Ekaterina Stolyarevich

Immunosuppressive Treatment for Lupus Nephritis: Long-Term Results in 178 Patients

Lupus nephritis is one of the most severe Systemic Lupus Erythematosus features, defining treatment modality and prognosis. Our retrospective study, including 178 patients treated for lupus nephritis during 23 years with mostly cyclophosphamide-based initial regimens followed by azathioprine or mycophenolic acid, demonstrates 84.8% of renal response with 19.2% of flares, 15-year patient survival 78.7% and kidney survival 76.3%, and low damage accrual. Both patient and kidney survival significantly differ for subgroups that achieved complete or partial renal response and nonresponders: patient 15-year survival 95% versus 65% versus 35%; kidney 15-year survival 100% versus 58% versus 0%, respectively. 51% (24 out of 47) of patients evaluated at the end of the study period sustained complete renal response; however, only 9 of them had 0 disease activity according to SELENA SLEDAI scale, while 13 patients had scores 2–4 due to the serological abnormalities only. We conclude that (1) initial treatment with cyclophosphamide followed by azathioprine is effective and can be used in agreement with International Guidelines until the evidence for biological treatments benefits becomes available; (2) complete and even partial renal response have positive prognostic value, and failure to achieve renal response negatively influences kidney and patient survival; (3) the validity of complete renal response in SLE is questioned by the absence of conventional definition of SLE remission.

The Prognostic Value of Late Kidney Transplant Rejection Pathology Characteristics

Renal allograft rejection, represented by the wide spectrum of lesions with different pathogenesis, pathology patterns, clinical course and prognosis, still remains the most often cause of late graft dysfunction. Moreover, a combination of several factors, either of which may impact the post-transplant course, generally take place. We aimed to analyze the incidence of late renal allograft rejection variants, and to determine clinical factors and pathology features, influencing prognosis in the specific types of late renal allograft rejection. The data obtained from 361 patients with acute (n=227) or chronic (n=134) late allograft rejection (mean time after kidney transplantation 48.8 ± 46.1 months) were analyzed retrospectively. C4d expression was found in 34% cases of acute rejection and in 58% cases of chronic rejection (64% in chronic transplant glomerulopathy and 52% in transplant vasculopathy). 5-year graft survival comprised 48% and 24% for acute and chronic transplant rejection respectively (Р<0.01). Combination of acute cell-mediated rejection with chronic transplant rejection did not influence significantly the prognosis for the latter. Diffuse C4d expression on peritubular capillaries turned to be an independent prognostic factor regardless the pathology variant of renal allograft rejection. In contrast, focal C4d expression had no impact on the prognosis, which did not differ significantly from C4d-negative type. On the other hand, in acute rejection prognosis for C4dpositive forms was worse compared to C4d-negative (55% vs 25%; P <0.01), while in chronic rejection there was no difference between C4d-positive and C4d-negative forms (26% vs 24%; P=NS). In multivariate Cox-model analysis, the following factors appeared to influence the prognosis: presence of chronic transplant glomerulopathy, features of vasculitis, severity of tubulitis, presence of thrombotic micrioangiopathy and prominence of interstitial fibrosis.

МОРФОЛОГИЧЕСКАЯ СТРУКТУРА ПАТОЛОГИИ ПОЧЕЧНОГО АЛЛОТРАНСПЛАНТАТА И ЕЕ ВЛИЯНИЕ НА ОТДАЛЕННЫЙ ПРОГНОЗ

Aim: to analyze the frequency of different histological diagnoses and it simpact on graft survival in a cohort of patients with renal allograft dysfunction, and to determine pathology features, infl uencing prognosis. Materials and methods. The data obtained from 1470 biopsies, performed by indication at different time after kidney transplantation (48.8 ± 46.1 months) were analyzed retrospectively according to the Banff 2013 classifi cation. Results. The majority of graft dysfunction episodes were attributed to fi ve causes: acute (26,8%) and chronic (12,4%) rejection; chronic nephrotoxicity of СNI (19,3%), interstitial fi brosis/tubular atrophy (15,8%) and recurrent or de novo glomerulonephritis (10,6%). T-cell-mediated acute rejection and functional disorders were the most often cause of dysfunction during the fi rst year after transplantation (40,5% and 21% respectively) but decreased over time. On the other hand, the frequency of chronic rejection, interstitial fi brosis/tubular atrophy with or without СNI nephrotoxicity and recurrent or de novo glomerulonephritis increased from 13%, 26% and 5,5% at the fi rst year to 26,4%, 35,3% and 22,8% respectively at 8 year after transplantation. Chronic rejection represented a major risk for graft loss – 8-year graft survival did not exceed 5%. The prognosis of acute rejection as well as de novo or recurrent glomerular pathologies was more favorable (38% and 42% respectively). In cases of interstitial fi brosis/tubular atrophy with or without СNI nephrotoxicity 8-year graft survival was slightly lower than in the functional disorders (62% and 76%). In acute rejection prognosis for C4d-positive forms was worse compared to C4d-negative, while in chronic rejection there was no difference between C4d-positive and C4d-negative forms. The features of СNI nephrotoxicity did not infl uence the prognosis of non-specifi c interstitial fi brosis and tubular atrophy. Conclusion. Transplant pathology in patients with allograft dysfunction is heterogeneous and changes over time. Acute and chronic rejection; interstitial fi brosis/tubular atrophy with or without СNI nephrotoxicity and recurrent/ de novo glomerular pathology are the most often causes of graft dysfunction, but only rejection (mostly chronic) and glomerular pathology are associated with unfavorable prognosis.

Combined immunoglobulin G kappa nephropathy: monoclonal immunoglobulin deposition disease and proximal tubulopathy: monoclonal gammopathy of renal significance or smoldering multiple myeloma? Case report and review of literature

Multiple myeloma (MM) is consistently preceded by precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). These represent a continuum of progression of the tumor burden from the absence of symptoms or signs of end-organ damage towards full-blown symptomatic disease. MGUS, by definition presenting by monoclonal gammopathy without end organ damage, in fact might be associated with the numerous end organ lesions, first of all pathologic renal conditions. The term monoclonal gammopathy of renal significance (MGRS) was proposed by International Kidney and Monoclonal Gammopathy Research Group in order to discriminate the pathologic nature of these diseases from the truly benign MGUS. Spectrum of MGRS, caused by the deposition of monoclonal immunoglobulin’s or fragments thereof as organized and non-organized deposits, includes more commonly AL amyloidosis, monoclonal immunoglobulin deposition disease (MIDD) and light-chain proximal tubulopathy (LCPT). Same variants are seen in patients with MM and SMM. We present a rare case of combined immunoglobulin G kappa nephropathy: MIDD and proximal tubulopathy in a patient, manifested with acute kidney injury and diagnosed with SMM after 6 years of scrutinous repeated evaluation. .

Two cases of multiple myeloma, presenting with light-chain tubulopathy

Multiple myeloma is a plasma-cell dyscrasia presenting with generalized neoplastic changes in bones, accompanied by impaired haematopoiesis, susceptibility to infections, and end-organ damage. However, the clinical picture of myeloma might be quite different from the classic manifestation, patients can present with renal disease, dominating or precluding multiple myeloma features. Diagnosis and differential diagnosis demand renal tissue pathology evaluation, most often kidney pathology demonstrate cast-nephropathy, AL amyloidosis, and light-chain deposition disease. Light-chain proximal tubulopathy is less frequently reported variant of paraproteinemic kidney damage in patients mostly not demonstrating overt clinical features of multiple myeloma. This lesion is almost always induced by the excess of kappa light chains, excreted through the kidney and reabsorbed in the proximal tubule cells, which manifests with moderate CKD, and, rarely, with acquired adult Fanconi syndrome. We present two cases of myeloma with light-chain proximal tubulopathy. None of our two patients met multiple myeloma criteria at admission, and only kidney biopsy, which discovered light-chain proximal tubulopathy, prompted further work-up, in turn resulted in the diagnosis of multiple myeloma. Our cases demonstrate some peculiarities, making them rare even in the setting of light-chain proximal tubulopathy, which is rare itself. Case one is an extremely infrequent example of light chain lambda deposition in the proximal tubules, case two demonstrates acute kidney injury on the top of chronic kidney disease, unusual for the light-chain proximal tubulopathy. We conclude that kidney biopsy should be performed, unless contraindicated, in all patients with proteinuria and/ or impaired kidney function of unknown origin; and that the chemotherapy with bortezomib-based regimens is effective for treatment of myeloma with light-chain proximal tubulopathy. Introduction Multiple myeloma (MM) is a plasma-cell dyscrasia presenting with generalized neoplastic changes in bones, accompanied by impaired haematopoiesis and susceptibility to infections. To distinguish MM from other plasma cell dyscrasias, the diagnosis is based on histologic, serologic, and radiographic features: bone marrow clonal plasma cells; monoclonal protein in the serum or urine; and end-organ damage, evidenced by renal impairment, hypercalcemia, anemia, or lytic bone lesions. Sometimes, however, the clinical picture of MM is quite different from the classic manifestation, which can cause diagnostic difficulties, thereby delaying treatment. Importantly, symptoms of kidney damage may dominate over MM symptoms, and even preclude overt MM, and the diagnosis of MM often results from the workup of unexplained renal disease. Renal disease clinical presentation in MM includes acute kidney injury (AKI), nephrotic syndrome, proteinuria and/or haematuria, arterial hypertension and chronic kidney disease (CKD), occasionally, patients with MM present with renal tubular dysfunction [1-8]. Renal involvement is mainly caused by the deposition of monoclonal immunoglobulin’s or fragments thereof, mostly light chains (LC), as organized (crystals, fibrils, microtubules) and non-organized deposits, involving all compartments of the renal parenchyma: glomeruli, tubules, interstitial space and vessels. Organized deposits induce cast-nephropathy, light-chain proximal tubulopathy (LCPT), AL amyloidosis, glomerulonephritis with organized microtubular monoclonal deposits, and cryoglobulinemic glomerulonephritis, while non-organized deposits lead to the light chain deposition disease or proliferative glomerulonephritis with monoclonal deposits of IgG/ IgA. It appears that amino acid sequence of the monoclonal LC and other monoclonal proteins, defining inherent biochemical properties, is the primary determinant of the specific pattern of renal parenchymal deposition and clinical disease. Differential diagnostics is the major challenge, demanding pathology evaluation of kidney tissue, as the above mentioned lesions cannot be differentiated solely on the base of clinical features. Most often kidney pathology in patients with MM demonstrate cast-nephropathy, AL amyloidosis, and light-chain deposition disease, less frequently cryoglobulinemic glomerulonephritis proliferative glomerulonephritis can be seen [9-18]. LCPT is a unique entity which is less frequently reported as case reports and small case series. In LCPT the excessive LC, almost always of kappa type, are excreted through the kidney and reabsorbed in the proximal tubule cells, leading to tubular damage, sometimes resulting in the defects in acidification and concentration and, rarely, the features of complete acquired Fanconi syndrome (FS). Of interest, in many of the LCPT cases renal manifestations dominated in the clinical *Correspondence to: Elena V Zakharova, Department Nephrology, Head, Botkin Memorial Hospital, 125284, 2-nd Botkinsky proezd, 5, Moscow, Russian Federation, Tel: +7 967 134 6936; Fax: +7 495 945 1756; E-mail: helena. zakharova@gmail.com

Two cases of moderate proteinuria and hematuria with unexpected diagnosis of renal amyloidosis

The diagnosis of renal amyloidosis is sometimes elusive. In this manuscript, we present and discuss two cases, presenting with proteinuria, subsequently diagnosed with rare variants of renal amyloidosis: AH amyloidosis in patient with lymphoplasmacytic lymphoma, and AA amyloidosis in patient with hyperimmunoglobulinemia D syndrome.