Granulomatous myocarditis arising from intravesical Bacillus Calmette-Guérin therapy leading to death diagnosed by postmortem examination: a case report.

BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) is used as a standard adjuvant therapy for non-muscle invasive urothelial cancer. Most patients tolerate the treatment well, with mild side effects. Systemic complications are extremely rare, occur due to BCG dissemination and are associated with immunocompromised state and urothelial breach. CASE PRESENTATION: We present a case of a 78-year-old male, a former smoker, with history of non-muscle invasive urothelial carcinoma status post partial resection followed by intravesical BCG therapy. An autopsy was performed due to the sudden nature of his death. Autopsy showed multiple necrotizing granulomas in the brain, atrium, ventricles, lungs, kidneys, and urinary bladder. Stains for acid-fast bacilli and fungi were negative. In addition, bilateral lungs showed evidence of bronchopneumonia secondary to cytomegalovirus. CONCLUSION: Granulomatous myocarditis arising from BCG therapy is extremely rare. Our patient with urothelial cancer treated with BCG developed multiorgan granulomas, most likely due to a hypersensitivity reaction to intravesical BCG. Arrhythmia induced by granulomatous myocarditis was the cause of his death. Although there have been few cases of systemic BCG-osis causing fatal sepsis leading to death, a cardiac cause of death is unique.

COL4A4 variant recently identified: lessons learned in variant interpretation-a case report.

BACKGROUND: Alport syndrome is a hereditary kidney disease characterized by hematuria and proteinuria. Although there have been reports of autosomal dominant COL4A4 variants, this is likely an underdiagnosed condition. Improved access to affordable genetic testing has increased the diagnosis of Alport syndrome. As genetic testing becomes ubiquitous, it is imperative that clinical nephrologists understand the benefits and challenges associated with clinical genetic testing. CASE PRESENTATION: We present a family of Mexican descent with a heterozygous COL4A4 variant (c.5007delC, ClinVar accession numbers: SCV001580980.2, SCV001993731.1) not previously discussed in detail in the literature. The proband received a biopsy diagnosis suggestive of Fabry disease 18 years after she first developed hematuria and progressed to chronic kidney disease stage III. One year later, the proband was provisionally diagnosed with Alport syndrome after a variant of uncertain significance in the COL4A4 gene was identified following targeted family variant testing of her daughter. Upon review of the medical histories of the proband's children and niece, all but one had the same variant. Of the four with the variant, three display clinical symptoms of hematuria, and/or proteinuria. The youngest of the four, only months old, has yet to exhibit clinical symptoms. Despite these findings there was a considerable delay in synthesizing this data, as patients were tested in different commercial genetic testing laboratories. Subsequently, understanding this family's inheritance pattern, family history, and clinical symptoms, as well as the location of the COL4A4 variant resulted in the upgrade of the variant's classification. Although the classification of this variant varied among different clinical genetic testing laboratories, the consensus was that this variant is likely pathogenic. CONCLUSIONS: This COL4A4 variant (c.5007delC) not yet discussed in detail in the literature is associated with Alport syndrome. The inheritance pattern is suggestive of autosomal dominant inheritance. This report highlights the intricacies of variant interpretation and classification, the siloed nature of commercial genetic testing laboratories, and the importance of a thorough family history for proper variant interpretation. Additionally, the cases demonstrate the varied clinical presentations of Alport syndrome and suggest the utility of early screening, diagnosis, monitoring, and treatment.

Oxalate nephropathy: a review.

This review describes the clinical and pathological features of oxalate nephropathy (ON), defined as a syndrome of decreased renal function associated with deposition of calcium oxalate crystals in kidney tubules. We review the different causes of hyperoxaluria, including primary hyperoxaluria, enteric hyperoxaluria and ingestion-related hyperoxaluria. Recent case series of biopsy-proven ON are reviewed in detail, as well as the implications of these series. The possibility of antibiotic use predisposing to ON is discussed. Therapies for hyperoxaluria and ON are reviewed with an emphasis on newer treatments available and in development. Promising research avenues to explore in this area are discussed.

Deep learning for the classification of medical kidney disease: a pilot study for electron microscopy.

Artificial intelligence (AI) is a new frontier and often enigmatic for medical professionals. Cloud computing could open up the field of computer vision to a wider medical audience and deep learning on the cloud allows one to design, develop, train and deploy applications with ease. In the field of histopathology, the implementation of various applications in AI has been successful for whole slide images rich in biological diversity. However, the analysis of other tissue medias, including electron microscopy, is yet to be explored. The present study aims to evaluate deep learning for the classification of medical kidney disease on electron microscopy images: amyloidosis, diabetic glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), and thin basement membrane disease (TBMD). We found good overall classification with the MedKidneyEM-v1 Classifier and when looking at normal and diseased kidneys, the average area under the curve for precision and recall was 0.841. The average area under the curve for precision and recall on the disease only cohort was 0.909. Digital pathology will shape a new era for medical kidney disease and the present study demonstrates the feasibility of deep learning for electron microscopy. Future approaches could be used by renal pathologists to improve diagnostic concordance, determine therapeutic strategies, and optimize patient outcomes in a true clinical environment.

Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury.

In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-control study and studies in mice. Seventy-three mice underwent cecal ligation and puncture (a sepsis model) or sham operation. Additionally, 94 septic mice received losartan (selective AT1R antagonist), angiotensin II without or with losartan, or vehicle. Cumulative urine output, kidney blood flow, blood urea nitrogen, and creatinine were measured. AT1R expression was assessed using ELISA, qPCR, and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. AT1R expression was compared in autopsy tissue from seven patients with sepsis to that of the non-involved portion of kidney from ten individuals with kidney cancer and three non-infected but critically ill patients. By six hours post ligation/puncture, kidney blood flow doubled, blood urea nitrogen rose, and urine output fell. Concurrently, AT1R expression significantly fell 2-fold in arterioles and the macula densa. Creatinine significantly rose by 24 hours and sham operation did not alter measurements. Losartan significantly exacerbated ligation/puncture-induced changes in kidney blood flow, blood urea nitrogen, creatinine, and urine output. There was no histologic evidence of cortical ischemia. Significantly, angiotensin II prevented changes in kidney blood flow, creatinine, and urine output compared to vehicle. Co-administering losartan with angiotensin-II reversed this protection. Relative to both controls, patients with sepsis had low AT1R expression in arterioles and macula densa. Thus, murine cecal ligation/puncture and clinical sepsis decrease renal AT1R expression. Angiotensin II prevents functional changes while AT1R-blockade exacerbates them independent of ischemia in mice.

Adult primary nephrotic syndrome trends by race: a diminished frequency of focal segmental glomerulosclerosis in non-black patients.

PURPOSE: There have been conflicting data on the relative frequency of common forms of primary nephrotic syndrome (PNS). We undertook this study to look at the causes of PNS in the latest decade from our biopsy population, with a special attention to breakdown by race. METHODS: Retrospective chart review of all cases of adult PNS extracted from a database of 1388 cases for the last 10 years. We were careful to exclude patients with secondary disease and without the full nephrotic syndrome. RESULTS: There were 115 cases of PNS. Overall, MN was the most common lesion (40.0%), followed by minimal change disease (MCD) (34.0%), focal segmental glomerulosclerosis (FSGS) (13.0%), and IgA nephropathy (IgAN) (11.3%). Among whites, MN was the most common cause of NS (41.7%), followed by MCD (33.3%), IgAN (16.7%), and FSGS (6.3%). Among blacks, FSGS was the most common lesion (33.3%) followed closely by MN (29.6%), and MCD (26.0%). IgAN was present in 7.4%. Among multiracial patients (MR), MGN was the most common (50%) followed by MCD (45.5%) and FSGS (4.5%). In Asians, MCD (50.1%) and MGN (33.3%) were the most common, followed by FSGS and IgAN with 8.3% each. CONCLUSIONS: MN and MCD were the most common causes of PNS in our population, with FSGS much less common overall. This is especially the case among whites and MR. Among blacks, MN and FSGS were almost codominant causes. The apparent decreased prevalence of FSGS may be related to more effective exclusion of secondary and maladaptive causes.

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings.

BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.

COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Kidney oxalate crystal deposition in adult patients: A relatively common finding
.

AIMS: We aim to describe the clinical and histological findings in patients with the finding of any tubular oxalate deposits in kidney biopsy specimens. BACKGROUND: The prevalence, manifestation, and outcome of secondary oxalate nephropathy have not been extensively studied. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed the clinical and histological findings in all patients with the finding of any tubular oxalate deposits in kidney biopsy specimens between July 1, 2017, and December 31, 2018, at Northwell Health Pathology Department (Manhasset, NY, USA). RESULTS: The prevalence of oxalate deposition on a kidney biopsy was 4.07% (25/615), and in 88% of cases was a major finding. Prior to biopsy, oxalate was anticipated in only 1 case. The etiology of oxalosis was clarified retrospectively in 14 cases, most commonly due to GI surgery (n = 10) and increased oxalate intake (n = 4). In 11 cases, etiology remained unknown, although at least 3 cases were exposed to antibiotics associated with secondary oxalosis. There was no significant clinical/pathological or survival difference between known vs. unknown cause groups. The overall 3-month renal survival rate was 76.0 ± 8.5%. Multivariate Cox regression showed that creatinine at the time of biopsy (HR: 1.79, 95% CI: 0.71 - 4.51), background histological chronicity change (HR: 1.82, 95% CI: 0.70 - 4.72) and oxalate density (HR: 2.27, 95% CI: 0.49 - 10.55) are associated with end-stage kidney disease. CONCLUSION: Oxalate deposition is common but rarely anticipated biopsy finding. Nephrologists need to consider surgical history and other secondary causes of oxalosis as causes of acute kidney injury and chronic kidney disease.

Kidney diseases associated with Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma characterized by lymphoplasmacytic cell infiltration in the bone marrow and other organs and the presence of a monoclonal immunoglobulin M protein in the serum. Although uncommon, several kidney diseases have been associated with WM. In addition to kidney diseases related to lymphoplasmacytic lymphoma infiltration, a variety of glomerular and tubular lesions have been described in patients with WM. Immunoglobulin light chain (AL) amyloidosis and cryoglobulinemic glomerulonephritis are the two predominant glomerular pathologies seen in WM. In this article we review the kidney diseases associated with WM. We also briefly review some nephrotoxicities of novel chemotherapeutic and targeted therapies used for the treatment of WM.

Kidney Biopsy Findings in a Patient With Valproic Acid-Associated Fanconi Syndrome.

A 7-year-old boy with a history of febrile illness-related epilepsy syndrome presented with proteinuria and elevated creatinine. His severe epileptic disorder has been treated since age 2 with multiple antiepileptic medications, including valproic acid. More recently, he was noted to have features of Fanconi syndrome with acidosis, hypophosphatemia, hypokalemia, glucosuria, and nephrotic-range proteinuria. This was managed with supplements; however, in the setting of rising creatinine and prominent proteinuria, a kidney biopsy was performed. Renal cortex revealed markedly decreased expression of proximal tubule markers and increased expression of markers of distal nephron differentiation. Such findings have been described in several genetic and acquired conditions, including renal tubular dysgenesis, severe hypoxic injury following renal artery stenosis, and toxic injury related to in utero exposure to angiotensin-converting-enzyme inhibitors. Such changes have not been reported before in valproic acid-associated Fanconi syndrome, although in general, morphologic findings in this condition have not been well established in the literature.

Congophilic Fibrillary Glomerulonephritis: A Case Series.

RATIONALE & OBJECTIVE: Congo Red positivity with birefringence under polarized light has traditionally permitted classification of organized glomerular deposits as from amyloid or nonamyloid diseases. The absence of congophilia has been used to differentiate fibrillary glomerulonephritis (GN) from amyloidosis. We describe a series of fibrillary GN cases in which the deposits are Congo Red-positive (congophilic fibrillary GN) and discuss the role of DNAJB9 in distinguishing congophilic fibrillary GN from amyloidosis. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Analysis of the clinicopathologic characteristics of 18 cases of congophilic fibrillary GN. Mass spectrometry was performed and compared with 24 cases of Congo Red-negative fibrillary GN, 145 cases of amyloidosis, and 12 apparently healthy individuals. DNAJB9 immunohistochemistry was obtained for a subset of cases. RESULTS: The proteomic signature of amyloid was not detected using mass spectrometry among cases of congophilic fibrillary GN. DNAJB9, a recently discovered proteomic marker for fibrillary GN, was detected using mass spectrometry in all cases of fibrillary GN regardless of congophilia and was absent in cases of amyloidosis and in healthy individuals. DNAJB9 immunohistochemistry confirmed the mass spectrometry findings. The congophilic fibrillary GN cases included 11 men and 7 women with a mean age at diagnosis of 65 years. Concomitant monoclonal gammopathy, hepatitis C virus infection, malignancy, or autoimmune disease was present in 35%, 22%, 17%, and 11% of patients, respectively. No patient had evidence of extrarenal amyloidosis. Patients presented with proteinuria (100%), nephrotic syndrome (47%), hematuria (78%), and chronic kidney disease (83%). After a mean follow-up of 23 months, 31% of patients progressed to end-stage kidney disease and the remaining 69% had persistently reduced kidney function. LIMITATIONS: Retrospective nature. Blinded pathology evaluations were not performed. CONCLUSIONS: The congophilic properties of organized fibrillary deposits should not be solely relied on in differentiating fibrillary GN from renal amyloidosis. Mass spectrometry and DNAJB9 immunohistochemistry can be useful in making this distinction.

Plasmapheresis for treatment of immune complex-mediated glomerulonephritis in infective endocarditis: a case report and literature review.

We report the case of a 57-year-old man who presented with subacute bacterial endocarditis secondary to Streptococcus mutans complicated by biopsy-proven immune complex-mediated glomerulonephritis (ICGN). Despite initial treatment with antibiotics and a short course of corticosteroids, the kidney function further deteriorated, and plasmapheresis was introduced as third-line therapy to remove circulating immune complexes. Following 7 treatment sessions, the patient recovered kidney function. We discuss the potential merit of plasmapheresis for patients with subacute bacterial endocarditis who develop ICGN.