Glomerular diseases occurring in the course of malignancies remain rare. Diverse glomerular lesions can be observed in a variety of neoplasms and involve different pathophysiologic links between the glomerulopathy and the cancer. The pathophysiology of solid tumor-associated glomerulopathies remains obscure, whereas in hematologic malignancy-induced paraneoplastic glomerulopathies, a molecular link can usually be demonstrated. The aim of this review is to provide an update on glomerular diseases associated with carcinoma and hematologic malignancies, covering epidemiology, pathophysiology, clinical presentation, and therapy. Special emphasis will be placed on the potential usefulness of novel biomarkers, such as antiphospholipase A2 receptor antibodies, for the diagnosis of membranous nephropathy, and on new associations and recent entities, including (proliferative) GN with nonorganized monoclonal immunoglobulin deposits and myeloproliferative neoplasm-related glomerulopathy.

Onco-Nephrology: Glomerular Diseases with Cancer

Antidepressants and antipsychotics affect multiple molecular targets Consequently, these drugs exhibit not only unique profiles of therapeutic effects but also several undesired effects Histamine receptors (H₁R, H₂R, H₃R, and H₄R) belong to the large family of G protein-coupled receptors and are very important drug targets All four H(x)R subtypes are expressed in the CNS Interactions of lipophilic, blood-brain barrier-penetrating drugs with H(x)Rs could contribute to therapeutic and unwanted effects Therefore, we investigated potencies H(x)R as well as potencies and (inverse) agonistic efficacies of 34 antidepressants and antipsychotics at HxRs in functional assays We expressed human H(x)Rs in Sf9 insect cells and conducted radioligand competition binding experiments and functional steady-state GTPase assays Ligand affinities and potencies were compared with literature data and related to therapeutic reference ranges Almost all antidepressants and antipsychotics displayed high binding affinities to H₁R and behaved as antagonists The atypical antidepressant trimipramine behaved as a high-affinity/high-potency H₂R antagonist (pK(i), 739; pK(B), 736; pA₂, 755) Docking to an H₂R model suggested a probable binding mode The affinity of antidepressants and antipsychotics for H₃R was low The atypical antipsychotic clozapine, known to induce agranulocytosis, exhibited partial H₄R agonism for which docking experiments provided a molecular basis Clozapine also exhibited H₂R antagonism We observed dissociations between pK(i) and pK (B) values as well as between pK(i) and pIC₅₀ values for H(x)Rs Antidepressants and antipsychotics interact differentially with H(x)Rs The concept of functional selectivity (also referred to as ligand-specific receptor conformations or biased signaling) explains dissociations between pK(i) and pK(B) values as well as differences between pK(i) and pIC₅₀ values The H₁R antagonism of numerous antidepressants and antipsychotics is very pronounced The H₂R antagonism of trimipramine and partial H₄R agonism of clozapine may be clinically relevant We also discuss the possible role of the H₂R antagonism of clozapine for neutropenia/agranulocytosis induced by this compound Finally, we discuss the methodological, conceptual, and clinical limitations of our study

Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics.

In routine diagnosis on renal biopsy, one of the confusing fields for pathological diagnoses is the glomerulopathies with fibrillary structure. The primary glomerulopathies with a deposit of ultrastructural fibrillary structure, which are negative for Congo-red stain but positive for immunoglobulins, include fibrillary glomerulonephritis and immunotactoid glomerulopathy. Several paraproteinemias including cryoglobulinemia, monoclonal gammopathy, and light chain deposition disease as well as hematopoietic disorders including plasmacytoma, plasma cell dyscrasia, and B cell lymphoproliferative disorders involve glomerulopathy with an ultrastructural fibrillary structure. A rare glomerulopathy with fibrillary structure that stains negative for Congo-red as well as for immunoglobulins has been also reported. The pathological diagnoses of these glomerulopathies can include either glomerular diseases, or paraproteinemic diseases, or hematopoietic diseases. The terminology is still confusing when glomerular diseases can be combined with paraproteinemic diseases and/or hematopoietic diseases. Therefore, the generic term, 'glomerular deposition disease' (GDD), has been proposed by pathologists with a requirement for clinicians to detect autoantibodies, paraproteins as well as to carry out a bone marrow check. An attempt has been made to rearrange the diseases with related disorders of fibrillary deposits, based on detailed clinical and pathological finding and to elucidate the correlation between GDD, paraproteinemia, and hematopoietic disorder.

Pathology of glomerular deposition diseases.

INTRODUCTION Clozapine, an atypical antipsychotic with documented efficacy in the management of treatment-resistant schizophrenia, is associated with the risk of adverse hematological outcomes. Of particular concern are reductions in white blood cells (WBC) and absolute neutrophil counts (ANC). Individuals who display moderate leukopenia (3000/mm(3) > WBC ≥ 2000/mm) upon initiation of clozapine therapy are at increased risk of developing agranulocytosis, defined as an ANC less than 500/mm. Complications of agranulocytosis can be severe and include increased risk of infection and mortality. OBJECTIVES The primary objective of this study was to examine data on clozapine recipients who experienced adverse drug reactions (ADRs) related to decreases in WBC or ANC and ascertain whether other drugs and/or drug interactions had played a role. The analysis included multiple classes of medications. METHODS A retrospective chart review was performed of open and closed medical records of all inpatient recipients of clozapine at a state psychiatric center between January 1, 2004 and June 30, 2011. Laboratory records of patients prescribed clozapine were examined for abnormal WBC counts or ANC. A hematological ADR was considered to have occurred if there was a substantial drop in either WBC or ANC or mild or moderate leukopenia or granulocytopenia. Each episode was analyzed for medications that might have contributed to the ADR. Data were collected for all scheduled and STAT medications started at any point during the clozapine patient's hospitalization. The following seven medication groups, based on the Therapeutic Classification System of the American Hospital Formulary System (AHFS), were chosen for analysis because they were consistently used in the majority of the patient population: antihistamines, anti-infectives, autonomic agents, cardiovascular agents, antipsychotics, vitamins, and gastrointestinal agents. Pearson correlation coefficients were calculated to identify associations between the presence of hematological ADRs and medications administered concomitantly with clozapine. RESULTS The following significant correlation coefficients were found between the use of a class of medications and the occurrence of a hematological ADR: antiinfective agents 0.409 (p < 0.01), gastrointestinal agents 0.329 (p < 0.01), and autonomic agents 0.309 (p < 0.01). In the subset of patients who were prescribed a proton-pump inhibitor or ranitidine concomitantly with clozapine, 24/26 (96%) experienced a hematological ADR. CONCLUSIONS Autonomic agents, anti-infective agents, and proton pump inhibitors and other gastrointestinal agents were all associated with hematological ADRs when co-prescribed with clozapine. Medications from these classes should be initiated cautiously in patients being treated with clozapine to avoid precipitous drops in ANC or WBC that may increase the risk of agranulocytosis.

Exploring the potential effect of polypharmacy on the hematologic profiles of clozapine patients.

Renal involvement is observed frequently in association with malignant gammopathies, mainly those related to light chain deposition [1]. Nevertheless, light chain deposition renal disease has also been described in non-malignant monoclonal gammopathy, namely in IgG or IgA plasma cell dyscrasia [2,3]. Renal involvement in IgM monoclonal disorders is traditionally described in patients with malignant disease (Waldenstrom’s macroglobulinaemia) that includes the deposition of monoclonal IgM and light chains on mesangium and glomerular capillary wall [4–6]. IgM monoclonal gammopathy without malignant criteria can be found in asymptomatic patients or associated with polyneuropathic disease, but renal involvement has rarely been described in this clinical setting [7,8]. We report the case of a patient with non-malignant IgM/k gammopathy, who developed nephrotic proteinuria and progressive renal failure in association with renal deposition of IgM and k light chains.

/pdf/renal-involvement-in-non-malignant-igm-gammopathy-1ch09rlqn8.pdf

Renal involvement in non-malignant IgM gammopathy.

Immunotactoid glomerulopathy with massive bone marrow deposits in a patient with IgM kappa monoclonal gammopathy and hypocomplementemia

OBJECTIVE:To report a case of agranulocytosis associated with initiation of famotidine.CASE SUMMARY:An 87-year-old white man was admitted to the internal medicine department of an acute care hospital because of fever and agranulocytosis (granulocyte count 0). Eight days prior to admission, famotidine therapy had been initiated. Famotidine was discontinued and granulocyte—macrophage colony stimulating factor was administered, with concomitant recovery of the granulocyte count and subsequent development of a leukemoid reaction.DISCUSSION:According to the Naranjo probability scale, famotidine was the probable cause of agranulocytosis. This is a rare adverse effect of this medication; only a few other cases have been reported.CONCLUSIONS:Although agranulocytosis is a rare adverse effect of famotidine, the pharmacist and physician should be aware of this potentially fatal event. If any patient treated with famotidine develops fever, the clinician should consider, among other things, performing a white blood ce...

Agranulocytosis Associated with Initiation of Famotidine Therapy

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Immunotactoid glomerulopathy with massive bone marrow deposits in a patient with IgM kappa monoclonal gammopathy and hypocomplementemia

Agranulocytosis Associated with Initiation of Famotidine Therapy