Lupus Nephritis (LN) - Past Lecture Notes PDF

System vasculitis, connective tissue diseases and kidney damage. Kidney amyloidosis. Thrombotic microangiopathies, paraproteinemic disease, myeloma. PHD.MD.Mammadzada A.Y. PHD.MD.Ismaylova SH.G.  Lupus nephritis (LN) is a frequent and potentially serious complication...

System vasculitis, connective tissue diseases and kidney damage. Kidney amyloidosis. Thrombotic microangiopathies, paraproteinemic disease, myeloma. PHD.MD.Mammadzada A.Y. PHD.MD.Ismaylova SH.G.  Lupus nephritis (LN) is a frequent and potentially serious complication of systemic lupus erythematosus (SLE). Renal involvement worsens morbidity and mortality rates in lupus; patient outcomes are also adversely affected through complications of therapy. Approximately 25% to 50% of unselected lupus patients have clinical renal disease at disease onset and up to 60% of adults with SLE develop renal disease during their lifetime. Renal involvement in SLE is defined for diagnostic purposes as persistent proteinuria exceeding 500 mg daily or the presence of cellular casts. The deposition of circulating immune complexes plays a major role in the development of LN. Glomerular and vascular damage may also be potentiated by hypertension and a thrombotic microangiopathy triggered by the presence of antiphospholipid (APL) antibodies.  The renal biopsy in LN may show a number of different histopathologic patterns. In addition, overlapping patterns may be present and histologic progression from one lesion to another may occur spontaneously or with therapy. The World Health Organization (WHO) has developed a uniform classification system that is both accurate and precise. In the most recent 2003 WHO classification, biopsies of lupus patients are classified into one of six categories according to glomerular changes by light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM)  Abnormal autoantibody production is the hallmark of SLE. The presence of antibodies directed against nuclear antigens (antinuclear antibodies [ANAs]), and especially against DNA (anti-DNA), are included in the American Rheumatism Association’s diagnostic criteria for SLE, and are commonly used to monitor the course of patients with SLE. However, the ANA titer does not correlate well with the severity of renal involvement in SLE. Autoantibodies directed against doublestranded DNA (anti-dsDNA) are a more specific but less sensitive marker of SLE. A variety of other autoantibodies are commonly present in lupus patients including anti- Sm, antinRNP, anti-Ro/serum amyloid A, and anti-La/SSB, but are not predictive of renal involvement. Pregnancy in patients with LN has also been associated with worsening of renal function. Risk factors for loss of renal function include active disease within the previous 6 months, coexistent hypertension, proteinuria, and renal impairment at baseline. Patients with elevated serum creatinine levels are most likely to suffer worsening of renal function and are at highest risk for fetal loss (which may exceed 50%). Both high- dose corticosteroids and azathioprine have been used in pregnant lupus patients, but mycophenolate and cyclophosphamide are contraindicated.  The percentage of patients with LN who progress to end-stage renal disease (ESRD) ranges from 10% to 30%. Most patients who develop ESRD have a resolution of their extrarenal manifestations of disease and serologic activity. In general, most renal transplant programs allow patients with active SLE to undergo a period of dialysis for 3 to 12 months to allow clinical and serologic disease activity to become quiescent. Allograft survival rates in patients with ESRD due to LN are comparable to the rest of the ESRD population. The rate of recurrent SLE in the allograft is less than 5%.  Patients with mixed connective tissue disease (MCTD) share many overlapping features with patients with SLE, scleroderma, and polymyositis. They typically have a distinct serologic profile characterized by a very high ANA titer, often with a speckled pattern, and antibodies directed against a specific ribonuclease-sensitive extractable nuclear antigen (ENA). Most patients with renal involvement have mild or minimal clinical manifestations, with only microhematuria and less than 500 mg proteinuria daily. However, heavier proteinuria and the nephrotic syndrome occur in up to one third of patients. Other patients have severe hypertension and acute kidney injury reminiscent of “scleroderma renal crisis” (see later discussion). In general, the glomerular lesions resemble the spectrum found in SLE, whereas vascular lesions, when present, resemble those found in scleroderma. Corticosteroid therapy in MCTD is effective in treating the inflammatory features of joint disease and serositis. Glomerular involvement can vary as in SLE, and treatment is generally directed at the glomerular lesion in a similar fashion to treating active LN.  Algorithm for treating ANCA-associated vasculitis. AAV = antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides; AZA = azathioprine; CYC = cyclophosphamide; GC = glucocorticoids; MMF = mycophenolate mofetil; MTX = methotrexate; PLEX = plasma exchange; RTX = rituximab. Reproduced with permission from Ntatsaki et al. 11 Thrombotic microangiopathy (TMA) represents a group of disorders with common pathologic features including alteration in the microvasculature with detachment and swelling of the endothelium, deposition of amorphous material in the subendothelial space, and luminal platelet aggregation leading to microthrombosis. Laboratory features include thrombocytopenia, hemolytic anemia, and schistocytes. Among TMAs, hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are the most prominent diseases. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Microangiopathic Hemolytic Anemia (MAHA) The diagnosis of HUS/TTP should be considered in the presence of the following clinical findings: Microangiopathic hemolytic anemia Thrombocytopenic purpura Acute kidney injury (AKI) Fever Neurologic symptoms The hallmark laboratory finding, essential for the diagnosis of HUS/TTP, is a microangiopathic hemolytic anemia. The laboratory findings include the following: Schistocytes on the peripheral smear (burr cells, helmet cells, and other fragments) Anemia (hemoglobin levels < 6.5 mg/dL in 40%) Reticulocytosis Elevated lactate dehydrogenase (LDH)/low haptoglobin level Negative Coombs test Thrombocytopenia (cell count usually < Amyloidosis comprises a diverse group of systemic and local diseases characterized by the deposition of fibrils in various organs. Amyloid fibrils bind Congo red (leading to characteristic apple-green birefringence under polarized light), have a characteristic ultrastructural appearance, and contain a 25-kD glycoprotein, serum amyloid P component. In primary (AL) amyloidosis, the deposited fibrils are derived from the variable portion of immunoglobulin light chains produced by a clonal population of plasma cells. Secondary (AA) amyloid is due most frequently to the deposition of serum amyloid A protein in chronic inflammatory states. Forms of hereditary amyloid involving the kidney include mutations in  In primary (AL) amyloidosis, fibrils are composed of the Nterminal amino acid residues of the variable region of an immunoglobulin light chain. The kidneys are the most common major organ to be involved by AL amyloid, and the absence of other organ involvement does not exclude amyloidosis as a cause of major renal disease. From 10% to 20% of patients over 60 years old with the nephrotic syndrome will have amyloidosis. Amyloidosis should be suspected in all patients with circulating serum monoclonal M proteins, and approximately 90% of primary amyloid patients will have a paraprotein spike in the serum or urine by immunofixation. The median age at presentation is approximately 60 years; fewer than 1% of patients are younger than 40 years. Men are affected twice as often as women. Presenting symptoms include weight loss, fatigue, lightheadedness, shortness of breath, peripheral edema, pain due to peripheral neuropathy, and purpura. Patients may have hepatosplenomegaly, macroglossia, or rarely enlarged lymph nodes. Secondary amyloidosis is due to the deposition of amyloid A (AA) protein in chronic inflammatory diseases. Secondary amyloid is observed in rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, bronchiectasis, and occasionally in poorly treated osteomyelitis. The diagnosis of amyloid is usually established by tissue biopsy of an affected organ. Liver and kidney biopsy are positive in as many as 90% of clinically affected cases. A diagnosis may be made with less invasive techniques including fat pad aspirate (60–90%), rectal biopsy (50– 80%), bone marrow aspirate (30–50%), gingival biopsy (60%), or dermal biopsy (50%) in selected series.  The optimal treatment for AL amyloid is unclear. Most treatments focus on methods to decrease the production of monoclonal light chains akin to myeloma therapy using chemotherapeutic drugs such as melphalan and prednisone, high-dose dexamethasone, chlorambucil, and cyclophosphamide. Recent reports using high- dose melphalan followed by allogeneic bone marrow transplant or stem cell transplant have given promising results. Thus, for younger patients with predominantly renal involvement, stem cell transplantation is a reasonable alternative therapy for AL amyloid. Regardless of whether chemotherapy or marrow transplant is used, the treatment of amyloid patients with nephrotic syndrome involves supportive care measures. These may include judicious use of diuretics and salt restriction in those with nephrotic edema, treatment of orthostatic hypotension (autonomic neuopathy) with compression stockings, fludrocortisone, and midodrine, an oral a-adrenergic agonist The treatment of AA amyloid focuses on the treatment of the underlying inflammatory disease process. Alkylating agents have been used to control AA amyloidosis secondary to rheumatologic diseases in a number of studies, with responses including decreased proteinuria and prolonged renal survival noted. In familial Mediterranean fever, colchicine has long been used successfully to prevent the febrile attacks.  Myeloma cast nephropathy (myeloma kidney) is an important cause of acute kidney injury in myeloma. The underlying pathogenesis involves the precipitation of filtered light chains within the tubule lumen and the subsequent obstruction of urine flow. Light chains may also be directly toxic to the proximal tubule cells and can trigger the development of the Fanconi syndrome. Patients are equally susceptible to cast nephropathy whether the filtered light chain is of the k or l variety; an inherent ability to bind with Tamm-Horsfall protein is an important determinant of whether or not the light chain precipitates. Other factors favoring the development of cast nephropathy include a low urine flow rate as may occur during volume depletion, hypercalcemia, and diuretic or NSAID use. Clinical findings include  Management involves treatment of exacerbating factors including removal of offending agents (diuretics, NSAIDs, ACE inhibitors), volume expansion, treatment of hypercalcemia, and, possibly, the induction of an alkaline diuresis, though this last point remains controversial. Ultimately, clearance of the paraprotein is required and this may be achieved by chemotherapy aimed at the underlying plasma cell dyscrasia. Plasmapheresis had been suggested in the management of patients with a high paraprotein burden and acute kidney injury in whom conservative measures have failed to improve renal function.  Waldenstrom macroglobulinemia is a syndrome characterized by a circulating monoclonal IgM protein in association with a B-cell lymphoproliferative disorder. This slowly progressive disorder occurs in older patients who present with fatigue, weight loss, bleeding, visual disturbances, peripheral neuropathy, hepatosplenomegaly, lymphadenopathy, anemia, and often a hyperviscosity syndrome. Renal involvement is uncommon but may manifest as microscopic hematuria and proteinuria, which may be nephrotic. Patients may have enlarged kidneys. Treatment of Waldenstrom macroglobulinemia consists of therapy directed against the lymphoproliferative disease with alkylating agents and, at times, plasmapheresis for hyperviscosity signs and symptoms. Newer therapies include fludarabine, cladribine, interferon alfa, rituximab, and marrow transplantation. Thanks for your attention