Andrea G. Kattah

C3 glomerulonephritis associated with monoclonal gammopathy: a case series.

BACKGROUND C3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy. STUDY DESIGN Case series. SETTING & PARTICIPANTS 32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum. OUTCOMES Clinical features, hematologic and bone marrow biopsy findings, kidney biopsy findings, kidney measures, complement pathway abnormalities, treatment, and follow-up of patients with C3 GN that was associated with a monoclonal gammopathy. RESULTS Mean age of patients with C3 GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia in one patient, and no abnormal clones in the other 3 patients. Kidney biopsy showed membranoproliferative GN with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of 9 patients tested. No mutation in complement-regulating proteins was detected in any patient. As an index case, one patient with C3 GN and chronic lymphocytic leukemia was treated with rituximab, cyclophosphamide, vincristine, and prednisone, and one patient with C3 GN and monoclonal gammopathy of undetermined significance was treated with dexamethasone and bortezomib. Both patients showed significant decreases in hematuria and proteinuria and stabilization of kidney function. LIMITATIONS Studies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done. CONCLUSIONS The study highlights the association of C3 GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3 GN.

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

Rituximab is a monoclonal antibody to the CD20 antigen on B-cells that was initially designed and approved for the treatment of non-Hodgkins B-cell lymphoma in 1997. In the last 15years, it has emerged as a potent immunosuppressant for many immune-mediated diseases, beginning initially with rheumatoid arthritis, and now extending into several other fields, including clinical nephrology. Based on recent large clinical trials, it is FDA-approved for the treatment of ANCA-associated vasculitis and continues to be studied in off-label usage for many glomerular diseases, including membranous nephropathy, lupus nephritis, and mixed cryoglobulinemia. It has been used as a treatment in nephrotic syndrome in children and adults, including both minimal change disease and focal segmental glomerulosclerosis. Given its efficacy, tolerability and safety profile in comparison to more conventional treatment regimens, RTX is rapidly emerging as a critical treatment modality in glomerular disease.

The Management of Hypertension in Pregnancy

Hypertensive pregnancy disorders complicate 6% to 8% of pregnancies and cause significant maternal and fetal morbidity and mortality. The goal of treatment is to prevent significant cerebrovascular and cardiovascular events in the mother without compromising fetal well-being. Current guidelines differentiate between the treatment of women with acute hypertensive syndromes of pregnancy and women with preexisting chronic hypertension in pregnancy. This review will address the management of hypertension in pregnancy, review the various pharmacologic therapies, and discuss the future directions in this field.

Hypertension in Pregnancy Is a Risk Factor for Microalbuminuria Later in Life

The authors aimed to compare renal function by estimated glomerular filtration rate and albuminuria in 3 groups of women: nulliparous women, women with a history of normotensive pregnancies, and women with a history of at least one hypertensive pregnancy. Women who participated in the second Family Blood Pressure Program Study visit (2000–2004) and had serum creatinine and urine albumin measurements (n=3015) were categorized as having had no pregnancy lasting >6 months (n=341), having had only normotensive pregnancies (n=2199), or having had at least 1 pregnancy with hypertension (n=475) based on a standardized questionnaire. Women who reported having had at least one pregnancy with hypertension were significantly more likely to be hypertensive (75.6% vs 59.4%, P<.001), diabetic (34.2% vs 27.3%, P≤.001), and have higher body mass index (32.8 vs 30.5, P<.001) than those who reported normotensive pregnancies. There was a significantly greater risk of microalbuminuria (urine albumin‐creatinine ratio >25 mg/g) in those who reported at least one pregnancy with hypertension (odds ratio, 1.37; confidence interval, 1.02–1.85; P=.04) than in those with normotensive pregnancies, after adjusting for risk factors for chronic kidney and cardiovascular disease. Hypertension in pregnancy is associated with an increased risk of future microalbuminuria.

Rituximab: emerging treatment strategies of immune-mediated glomerular disease

The use of monoclonal antibodies in the treatment of malignancy and autoimmune diseases has rapidly expanded in the last decade. Rituximab, a monoclonal antibody to the CD20 antigen on B cells, was first approved by the US FDA in 1997 to treat non-Hodgkin’s B-cell lymphoma. It is now used, however, for a variety of diseases in both on- and off-label uses. It was approved by the FDA for use in refractory rheumatoid arthritis in 2007, and in April 2011 it was approved for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (including granulomatosis with polyangiitis [Wegener’s granulomatosis] and microscopic polyangiitis), based on the promising results of the RAVE trial. Within the field of nephrology, in addition to its use in anti-neutrophil cytoplasmic antibody-associated vasculitides, it is has been used in the treatment of membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.

Temporal IgG Subtype Changes in Recurrent Idiopathic Membranous Nephropathy

Determination of the IgG subtypes within the immune deposits in membranous nephropathy (MN) may be helpful in the differential diagnosis. IgG4 is the predominant subtype in idiopathic MN and recurrent MN, while IgG1, IgG2, and IgG3 subtypes are more common in secondary MN and de novo disease in the allograft. The temporal change of IgG subclasses in individual patients and its correlation with clinical variables have not been studied. We reviewed all posttransplantation protocol and indication biopsies (49) in 18 patients with recurrent MN who underwent transplantation at our center between 1998 and 2013 and performed IgG subtyping (IgG1–4). We tested serum for M‐type phospholipase A2 receptor (PLA2R) autoantibodies or performed PLA2R antigen staining on the kidney biopsy. IgG4 was the (co)dominant IgG subtype in 10 of 14 biopsies at the diagnosis of recurrence regardless of PLA2R association. In 8 of 12 transplantations with serial biopsies, the (co)dominant subtype did not change over time. There was a trend toward IgG1 and IgG3 (co)dominance in biopsies >1 year from recurrence and more IgG1 (co)dominant subtyping in the setting of more‐advanced EM deposits. Treatment with rituximab did not affect the IgG subtype. In conclusion, the dominant IgG subtype did not change over time in recurrent MN.

Pregnancy and Lupus Nephritis.

The management of lupus nephritis in pregnancy presents a diagnostic and therapeutic challenge for providers. Pregnancy creates a series of physiologic changes in the immune system and kidney that may result in an increased risk of disease flare and adverse maternal and fetal outcomes, such as preeclampsia, fetal loss, and preterm delivery. Conception should be delayed until disease is in remission to ensure the best pregnancy outcomes. Maternal disease activity and fetal well-being should be monitored closely by an interdisciplinary team, including obstetricians, rheumatologists, and nephrologists throughout pregnancy. Careful attention must be paid to the dosing and potential teratogenicity of medications.

Lithium-Induced Nephropathy

Lithium-Induced Nephropathy A 59-year-old man with a history of bipolar disorder was admitted to the hospital after a fall and was incidentally found to have numerous small renal cysts, a finding consistent with previous lithium treatment.

Impact of a History of Hypertension in Pregnancy on Later Diagnosis of Atrial Fibrillation

Background Atrial fibrillation/flutter (AF) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders (HPDs) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without. Methods and Results A nested case–control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57±8 (mean±SD) years, (controls 56±8 years), 32±8 years (controls 31±8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPDs, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21–6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92–5.23). Conclusions Women with AF are more likely to have had a HPD, a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF, studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed.

Renal Disorders in Pregnancy: Core Curriculum 2019

As the incidence of chronic kidney disease increases and women pursue pregnancy at more advanced ages, the management of kidney disease in pregnancy has become increasingly relevant to the practicing nephrologist. Women with kidney disorders face several challenges in pregnancy due to increased physiologic demands on the kidney and risk for disease progression, the potential teratogenicity of medications, and the increased risk for complications such as preeclampsia and preterm delivery. Challenges posed by an underlying disease process in pregnancy, such as autoimmune disease or diabetes mellitus, necessitate an interdisciplinary team to ensure good maternal and fetal outcomes. Rates of acute kidney injury in pregnancy are generally declining worldwide, but remain a significant public health concern in developing countries. Pregnancy may also be the first time that a woman has kidney disease or hypertension diagnosed. An understanding of what constitutes normal physiologic changes in pregnancy is critical in a diagnostic evaluation. In this review, we review physiologic changes in pregnancy, causes and management of acute kidney injury in pregnancy, hypertensive disorders of pregnancy, and how to care for women with chronic kidney disease of various causes, including the use of antihypertensives and immunosuppressants.