Case Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate consisting of the monoclonal antibody trastuzumab linked to the maytansinoid DM1 with potential antineoplastic activity and is approved for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified 124/1,243 (10%) renal adverse events for trastuzumab. However, there are no published case reports describing kidney biopsy findings related to nephrotoxicity of either trastuzumab or T-DM1. We report kidney biopsy findings in a case of nephrotic range proteinuria due to collapsing focal segmental glomerulosclerosis (FSGS) and tubular injury after initiation of T-DM1 therapy. After systematic exclusion of other causes, it is likely that the observed collapsing FSGS was associated with the prior initiation of T-DM1 therapy. This is further supported by the clinical course with improvement of proteinuria and kidney function 3 weeks after discontinuation of T-DM1 therapy without further specific treatment. In summary, we provide the first report of kidney biopsy findings in a case of nephrotic range proteinuria after initiation of T-DM1 therapy due to collapsing FSGS. This issue is especially relevant since T-DM1 is widely used, and nephrologists have to be aware of this potentially rare but severe complication.

Recurrent Focal Segmental Glomeruloscleosis Progressing to Collapsing Glomerulopathy in Renal Graft of an Autopsy study

Introduction/Objective Collapsing glomerulopathy (CGN) mainly occurs in patients of African descent because a majority of these patients have APOL-1 gene mutations that results in damage of terminally differentiated podocytes, diffuse fusion of foot processes, and podocyte hyperplasia. Idiopathic FSGS is associated with high rates of recurrent FSGS in renal transplants and can be seen in patients with APOL-1 gene mutations as well, but recurrent FSGS progressing to CGN is not reported. Here we report an autopsy case with renal transplant showing recurrent FSGS progressing to CGN. Methods/Case Report Our patient was a 32 year old African American man who had a native renal biopsy which showed primary FSGS (with no infectious history) 8 years ago. Last year he received a renal transplantation (complex donor kidney from a deceased 25 year old man with pre-mortem serum creatinine (sCr) at 0.7 mg/dl). His initial post- transplant sCr level was as low as 1.17 mg/dl. However, in 4 months his sCr went up and he began to have higher levels of proteinuria. Sequential biopsies indicated that the patient developed a recurrent FSGS that progressed to show features of CGN. In his autopsy kidney graft, approximately 50% of glomeruli show collapsed loops with various degrees of hyperplasic podocytes, confirmed by positive CD133 staining (a progenitor cell marker). In addition, the hyperplastic podocytes lost WT-1 expression and were positive for Ki-67 staining. Distal tubules showed obvious cystic dilation. Overall findings were consistent with a severe form of CGN. Results (if a Case Study enter NA) NA Conclusion The clinical presentation of recurrent FSGS progressing to collapsing FSGS in our patient suggests that CGN and idiopathic FSGS may share a common pathophysiologic mechanism of disease.

Collapsing FSGS with Concurrent Class 2 and 3 Lupus Nephritis: A Case Report and Review of the Literature

Lupus nephritis (LN) and the collapsing variant of focal segmental glomerulosclerosis (cFSGS) are separate histologic diagnoses that are generally thought to have separate etiologies. We describe the presentation of a 20-year-old African American female with advanced renal failure (creatinine 7.16 mg/dL), nephrotic-range proteinuria, and a 30-pound weight loss. Renal biopsy demonstrated class 2 and 3 LN as well as cFSGS. A review of the current literature demonstrates that the dual diagnosis of LN and cFSGS may not be as rare as previously understood. Whether the presence of one of these pathophysiologic processes predisposes a patient to the development of the other, or whether genetic variation increases the risk for development of both conditions, remains unclear. Currently there is no standard therapy to manage these patients, and overall renal prognosis is poor.

Successful treatment of collapsing focal segmental glomerulosclerosis in a patient

Focal segmental glomerulosclerosis (FSGS) is a recognized cause of renal disease worldwide. The collapsing variant is distinct from the others, characterized clinically by a more severe nephrotic syndrome generally resistant to immunosuppressive therapy. It is known that a great number of patients progress to end-stage renal disease. Recognizing this lesion in biopsy is frequently challenging owing to the focal nature of the process which highlights the need for keeping a high index of suspicion for the diagnosis. We report and discuss a case of a non-HIV collapsing FSGS, followed by a complete (unexpected) renal recovery after an oral corticosteroid course.

Postmortem Kidney Pathology Findings in Patients with COVID-19

BackgroundAKI is common among hospitalized patients with coronavirus disease 2019 (COVID-19) and is an independent risk factor for mortality. Although there are numerous potential mechanisms underlying COVID-19–associated AKI, our current knowledge of kidney pathologic findings in COVID-19 is limited.MethodsWe examined the postmortem kidneys from 42 patients who died of COVID-19. We reviewed light microscopy findings in all autopsies and performed immunofluorescence, electron microscopy, and in situ hybridization studies for SARS-CoV-2 on a subset of samples.ResultsThe cohort had a median age of 71.5 years (range, 38–97 years); 69% were men, 57% were Hispanic, and 73% had a history of hypertension. Among patients with available data, AKI developed in 31 of 33 patients (94%), including 6 with AKI stage 1, 9 with stage 2, and 16 with stage 3. The predominant finding correlating with AKI was acute tubular injury. However, the degree of acute tubular injury was often less severe than predicted for the degree of AKI, suggesting a role for hemodynamic factors, such as aggressive fluid management. Background changes of hypertensive arterionephrosclerosis and diabetic glomerulosclerosis were frequent but typically mild. We identified focal kidney fibrin thrombi in 6 of 42 (14%) autopsies. A single Black patient had collapsing FSGS. Immunofluorescence and electron microscopy were largely unrevealing, and in situ hybridization for SARS-CoV-2 showed no definitive positivity.ConclusionsAmong a cohort of 42 patients dying with COVID-19, autopsy histologic evaluation revealed acute tubular injury, which was typically mild relative to the degree of creatinine elevation. These findings suggest potential for reversibility upon resolution of SARS-CoV-2 infection.

Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis

BackgroundThe mechanisms leading to extracellular matrix (ECM) replacement of areas of glomerular capillaries in histologic variants of FSGS are unknown. This study used proteomics to test the hypothesis that glomerular ECM composition in collapsing FSGS (cFSGS) differs from that of other variants.MethodsECM proteins in glomeruli from biopsy specimens of patients with FSGS not otherwise specified (FSGS-NOS) or cFSGS and from normal controls were distinguished and quantified using mass spectrometry, verified and localized using immunohistochemistry (IHC) and confocal microscopy, and assessed for gene expression. The analysis also quantified urinary excretion of ECM proteins and peptides.ResultsOf 58 ECM proteins that differed in abundance between cFSGS and FSGS-NOS, 41 were more abundant in cFSGS and 17 in FSGS-NOS. IHC showed that glomerular tuft staining for cathepsin B, cathepsin C, and annexin A3 in cFSGS was significantly greater than in other FSGS variants, in minimal change disease, or in membranous nephropathy. Annexin A3 colocalized with cathepsin B and C, claudin-1, phosphorylated ERK1/2, and CD44, but not with synaptopodin, in parietal epithelial cells (PECs) infiltrating cFSGS glomeruli. Transcripts for cathepsins B and C were increased in FSGS glomeruli compared with normal controls, and urinary excretion of both cathepsins was significantly greater in cFSGS compared with FSGS-NOS. Urinary excretion of ECM-derived peptides was enhanced in cFSGS, although in silico analysis did not identify enhanced excretion of peptides derived from cathepsin B or C.ConclusionsECM differences suggest that glomerular sclerosis in cFSGS differs from that in other FSGS variants. Infiltration of activated PECs may disrupt ECM remodeling in cFSGS. These cells and their cathepsins may be therapeutic targets.

Collapsing focal segmental glomerulosclerosis probably triggered by dengue virus infection - two case reports

The reported cases describe the association between collapsing focal segmental glomerulosclerosis (FSGS) and acute dengue virus infection. In both cases, patients were diagnosed with dengue virus infection and had a severe kidney disease, with nephrotic syndrome and acute kidney injury. Kidney biopsy was performed and showed collapsing FSGS. The first patient, a 27-year-old man, was diagnosed with dengue virus infection and developed nephrotic syndrome after two weeks of illness. He was treated with methylprednisolone for three days and intravenous furosemide. This patient evolved well, although his renal function did not fully recover. The second patient, a 32-year-old man, was diagnosed with a milder clinical presentation of dengue virus infection. He had a past medical history of nephrotic syndrome in childhood, which might have caused its relapse. This patient was treated with intravenous furosemide and also did not fully recover renal function. These cases highlight the possible implication of dengue virus infection in the etiology of collapsing variant of FSGS. Healthcare professionals should be prepared to identify similar cases.

Collapsing Focal Segmental Glomerulosclerosis and Acute Oxalate Nephropathy in a Patient With COVID-19: A Double Whammy

As COVID-19 (coronavirus disease 2019) spreads across the world multiple therapeutic interventions have been tried to reduce morbidity and mortality. We describe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and acute oxalate nephropathy in a patient treated with high-dose intravenous vitamin C for severe COVID-19 infection. Collapsing FSGS has been described in patients with COVID-19 infection associated with APOL-1; however, this case had collapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we postulate that the intensity of the COVID-19 cytokine storm overwhelmed the protective state of APOL-1 heterozygosity. This case illustrates the importance of assessing the risk and benefit of planned therapeutic interventions on a case-by-case basis especially when there are still so many unknowns in the management of COVID-19 infection. Strong consideration should be given for performing a renal biopsy in patients who develop multifactorial acute kidney injury.