Combined crystal-storing histiocytosis,light chain proximal tubulopathy,and light chain crystalline podocytopathy in a patient with multiple myeloma: a case report and literature review

BackgroundCrystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging.Case presentationIn this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period.ConclusionsIn conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.     

Glomerular filtrate affects the dynamics of podocyte detachment in a model of diffuse toxic podocytopathy

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Myeloma kidney with isolated tubulointerstitial light chain deposition in a renal allograft

Abstract: Myeloma kidney and myeloma‐associated renal disorders including light chain deposition disease can occur as recurrent or de novo disease in renal allografts. These kidney disorders usually manifest with worsening allograft function and proteinuria. Identification of the precise cause of kidney disorder often requires kidney biopsy and demonstration of monoclonal light chains in the kidney. Here, we present an unusual case of light chain nephropathy in a living‐related kidney transplant recipient involving light chain crystallization in the proximal tubule occurring within less than three months after transplant. The etiology of renal failure prior to transplant in our patient is not clear. To the best of our knowledge, the ultrastructural changes seen in our patient have not been described in literature previously. Our patient was treated with steroids, which resulted in short‐term improvement in allograft dysfunction.     

Recurrent nephrotic syndrome in a renal allograft recipient with focal and segmental glomerulosclerosis: Efficacy of plasmapheresis

Summary: We report a 29-year-old man with renal failure due to focal and segmental glomerulosclerosis (FSGS) who received a well-matched cadaveric renal allograft and had the early appearance of the nephrotic syndrome and renal insufficiency. His condition responded dramatically to plasmapheresis. the pathogenesis of FSGS recurring in a renal allograft may involve a recently identified circulating factor. the possible efficacy of plasmapheresis in the treatment of recurrent FSGS may be attributable to the removal of this factor.     

Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients.

BACKGROUND: Recurrence of nephrotic syndrome (NS) after renal transplantation for primary focal segmental glomerulosclerosis (FSGS) is a frequent and still unpredictable complication. However, risk factors for recurrence have not yet been clearly identified. METHODS: Data from 33 patients who underwent 35 renal transplantations for FSGS in two French centres are reported. RESULTS: Recurrent NS occurred in 12 transplant recipients (34%). A significantly higher number of patients in the group with recurrence (R group) compared with the group without recurrence (NR group) received cyclosporine for FSGS treatment before transplantation (83.3% vs 43.4%, P<0.02). Donors of R group recipients were significantly older than those of the non-NR group recipients (42.8 years vs 35 years, P<0.05). A higher number of patients from the R group required post-transplantation dialysis (33.3% vs 17.4%, P = 0.002). Surprisingly, acute rejection occurred more frequently in patients of the NR group compared with the R group, although the difference was not significant. Among the 12 patients with NS relapse, 9 were treated with plasmapheresis. Graft loss related to recurrence occurred in 6 cases. The 5-year graft survival was significantly lower in patients with recurrent NS compared with patients without recurrence (57% vs 82%, P<0.001). CONCLUSION: This study confirms the benefit to identify in the future clinical or biological predictive risk factors for NS recurrence after renal transplantation. It also indicates that donor age is a reliable risk factor for recurrence in adult recipients and suggests for the first time a possible opposite relationship between recurrent FSGS and acute rejection.     

Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis.

BACKGROUND: Several cases of obesity-associated focal segmental glomerulosclerosis (OB-FSG) have been reported but little is known about the clinico-pathological features of this entity and its long-term outcomes. METHODS: We studied 15 obese patients (BMI 35+/-5.2 kg/m(2)) with biopsy-proven FSG. They were compared with a control group of 15 non-obese patients with idiopathic FSG (I-FSG). RESULTS: Mean proteinuria at the time of renal biopsy was 3.1+/-2 g/24 h in OB-FSG; it reached the nephrotic range (> or =3.5 g/24 h) during follow-up in 12 patients (80%), but none of them had oedema, hypoproteinaemia, or hypoalbuminaemia. Proteinuria was more marked amongst I-FSG (6.5+/-4.2 g/24 h) and most of them developed oedema and biochemical nephrotic syndrome. Glomerulomegaly was observed in all renal biopsies from OB-FSG patients (mean glomerular diameter 256+/-24 microm in OB-FSG vs 199+/-26 microm in I-FSG, P<0.001). Twelve OB-FSG patients (80%) were treated with ACE inhibitors (ACEI) and proteinuria significantly decreased within the first 6 months of treatment but showed a later increase. None of the obese patients achieved a sustained weight loss. Seven (46%) patients with OB-FSG experienced a progressive renal insufficiency and five of them started intermittent dialysis. Kaplan-Meier estimated probabilities of renal survival after 5 and 10 years were 77 and 51%, respectively, in OB-FSG patients, and 52 and 30% in I-FSG (P<0.05). The risk of developing progressive renal failure among OB-FSG patients was statistically correlated with serum creatinine and creatinine clearance at presentation. CONCLUSIONS: OB-FSG indicates a poor prognosis with almost one-half of patients developing advanced renal failure. Knowledge of the clinico-pathological features of this entity (obesity, FSG lesions with glomerulomegaly, absence of nephrotic syndrome despite nephrotic-range proteinuria) should be helpful in establishing an accurate and early diagnosis.     

A fast and simple clearing and swelling protocol for 3D in-situ imaging of the kidney across scales

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血清游离轻链比值测定对鉴别骨髓瘤肾病致尿毒症的指导意义

目的探讨血清游离轻链比值（serum free light chain ratio, rFLC）测定对鉴别骨髓瘤肾病致尿毒症的指导意义。方法采用免疫比浊法测定39例初诊为尿毒症患者的血清游离轻链值,根据其临床诊断分为多发性骨髓瘤致尿毒症组12例;非多发性骨髓瘤致尿毒症组27例;比较2组．c血清游离轻链（κ-sFLC）、x血清游离轻链（κ-sFLC）及rFLC的差异,并分析其相关性。结果多发性骨髓瘤致尿毒症患者κ-sFLC、λ—sFLC高于正常范围的比例分别为83．3％和66．6％;非多发性骨髓瘤致尿毒症患者k-sFLC、λ-sFLC高于正常范围的比例分别为96．3％和96．3％,无统计学差异（P〉0．05）;多发性骨髓瘤致尿毒症组rFLC均不在正常范围内,非多发性骨髓瘤致尿毒症组rFLC均在正常范围内,具有统计学差异（P〈0．05）。多发性骨髓瘤致尿毒症组κsFLC与λ-sFLC无显著相关性（P〉0．05）;非多发性骨髓瘤致尿毒症组κ-sFLC与λ-sFLC呈正相关（P〈0.01,r=0．675）。结论rFLC可以反映κsFLC和λsFLC是否是单克隆性增高,可以作为鉴别骨髓瘤肾病所致尿毒症的可靠指标。     

Long‐term outcome of renal transplantation in adults with focal segmental glomerulosclerosis

Little information is available about the long‐term results of kidney transplantation in adults with focal segmental glomerulosclerosis (FSGS). The outcomes of 52 renal transplants performed between 1988 and 2008 in 47 adults with FSGS were compared with those of 104 matched controls (median follow‐up 93.4 vs. 109.4 months respectively). At 15 years, patient survival was 100% and graft survival 56% in FSGS patients vs. 88.3% and 64% respectively in controls (P = NS). FSGS recurred in 12 out of 52 grafts (23%) and led to graft failure in seven within 10 months (median). In the other five cases, proteinuria remitted and grafts are functioning 106 months (median) after transplantation. A second recurrence developed in five out of eight re‐transplanted patients (62.5%) who lost their first graft because of recurrence; only one graft was lost. Patients with recurrence were more frequently male subjects (83% vs. 40%, P = 0.02), younger at diagnosis of FSGS (16.3 ± 6.8 vs. 24.1 ± 11.5 years, P = 0.03) and of younger age at transplantation (28.4 ± 7.8 vs. 35.8 ± 12.2 years, P = 0.05). Treatment with plasmapheresis plus ACE inhibitors achieved either complete or partial remission in 80% of the cases. Long‐term patient and renal allograft survivals of adults with FSGS were comparable to those of controls. Recurrence was more frequent in young patients and in patients who lost a previous graft from recurrence. Graft loss resulting from a second recurrence is lower than expected.     

Unusual post-transplantation recurrence of focal segmental glomerulosclerosis which resolved with cyclosporine but not with sirolimus

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) is frequent after the first kidney transplantation (KT), but a recurrence that only occurred after the second KT has never been reported. Although cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulosclerosis, the effectiveness of sirolimus for this condition is still not known. We report, for the first time as far as we know, the case of a 35-year-old black male patient who experienced a recurrence of FSGS, 10 days after a second KT, although no recurrence had occurred after the first. Cyclosporine treatment led to a decrease in proteinuria, whereas mycophenolate mofetil and angiotensin-converting enzyme inhibitor had no effect. Cyclosporine was replaced by sirolimus as treatment for chronic allograft nephropathy 24 months after KT. Nephrotic syndrome, which reappeared 3 weeks after the switch, was cured by cyclosporine re-introduction. The absence of FSGS recurrence after the first graft does not totally preclude its recurrence after the second. This observation points to the effectiveness of cyclosporine for the recurrence of FSGS and indicates that sirolimus should be given with caution in such cases.     

Role of Myeloid-Derived Suppressor Cells in Glucocorticoid-Mediated Amelioration of FSGS

The mechanism by which glucocorticoids alleviate renal inflammatory disorders remains incompletely understood. Here, we report that the efficacy of glucocorticoids in ameliorating FSGS depends on the capacity to expand myeloid-derived suppressor cells (MDSCs). After glucocorticoid treatment, the frequency of CD11b⁺HLA-DR⁻CD14⁻CD15⁺ MDSCs in peripheral blood rapidly increased in patients with glucocorticoid-sensitive FSGS but remained unchanged in patients with glucocorticoid-resistant FSGS. The frequency of CD11b⁺Gr-1⁺ MDSCs in mouse peripheral blood, bone marrow, spleen, kidney-draining lymph nodes (KDLNs), and kidney also increased after glucocorticoid treatment. The induced MDSCs from glucocorticoid-treated mice strongly suppressed T cells, dendritic cells, and macrophages but induced regulatory T cells in spleen, KDLNs, and kidney. Moreover, glucocorticoid treatment suppressed doxorubicin-induced T cell proliferation, dendritic cell and macrophage infiltration, and proinflammatory cytokine production, whereas this protective effect was largely abolished by depleting MDSCs using anti–Gr-1 antibody. Finally, the adoptive transfer of induced MDSCs into the doxorubicin-treated mice not only confirmed the protective role of MDSCs in doxorubicin-induced renal injury but also showed that the transferred MDSCs rapidly migrated into the lymphocyte-accumulating organs, such as the spleen and KDLNs, where they suppressed T cell proliferation. Taken together, these results demonstrate that glucocorticoid treatment ameliorates FSGS by expanding functional MDSCs and that this rapid elevation of MDSCs in peripheral blood may serve as an indicator for predicting the efficacy of glucocorticoid treatment.     

Development of focal segmental glomerulosclerosis in the renal allograft of a patient with lupus

Nephritis has been a recognized complication of systemic lupus erythematosus since the early 1900s. Almost all lupus patients have some degree of renal involvement related to their condition, but a considerably smaller proportion of these patients actually progress to end-stage renal disease (ESRD). However, lupus patients are also susceptible to other primary renal insults that may significantly contribute to the deterioration in their renal function. We present a case of a patient with clinical and pathological evidence of lupus nephritis that progressed to ESRD and subsequently developed “recurrent” focal segmental glomerulosclerosis in her transplant kidney. Retrospective clinicopathologic correlation suggested the possibility of more than 1 primary renal process that eventually led to her dialysis-dependent state. This case illustrates the importance of meticulously examining both clinical and renal biopsy data in patients with lupus nephritis and considering the presence of co-existing renal pathologies to resolve an otherwise discordant picture of disease progression. These considerations may have important therapeutic and prognostic implications.     

Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab

A 22-year-old patient whose primary kidney disease was focal segmental glomerulosclerosis (FSGS) developed severe recurrence of proteinuria (up to 57 g/24 h) immediately after a haploidentic living donor kidney transplantation despite pre-operative plasmapheresis. The immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil, basiliximab and steroids. He underwent 10 plasmapheresis sessions in the first 3-week post-transplantation. In addition, he received 2 i.v. doses of rituximab (RTX) 600 mg (375 mg/m(2)) on days 7 and 15. Proteinuria decreased below nephrotic range at day 14 and serum creatinine returned progressively to normal values. A short course of oral ciclophosphamide (100 mg/j) was administrated between days 22 and 40 and three additional plasmapheresis sessions on days 34, 39 and 49. This strategy allowed obtaining sustained full remission of the nephrotic syndrome (NS) and excellent graft function, which persists over 2 years after transplantation. No notable adverse events related to RTX or plasmapheresis were observed. This case suggests that RTX associated with plasmapheresis may be an effective treatment of recurrent NS because of FSGS.     

Acute kidney injury due to tubular intraluminal monoclonal light chain crystals mimicking acute pyelonephritis

Tubular intraluminal inflammatory cells may be seen in kidney biopsies of patients with pyelonephritis, cell-mediated transplant rejection, autoimmune tubulointerstitial nephritis, allergic reactions, or in association with monoclonal light chain casts. When casts in a native kidney are primarily composed of granulocytes, the cause is most commonly acute pyelonephritis due to an ascending bacterial urinary tract infection. We report a 57-year-old man with acute kidney injury and an intense intraluminal neutrophil response to monoclonal lambda light chain crystal containing casts.     

A case of primary immunoglobulin light chain amyloidosis with a delayed appearance of Bence Jones protein in urine

We report here a case of a 58-year-old man who had nephrotic syndrome and immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal biopsy to confirm the diagnosis. Treatment with permanganate before Congo red staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive to permanganate oxidation. Although this patient was initially diagnosed as having AA amyloidosis, he did not have any chronic inflammatory disease and/or malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the precursor protein (amino terminus of constant region: kappa and lambda light chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis. Immunostaining was positive for the amino terminus of constant region of the lambda light chain, and negative for the amino terminus of constant region of the kappa light chain and AA protein. No plasma cell proliferation in the bone marrow was observed. We finally diagnosed this patient as having primary AL amyloidosis. It appears that a pathological diagnosis must be performed by immunostaining the precursor proteins with the permanganate digestion technique in tissue of patients with amyloidosis. There were no abnormalities in serum and urine immunoelectrophoresis at the time of renal biopsy in this patient. During the follow-up period, after discharge, Bence Jones protein appeared in the urine, but not in the serum. It is necessary to observe patients with primary AL amyloidosis carefully to determine if they their condition will progress to multiple myeloma.     

Distribution of pathologic findings in individuals with nephrotic proteinuria according to serum albumin.

BACKGROUND: Previous studies of the nephrotic syndrome have not carefully examined the relationship between serum albumin and the distribution of pathologic diagnoses found at the time of biopsy. The spectrum of pathologic findings in individuals with nephrotic proteinuria and a normal serum albumin has not been determined. Knowledge regarding the spectrum of findings in nephrotic proteinuria according to serum albumin levels may help nephrologists in the clinical decision making of when to perform a renal biopsy and in determining proper management of these patients. METHODS: Pathologic reports of native kidney biopsies performed for idiopathic proteinuria >3 g/24 h were reviewed. Clinical characteristics and biopsy findings were compared for individuals with serum albumin <30 g/L (Group I), 30 to <35 g/L (Group II) and >/=35 g/L (Group III). RESULTS: There were 57 patients in Group I, 20 in Group II and 35 in Group III. The proportion of individuals with focal and segmental glomerulosclerosis (FSGS) increased according to group: 26% in Group I, 45% in Group II and 74% in Group III. Of 35 patients in Group III, 34 had FSGS or advanced nephrosclerosis from another cause. Seven of 17 Group III patients with follow-up required dialysis after a mean interval of 6 years. Few of these patients received immunosuppressive therapy. CONCLUSIONS: As serum albumin increases in the nephrotic syndrome, the proportion of patients with FSGS increases. Patients with nephrotic proteinuria and a serum albumin >35 g/L suffer from FSGS, nephrosclerosis and have poor renal survival. When evaluating nephrotic patients, nephrologists should use this knowledge about the spectrum of disease in the clinical decision making of when to perform a biopsy and in providing the patient more precise information regarding risks, benefits and alternatives of the kidney biopsy procedure.