Estelle Desport

Glomerulonephritis With Isolated C3 Deposits and Monoclonal Gammopathy: A Fortuitous Association?

BACKGROUND AND OBJECTIVES Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. RESULTS All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (κ four of six, λ two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal λLC deposits were observed on a follow-up kidney biopsy after 4 years. CONCLUSIONS GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.

Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients

BACKGROUND Light chain myeloma cast nephropathy (MCN) is the major cause of renal failure in multiple myeloma and strongly impacts patient survival. The role of kidney biopsy in the management of MCN is unclear. METHODS Renal pathological findings were retrospectively studied in 70 patients with multiple myeloma and MCN. Patients were categorized according to the achievement or not of renal response, as defined by estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m(2) and/or dialysis independence at 3 months. RESULTS Thirty-two patients (46%) achieved a renal response. In the whole study population, the following parameters differed significantly between patients with and without renal response, respectively: baseline median eGFR (13.3 versus 9.3 mL/min/1.73 m(2), P = 0.017), Acute Kidney Injury Network Stage 3 (68.8 versus 92.1%, P = 0.019), haematological response rate (94 versus 34%, P < 0.0001), median percentage of free light chain (FLC) reduction at Day 21 (92 versus 24%, P = 0.006) and median number of casts/10 fields (14 versus 25, P = 0.005). The extent of interstitial fibrosis and tubular atrophy was similar. In multivariate analysis, only FLC reduction at Day 21 was significantly associated with renal response. However, when considering only the subgroup of haematological responders, both median number of casts [odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.88-0.98, P = 0.01] and extent of tubular atrophy (OR = 0.03, 95% CI: 0.00-0.52, P = 0.02) were independent predictors of renal response. CONCLUSIONS In MCN, the presence of numerous casts and diffuse tubular atrophy is associated with poor renal prognosis. These data suggest that additional strategies to reduce FLC burden should be considered in patients with extensive cast formation.

Acute immuno-allergic interstitial nephritis caused by fluindione.

Fluindione is a vitamin K antagonist that is commonly prescribed for the treatment of cardiovascular disease and venous thromboembolism in France. Bleeding is the most common side effect of fluindione, whereas hypersensitivity reactions are rare. We describe here a patient with acute immuno-allergic interstitial nephritis caused by fluindione. Initial symptoms included fever, eosinophilia, low albuminuria, microscopic hematuria, eosinophiluria and acute renal failure. Kidney biopsy showed severe interstitial nephritis with interstitial edema, inflammatory infiltrates and tubulorrhexis. Fluindione withdrawal and corticosteroid treatment resulted in rapid recovery of renal function. A review of the literature revealed a very low incidence of fluindione-induced interstitial nephritis, with variable renal and extra-renal signs. Early recognition of this rare complication may prevent the development of severe chronic renal injury.

Comparison of hemodialysis with medium cut-off dialyzer and on-line hemodiafiltration on the removal of small and middle-sized molecules

BACKGROUND Recent data suggest that the use of medium cut-off (MCO) dialyzers in hemodialysis (HD) promotes greater clearance and reduction ratio (RR) for myoglobin and other large-sized molecules than on-line hemodiafiltration (ol-HDF), but its effects on β2-microglobulin are not clear. We compared RR and clearances of small and middle-sized molecules between high-flux ol-HDF and MCO (Theranova) dialyzer in HD (MCO-HD) as well as nutritional parameters. MATERIALS AND METHODS We retrospectively analyzed 10 patients treated first with ol-HDF who were thereafter switched to MCO-HD over a 1-year period. Three dialysis sessions in each 6-month period were examined. We calculated RR and clearance of small and middle-sized molecules. RESULTS There was no significant difference between ol-HDF and MCO-HD for median serum albumin and prealbumin level, mean KT/V, mean urea and creatinine RR, mean β2-microglobulin (81 ± 5 vs. 81 ± 6%, p = 0.72) and myoglobin (60 ± 9% vs. 61 ± 7%, p = 0.59), RR or clearances. CONCLUSION The use of MCO (Theranova) dialyzer in HD produces similar removal of urea, creatinine, β2-microglobulin and myoglobin as does ol-HDF, with good tolerance profile and without modification of nutritional status.
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New insights in the treatment of myeloma with renal failure

Renal failure, mostly related to myeloma cast nephropathy (MCN), is a frequent complication of multiple myeloma (MM), which occurs in up to 50% of patients during the course of the disease. Persistent renal failure in MM is associated with poor survival. Treatment of MCN relies on urgent symptomatic measures (alkalinisation, rehydration, correction of hypercalcemia, and withdrawal of nephrotoxic drugs), with rapid introduction of chemotherapy to efficiently reduce the production of monoclonal light chains (LC). Recent studies suggest that, in patients with MM and severe renal failure due to MCN, rapid removal of circulating LC, through intensive hemodialysis sessions using a new generation high cut-off dialysis membrane, might result in dialysis withdrawal in most patients. If the development of intensive therapy and new efficient chemotherapy agents (thalidomide, bortezomib, lenalidomide) has transformed the care and prognosis of MM, the modalities and safety of these therapeutic regimens in patients with renal failure remain to be defined. The association of bortezomib with dexamethasone should be considered currently as first-line treatment in patients with MM and impaired renal function.

Fanconi syndrome and chronic kidney disease in paroxysmal nocturnal hemoglobinuria: effect of eculizumab therapy.

The association of Fanconi syndrome (FS) and chronic kidney disease (CKD) has been rarely described during the course of paroxysmal nocturnal hemoglobinuria (PNH). We report 2 patients with PNH and CKD associated with proximal tubule dysfunction, which manifested as full-blown FS in one case. In both patients, abnormal iron load within the kidneys was demonstrated by magnetic resonance imaging, which correlated with diffuse and numerous hemosiderin inclusions within proximal tubular cells. After 12 months, eculizumab treatment resulted in significant decrease in the kidney iron load in both cases. Glomerular filtration rate improved in one case and was stabilized in the other, in whom pretreatment kidney biopsy had shown severe extensive interstitial fibrosis. However, symptoms of proximal tubular dysfunction persisted in both patients. These data suggest that hemosiderin deposition in proximal tubules is probably an important mechanism involved in the development of FS, an under recognized and early manifestation of CKD in PNH. Prolonged treatment with eculizumab may improve long-term renal function in PNH patients with CKD.

Hepatocyte growth factor measurement in AL amyloidosis

Abstract Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95–max: 200.4] versus 1.4 ng/mL [min: 0.82–max: 6.2] (p < 0.0001). The threshold value of 2.2 ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies.

Effectiveness of second-line treatment in AL amyloidosis patient's refractory to M-Dex.

Oral melphalan and dexamethasone (MDex) is now widely considered to be the standard conventional treatment for patients with AL amyloidosis. With M-Dex median survival is around 5 years but survival of non-responders is poor in the absence of rescue treatment. We examined whether utilization of new drugs in non-responders to M-Dex is associated with an improved survival. We included 32 patients who received, as salvage therapy, thalidomide (n1⁄4 5), lenalidomide (n1⁄4 7), or bortezomib (n1⁄4 20). Hematological response occurred in 71%, with 34% complete response (CR). Partial response was obtained in 4/5 patients with thalidomide and 2/7 with lenalidomide; 17/20 patients (85%) in the bortezomib group responded with 11 CR (55%). With a median follow-up of 21 months, 23 patients (72%) are alive. Introduction of new drugs in refractory patients to MDex gives a high level of response leading to a better survival. Bortezomib seems to be particularly attractive with response rate of 85%, and 55% CR. Introduction: Since the randomized trial published in 2007 [1] comparing intensive treatment with stem cell support (melphalan 140 or 200 mg/m depending on age and clinical status supported with autologous stem cell transplant (ASCT) collected with granulocyte colony-stimulating factor (G-CSF) alone) and the oral regimen melphalan and dexamethasone (MDex) (melphalan 10 mg/m and dexamethasone 40 mg for 4 days each months, up to 18 months), M-Dex is our reference front-line therapy in patients with AL whatever be the risk group. With M-Dex, median survival is longer than with MP (melphalan and prednisone), being around 5 years, in our study as well as in the Italian series [2]. Patients with hematologic response (at least 50% drop in the monoclonal protein) after M-Dex have a very good median survival but survival was very poor for refractory patients in our study. The 12 nonresponder patients in the M-Dex arm (patients who received at least three cycles of M-Dex and had a measurable disease) had a median survival of only 6 months (Figure 1), in the absence of valuable rescue treatment between 2000 and 2005. The new drugs used in myeloma, thalidomide, lenalidomide, and bortezomib have been reported to be effective in patients with AL amyloidosis [3–8]. We examined whether utilization of these drugs in patients refractory to M-Dex has translated into improved outcome. Method: We performed a retrospective multicentric study in 11 centers belonging to the French network for AL amyloidosis. Patients with AL amyloidosis, treated front line with M-Dex, since June 2006 were included if they were considered as refractory by their referent physician and had received, as salvage treatment, thalidomide, lenalidomide, or bortezomib, associated to sequential dexamethasone and/or alkylating agents. We recorded the hematological response, monitored by the free light chain (FLC) assay, with second-line treatment. All patients but one enrolled in this study had measurable disease, only one patient had a monoclonal light chain level below 30 mg/l with an abnormal serum-free light chain ratio, he was considered as non-responder after the second-line treatment and normalized the ratio after third-line treatment with bortezomib and dexamethasone. Survival was analyzed from the first day Figure 1. Randomized trial (high-dose melphalan versus melphalan plus dexamethasone), 2000–2005 [1]. Survival according to the hematologic response in the 38 patients in the M-Dex arm who could be evaluated. Blue curve: patients with at least a 50% response. Red curve: patients with less than a 50% response, median survival: 6 months. 145

Atteintes rénales au cours du myélome multiple et des gammapathies monoclonales

Les nephropathies associees aux gammapathies monoclonales sont variees. Elles sont liees majoritairement au depot ou a la precipitation d’une immunoglobuline (Ig) monoclonale entiere ou d’un fragment de celle-ci, (le plus souvent une chaine legere [CL] monoclonale), et exceptionnellement a l’activite anticorps de l’Ig monoclonale. Leur diagnostic repose sur la confrontation des donnees cliniques, immuno-hematologiques et histologiques. L’analyse de la biopsie renale permet de preciser la nature, la localisation et le caractere organise ou non des depots d’Ig monoclonale. Les nephropathies tubulaires sont toujours secondaires a la precipitation intracytoplasmique (syndrome de Fanconi [SF]) ou intratubulaire (nephropathie a cylindres myelomateux [NCM]) des CL monoclonales, souvent organisees en cristaux. La NCM est la principale cause d’insuffisance renale (IR) au cours du myelome multiple (MM), notamment des MM a CL et de forte masse tumorale. Elle se manifeste typiquement par une IR aigue avec proteinurie faite majoritairement de CL, souvent revelatrice du MM et precedee de facteurs favorisant la precipitation intratubulaire des CL : infections, deshydratation, hypercalcemie, medicaments nephrotoxiques. Son pronostic est sombre, avec une reponse renale dans environ 50 % des cas, chiffre encore abaisse en dessous de 20 % en cas d’IR severe necessitant la dialyse. La persistance d’une IR reduit considerablement la survie des malades. Le traitement repose sur des mesures symptomatiques urgentes et l’introduction rapide d’une chimiotherapie adaptee, reposant en premiere intention sur l’association bortezomib-dexamethasone (BD). En situation d’IR necessitant la dialyse, l’utilisation de nouvelles membranes de dialyse de tres haute permeabilite aux proteines, permettant une epuration efficace des CL, pourrait ameliorer le pronostic renal et vital. Les nephropathies glomerulaires sont surtout representees par l’amylose AL, caracterisee par des depots fibrillaires de CL (habituellement λ), positifs au rouge Congo, et la maladie de depots d’Ig monoclonale de type Randall, definie par des depots lineaires non organises le plus souvent de CLκ de topographie peritubulaire, glomerulaire et vasculaire, non colores par le rouge Congo. L’atteinte renale se manifeste par une proteinurie abondante, avec syndrome nephrotique et IR dans la moitie des cas. La presence d’une hypertension arterielle et d’une hematurie microscopique est rare dans l’amylose AL, mais les manifestations extrarenales sont frequentes, dominee par la cardiopathie hypertrophique et restrictive, facteur pronostique majeur. L’association melphalan-dexamethasone constitue le traitement de reference actuel, visant a l’obtention rapide d’une reponse evaluee par la mesure reguliere des CL libres seriques et des marqueurs d’atteinte cardiaque (Nt-proBNP). L’adjonction du bortezomib semble efficace dans les formes resistantes.