Aishwarya Ravindran

Thrombotic microangiopathy associated with monoclonal gammopathy

Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA.

Prevalence, incidence and survival of smoldering multiple myeloma in the United States

Smoldering multiple myeloma (SMM) is currently defined as MM without evidence of impending (⩾60% clonal bone marrow plasma cells, serum involved to uninvolved free light chain ratio of ⩾100 with absolute involved light chain level of ⩾100 mg/L, or >1 focal lesion on magnetic resonance imaging ⩾5 mm in size) or active (hypercalcemia, renal insufficiency, anemia or bone lesion – crab signs) end organ damage, which are considered indications for treatment.1 Although institutional studies show that ~8–20% of patients with MM are smoldering at the time of diagnosis,2 the actual prevalence of SMM in the United States (US) is unknown. Epidemiologic studies have been difficult to perform due to the lack of International Classification of Diseases (ICD) codes differentiating smoldering from active MM.

C3 glomerulopathy associated with monoclonal Ig is a distinct subtype

Monoclonal immunoglobulins (MIg) may play a causal role in C3 glomerulopathy (C3G) by impairing regulation of the alternative pathway of complement. Ninety-five patients with C3G were tested for MIg of which 36 were positive. Their mean age at diagnosis was 60 years and among patient 50 years and older, 65.1% had a MIg. At presentation, median serum creatinine and proteinuria were 1.9 mg/dL and 3.0 g/24 hours. Hematuria was present in 32 (88.9%) patients. Twelve (34.3%) patients had low C3 levels. C3 nephritic factor was detected in 45.8% patients; pathogenic variants in complement protein genes were rare. Hematologic evaluation revealed monoclonal gammopathy of renal significance in 26 patients, multiple myeloma in five, smoldering multiple myeloma in two, and chronic lymphocytic leukemia, lymphoma, or type I cryoglobulin each in one patient. After a median follow-up of 43.6 months, the median serum creatinine and proteinuria were 1.4 mg/dL and 0.8g/24 hours. Nine patients developed ESRD. Sixteen patients received MIg-targeted treatment, 17 patients received non-targeted treatment while three patients were managed conservatively. Of the 16 patients receiving MIg-targeted treatment, ten achieved complete/very good/partial hematologic response. Of these, seven achieved a complete/partial/stable renal response. Five patients receiving targeted treatment did not achieve hematologic response, none had a renal response. Patients receiving targeted treatment were more likely to have multiple myeloma/smoldering multiple myeloma. Patients receiving non-targeted treatment were more likely to have monoclonal gammopathy of renal significance. Thus, C3G with MIg is seen in older patients, C3 nephritic factor is the most common autoantibody detected, and MIg-targeted treatment may result in remission and stabilization of kidney function in a subset of these patients.

Estimating the annual volume of hematologic cancer cases per hematologist–oncologist in the United States: are we treating rare cancers too rarely?

Among all malignancies, hematologic cancers are perhaps the most challenging to manage in clinical practice due to their relative rarity, broad diversity, and ever-growing complexity. Even though hematologic cancers comprise only about 10% of all malignancies,[1] they are divided into over 100 distinct World Health Organization subtypes.[2] The latter is matched by nearly 30 National Comprehensive Cancer Network disease-specific clinical practice guidelines and a similar number of risk stratification or prognostication tools and staging systems.[3] In the surgical management of solid cancers, it is known that higher treatment facility or care provider caseload is generally associated with better clinical outcomes.[4] However, such a volume–outcome relationship in the medical management of malignancies, in particular hematologic cancers, remains relatively unexplored.[5] The Institute of Medicine has recommended additional research into exploring the volume–outcome relationship in the medical management of chronic non-surgical conditions including malignancies.[6] As an initial step into such investigation, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist–oncologist in the United States (US) in 2011. The year 2011 was chosen because this was the most recent year wherein we have the most adequate information on hematology–oncology workforce as well as specific cancer incidences and prevalences. We obtained the number of hematologist–oncologists working in the US using the American Society of Clinical Oncology (ASCO) Workforce Information System (WIS) data from 2011.[7] The WIS is a database that contains information about cancer incidence, prevalence, and the number of practicing oncologists in the US obtained from the American Medical Association Physician Masterfile. For incident cancer cases from 2006 to 2011, we used data from the American Cancer Society and the Surveillance, Epidemiology, and End Results Program (SEER). To estimate the prevalence of cases in 2011, we classified the hematologic cancers according to their potential curability. For potentially curable hematologic cancers (acute myeloid leukemia, acute lymphocytic leukemia, Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), because relapses are rare after 5 years, we calculated the number of patients diagnosed in 2006–2010 who would be alive in 2011 using expected survival rates derived from SEER*Stat version 8.2.1. For the non-curable cancers, we calculated the 37-year limited-duration prevalence in 2011 using the same program. The only exception was myeloproliferative neoplasms in which the prevalence was obtained from a recent study as this was not available in SEER.[8] Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and the non-curable subtypes of non-Hodgkin lymphoma were unavailable, the actual numbers of annual established cases per hematologist–oncologist for these cancers could not be calculated. In 2011, there were 1,596,670 new cancer cases in the US. Of these, 140,310 (8.8%) were hematologic cancers.[1] In the same year, the WIS reported 13,084 hematologist–oncologists practicing in the US.[7] Table 1 summarizes the average number of specific hematologic cancer cases (new and established) seen per hematologist–oncologist in 2011. Our study shows that a hematologist–oncologist in the US on average cares for only 1–2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. While these numbers are expected to vary by practice setting and location, disease specialization is relatively uncommon outside of academic setting. Based on the 2011 ASCO National Census of Oncology Practice, the majority (71%) of hematologist–oncologists in the US has a general or combined hematology–oncology practice.[9] Most hematologic cancers are treated in the nonacademic setting. Approximately 69%, 62%, 57% of non-Hodgkin

Desiderosmia (olfactory craving): A novel symptom associated with iron deficiency anemia

Patients with iron deficiency anemia (IDA) may develop a compulsive craving and purposive consumption of substances that the individual does not define as food, a condition known as pica. The hypothesis that such behavior may ameliorate iron deficiency is not substantiated, since most pica substances do not have much bioavailable iron. Experience from our practices (unpublished) and others suggest that the cravings may not necessarily be for consumption of the pica substances, but rather a desire for their taste, a sensation of the presence in the mouth, or sensation produced by mastication. To our knowledge, non-oro-gustatory craving in the setting of IDA has not been previously described. In this study, we will describe 3 patients with IDA who presented with olfactory cravings. The first case was a 49-year old woman who sought medical consultation because of a 2-month history of a compulsion to smell the odor of charcoal. After barbecuing, her family would put charcoal in their backyard. She could not resist the scent and would go out several times a week to pick up and smell the charcoal. This craving was especially strong after raining, during which the odor of charcoal would be more intense. She denied eating the charcoal. Because she also complained of dizziness, laboratory tests were performed, which led to the diagnosis of IDA (hemoglobin of 7.4 g/dL [normal, 12-15.5]; ferritin 2 mg/L [normal, 11-307]). The cause of IDA was determined to be menorrhagia. She took oral iron supplementation with resolution of IDA. During her 3 month follow-up visit, she reported that her olfactory craving had disappeared. Ten years later, her symptoms have not recurred. We report 2 other cases with similar presentation and clinical course. The salient findings of all 3 cases are summarized in Table 1. We report a novel olfactory craving symptom associated with IDA. All 3 patients presented with such symptom, albeit attraction toward odors from different substances. A similar olfactory phenomenon was previously reported over a decade ago in a survey of 300 pregnant women by Nancy Rumsey Cooksey, RN, a very astute certified childbirth educator. In her study, 40 patients described smelling one or more substances, the most common of which were pine oil cleaning solutions and gasoline. However, the women were neither tested nor treated for iron deficiency and their outcomes were not reported. Interestingly, 20% of the women also had concurrent pica. The effects of IDA on the olfactory system have only been minimally explored. In an animal study, iron-deficient rats had prolonged exploratory time (sniffing) for attractive odorants compared to controls. The hypothesis was that IDA would decrease the activity of these enzymes resulting in a net reduction of inhibitory olfactory inputs. Another study compared the olfactory function of IDA patients with healthy subjects and found a heightened sensitivity (lower threshold) in detecting odorant among patients with IDA. These reports support an association between the physiological changes in olfaction and iron store. These findings and our patient experience provide suggestive evidence that an olfactory craving symptom, entirely separate from pica, exists in certain patients suffering from IDA or during pregnancy. For this, we propose the term, desiderosmia, derived from the Latin word

Incidence, prevalence, mortality and chronic renal damage of anti-neutrophil cytoplasmic antibody–associated glomerulonephritis in a 20-year population-based cohort

Background True population-based clinical and outcomes data are lacking for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Therefore we aimed to estimate the incidence, prevalence and mortality of AAGN, as well as the relationship between the grade of chronic renal damage at presentation and renal and non-renal outcomes. Methods Patients with AAGN were identified among a population-based incident cohort of 57 Olmsted County residents diagnosed with ANCA-associated vasculitis (AAV) in 1996-2015. Incidence rates were age and sex adjusted to the 2010 US white population. Age- and sex-adjusted prevalence was calculated for 1 January 2015. Survival rates were compared with expected rates in the Minnesota population. Chronic renal damage was assessed by chronicity score (CS) on biopsies performed at diagnosis. Results Thirty-four (60%) patients had AAGN. Of these, 65% had microscopic polyangiitis (MPA) and 74% were myeloperoxidase (MPO)-ANCA positive. The annual incidence of AAGN was 2.0/100 000 population [95% confidence interval (CI) 1.3-2.7] and the overall prevalence was 35/100 000 (95% CI 24-47). Mortality for AAGN was increased (P < 0.001), whereas mortality for AAV without glomerulonephritis did not differ from the general population. Minimal to mild CS predicted recovery of renal function at 1 year; clinical diagnosis (granulomatosis with polyangiitis versus MPA) and ANCA specificity (proteinase 3 versus MPO) did not. This observation was replicated in an independent cohort of 38 newly diagnosed AAGN patients seen at our centre over the 1999-2014 period. Conclusions The annual incidence and prevalence of AAGN in Minnesota are 2.0/100 000 and 35/100 000, respectively. Mortality is worse compared with AAV patients without glomerulonephritis. More advanced renal damage at diagnosis predicts less renal recovery.

C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic

Objective: To describe the clinicopathological features, complement abnormalities, triggers, treatment, and outcomes of C3 glomerulopathy. Patients and Methods: A total of 114 patients with C3 glomerulopathy seen at Mayo Clinic from January 1, 2007, through December 31, 2016, were evaluated in this study. Results: The mean age at diagnosis for the entire cohort was 40.4±22.3 years, with a median serum creatinine level and proteinuria value of 1.6 mg/dL (range: 0.3‐14.7) (to convert to mmol/L, multiply by 0.0259) and 2605 mg/24 h (range: 233‐24,165), respectively. Hematuria was present in 100 patients (87.7%). The C3 and C4 levels were low in 50 of 112 (44.6%) and 13 of 110 (11.8%) patients, respectively. A history of infection, positive autoimmune findings, and monoclonal gammopathy (MIg) were present in 33 of 114 (28.9%), 28 of 114 (24.6%), and 36 of 95 (37.9%) patients, respectively. However, 28 of 43 patients 50 years or older (65.1%) had MIg. A genetic variant in complement genes, C3 nephritic factor (C3Nef), and other autoantibodies was present in 26 of 70 (37.1%), 30 of 69 (43.5%), and 9 of 67 (13.4%) patients, respectively. Membranoproliferative and mesangial proliferative glomerulonephritis were the common patterns of injury. Patients without MIg were younger (mean age, 32.3±20.6 years), with a median serum creatinine level and proteinuria value of 1.4 mg/dL (range: 0.3‐7.9) and 2450 mg/24 h (range: 250‐24, 165) and with low C3 and C4 levels in 38 of 77 (49.4%) and 9 of 75 (12.0%) patients, respectively. Most patients received corticosteroids and other immunosuppressive drugs. In patients without MIg, at a median follow‐up of 22.3 months (range: 0.1‐201.1), the median serum creatinine level and proteinuria value were 1.4 mg/dL (range: 0.3‐3.7) and 825.5 mg/24 h (range: 76‐22, 603), and 7 patients (9.2%) had progression to end‐stage renal disease. Conclusion: C3 glomerulopathy is a heterogeneous disease entity with complex triggering events and abnormalities of the alternative pathway of complement. The disease tends to be progressive and exhibits a variable response to immunosuppressive therapy.

Florid dermatopathic lymphadenopathy-A morphological mimic of Langerhans cell histiocytosis

The histopathology of reactive florid dermatopathic lymphadenopathy shows overlap with Langerhans cell histiocytosis (LCH) involving the lymph node, which may lead to misdiagnosis. These entities can be distinguished by recognition of the sinus‐based distribution of Langerhans cells in LCH, in contrast to the paracortical distribution of Langerhans cells, pigment‐laden histiocytes, and small lymphocytes in dermatopathic lymphadenopathy.

Evaluation of thrombocytopenia in the hematology clinic: A case series from a large tertiary care center

Infectious disease evaluation 27 (39.7%) Cytomegalovirus 6 (8.8%) 0 (0%) 6 (100%) Epstein-Barr virus 5 (7.4%) 1 (20%) 4 (80%) Hepatitis A virus 2 (2.9%) 0 (0%) 2 (100%) Hepatitis B virus 10 (14.7%) 0 (0%) 10 (100%) Hepatitis C virus 22 (32.4%) 0 (0%) 22 (100%) Human immunodeficiency virus 22 (32.4%) 0 (0%) 22 (100%) Helicobacter pylori 4 (5.9%) 0 (0%) 4 (100%) Peripheral blood smear 3 (63.2%) 4 (9.3%): large, elongated, well-granulated platelets (N=2); rouleaux formation; target cells; lymphocytes with circumferential hairy cytoplasmic projections 39 (90.7%)

Karyomegalic interstitial nephritis in a renal allograft

Karyomegalic interstitial nephritis (KIN) is a rare renal interstitial disease entity characterized by large tubular nuclei, accompanied by interstitial inflammation, tubular atrophy, and interstitial fibrosis. Approximately 50 cases of KIN have been described in the native kidney. In this case study, we describe the first case of KIN in a kidney allograft. A 41‐year‐old man presented with declining kidney function and a serum creatinine of 2.7 mg/dL. The native kidney biopsy showed large pleomorphic nuclei in the proximal and distal tubular epithelial cells, which was associated with interstitial inflammation, and extensive interstitial fibrosis and tubular atrophy. Immunohistochemistry for cytomegalovirus, adenovirus, and simian virus 40 were negative. A diagnosis of KIN was rendered. The patient received a living‐related kidney transplant from his sister. At 4‐, 12‐, and 24‐months posttransplant, protocol allograft biopsies showed KIN with large pleomorphic nuclei in the proximal and distal tubules with mild interstitial inflammation, minimal tubular atrophy, and interstitial fibrosis. At 24.7 months of follow‐up, the patient has stable renal function with a serum creatinine of 1.6 mg/dL. The KIN may represent recurrent KIN or donor‐associated KIN. Recognition of this rare disease entity is important as it can be mistaken for a viral infection.