Mazdak A. Khalighi

American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

In the United States, approximately 35% of adults with Systemic Lupus Erythematosus (SLE) have clinical evidence of nephritis at the time of diagnosis; with an estimated total of 50–60% developing nephritis during the first 10 years of disease [1–4]. The prevalence of nephritis is significantly higher in African Americans and Hispanics than in Caucasians, and is higher in men than in women. Renal damage is more likely to develop in non-Caucasian groups [2–4]. Overall survival in patients with SLE is approximately 95% at 5 years after diagnosis and 92% at 10 years [5, 6]. The presence of lupus nephritis significantly reduces survival, to approximately 88% at 10 years, with even lower survival in African Americans [5, 6]. The American College of Rheumatology (ACR) last published guidelines for management of systemic lupus erythematosus (SLE) in 1999 [7]. That publication was designed primarily for education of primary care physicians and recommended therapeutic and management approaches for many manifestations of SLE. Recommendations for management of lupus nephritis (LN) consisted of pulse glucocorticoids followed by high dose daily glucocorticoids in addition to an immunosuppressive medication, with cyclophosphamide viewed as the most effective immunosuppressive medication for diffuse proliferative glomerulonephritis. Mycophenolate mofetil was not yet in use for lupus nephritis and was not mentioned. Since that time, many clinical trials of glucocorticoids-plus-immunosuppressive interventions have been published, some of which are high quality prospective trials, and some not only prospective but also randomized. Thus, the ACR determined that a new set of management recommendations was in order. A combination of extensive literature review and the opinions of highly qualified experts, including rheumatologists, nephrologists and pathologists, has been used to reach the recommendations. The management strategies discussed here apply to lupus nephritis in adults, particularly to those receiving care in the United States of America, and include interventions that were available in the United States as of April 2011. While these recommendations were developed using rigorous methodology, guidelines do have inherent limitations in informing individual patient care; hence the selection of the term “recommendations.” While they should not supplant clinical judgment or limit clinical judgment, they do provide expert advice to the practicing physician managing patients with lupus nephritis.

Intratubular hemoglobin casts in hemolysis-associated acute kidney injury.

Kidney injury is a complication of intravascular hemolysis associated with many forms of hemolytic disease. Reports of kidney biopsy findings in patients with hemolysis-related kidney injury have focused primarily on the accumulation of hemosiderin pigment within proximal tubular epithelial cells (hemosiderosis), a feature of chronic hemolysis. The nephrotoxic effects of hemoglobin include direct cytotoxicity to tubular cells, but hemoglobin also can precipitate in distal nephron segments, forming obstructive casts. We present a case of hemolysis-associated tubular injury, characterized by acute onset of intravascular hemolysis followed by acute kidney injury with acute tubular injury and abundant intratubular casts containing hemoglobin.

Bartonella Endocarditis–Associated Glomerulonephritis: A Case Report and Review of the Literature

Infectious endocarditis is associated with a number of systemic manifestations, including kidney disease. Kidney manifestations, including hematuria, parenchymal infarction, and glomerulonephritis, may affect as many as 40%-50% of patients with infective endocarditis. In a minority of cases of infective endocarditis, routine bacterial cultures do not yield an offending organism. Bartonella species are a known and relatively common cause of culture-negative endocarditis and have been associated with the development of endocarditis-associated glomerulonephritis. We present a case of Bartonella endocarditis-associated glomerulonephritis in which recognition of a characteristic immunofluorescent pattern and thorough investigation of the clinical history led to this uncommon diagnosis.

C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome

Background C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen. Methods Fourteen biopsies from 12 patients meeting diagnostic criteria for C3G were identified in patients > 49 years of age from 2005 to 2015 after exclusion of cases containing masked monotypic immunoglobulin deposits. Pathologic and clinical features were reviewed. Results The median age was 63.5 years and 75% of patients were male. All had renal insufficiency at presentation. Kidney biopsy showed DDD in three patients and C3GN in the remainder. Serum protein electrophoresis revealed a paraprotein in 10 patients, 8 of which had a plasma cell dyscrasia on bone marrow biopsy. A membranoproliferative pattern of glomerular injury was seen in 64% of biopsies, while mesangial proliferative and endocapillary proliferative patterns were seen less frequently. Among patients with at least 1 year of follow-up (n = 9), five were on renal replacement therapy, three showed stable (but impaired) kidney function and one demonstrated improvement. Conclusions C3G is an uncommon but important cause of kidney injury in older adults and associates with a high prevalence of paraproteinemia. In adult patients with C3G, prognosis is guarded as most patients showed either progression to end-stage kidney disease or stable but impaired kidney function.

Leukocyte chemotactic factor 2 (LECT2) amyloidosis presenting as pulmonary-renal syndrome: a case report and review of the literature

Leukocyte chemotactic factor-2 (LECT2) amyloidosis has been described as being associated with kidney disease; however, no clinical manifestations outside of the kidney have been previously reported. We describe a patient presenting with pulmonary-renal syndrome found to have deposition of amyloidogenic LECT2 (ALECT2) within both the lung and the kidney. This case is unique in regard to both the patients clinical presentation of pulmonary-renal syndrome in the setting of amyloidosis and the biopsy finding of ALECT2 deposition within the lung. It also emphasizes the importance of tissue diagnosis in such cases, given that amyloidosis was not initially considered in the differential diagnosis.

Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy.

Background Post-infectious glomerulonephritis (PIGN) is an immune complex-mediated glomerular injury that typically resolves. Dominant C3 deposition is characteristic of PIGN, but with the emergence of C3 glomerulonephritis (C3GN) as a distinct entity, it is unclear how the pathologic similarities between PIGN and C3GN should be reconciled. Therefore, nephrologists and nephropathologists need additional guidance at the time of biopsy. Methods We studied 23 pediatric and young adult patients diagnosed with PIGN. Patients were divided into two groups, one with co-dominance between C3 and immunoglobulins and the other meeting proposed diagnostic criteria for C3GN. Clinical and pathological features were compared. Results No clinical and/or pathological features could distinguish between those with C3-co-dominant deposits and those with C3 dominance. Nearly all patients in both groups regained their baseline renal function without clinical intervention. Conclusions Although the identification of abnormalities of the alternative pathway of complement is characteristic of C3GN, testing is not widely available and the turnaround time often exceeds 1 month. Our study found that PIGN with either co-dominant or dominant C3 deposition in a cohort of young patients has excellent short-term outcomes. Close clinical observation for persistent abnormalities, such as hypocomplementemia, prolonged hematuria or proteinuria, is recommended to single out patients that may harbor intrinsic complement abnormalities.

Light chain podocytopathy mimicking recurrent focal segmental glomerulosclerosis

Kidney injury related to paraproteinemia is common and typically occurs after the fourth decade of life in association with an underlying plasma cell dyscrasia or other lymphoproliferative disease. Kidney transplantation in paraprotein‐related kidney disease can be successful in conjunction with treatment of the underlying hematopoietic process; however, when hematologic response to therapy is not achieved, recurrent kidney injury is frequently seen. We describe a young male patient who presented at the age of 23 years with end‐stage kidney disease thought to be secondary to focal segmental glomerulosclerosis; this patient ultimately received two kidney allografts. He experienced recurrent proteinuria in both kidneys, with a biopsy from his second allograft showing kappa‐restricted crystalline light chain podocytopathy, which was identified in both his native and first allograft kidneys upon retrospective review. Recurrent light chain podocytopathy has not been previously reported but poses a diagnostic challenge as it can mimic focal segmental glomerulosclerosis, particularly in young patients in whom paraprotein‐related kidney injury is usually not suspected.

Lambda Light Chain Crystalline Cast Nephropathy and Proximal Tubulopathy

INTRODUCTION P lasma cell dyscrasias such as multiple myeloma (MM) result from clonal proliferation of plasma cells and subsequent overproduction of Igs, including free light chains. Renal dysfunction is a core manifestation of plasma cell dyscrasias. A broad range of kidney pathologies can occur, including light chain cast nephropathy, monoclonal Ig deposition disease, light chain amyloidosis, light chain proximal tubulopathy, and tubulointerstitial nephritis. Light chain proximal tubulopathy (LCPT) is a rare manifestation of monoclonal gammopathy and is characterized by the accumulation of monotypic light chains within the proximal tubule epithelial cells. The accumulated light chains frequently form crystals; however, noncrystalline forms of LCPT have been described. LCPT with crystals is associated with a kappa light chain in the vast majority of cases, which is discovered by either routine immunofluorescence (IF), IF, or immunohistochemistry after protease digestion of the paraffin-embedded tissue. LCPT without crystals can be seen with both kappaand lambda-restricted disease. When crystals are present, ultrastructural examination is often essential to the diagnosis as crystals may be easily missed by light microscopy. The diagnosis of LCPT is of great clinical importance. In up to 85% of patients, kidney biopsy showing LCPT is the initial clue to an underlying plasma cell dyscrasia before a diagnosis has been established or the disease has come to clinical attention. Therefore, the diagnosis of LCPT is crucial for appropriate patient management. We report an unusual case of LCPT in a 59-year-old woman associated with lambda light chain restriction with prominent intraluminal crystalline casts.

Glomerulonephritis With Masked Monotypic Immunoglobulin Deposits and Concurrent Lymphomatous Infiltration

Kidney injury can be a complication of hematopoietic neoplasia by both direct and indirect mechanisms. Virtually all lymphomas and plasma cell dyscrasias can show kidney involvement, including parenchymal infiltration and by secondary injury. Recently, a unique form of glomerulonephritis with masked monotypic immunoglobulin deposits has been reported, which shows frequent association with hematopoietic neoplasia and a propensity for progressive kidney disease. In many instances, these cases are likely diagnosed as glomerulonephritis with dominant C3 due to the absence of immunoglobulin staining by routine immunofluorescence microscopy. The patient reported here showed lymphomatous infiltration on kidney biopsy and mesangial proliferative glomerulonephritis with dominant staining for C3 without immunoglobulins on initial immunofluorescence; however, monotypic immunoglobulin G κ light chain was revealed after additional immunofluorescence staining was performed on the paraffin-embedded tissue. This patients case highlights the evolving state of kidney biopsy interpretation and the expanding spectrum of kidney disease in the setting of hematopoietic neoplasia.

Medullary peritubular capillary thrombi: a harbinger of sickle cell nephropathy

A previously healthy, 14-year-old African-American female presented with a 1-week history of fatigue, scleral icterus, and darkened urine. Transaminases were elevated with an aspartate transaminase of 1258 U/l and an alanine aminotransferase of 1636 U/l. Serologic work-up was negative for hepatitis A, B, and C viral infection but positive for antinuclear antibody (1:1280) and anti-smooth muscle antibody (200, reference: <25). Additional serologic studies for anti-double-stranded DNA, anti-SSA, and anti-SSB antibodies were negative. A liver biopsy showed severe autoimmune hepatitis, and immunosuppressive therapy was initiated. One week later, the patient noted a change in urine color to maroon. A urinalysis revealed 3+ blood and 1+ protein. Serum creatinine was 0.6 mg/dl. Due to concern for a systemic autoimmune process, a kidney biopsy was performed.