Treatment of idiopathic light chain deposition disease : complete remission with bortezomib and dexamethasone

Doença de depósito de cadeias leves (DDCL) pertence à família de doenças de deposição de imunoglobulina monoclonal, causada por uma discrasia de clones de células plasmáticas subjacentes, em que as cadeias leves de imunoglobulinas monoclonais são secretadas e depositadas nos tecidos, resultando em graus variados de perda de função do órgão.1,2 Mais de 50% dos casos são secundários ao mieloma múltiplo (MM) Tratamento da doença de depósito de cadeia leve idiopática: remissão completa com bortezomib e dexametasona


cAse report
A 55-year old male patient, brown color, married, an oil refining production technician, Brazilian, started about 6 months ago with edema in his lower limbs, dyspnea upon exertion and hypertension of difficult control.During this period, his clinical and laboratory diagnosis was that of nephrotic syndrome, and he was under prednisone 80mg/day; 0.1mg clonidine bid, spironolactone 25mg tid, furosemide 40mg tid, losartan 50 mg bid, captopril 50mg tid and allopurinol 100 mg.
He had no past of diabetes, previous surgery, alcohol consumption and smoking.He had a family history of hypertension (father).
Upon examination, the patient was pallor +/4+, anicteric, acyanotic, afebrile.Cardiovascular system: regular heart rate in two stages with normal heart sounds; blood pressure: 220x120 mm Hg; Heart rate: 86 bpm.Respiratory system: clearly audible breath sounds with crackles in both lung bases and SpO 2 : 94%.Abdomen: flaccid, painless, with no visceromegaly and normal peristalsis.lower limbs: edema ++++/4+ in the leg all the way to the thigh.
The renal biopsy was performed by needle puncture, with histopathological results indicating 18 glomeruli with increased volume, diffuse hyaline nodular enlargement at a mesangial level with moderate cellularity in this area, distributed mostly on the periphery of the nodules.
We used immunofluorescence to look for antibodies kappa light-chain, with strongly positive result in the glomerular mesangial region and on the periphery of glomerular capillary.Moreover, we found C3 in the mesangium in a granular pattern.Congo red staining was negative.Thus, the diagnostic conclusion was nodular glomerulopathy with kappa light-chains found upon immunofluorescence.
Due to the presence of light-chain depositassociated nephropathy, there was a need to assess the association with MM, nor looking for light-chain deposition in other organs.
CT scans of the chest, abdomen and pelvis did not show noteworthy changes.Echocardiography and electrocardiography were also normal.
Bone stock with chest, skull, pelvis, upper and lower limbs radiographs, as well as magnetic resonance imaging of the spine showed no evidence of lytic lesions.
Bone marrow biopsy came back normal.We also biopsied his abdominal fat, looking for amyloidosis, and it was negative when stained with Congo red.
Thus, kidney damage with evidence of tissue deposit kappa light-chain concomitant with elevated blood levels of kappa light-chain associated with negative results for MM and amyloidosis were instrumental in establishing the diagnosis of LCDD.
The patient underwent treatment for LCDD with bortezomib and dexamethasone associated with prophylaxis with trimethoprim-sulfamethoxazole and acyclovir, with the goal of preventing infection by Pneumocystis jirovecii and herpes viruses, respectively.
During treatment, the patient complained of epigastric pain and appetite loss.We ordered an endoscopy, which showed signs of recent bleeding with gastric ulcer activity, and he was treated with omeprazole.
During the treatment cycles, the patient developed paresthesia in his limbs.Gradually, the patient developed asthenia, dyspnea upon exertion, anemia and hypotension.We suspected of a side effect associated with bortezomib, with peripheral motor and sensory neurological involvements.Thus, we suspended the chemotherapeutic treatment and the antihypertensive agents he was on.
He was submitted to electroneuromyography to confirm the development of peripheral neuropathy, and the result was: chronic, acquired, symmetrical, focal and diffuse myelinic and axonal, sensory and motor, peripheral polyneuropathy.Thus, he was started on gabapentin and analgesics.He improved slowly, but progressively.
Six months after completion of chemotherapy, the patient described significant improvement of his paresthesia, making sporadic use of painkillers.At that time, his creatinine clearance was 101 mL/min and a 24-hour proteinuria was 180 mg/24h, both normal.
The patient evolved favorably, having returned to his professional activities after one year of treatment.After 36 months of follow-up, he is in good health, making use of omeprazole, atorvastatin and calcium.His blood pressure was within normal limits, without signs of edema, remaining with mild residual paresthesia in his limbs.

dIscussIon
LCDD is a rare clinical pathologic condition characterized by tissue deposition of non-amyloid immunoglobulin light-chains (kappa or lambda) in granular form, which are not stained by the red Congo. 2 These light-chains will primarily deposit in the kidneys; however, the liver, heart, spleen, small bowel, skin and nervous system may also be affected. 1hus, the resulting clinical manifestations depend on what tissues are involved in the deposition of the substance and the consequent organ dysfunction caused. 2 The mean age of LCDD diagnosis is 58 years, representing a young population when compared to those affected by MM. 1 In addition, men are 2.5 times more affected than women.Approximately 65% of cases are associated with MM, and 3% to other lymphoproliferative disorders (chronic lymphocytic leukemia).Moreover, 32% of the cases are of idiopathic origin. 3he light chains produced are filtered by the glomerulus and reabsorbed in the proximal tubules via receptor-mediated endocytosis; therefore, the kidney becomes an important target for the deposition of these light chains.The kidney lesion is manifested by proteinuria and microscopic hematuria, progressing to decline in function and glomerulonephritis or tubulointerstitial nephritis.
In the liver, often affected in 23% of cases, patients may develop liver failure and portal hypertension.In the heart, there may be an increased heart area, restrictive heart diseases and severe congestive heart failure.In the lungs, there is preferential parenchymal involvement.And finally, in the nervous system, the patient develops neuropathy due to tissue protein deposition. 1,2t is a condition that is difficult to diagnose because in 40% of cases the patients may not have a known lymphoproliferative disorder.If the monoclonal light chains are present in the serum and/or urine, the diagnosis becomes easier.However, the LCDD diagnosis can only be confirmed with the immunohistological analysis of affected tissue. 1 To rule out the differential diagnoses, we need the aspirate and biopsy the bone marrow to rule out MM and/or light-chain amyloidosis.CT and PET scans can also be done to assess systemic diseases. 1,2reatment for Idiopathic LCDD is still controversial, there is no clinical studies or consensus, due to its rarity. 4,6Treatment depends on the number and nature of the affected organs, and the deposition of different light chains do not seem to affect its clinical evolution. 2he prognosis of patients with this clinical entity depends on the age, presence of MM and the presence of light-chain deposition in other organs, apart from the kidney.Therefore, treatment is indicated when there is systemic disease manifestation, severe symptomatic renal dysfunction and when there is concomitant MM activity. 2arious treatments have been proposed, all with the aim of suppressing the production of light chains and improve renal function.In the reported case, the treatment employed was bortezomib associated with dexamethasone.
Bortezomib, a proteasome inhibitor, acts in part by inhibiting the action of NFқB, since its activation induces a pro-inflammatory cascade with collagen deposition and changes to the mesangial matrix, which results in pathological changes in the form of glomeruloesclerosis. 1,4,5 Thus, the action of this drug is aimed at reducing kidney damage and improving its function.
The association of this drug with dexamethasone significantly reduces proteinuria, promotes rapid hematologic response, and improvements in renal function.Moreover, this association improves blood pressure, reducing the amount of antihypertensive medications administered to the patient. 3,4This could be demonstrated in our patient.His proteinuria levels reduced from 12,100 mg/24h to 112 mg/24h after treatment, concomitant to antihypertensive suspension and blood pressure normalization.
The main side effect associated with bortezomib was the development of sensory and motor peripheral neuropathy.It is a considerable problem, but manageable in clinical practice, with dose reduction, switching to subcutaneous administration or its entire suspension.][5][6] The patient had a deteriorated function at the beginning of treatment, improved in his glomerular filtration, with a drop in his 24h-proteinuria values and normalization of creatinine clearance.In addition, the side effects he developed were those expected for individuals who are treated with bortezomib and dexamethasone.
Should the patient progress poorly, other treatments can be proposed, including the autologous transplantation of hematopoietic stem cells.This treatment produces long-term beneficial outcomes, with a reduction in proteinuria and an increased glomerular filtration rate.][7][8][9] It is also possible to treat the patients with immunomodulators, including thalidomide and lenalidomide.The combination of this agent with dexamethasone is able to cause a durable hematologic response and improvements to the renal failure. 10,11nally, a treatment of last resort is renal transplantation, which should be reserved for those patients with relative benign course of their disease, whom the production of light chains can be controlled. 1,2nclusIon LCDD is caused by the presence of immunoglobulin light chains in different organs.Among them, the most common are the kidneys, which cause a nephrotic syndrome with marked proteinuria and rapid deterioration of renal function.Most cases are secondary to MM or other lymphoproliferative disease, having a well-established treatment, aimed at controlling the underlying disease.
However, in the infrequent cases in which there is no detection of an associated hematologic disease, called idiopathic LCDD, there is no consensus about its therapeutic approach, and its treatment is based on the experience of reported cases.The reported patient was treated with bortezomib and dexamethasone, but in spite of the side effects, he improved clinically and had resolution of proteinuria and lasting recovery of renal function.