Spontaneous Regression Of Hodgkin’s Disease: Two Case Reports And A Review Of The Literature

Abstract

S. Marinaki graduated from Medical School of the University of Athens in 1994. After 2 years of training in internal medicine she worked as a resident focusing on nephrology in the Department of Nephrology and Transplantation. She obtained specialist qualifications in nephrology in 2002. She worked as a senior resident in the V. Medizinische Klinik (Nephrologie/Rheumatologie/Endokrinologie) of the Universitätsklinikum Mannheim, in Germany, from 2002 to 2004. Since 2006, she has worked as a consultant nephrologist in the Department of Nephrology and Transplantation in the ‘Laiko’ General Hospital in Athens. She received her PhD from the Medical School of the University of Heidelberg in 2007 and has published 11 articles in international medical journals.A 57-year-old male was referred for nephrology consultation due to nephrotic syndrome and impaired renal function. He presented with leg edema which had appeared 3 months prior to his admission. The patient had a long-lasting history of diabetes mellitus, diagnosed 20 years earlier, and was on glimepiride, metformin and pioglitazone. He also had arterial hypertension for 10 years, currently treated with lercanidipine hydrochloride, perindopril and atenolol. Furthermore, he was on atrovastatin for hyperlipidemia and on acetylsalicylic acid. He had a history of smoking, which he had quitted 10 years previously. His BMI was 26.5.The physical examination revealed peripheral, pitting leg edema. His blood pressure was 120/170 mm Hg with 85 beats/min. His full blood count showed WBC 6,800 cells/µl (64% neutrophils, 30.2% lymphocytes), Hb 11.7 g/dl, Hct 36.7% and platelets 283,000 cells/µl. He had a serum creatinine of 1.4 mg/dl with a glomerular filtration rate estimated by the MDRD Study equation at 57 ml/min. Biochemical evaluation showed: gluose 224 g/dl, urea 71 mg/dl, total protein 6.4 g/dl, albumin 3.1 g/dl, cholesterol 265 mg/dl, triglycerides 175 mg/dl, Na 140 mmol/l, K 4.6 mmol/l, and HbA1c 7.6 g/dl. Urinary sediment showed 30–35 red blood cells/HPF, 75% of glomerular origin and urinary protein excretion was 4.2 g/24 h. Serum electrophoresis was normal and C3 and C4 fraction levels of complement were within the normal range. Antinuclear, anti-dsDNA and antineutrophil cytoplasmic antibodies as well as hepatitis B, C and HIV serology were negative.The chest radiograph was normal. Renal ultrasound showed a right kidney of 11.5 cm and a left kidney of 11.2 cm, with no obstruction.Doppler ultrasound of the renal arteries and veins was normal. Cardiovascular evaluation with ECG and echocardiogram showed a mild left ventricular hypertrophy, with an ejection fraction of 65%. Fundoscopic examination was negative for diabetic retinopathy but on fluoroangiography, diabetic retinopathy was present.We presented a 57-year-old diabetic male patient with nephrotic syndrome, microscopic hematuria and impaired renal function at diagnosis. Indeed, other glomerular diseases can be superimposed on diabetes mellitus [1]. The reported frequency of other renal diseases depends upon multiple factors, including different biopsy policy among centers and it varies between 33 and 57% [2]. In a diabetic patient, the major clinical criteria suggesting nondiabetic glomerular disease [3] are:(1) Onset of proteinuria less than 5 years from the documented onset of type 1 diabetes.(2) Acute onset of renal disease.(3) Presence of an active urinary sediment containing red cells (particularly acanthocytes) and cellular casts.(4) In type 1 diabetes, the absence of diabetic retinopathy.(5) Signs and/or symptoms of another systemic disease. Our patient presented with nephrotic syndrome, microscopic hematuria with acanthocytes in urinary sediment, a calculated estimatedglomerular filtration rate of 57 ml/min but unknown onset of renal disease. Although he had had type 2 diabetes mellitus for more than 20 years, he had no findings of diabetic retinopathy on fundus examination but fluoroangioscopy revealed diabetic lesions. With this clinical presentation we performed a renal biopsy. On light microscopy we had 30 glomeruli per incision with a total glomerulosclerosis of 16%. Ten glomeruli showed prominent subendothelial hyaline deposition. Mesangial hypercellularity was also present. Interstitial fibrosis and tubular atrophy were about 25%. The glomerular basement membrane (GBM) showed diffuse thickening with the formation of ‘spikes’. Immunofluorescence revealed a diffuse mixed granular and linear pattern of IgG and C3 deposition along the GBM and staining for C4d along the GBM was also positive.The diagnosis of membranous nephropathy (MN) with chronic lesions suggestive of diabetic nephropathy was established (fig. 1, 2).Primary nephrotic syndrome is attributed to MN in nearly 30% of cases in adults with a higher prevalence in the older population (over 60 years of age). The disease shows a predominance for white males [4].Usually no specific etiology is revealed. Therefore, two thirds of the cases are referred as idiopathic. On the other hand, 20–25% of patients develop MN secondary to a variety of agents or conditions such as systemic lupus erythematosus, drugs, chronic hepatitis B and rarely hepatitis C infection.In patients with MN, the following tests are recommended in order to identify a possible secondary cause:(1) Antinuclear antibody titer. If positive, it strongly suggests membranous lupus nephritis. A positive titer should be confirmed with an anti-double-stranded DNA assay.(2) Serum complement levels C3 and C4.(3) Hepatitis B and C serologies.(4) Screening for malignancy.Regarding the screening for malignancy,the diagnosis of MN should not prompt an extensive search for occult malignancy. Only routine age-appropriate screening is indicated. More extensive screening is indicated only if there is some suggestive clinical finding [5].In our patient we performed the following as routine screening for malignancy: chest X-ray, gastroscopy, colonoscopy and prostate-specific antigen, which revealed no pathology. Six months after the induction of therapy and while he was still nephrotic, he had an episode of macroscopic hematuria. We extended our screening to urine cytology, cystoscopy, prostate ultrasound and urologic examination, which again revealed no pathology. So, we come to the diagnosis of idiopathic MN (IMN) superimposed on chronic lesions due to type 2 diabetes mellitus. For diabetic nephropathy, there is no specific treatment besides slowing disease progression. Regarding the treatment of IMN, we must consider the pathogenesis, the natural history and course and also the factors that are associated with disease progression. Finally, the most important point is to individualize our therapy.Pathogenesis of IMNThe subepithelial immune deposits are formed in situ as a result of binding of circulating autoantibodies to a native target antigen normally expressed on podocytes.Studies of IMN in a rat model (Heymann’s nephritis) first described circulating autoantibodies against megalin, an intracellular receptor (gp330) located at the foot processes of podocytes. Subepithelial deposits are formed and the immune injury of the podocytes is induced by complement activation. Megalin is not expressed in human podocytes [6]. The first human model of IMN is a rare antenatal form, in which the target antigen is neutral endopeptidase (NEP) which is expressed in human podocytes. Transplacental passage of anti-NEP antibodies from mothers genetically deficient in NEP, who were alloimmunized during a prior pregnancy, caused MN in the neonate [7]. Recently, the M-type phospholipase A2 receptor (PLA2R) has been identified as the major target antigen in human IMN [8]. PLA2R is expressed in normal podocytes and it is present in patients with the disease. In this study, circulating autoantibodies against PLA2R were identified in 26 of 37 patients (70%) with IMN but not in secondary forms of MN. The presence of anti-PLA2R antibodies also correlated with disease activity. Additionally to the identification of the PLA2R autoantibody, in a more recent study by Stanescu et al. [9], published in the New England Journal of Medicine in 2011, two alleles, one at chromosome 2q24 and one at chromosome 6p21(HLADQA1) associated with PLA2R1, were identified. It seems that in persons of white ancestry, IMN is strongly associated with risk alleles within the HLA locus in general and with HLADQ1 in particular, as well as with PLA2R1 alleles on chromosome 2. Natural History and Course of MNThe course of MN is characterized by a relatively high spontaneous remission rate (about 30% of patients) [10], and late progression to end-stage renal disease (ESRD) with a reported 10-year renal survival of 60–80% [11]. The main factors associated with disease progression are: disease onset at an age of more than 50 years, male gender, proteinuria of more than 8–10 g/24 h and impaired renal function at diagnosis [12]. Another important issue is the positive impact of a partial remission on outcome [13]. Therapy of IMN can be categorized into three parts: (1) supportive treatment, (2) nonspecific immunointervention: immunosuppressive agents, i.e. corticosteroids and cyclosporine (the main studies concern conventional, nonspecific immunointervention and their results are depicted in table 1[11,14,15,16,17]), and (3) specific immunointervention: B cell depletion.It consists of sodium restriction, loop diuretics, ACE inhibitors and angiotensin receptor II antagonists.It comprises cytotoxic agents, corticosteroids and cyclosporine, i.e. ‘conventional immunosuppression’.There are several randomized controlled trials with good results regarding the efficacy of cytotoxic agents, mainly cyclophosphamide, for IMN treatment. Among them, two trials also showed long-term benefit, i.e. after 10 years’ follow-up [11,14]. Cyclosporine has also been used for IMN therapy for a long time. Cyclosporine reduces proteinuria by its immunosuppressive and vasoconstrictive properties and also by acting on the glomerular filter barrier and thereby selectively inhibiting protein permeability. In an interesting study [18], the efficacy of cyclosporine and the mechanism of proteinuria reduction were studied in 41 patients with IMN and nephrotic syndrome. The antiproteinuric effect of CsA was related to its immunosuppressive rather than its vasoconstrictive properties. In 6 patients, a repeat biopsy showed more prominent immune deposits than at baseline. Therefore, it seems that cyclosporine is effective in reducing proteinuria in IMN, but it does not interfere with the pathogenetic mechanism. There are few randomized controlled trials for the use of cyclosporine in IMN showing good results in reducing proteinuria and a relapse rate of about 30% after discontinuation of the drug [16].The side effects and long-term risks of cyclophosphamide and corticosteroids are numerous. Cyclosporine also has side effects; it is nephrotoxic and it is associated with a high relapse rate after discontinuation. We use cytotoxic and nephrotoxic drugs to treat a disease with a high spontaneous remission rate and late progression to ESRD. In addition, another important point is raised in a systematic review [19]. The authors point out that with the exception of two [11,14] all trials lack hard end points such as ESRD and death. We have targeted immunointervention with B cell depletion. It is especially important to target the B cell, because abnormal B cells play a major role in autoimmunity. B cells can interact with antigen-presenting cells, act as antigen-presenting cells themselves and provide costimulatory support to T cells. Abnormal interactions with T cells can be amplified by T cell-derived cytokines that bind to receptors of the B cell. B cells can also clonally proliferate and differentiate into plasma cells that produce autoantibodies [20]. Treatment modalities comprise direct and indirect B cell targeting. Using monoclonal antibodies against B cell-specific antigens such as CD20, CD22 or CD19, highly specific direct B cell targeting can be achieved. Several anti-CD20 antibodies that deplete B cells have been developed. Among those, rituximab (anti-CD20 chimeric antibody), ocrelizumab (anti-CD20, humanized), ofatumumab (anti-CD20, human), TRU015 (engineered protein) and hA20 (humanized antibody) are either licensed for the treatment of non-Hodgkin’s lymphoma and/or rheumatoid arthritis, or currently under clinical development. B cell-modulating approaches are B cell receptor modulators (Epratide; abetimus) and antibodies that block B and T cell costimulation such as abatecept. Indirect B cell targeting comprises blockade of cytokine pathways: the specific anti-B-cell-activating factor antibody (anti-BAFF/BLyS, belimumab) and a decoy receptor TACI-Ig that prevents binding of T cell-derived cytokines to the TACI receptor of the B cell [21]. Most trials in glomerular diseases are conducted with rituximab. Rituximab is a chimeric mouse-human monoclonal antibody against the B cell surface antigen CD20, which is expressed mostly on mature B cells and not on long-lived plasma cells. It depletes B cells either by antibody-dependent cell-mediated cytotoxicity, by complement-mediated cytotoxicity or by apoptosis. It has been licensed for non-Hodgkin’s lymphoma since 1997 and for rheumatoid arthritis since 2006. It is tolerated very well, with minimal and uncommon side effects. A summary of efficacy data in glomerular diseases shows good results especially in those diseases that are associated with autoantibody formation and immune complex deposition. Case reports and small case series with good results have been reported in many glomerulonephritides [22]. Prospective, randomized controlled trials have been conducted only for the use of rituximab in SLE nephritis and ANCA-associated vasculitis Regarding IMN, there is for its since IMN is characterized by autoantibody formation and immune complex deposition. The first from et al. in 2002. Rituximab was used as therapy in patients with After 20 there was a of in extended the follow-up to there was a remission with reduction of proteinuria at study end Since there have been many case series and small trials that good efficacy of rituximab in A published in the of rituximab use in 85 patients with It showed good remission remission and partial and Rituximab also seems effective in MN after the two main of rituximab of or 2 of 1 with 2 for IMN therapy were showed efficacy in of proteinuria reduction A very interesting study from et al. the effect of rituximab on of showed that after the induction of besides of kidney there was also of the glomerular proteinuria with of the subepithelial deposits in repeat strongly suggests that rituximab interfere with the pathogenetic mechanism. Regarding our patient, we treated with a of of of rituximab as We his treatment with an ACE in with angiotensin II receptor after we from to because of B cells were after the of rituximab After months but were still i.e. after rituximab he had the of proteinuria as the treatment while at months he had a proteinuria of h and at months he had a partial remission of 1 g/24 months after treatment induction he had remission of proteinuria g/24 which has been i.e. 3 years after treatment. In this is a case of IMN superimposed on diabetes mellitus with chronic lesions on kidney treated with rituximab as that this was a late to rituximab and not a spontaneous to treat the patient after diagnosis rather than with supportive treatment There are two by The first is we that this is a late and not a spontaneous Indeed, IMN is characterized by a high rate of spontaneous remission that approaches 30% of we but there are data to support that rituximab with the pathogenetic mechanism and late remission in the studies have this is especially in the study with rituximab for MN after kidney In this study, there was a late with remission in after months and an higher rate with remission in of patients after to again the study with the evaluation of the effects of rituximab on of MN. In this study, repeat which showed of the deposits in patients with IMN were performed after remission at a of months after diagnosis. Our patient partial remission months and remission months after So, it be it seems that this be a late to rituximab is we treat the patient after diagnosis and we not for a spontaneous We have the factors that are associated with disease progression in We had a male patient, more than 50 years with syndrome, impaired renal function with a calculated estimatedglomerular filtration rate of 57 ml/min and arterial hypertension at he had long-term diabetes mellitus, which is also associated with progression to ESRD. to risk factors we as at high risk for progression and we to therapy used rituximab as treatment in this of we had the to treat our patient with i.e. either with a course of corticosteroids and cyclophosphamide on months or with cyclosporine in with we have to consider is that our patient has IMN and diabetes mellitus. The course of have to high of Using this we with three of of and we a of of We out that our was we estimated that high of for a of have been for Regarding our treatment with cyclosporine, we had the of its We have a patient with impaired renal function and chronic lesions on kidney biopsy at diagnosis and we that we should long-term to a nephrotoxic about the we all rituximab is a very Indeed, the of rituximab is high but as we it that we had no good for this In some cases we have to individualize at a higher this to that we are from our routine patients with IMN, those who are nephrotic and/or at high risk for with rituximab as is the exception and not the in our The that to is which treatment and for which patient with patients treat with cyclosporine, which with and which with supportive treatment with IMN who are at to risk for progression of IMN can be treated with treatment Our is to months for remission and if the proteinuria blood pressure with ACE and/or angiotensin II blockade and all the other we either with cyclosporine at an of 3 with of for at 1 or with the course of on the with cyclosporine for patients with nephrotic syndrome but with normal renal function and with minimal chronic lesions on kidney patients at risk for cyclosporine also it for or diabetic patients, who the and cyclophosphamide For patients, who can the course well, it is since we can cyclosporine and we have high remission and relapse with a about supportive have a diabetic patient with nephrotic syndrome. about sodium restriction, ACE about his his and the use of we have to that this was not an or diabetic He had a BMI of and he was an ACE and the onset of his nephrotic syndrome. His on was but after the to it was about the of rituximab. this therapy the and not the other one with 2 of 1 of rituximab at a We have calculated the of this We treated our patient with of of rituximab. to of i.e. in The total the with 2 of 1 of rituximab have been We not use this because our with this is especially in Most from the centers in and most patients are treated with the There are also some about the of with the in nephrotic we to treat this patient with the Marinaki has this patient was a rather case of of MN and diabetes mellitus. he was a for a nephrotoxic drug such as cyclosporine because of the chronic lesions fibrosis and at the biopsy. lesions can be attributed to his arterial hypertension and diabetes mellitus. of his diabetes, it also have been very to treat with the with high of we have from the that rituximab be a therapy for IMN, since it seems to interfere with the mechanism. Since is an important we not use rituximab as a routine therapy in our IMN we the of this therapy to the less and cyclophosphamide or In the of rituximab should be to the other on the one also the of a remission with a treatment and on the other the and of is the clinical of the anti-PLA2R antibodies and we not in our those antibodies have some clinical since to be specific for In the study by et al. were in patients (70%) with IMN, but were in secondary forms of MN. if we the routine screening we can identify the most forms of secondary MN. antibodies be more in MN in order to from disease. but also have clinical in the this is but the of treatment on the of proteinuria and serum The of anti-PLA2R evaluation also in order to the a repeat biopsy in this we a biopsy 1 after microscopy revealed again chronic lesions with a more progression. We to microscopy to the effect of rituximab on subepithelial but was not for chronic lesions that were present at the first biopsy were more prominent at the biopsy. remission of proteinuria there seems to be progression of the first we had 30 glomeruli per incision with glomerulosclerosis and subendothelial hyaline deposits in about was also present. Interstitial fibrosis and tubular atrophy was about at the first biopsy showed progression of i.e. glomeruli with and fibrosis and tubular atrophy showed diffuse thickening with In showed the pattern of granular deposition of IgG and C3 along the was positive for C4d along the be but not to the diagnosis to have We performed the biopsy 3 years after therapy and while the patient was in and our was to microscopy to possible in GBM thickening and immune but as we described it was not possible for we must end and all for in this interesting and of of Nephrology University Hospital of University of General and of Renal University of Department of Medical University of PhD Department of General Hospital of