Repurposing drugs for diseases associated with podocyte dysfunction.

The majority of podocyte disorders are progressive in nature leading to chronic kidney disease and often kidney failure. The scope of current therapies is typically nonspecific immunosuppressant medications, which are accompanied by unwanted and serious side effects. However, many exciting clinical trials are underway to reduce the burden of podocyte diseases in our patients. Major advances and discoveries have recently been made experimentally in our understanding of the molecular and cellular mechanisms underlying podocyte injury in disease. This begs the question of how best to take advantage of these impressive strides. One approach to consider is the repurposing of therapeutics that have already been approved by the Food and Drug Administration, European Medicines Agency, and other regulatory agencies for indications beyond the kidney. The advantages of therapy repurposing include known safety profiles, drug development that has already been completed, and overall reduced costs for studying alternative indications for selected therapies. The purpose of this mini review is to examine the experimental literature of podocyte damage and determine if there are mechanistic targets in which prior approved therapies can be considered for repurposing to podocyte disorders.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

ANCA-Associated Vasculitis: Core Curriculum 2020.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3-ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD's Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.

Nephrotic syndrome in pregnancy poses risks with both maternal and fetal complications.

In the absence of uncontrolled hypertension or renal insufficiency, many consider the perinatal outcomes in pregnant women with nephrotic syndrome to be good. To further investigate this we performed a retrospective chart review of women with biopsy-proven nephrotic syndrome due to primary glomerular disease during pregnancy at a single tertiary center. Our review determined characteristics, presentation, management, pathologic diagnoses, and associated renal and maternal-fetal outcomes of 19 individuals with 26 pregnancies and 26 offspring. The mean age was 27.6 years, the mean gestational age at the presentation of nephrotic syndrome was 18.6 weeks, the mean creatinine was 0.85 mg/dL, mean serum albumin was 1.98 g/dL, and the mean proteinuria was 8.33 g/24 hours. The mean cardiac output was 8.6 L/minute, which was elevated compared to normal pregnancy. A kidney biopsy was performed during pregnancy in 8 individuals (median gestational age at time of biopsy was 21 weeks), changing management in six. Of the 26 pregnancies, maternal complications included preeclampsia in seven, acute kidney injury in six, premature rupture of membranes in two, and cellulitis in three. The mean age of gestation at delivery was 35.5 weeks. Fetal complications included low birth weight (under 2,500 g) in 14, intra-uterine growth restriction in three, and neonatal intensive care unit admission in eight. Thus, pregnant women with nephrotic syndrome are at high risk for developing both maternal and fetal complications, even in the absence of significant renal impairment or uncontrolled hypertension at the time of presentation of nephrotic syndrome.

Collapsing Glomerulopathy.

Collapsing glomerulopathy (CG) is a pattern of kidney injury characterized by segmental or global collapse of the glomerular tuft associated with overlying epithelial cell hyperplasia. Although CG may be idiopathic, a wide range of etiologies have been identified that can lead to this pattern of injury. Recent advances have highlighted the role of inflammatory and interferon signaling pathways and upregulation of apolipoprotein L1 (APOL1) within podocytes in those carrying a high-risk APOL1 genotype. In this review, we describe the etiology, pathogenesis, pathology, and clinical course of CG, focusing on nonviral etiologies. We also describe current treatments and explore potential therapeutic options targeting interferon/APOL1 pathways in CG.

Antibrush Border Antibody Disease: A Case Series.

Antibrush border antibody (ABBA) disease is a rare cause of kidney disease characterized by progressive renal tubular injury associated with immune complex deposition along the basement membranes of the proximal tubule and circulating autoantibodies to brush border antigens. Several antigens have been identified as targets of autoantibodies in this disease, including low-density lipoprotein receptor related protein 2 (LRP2), cubilin, and amnionless proteins. We present 9 patients from 2 academic medical centers and describe the clinicopathologic characteristics and outcome data. All patients presented with acute kidney injury and proteinuria. Pathology confirmed immune complex deposition along proximal tubular basement membranes in all patients, but the majority (6/8) also showed segmental glomerular subepithelial immune complexes. Two of 3 patients treated with rituximab demonstrated stabilization of kidney function; 1 of these patients had mantle cell lymphoma. One patient with lung cancer showed stabilization of disease after treatment of the malignancy. The remaining patients progressed to end-stage kidney disease with either conservative therapy (3 patients) or immunosuppression with glucocorticoids (2 patients). This series highlights the poor prognosis of ABBA disease, but a potential benefit of anti-B cell therapy or treatment of an underlying malignancy in some cases.

Has the circulating permeability factor in primary FSGS been found?

A circulating permeability factor has long been implicated in the pathogenesis of primary focal segmental glomerulosclerosis (FSGS). Evidence in animal models and now in several cohorts of patients with primary FSGS suggests a role for the soluble urokinase-type plasminogen activator receptor (suPAR) as a biomarker and perhaps as a contributing factor. Confirmation of these findings might lead to new diagnostic and therapeutic strategies for FSGS as well as a better understanding of podocyte dysfunction.

Migration of an intrauterine device and peritonitis in a peritoneal dialysis patient.

Peritonitis is a frequent complication of peritoneal dialysis. Infection is most commonly introduced into the peritoneal cavity through the indwelling catheter during the dialysis procedure. Occasionally peritonitis is associated with underlying abdominal pathology rather than secondary to the dialysis procedure itself. Here we present a case of polymicrobial peritonitis in a patient on automated peritoneal dialysis (APD) in the setting of uterine perforation by an intrauterine device (IUD). Clinicians involved in the care of patients on peritoneal dialysis should remain vigilant for underlying abdominal pathology in cases of complicated peritonitis.

Management of Lupus Nephritis: New Treatments and Updated Guidelines.

Management of lupus nephritis has evolved considerably over the past years. Here, we provide a comprehensive review of clinical trials that form the basis for the Kidney Disease: Improving Global Outcomes and EULAR/ERA-EDTA updated guidelines and present day trials that will change the landscape of lupus nephritis therapy in years to come. In addition, we highlight the issues related to cost of therapy, resistant disease, and downstream adverse effects of specific therapies.

High altitude renal syndrome (HARS).

More than 140 million people live permanently at high altitude (>2400 m) under hypoxic conditions that challenge basic physiology. Here we present a short historical review of the populating of these regions and of evidence for genetic adaptations and environmental factors (such as exposure to cobalt) that may influence the phenotypic responses. We also review some of the common renal physiologic responses focusing on clinical manifestations. The frequent presentation of systemic hypertension and microalbuminuria with relatively preserved GFR coupled with the presence of polycythemia and hyperuricemia suggests a new clinical syndrome we term high altitude renal syndrome (HARS). ACE inhibitors appear effective at reducing proteinuria and lowering hemoglobin levels in these patients.

A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma.

Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

VEGF inhibition and renal thrombotic microangiopathy.

The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

Podocyte biology for the bedside.

The explosion of podocyte biology during the last decade has radically altered our views on the pathophysiologic process of proteinuria, glomerular disease, and progressive kidney disease. In this review, we highlight some of these landmark findings, but focus on recent advances in the field and implications for translating this biology into therapy for podocyte diseases.

Steroid Minimization in Adults with Minimal Change Disease.

Background: Minimal change disease (MCD) causes approximately 10% of nephrotic syndrome in adults. While glucocorticoids (GCs) effectively induce remission in MCD, the disease has a high relapse rate (50-75%), and repeated exposure to GCs is often required. The adverse effects of GCs are well recognized and commonly encountered with the high doses and recurrent courses used in MCD. Summary: In this review, we will discuss the standard therapy of MCD in adults and then describe new therapeutic options in induction therapy and treatment of relapses in MCD, minimizing the exposure to GCs. Key Messages: Steroid minimization strategies may decrease adverse effects in the treatment of MCD.

Calculating estimated glomerular filtration rate without the race correction factor: Observations at a large academic medical system.

BACKGROUND AND AIMS: Creatinine-based MDRD and CKD-EPI equations include a race correction factor, which results in higher eGFR in Black patients. We evaluated the impact on our patient population upon adoption of the CKD-EPI equation and the removal of the race correction factor from the equation. MATERIALS AND METHODS: Retrospective analysis of blood creatinine results and respective eGFR values calculated by the MDRD or CKD-EPI equation without the race correction factor (CKD-EPINoRace) in a large academic medical system over a 20.5-month period. RESULTS: In our population, when changing from MDRD to CKD-EPINoRace, we observed that 3.5% of all patients were reclassified to categorically have worse kidney function. However, we also observed fewer patients overall with eGFR below 60 mL/min/1.73 m2. Around 60 and 20 mL/min/1.73 m2, 2.96% and 0.16% of all patients > 65 years of age were reclassified, as were 4.29% and 0.03% of all Black patients, respectively. When calculated with CKD-EPINoRace, median eGFR was not meaningfully different between Black and non-Black patients (p = 0.02). CONCLUSIONS: Changing from MDRD to CKD-EPINoRace could lead to a lower referral rate to nephrology. The distributions of creatinine and eGFR calculated with CKD-EPINoRace were not meaningfully different in Black and non-Black patients.

Experimental Models of Membranous Nephropathy.

Membranous nephropathy (MN) is one of the commonest glomerular diseases, typically presenting in older males with nephrotic syndrome. The development and characterization of animal models of MN, in particular, the passive Heymann nephritis model (PHN), has greatly advanced our understanding of this disease. In this review we discuss the different animal models of human MN that are available, with an emphasis on the PHN model, including technical issues, the typical disease course and its application to human disease.

Fibrillary Glomerulonephritis: Clinicopathologic Features and Atypical Cases from a Multi-Institutional Cohort.

BACKGROUND AND OBJECTIVES: Fibrillary GN has been defined as an immune complex-mediated GN with amyloid-like fibrils larger than amyloid which are IgG positive and Congo red negative. With discovery of DNAJB9 as a highly sensitive and specific marker for fibrillary GN, the specificity of the morphologic criteria for establishing the diagnosis of fibrillary GN has come into question. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We sought to (1) determine anatomic characteristics that best define fibrillary GN and (2) identify clinical and pathologic features that predict outcomes. RESULTS: We retrospectively reviewed kidney biopsies from patients diagnosed with fibrillary GN or suspected fibrillary GN between 1997 and 2017 (n=266, 65% female, median age 61). Approximately 11% of kidney biopsies had one or more unusual feature including monotypic deposits, Congo red positivity, or unusual fibril diameter. Fibrillary GN as a possible monoclonal gammopathy of renal significance represented <1% of cases. Immunostaining for DNAJB9 confirmed fibrillary GN in 100% of cases diagnosed as fibrillary GN and 79% of atypical cases diagnosed as possible fibrillary GN. At a median time of 24 months (interquartile range, 8-46 months) after biopsy (n=100), 53% of patients reached the combined primary outcome of ESKD or death, 18% had CKD, and 18% had partial remission. On multivariable analysis, male sex (adjusted hazard ratio [aHR], 3.82; 95% confidence interval [95% CI], 1.97 to 7.37) and eGFR were the most significant predictors of primary outcome (aHR of 8.02 if eGFR <30 ml/min per 1.73 m2 [95% CI, 1.85 to 34.75]; aHR of 6.44 if eGFR 30 to <45 ml/min per 1.73 m2 [95% CI, 1.38 to 29.99]). Immunosuppressive therapy with rituximab was significantly associated with stabilization of disease progression. CONCLUSIONS: Detection of DNAJB9 is a useful diagnostic tool for diagnosing atypical forms of fibrillary GN. The outcomes for fibrillary GN are poor and progression to ESKD is influenced predominantly by the degree of kidney insufficiency at the time of diagnosis and male sex. Rituximab may help preserve kidney function for select patients with fibrillary GN. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_11_04_CJN03870319.mp3.

Complications of Immunosuppression in Glomerular Disease.

Most glomerular diseases are immunologically mediated disorders of the kidney and are common causes of ESKD. In addition to supportive therapy, a wide range of immunosuppressive agents are used in the management of patients with these conditions. Immunosuppression requires a careful balance of risk and benefits, and many of these agents have a narrow therapeutic window and require close monitoring. This review describes the side effects of immunosuppressive agents used in recent randomized, controlled trials of glomerular disease, and highlights some of the key adverse events that determine the choice and prescription of these medications.

IgA-dominant glomerulonephritis with a membranoproliferative pattern of injury.

Immunoglobulin A (IgA)-dominant membranoproliferative glomerulonephritis (MPGN) is a descriptive term for renal biopsies in which differential diagnoses of unusual IgA nephropathy (IgAN), infection-related GN, or other etiologies are considered. We sought to understand clinical and pathologic features of this finding. Native kidney biopsies with IgA-dominant immune deposits and diffuse MPGN features without significant exudative features or subepithelial deposits were retrospectively reviewed. Two groups (n = 27, 33 biopsies) were identified: patients with chronic liver disease and those without. Patients without chronic liver disease (n = 15) were men (73%, age 40) who presented with nephrotic-range proteinuria, hematuria, renal insufficiency, negative serologic studies, and no history of infection. At a median interval of 3 years, 11 had available follow-up information. Three (27%) progressed to end-stage renal disease. One had recurrent IgA-dominant GN in the renal allograft less than 1 year posttransplant. Four of 5 patients with repeat biopsies had persistent IgA-dominant MPGN. Patients with chronic liver disease (n = 12) had similar biopsy findings, but 42% had concurrent infections, some occult. At a median interval of 7 weeks, 8 patients (80% of those with follow-up) had died and 2 were dialysis dependent. In conclusion, IgA-dominant MPGN was seen in 2 clinical cohorts in this study. In patients without chronic liver disease, this appears to represent either a unique clinicopathologic entity with a poorer prognosis than IgAN or an aggressive variant of IgAN. Patients with chronic liver disease often have underlying infection, and regardless of treatment, die within 1 year because of complex medical conditions.