Guy Touchard

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long‐term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1‐year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m2, p = 0.035). In conclusion, SCI at 1‐year posttransplantation is associated with worsening renal function and is more frequent in SRL‐treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

Crystal-storing histiocytosis with renal Fanconi syndrome: pathological and molecular characteristics compared with classical myeloma-associated Fanconi syndrome

BACKGROUND Crystal-storing histiocytosis (CSH) is a poorly described complication of monoclonal gammopathy featuring histiocyte lysosomal storage of kappa light chain (kappa LC) crystals. Although CSH is usually associated with systemic manifestations, renal involvement is uncommon. METHODS To investigate the molecular mechanisms implicated in kappa LC crystallization, we performed immunopathological and molecular studies in three patients with CSH and renal Fanconi syndrome (CSH/FS). The V kappa sequences were determined, and resulting molecular models were compared with previously reported myeloma-associated FS kappa LC sequences. RESULTS All patients presented with chronic tubulo-interstitial nephritis and renal FS with accumulation of monoclonal kappa LC crystals within proximal tubular cells. They showed peri-renal and interstitial infiltration by histiocytes containing eosinophilic crystalline inclusions (pseudo-pseudo-Gaucher cells). LC sequences were determined and assigned to their germline counterparts, in strong homology with previously reported myeloma-associated FS sequences. Comparison of CSH/FS V kappa domain 3D structures with the germline-encoded structures and those from patients with myeloma-associated FS underlined distinct hydrophobic residues exposed to the solvent in two patients, likely favouring the formation of a variant form of crystals that may further resist degradation after phagocytosis. CONCLUSION Although CSH/FS and myeloma-associated FS are closely related disorders, peculiar mutations in the V domains of CSH/FS monoclonal kappa LCs, different from those in myeloma-associated FS, may account for crystal morphology, predominant accumulation within histiocytes and multiple organ involvement in CSH.

Long-term Kidney Disease Outcomes in Fibrillary Glomerulonephritis: A Case Series of 27 Patients

BACKGROUND Fibrillary glomerulonephritis (GN) is a rare disorder with poor renal prognosis. Therapeutic strategies, particularly the use of immunosuppressive drugs, are debated. STUDY DESIGN Case series. SETTING & PARTICIPANTS 27 adults with fibrillary GN referred to 15 nephrology departments in France between 1990 and 2011 were included. All patients were given renin-angiotensin system blockers and 13 received immunosuppressive therapy, including rituximab (7 patients) and cyclophosphamide (3 patients). OUTCOMES & MEASUREMENTS Clinical and histologic features of patients and kidney disease outcome. Renal response was defined as a >50% decrease in 24-hour proteinuria with <15% decline in estimated glomerular filtration rate (eGFR). RESULTS All patients presented with proteinuria, associated with nephrotic syndrome (41%), hematuria (73%), and hypertension (70%). Baseline median eGFR was 49 mL/min/1.73 m(2). Eight patients had a history of autoimmune disease and none had evidence of hematologic malignancy during follow-up. Light microscopic studies showed mesangial GN (70%), predominant pattern of membranous GN (19%), or membranoproliferative GN (11%). By immunofluorescence, immunoglobulin G (IgG) deposits (IgG4, 15/15; IgG1, 9/15) were polyclonal in 25 cases. Serum IgG subclass distribution was normal in the 6 patients tested. After a median 46-month follow-up, renal response occurred in 6 of 13 patients who received immunosuppressive therapy with rituximab (5 patients) or cyclophosphamide (1 patient). Of these, 5 had a mesangial or membranous light microscopic pattern, and median eGFR before therapy was 76 mL/min/1.73 m(2). In contrast, chronic kidney disease progressed in 12 of 14 patients who were not given immunosuppressive therapy, 10 of whom reached end-stage renal disease. LIMITATIONS Number of patients, retrospective study, use of multiple immunosuppressive regimens. CONCLUSIONS The therapeutic approach in fibrillary GN remains challenging. The place of immunosuppressive therapy, particularly anti-B-cell agents, needs to be assessed in larger collaborative studies.

Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy–associated C3 glomerulopathy

The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

Heart transplantation in systemic (AL) amyloidosis: a retrospective study of eight French patients.

BACKGROUND Immunoglobulinic (AL) amyloidosis is a complication of plasma cell dyscrasia, characterized by widespread deposition of amyloid fibrils derived from monoclonal light chains. Cardiac amyloid is the main prognostic factor, with a median survival of six months. Cardiac transplantation in AL amyloidosis is associated with high mortality, due to disease recurrence in the allograft and systemic progression. Suppression of light chain (LC) production with chemotherapy by melphalan plus dexamethasone (MD) or high dose melphalan followed by autologous stem cell transplantation (HDM/ASCT) improves survival. However, both the indications and results of chemotherapy in patients transplanted for cardiac AL amyloidosis remain unclear. AIMS To assess the outcome of cardiac transplantation and haematological therapy in patients with cardiac AL amyloidosis. METHODS Eight French patients, who underwent heart transplantation for cardiac AL amyloidosis between 2001 and 2006 were studied retrospectively. RESULTS Before transplantation, six patients received MD (n=5) or HDM/ASCT (n=1). Haematological remission was obtained in three patients treated with MD. In the three remaining patients, postoperative HDM/ASCT (n=2) or allogeneic bone marrow transplantation (n=1) resulted in haematological remission in one patient. In 2 patients not treated before transplantation, post-operative treatment with MD resulted in complete hematological remission in one. After a median follow-up of 26 months from cardiac transplantation, six patients were alive and four had sustained haematological remission, as indicated by normal serum free LC levels. CONCLUSION Appropriate haematological therapy, including MD, may result in a survival benefit in AL amyloidosis patients with advanced heart failure requiring transplantation.

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.

Endogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin

Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33Gt/Gt) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-γ/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells in vitro, inducing IFN-γ and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation.

Crystalline light chain proximal tubulopathy with chronic renal failure and silicone gel breast implants: 1 case report☆

A 39-year-old female patient was admitted to explore chronic renal failure. Clinical history included silicone breast implants. Clinical examination was normal. Urinalysis revealed tubular proteinuria with Bence-Jones κ protein. Monoclonal immunoglobulin G κ and free monoclonal κ-light chains (LCs) were revealed by serum protein immunoelectrophoresis. Bone marrow aspiration with karyotype analysis and skeletal radiologic survey were normal. Kidney biopsy revealed a peculiar pattern of proximal tubular cells with hypertrophy and clarification initially diagnosed as an osmotic nephrosis. Immunofluorescence study, including immunoglobulin LCs conjugates was normal. Immunoelectron microscopy finally revealed a crystalline LC proximal tubulopathy κ. Our case presents some peculiarities: the absence of hematologic malignancy sign and the young patients age. The silicone breast implants have been reported to be involved in the generation of monoclonal gammopathy.

IL-33 receptor ST2 deficiency attenuates renal ischaemia–reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice

AIM Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia-reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2-/-) on renal IRI in euglycaemic and hyperglycaemic mice. METHODS Hyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2-/- mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. RESULTS Urinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2-/- mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2-/- animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. CONCLUSION Our data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on alarmins and diabetes in ischaemia-related diseases.

Chapter 12 Renal Disease in Cryoglobulinemic Vasculitis

Publisher Summary This chapter discusses the renal disease in cryoglobulinemic vasculitis. Cryoglobulins are immunoglobulins (Ig) that precipitate as serum is cooled below body temperature and dissolve after rewarming at 37oC. They are classified into three types, on the basis of their Ig composition: Type-I cryoglobulins are entirely made up of a monoclonal Ig. Type-I cryoglobulinemia is usually observed in the context of lymphoplasmacytic proliferation, mainly Waldenstroms macroglobulinaemia, chronic lymphocytic leukemia, or multiple myeloma. Type II (or mixed) cryoglobulins are composed of two distinct components: a monoclonal Ig (usually IgMk, less frequently IgG) that displays a specific antibody activity against the polyclonal component of the cryoglobulin. Type III cryoglobulins are composed of one or several classes of polyclonal Ig. They are observed in various pathologic conditions with immune complex formation, including infectious diseases, autoimmune disorders, malignancies, or even in apparently healthy individuals.