Light chain deposition disease with concurrent myeloma multiplex - a successful treatment of AKI induced by lambda FLC

Light chain deposition disease with concurrent myeloma multiplex - a successful treatment of AKI induced by lambda FLCLight chain deposition disease with concurrent myeloma multiplex - a successful treatment of AKI induced by lambda FLC
'Department of Nephrology, Jagiellonian University Medical College, Cracow, Poland Head: Prof. dr hab. n. med. Marek Kuniewski
’Department of Haematology, Jagiellonian University Medical College, Cracow, Poland Head: Prof. dr hab. n. med. Tomasz Sacha
’Department of Haematology, Oncology and Internal Diseasese, Warsaw Medical University, Warsaw, Poland Head: Prof. dr hab. n. med. Grzegorz Wadysaw Basak
Additional key words: acute kidney injury high cut-off dialyzers light chain deposition disease multiple myeloma
Dodatkowe sowa kluczowe: ostre uszkodzenie nerek dializatory typu high cut-off choroba zogów acucha lekkiego szpiczak mnogi
Conflict of interest not declared
Received: 05. 08. 2019 Accepted: 31. 08. 2019
Address for correspondence: Woziwodzka Karolina, MD Department of Nephrology, Jagiellonian University, Collegium Medicum 31-501 Krakow, Kopernika 15 c e-mail: woziwodzka. karolina@gmail. com
Light chain deposition disease (LCDD) is a type of monoclonal im­ munoglobulins deposition disease (MIDD). The characteristic are im­ munoglobulin light chains deposits, most commonly kappa (k) that are neither fibrilar nor Congo red posi­ tive, in multiple organs, especially the kidney. The incidence of LCDD in patients with plasma cell dyscrasia is approximately 5%. Up to 50% of pa­ tients with LCDD may have concur­ rent multiple myeloma (MM). One of the most frequent syndrome of LCDD is a rapidly progressive renal failure. The remaining are proteinuria, micro­ scopic haematuria or acute tubuloin- testinal nephritis. The treatment of LCDD is the same as that for multiple myeloma (MM).
Light chain multiple myeloma (LCMM) is a variant of approximately 15-20% of patients with MM. The most frequent symptoms in this disease are: renal failure, bone disease, and systemic light chain AL amyloidosis. The patients are in earlier average age. LCMM appears to have a poorer prognosis when compared to IgG or IgA MM variant.
Some anticancer drugs are neph­ rotoxic and cannot be administered to older patients or those with renal impairment. In cases of AKI related to LCDD/MM, HCO (high cut-off) dialysis can be useful in removing free light chains (FLCs) from serum with effec­ tive chemotherapy.
Choroba zogów acucha lekkie­ go (LCDD) to rodzaj choroby z de­ ponowaniem zogów monoklonalnej immunoglobuliny (MIDD). Charakte­ rystyczne s odkadajce si w ró­ nych tkankach, w tym w nerkach, zogi depozytów acuchów lekkich, gównie kappa, które s bezpostacio­ we (niezorganizowane) i nie wykazu­ j cech barwienia czerwieni Kongo. LCDD stanowi do 5% paraproteine- mii, a u okoo 50% chorych z LCDD moe wspówystpowa szpiczak mnogi (MM). Jednym z najczciej wystpujcych objawów LCDD jest szybko postpujca niewydolno nerek. Pozostae objawy to biako­ mocz, krwinkomocz lub ostre cewko- wo-ródmiszowe zapalenie nerek. Leczenie LCDD jest takie samo jak w szpiczaku mnogim.
Choroba acuchów lekkich (LCMM) - wariant szpiczaka, w któ­ rym wytwarzane s tylko acuchy lekkie, wystpuje wród okoo 15- 20% chorych z MM. W tym przy­ padku najczstszymi objawami s niewydolno nerek, zmiany litycz­ ne w kociach i uogólniona amylo- idoza AL. Dotyczy chorych w mod­ szym wieku. Wydaje si, e pacjenci z LCMM maj gorsze rokowanie ni w pozostaych wariantach MM (IgG czy Ig A).
Z uwagi na nefrotoksyczno chemioterapii, niektóre z nowych le­ ków stosowanych wleczeniu MM nie mog by podawane w penych daw­ kach osobom w podeszym wieku lub z zaawansowan niewydolnoci ne­ rek. Dlatego w przypadkach ostrego uszkodzenia nerek (AKI) w przebiegu LCDD/LCMM uycie wysokoprze- puszczalnego dializatora typu high cut-off (HCO) moe by pomocne w usuwaniu acuchów lekkich z su­ rowicy i wzmaga efektywno che­ mioterapii.
452 K. Woziwodzka et al.
Introduction Monoclonal immunoglobulin deposition
disease (MIDD) is a rare paraproteinemia characterized by deposits of monoclonal immunoglobulin in multiple organs, also in the kidney. MIDD is classified into light cha­ in deposition disease (LCDD), heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD), depending on the composition of the de­ posits. LCDD is the most common form of MIDD (75-80%) [1, 2],
LCDD occurs most frequently in older men in 5lh-6th decade at presentation. The most common organ manifestation affects kidney (93-100%) with symptoms like: proteinuria, microscopic haematuria, hy­ pertension and variable degrees of renal insufficiency. Nephrotic-range proteinuria is common, however nephrotic syndrome occurs only in 25% of patients [2].
Other clinical features in LCDD con­ cern: liver disorder, polyneuropathy, heart and lung disorders.
The characteristic histological featu­ res of renal LCDD are: nodular sclerosing glomerulopathy in 60% (the nodules are a mixture of light chains and mesangial protein); diffuse linear staining of glome­ rular basement membranes (GBM) and tubular basement membranes (TBM) - predominantly along the loops of Henle and the distal tubules, but they also often are detected along the proximal tubules for a single light chain (LCDD) [3]. The depo­ sits in LCDD are composed of monotypic light chain deposits, most commonly kappa subtype (92%) and the majority VKIV sub­ group [4], These deposits are non-amylo- id and do not exhibit fibrillar structure ul- trastructurally. Several investigators have characterized the structural and biochemi­ cal properties of the light chains produced in patients with LCDD at the cDNA and pro­ tein levels [5, 6].
LCDD typically occurs in association with multiple myeloma (MM) or other lym- phoplasmacytic disorders. The incidence of LCDD in patients with plasma cell dys- crasia is approximately 5%. Up to 50% of patients with LCDD have concurrent MM. Moreover, LCDD with cast nephropathy has more severe course of disease than isolated LCDD [2, 7],
MM in around 15-20% of cases is con­ nected with proliferation of light chain, cal- ied light chain multiple myeloma (LCMM). The clinical diagnosis is based on presen­ ce of free light chains (FLCs) in serum or/ and urine, clonal bone marrow plasma cells dysplasia and end organ damage. The pa­ thogenesis of renal injury is associated with hyperproduction of clonal FLCs. In comparison to other types of MM like IgG, LCMM has poorer prognosis and appears in earlier age of patients [8, 9],
Both, in LCDD and LCMM the higher creatinine concentration (especially abo- ve 4 mg/dl) is associated with the poorer outcome, including progression to end-sta­ ge chronic kidney disease (ES-CKD) and Worse overall survival. Hence, early dia­ gnosis and appropriate treatment is impor­ tant to decrease the concentration of FLCs
promptly. Such treatment can contribute to improved survival. In case of LCDD 5 year survival rate is around 70%, less with co­ existing MM [10]. Furthermore, in patients with ES-CKD who underwent autologous stem cell transplantation (ASCT) without efficient FLCs control, recurrence of LCDD or LCMM was observed [9, 11].
Still, no standard treatment has been established. Conventional chemotherapy (alkylating agents and steroids) response has minor effects on kidney function. But, it is observed better response with a rele­ vant reduction of light chains in serum and/ or urine by novel agents treatment like bor- tezomib. Furthermore, in LCDD an ASCT is able to prolong the dialysis-free survival. However, the nephrotoxicity of new thera­ pies remains unknown [12, 13],
Case report A 61-years old female with history of
pharmacologically controlled hypertension and laparoscopic hysterectomy because of uterine myomatosis, without any other chronic diseases, was referred to our neph­ rology unit urgently due to elevated serum creatinine level as an acute kidney injury (AKI) and severe, life-threatening anaemia.
Personal and family history was unre­ markable for diabetes and renal disease. In laboratory test six months prior to admis­ sion serum creatinine level lied in reference ranges (89 pmol/l, eGFR (MDRD formula) > 60 ml/min/1, 73 m2). On admission patient mainly complained about weakness, nyctu­ ria, decreased appetite and loss of weight since few weeks. Two months earlier epi­ sodes of pruritus occurred.
Physical examination revealed haemo- dynamically stable, pale patient with mild hypertension at presentation (BP-150/70 mmHg).
Laboratory test revealed increased se­ rum urea level 29. 1 mmol/l and serum cre­ atinine level 1419 pmol/l, eGFR using the MDRD formula 2 ml/min/1, 73 m2 normocy­ tic, normochromic anaemia with decreased haematocrit (17. 5%) and haemoglobin le­ vel 5. 7 g/l. Moreover, acidosis, hyperpho­ sphatemia (P-3. 03 mmol/l), normocalce- mia and high lactate dehydrogenase level (LDH -1040. 3 U/l) were observed.
Ultrasound showed enlarged both kid­ neys with increased echogenicity without loss of corticomedullary differentiation. No organomegaly was noted.
Urine analysis detected erythrocytes (15-25/HPF) and leukocytes (5-10/HPF) with no bacteria.
A 24-hour urine protein excretion was increased (5. 97 g); although serum albu­ min levels (32 g/l) and total protein concen­ tration (78. 0 g/l) were normal.
Further laboratory work up showed el­ evated band in serum electrophoresis for gammaglobulins (13, 01 g/l) and betaglobu­ lins (18, 94 g/l), presence of monoclonal protein in serum with inappropriate k/A light chains ratio - 0. 07 (elevated A light chains concentration up to 12. 20 g/l) and abnormal k-FLC/A-FLC blood ratio 0. 0036 (A FLC 7810. 00 mg/l in serum) and high se­ rum beta2-microglobulin level 76. 20 mg/l.
Moreover, urine A light chains concentra­ tion 1710. 000 mg/l, with abnormal k/A urine ratio 0. 01, similar to elevated urine A FLC level to 8. 810 mg/l and urine beta2-mik- roglobulin level up to 199. 00 mg/l.
A skeletal X-ray survey identified small marked lytic lesion in the posterior part of VII rib and the similar one in the lateral edge of the scapula. Skull and pelvic bones imaging did not revealed lytic bone lesions.
Performed bone marrow biopsy re­ vealed cellularity of 50-99% with around 90% of atypical plasmocytes with interme­ diate malignancy, CD 138+ kappa-/lamb- da+ formed in diffuse infiltration. Congo- philic protein deposits were not detected. Histopathological image was characteristic to massive plasma cell myeloma (III grade).
On admission an immediate blood transfusion was given in a total numer of 6 unites. Since, light chain induced renal fail­ ure is an emergency situation, dialysis was immediately started via temporary hemo­ dialysis catheter inserted into right internal jugular vein. The patient underwent totally 27 hemodialysis procedures, 12 of them with using high cut-off (HCO) membrane - Theralite dialyzers.
The regimen of thalidomide, borte- zomib and dexamethasone (VTD scheme) was administered.
In the second week of therapy, tha­ lidomide therapy was interrupted due to severe hepatotoxicity. Afterwards, the pa­ tient was discharged home in stable con­ dition, with preserved diuresis (around 3000 ml per day). She continued hemodi­ alsis therapy 3 times per week in Dialysis Station. Then renal function parameters gradually improved. In 8th week from ad­ mission she did not require renal replace­ ment therapy. Stable serum creatinine level of 260 pmol/l with eGFR (MDRD formula) 17 ml/min/1, 73 m2was observed.
The patient received haematological treatment of 5 cycles of VD. Later, she was qualified for autologous bone marrow transplantation (ASCT). Cytarabine (ARA- -C) was used for stem cell mobilization. But, in 5lh month from diagnosis the recur­ rence of the disease was reported. Month later she underwent auto-peripherial blood stem cell transplantation (auto-PBSCT) and then tandem PBSCT.
Post-transplantation follow-up inclu­ ded physical examination and blood pulse, serum and urine laboratory tests. Further improvement of renal function parameters was noted with serum creatinine level of 208 pmol/l, eGFR 22 ml/min/1, 73 m2.
Discussion The patient was admitted with LCDD
with concurrent MM or LCMM manifesting as AKI and heavy proteinuria. The treat­ ment was intensive medical therapy regi­ men VTD (bortezomib, thalidomide, and dexamethasone), but because of severe heapototoxicity next 5 regimen were con­ tinued with VD. The first four dialysis ses­ sions were performed using the dialyzer Fresenius F7 and F8, the next 12 dialyzer using a HCO (high-cut-off) dialyzer therali­ te and the last 11 again Fresenius F7 and
Pr«gM Lekarski 2019 / 76 / 8 453
rigure i Concentrations of serum FLCs (kappa and lambda), serum monoclonal protein and serum creatinine at the diagnosis and during the treatment. The arrows show the HCO-HD. The dates are reported as a number of day after administration to the hospital. Wykres 1 Stenie FLC kappa i lambda, biaka monoklonalnego i kreatyniny w surowicy krwi w chwili rozpoznania i w trakcie leczenia. Strzaki oznaczaj leczenie HD przy uyciu dializy HCO. Daty podano w formacie liczby dni od przyjcia do szpitala.
F8. In total the renal replacement therapy time was 8 weeks with concurrent chemo­ therapy. This treatment resulted in clinical improvement and disappearance of ha­ ematological symptoms and AKI.
Overproduction of FLCs, responsi­ ble for kidney injury, can deposit on the glomerular and tubular basement mem­ brane as well as in mesangium leading to disruptions in the filtration barrier [14], If FLCs do not have organization structu­ re, this contributes to light chain deposit disease (LCDD). In clinic albuminuria and microhaematuria with renal dysfunction is observed. The treatment was introduced: inhibition of production of monoclonal FLC by chemotherapy and fast removal of FLCs via dialysis [15], According to various data, in LCDD, in case of proven MM criteria in bone marrow biopsy we can classify it as LCDD with concurrent MM or LCMM. Some authors suggest that with coexisting severe albuminuria LCDD should be reco­ gnised, whereas without it - LCMM [11, 16]. The adequate treatment of LCDD has not been established and is indicated for those patients with systemic disease, severe and symptomatic renal dysfunction, and active concomitant symptomatic MM. Hence, the treatment in both cases (LCDD with MM and LCMM) should be the same [11, 17].
Commonly used therapies of cortico­ steroids, cyclophosphamide, thalidomide, which suppress FLCs production, have excellent results in studies of the patients with LCMM. Also the use of novel thera­ peutic agents such as bortezomib, doxo­ rubicin or bendamustine shows good pa­ tients response to FLCs reduction [12, 13]. Moreover, bortezomib is effective in indu­ cing apoptosis of myeloma cells and may interrupt rapid renal dysfunction by inhi­
biting progression of glomerulosclerosis which reduced growth of myeloma cells and improve GFR and decrease proteinu­ ria [18, 19],
Also, the use of high-dose chemothera­ py for LCDD followed by autologous stem cell transplantation (ASCT) has been re­ ported. Furthermore, a long-term analysis of transplanted LCDD cases showed ASCT as effective therapy for renal dysfunction associated with LCDD [8, 17].
FLC catabolism takes part mainly in kidney. Circulating FLCs half-life is 3-6 ho­ urs in normal renal function, but may in­ crease by 10 times in patients with CKD stage 5. The functioning nephrons are overexposed to FLCs in AKI related to MM, even after successful chemotherapy [17]. Moderate renal impairment related to MM may be reversible when novel therapeutic agents used, however no decrease in the incidence of dialysis-dependent ES-CKD has been found [18, 19]. Patients with MM on dialysis still have a poor prognosis.
Moreover, Chang et al [20] demonstra­ ted that patients with MM on HD had a si­ gnificantly reduced survival rate, compared to those with MM and without HD, espe­ cially in the first year following diagnosis. Furthermore, in sub-analysis of cumulati­ ve overall survival between patients tre­ ated with HD and anti-myeloma therapy, and HD alone, no statistical differences between characteristics in these two gro­ ups were found. However, the anti-myelo­ ma therapy with HD group were associa­ ted with a relatively improved survival rate within the first year following diagnosis. We do not know the type of HD membrane used in this study.
High-cut-off hemodialysis (HCO-HD) using special protein-leaking dialysis filters
of polyethersulfone and polyvinylpyrrolido­ ne membrane dialyzers (including hco1100 theralite area 1. 1 m2, that was used in this case) enables to remove molecules with weight of 45 kDa and is an effective pro­ cedure to remove sFLC in MM patients in large amounts. Early reduction of serum FLCs is associated with renal recovery and better outcomes [21, 22]. Moreover, there is linear relationship between the FLC re­ duction (60%) and the probability of renal recovery (80% dialysis independence). Ho­ wever, only removal of FLC by HCO-HD wi­ thout chemotherapy is not sufficient. Accor­ ding to Dimopoulos’ [23] research among patients with MM and severe Rl requiring dialysis, there is a high probability of aboul 50% to become dialysis independent wi­ thout the use of special filters on HD.
Recently used new chemotherapy, especially bortezomib with its chemothera­ peutic and anti-inflammatory effect through the inhibition of nuclear factor kB could help prevent inflammation, renal fibrosis and the anti-apoptotic effects on renal proximal tu­ bular cells [24]. This results in more rapid reduction in FLC production rates than other regimes and subsequently higher rates of renal recovery [19], Furthermore, in the analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) study patients with relapsed MM treated with bortezomib had a superior disease re­ sponse and longer time to progression (in both groups: CrCI >50 ml/min group and CrCI <50 ml/min group) compared to treat­ ment with high-dose dexamethasone. The data shows progressive improvement in re­ nal function at the time of commencement of the fifth cycle of bortezomib (serum creatini­ ne 328. 6 ± 124 pmol/l before treatment vs 116 ± 26. 6 pmol/l after) [25, 26].
454 K. Woziwodzka et al-
Two trials conducted to prove the effica­ cy of HCO-HD like EuLITE and MYRE trial are in progress. [17]. According to Bridoux el al [27] among patients with myeloma cast nephropathy treated with a bortezo­ mib-based chemotherapy regimen, the use of HCO-HD compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis inde­ pendence at 3 months. However, among the secondary end points, more patients in the high-cutoff group vs the conventional group no longer required hemodialysis at 6 months.
In the phase 2 EuLITE study Hutchin­ son et al demonstrated that HCO-HD did not improve clinical outcomes for patients with de novo MM and myeloma cast ne­ phropathy who required haemodialysis for AKI and who received a bortezomib-based chemotherapy regimen relative to those re­ ceiving HF-HD [28],
Treatment with bortezomib allowed in our case rapid elimination of lambda FLCs with observed return of effective diuresis, normalization of biochemical abnormalities like creatinine level and FLCs levels, but the impact of HCO dialyzer on long term survival and prognosis, time of recovery from need of permanent renal replacement therapy require further investigations. Tho­ ugh, at the beginning prognosis for this patient was poor, HD with concurrent che­ motherapy and ASCT helped to obtain long survival.
Conclusions The most important in MIDD treatment
is chemiotherapy. Still the long lasting effect of therapy with HCO-HD for all pa­ tients suffering from high sFLC values not only in case of MM is unknown. Further studies, especially in MIDD cases are needed to prepare recommendations for treatment of renal impairment like AKI, nephrotic syndrome or haematuria in pa- rapoteinemias.
References 1. Motwani SS, Herlitz L, Monga D, J ha ver i KD,
Lam AQ: Paraprotein-related kidney disease: glo­ merular diseases associated with paraproteinemi- as. Clin J Am Soc Nephrol. 2016; 11: 2260-2272.
2. Arora D, Uppal M, Amitabh V, Agrawal U: Unu­
sual presentation of light chain deposition disease: a case report. J Clin Diagn Res. 2016; 10: EDOS­ EDOO.
3. Jimenez-Zepeda VH: Light chain deposition dise­ ase: novel biological insights and treatment advan­ ces. Int J Lab Hematol. 2012; 34: 347-55.
4. Magrangeas F, Cormier ML, Descamps G, Gouy N, Lodé L. et al: Light-chain only multiple myelo­ ma is due to the absence of functional (productive) rearrangement of the IgH gene at the DNA level. Blood. 2004; 103: 3869-3875.
5. Fabbian F, Stabellini N, Sartori S, Tombesi P, Aleotti A. et al: Light chain deposition disease presenting as paroxysmal atrial fibrillation: a case report. J Med Case Reports. 2007; 1: 187.
6. Kasagi T, Nobata H, Suzuki K, Miura N, Banno S. et al: Light chain deposition disease diagnosed with laser micro-dissection, liquid chromatography, and tandem mass spectrometry of nodular glome­ rular lesions. Intern Med. 2017; 56: 61-66.
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