione del danno renale e nella sindrome infiammatoria in corso di nefropatie croniche

Uric acid is a major inducer of inflammation in renal interstitium and may play a role in the progression of renal damage in hyperuricemic subjects with primary nephropathies, renal vascular disease, and essential hypertension. At the same time, UA also acts as a water-soluble scavenger of reactive oxygen species. We evaluated the cellular effects of UA on cultured HMC as a potential interstitial target for abnormally elevated levels in acute and chronic renal disease. Intracellular free Ca2+ ([Ca2+]i) was monitored by microfluorometry of fura 2-loaded cells, while oxidation of intracellularly trapped non-fluorescent 2,7-dichlorofluorescein diacetate (DCFHDA, 20 uM) was employed to assess the generation of reactive oxygen species during 12-hr incubations with various concentrations of UA or monosodium urate. Fluorescent metabolites of DCFH-DA in the culture media of HMC were detected at 485/530 nm excitation/emission wavelengths, respectively. UA dose-dependently lowered resting [Ca2+]i (from 102±9 nM to 95±3, 57±2, 48±6 nM at 1-100 uM UA, respectively, p <0.05), leaving responses to vasoconstrictors such as angiotensin II unaffected. The effect was not due to Ca2+/H+ exchange upon acidification of the bathing media, as acetate, glutamate, lactate and other organic acids rather increased [Ca2+]i (to max. levels of 497±42 nM with 0.1 mM acetate). The decrease of [Ca2+]i was abolished by raising extracellular Ca2+ and not due to effects on Ca2+ channels or activation of Ca2+-ATPases, since unaffected by thapsigargin. The process rather appeared sensitive to removal of extracellular Na+ in combination with blockers of Na+/Ca2+ exchange, such as 2’,4’-dichlorobenzamil, pointing to a countertransport mechanism. UA dose-dependently prompted the extracellular release of oxidised DCFH (control 37±2 relative fluorescence units (RFU)/ml, 0.1uM 47±2, 1 uM 48±2, 10 uM 51±4, 0.1 mM 53±4; positive control, 10 uM sodium nitroprusside 92±5 RFU/ml, p<0.01). In summary, UA interferes with Ca2+ transport in cultured HMC, triggering oxidative stress which may initiate a sequence of events leading to interstitial injury and possibly amplifying renal vascular damage and/or the progression of chronic disease

Acute Kidney Injury in Monoclonal Gammopathies

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as “cast nephropathy”. Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment

Diagnosis and follow-up of idiopathic retroperitoneal fibrosis. role of 18F-FDG-PET/CT and biochemical parameters in patients with renal involvment

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease characterized by fibro-inflammatory reaction surrounding ureters and other inner organs with possible secondary renal involvement. Symptoms are aspecific and recurrent phases of activity are generally associated with elevation of inflammatory indices. 18F-FDG-PET is nowadays an important tool for the detection of this disease, allowing differentiation between metabolically active tissue and fibrotic one. The purpose of this study was to investigate the role of 18F-FDG-PET in the management of IRF and to evaluate possible correlations between biochemical parameters and PET/CT findings of disease activity. We enrolled seven consecutive patients with IRF (in five histology proved the disease) observed from 2003 to 2012 (5 M:2 F, mean age 53.8 years, range 44-86 years). All patients presented with fever as first symptom; two had obstructive renal failure requiring hemodialysis; one underwent monolateral nephrectomy for parenchyma infiltration; six presented ureteral involvement; three underwent ureteral stent placement. For each patient, during a mean total follow-up of 26.5 months we evaluated serum creatinine, BUN, Hb, RBCs, WBCs, PLT, CRP, ESR. Periodic 18F-FDG-PET/CT scans (every 5.9 months-mean) were performed in all patients. Statistical evaluation was performed using "stepwise regression" analysis. Steroids and immunosuppressive agents induced a progressive normalization of PET/CT scans in all patients at the end of follow-up. Stepwise regression analysis showed that BUN, serum creatinine and CRP only if considered together, significantly correlated with SUV max (p value = 0.000003057). 18F-FDG-PET is a useful tool for clinical decision making in patient with IRF, allowing to evaluate the efficacy of the pharmacological treatment and to detect early recurrences, to modify the therapeutic approach. Acute phase reactants are not reliable alone for the management and the follow-up as they are often not concordant with metabolic assessment of the disease. In patients with ureteral involvement, CRP together with BUN and serum creatinine has a significant correlation with PET/CT results, and can help physicians in therapeutic approach, better than a single parameter

Safety and efficacy of denosumab in osteoporotic hemodialysed patients

Background and aims: In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients. Methods: We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6 months for an observation period of 24 months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated. Results: Over 24 months, we observed a gradual improvement of bone metabolism: β-CrossLaps from 2567.08 ± 1264 to 1492.5 ± 1182.5 pg/ml; bone alkaline phosphatase (BALP) from 33.5 ± 28.8 to 11.8 ± 3.7 mcg/l, and of QUS index (T-score from −5.33 ± 1.58 to −4.84 ± 1.2; risk of fracture from 13.9 ± 4.7 to 11.07 ± 5.3 %). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels. Conclusions: Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.