Kidney Biopsy Findings in Patients with COVID-19 Kudose, Satoru; Batal, Ibrahim; Santoriello, Dominick ...
Journal of the American Society of Nephrology,
09/2020, Letnik:
31, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury by a variety of mechanisms. To date, pathologic analyses have been limited to patient reports and autopsy series.
We evaluated ...biopsy samples of native and allograft kidneys from patients with COVID-19 at a single center in New York City between March and June of 2020. We also used immunohistochemistry,
hybridization, and electron microscopy to examine this tissue for presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The study group included 17 patients with COVID-19 (12 men, 12 black; median age of 54 years). Sixteen patients had comorbidities, including hypertension, obesity, diabetes, malignancy, or a kidney or heart allograft. Nine patients developed COVID-19 pneumonia. Fifteen patients (88%) presented with AKI; nine had nephrotic-range proteinuria. Among 14 patients with a native kidney biopsy, 5 were diagnosed with collapsing glomerulopathy, 1 was diagnosed with minimal change disease, 2 were diagnosed with membranous glomerulopathy, 1 was diagnosed with crescentic transformation of lupus nephritis, 1 was diagnosed with anti-GBM nephritis, and 4 were diagnosed with isolated acute tubular injury. The three allograft specimens showed grade 2A acute T cell-mediated rejection, cortical infarction, or acute tubular injury. Genotyping of three patients with collapsing glomerulopathy and the patient with minimal change disease revealed that all four patients had
high-risk gene variants. We found no definitive evidence of SARS-CoV-2 in kidney cells. Biopsy diagnosis informed treatment and prognosis in all patients.
Patients with COVID-19 develop a wide spectrum of glomerular and tubular diseases. Our findings provide evidence against direct viral infection of the kidneys as the major pathomechanism for COVID-19-related kidney injury and implicate cytokine-mediated effects and heightened adaptive immune responses.
Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with ...dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1–3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of ‘C3 only’ captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, ‘C3 only’ is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.
The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation ...of the membrane attack complex, may prove beneficial.
In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark.
The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.
Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.
Kidney allograft biopsy findings after COVID‐19 Daniel, Emily; Sekulic, Miroslav; Kudose, Satoru ...
American journal of transplantation,
December 2021, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Odprti dostop
COVID‐19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy ...findings in the setting of COVID‐19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS‐CoV‐2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID‐19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS‐CoV‐2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS‐CoV‐2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow‐up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID‐19, the most common being acute rejection with arteritis.
Allograft biopsies from kidney transplant recipients with COVID‐19 with acute kidney injury or proteinuria shows a high incidence of acute rejection with arteritis that is not always associated with decreased immunosuppression.
Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three ...patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.
In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this ..."stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis.
Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed.
Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98.
In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.
Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings ...in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.
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HIV-associated kidney disease is evolving rapidly. Few North American studies have addressed modern trends and none has applied the 2018 Kidney Disease Improving Global Outcomes (KDIGO) pathologic ...classification. Therefore we performed a retrospective clinical-pathologic analysis of all HIV-positive patients with kidney biopsy interpreted at Columbia University from 2010-2018 using the KDIGO classification. The biopsy cohort of 437 HIV-positive patients had median age 53 years, including 66% males, 80% on anti-retroviral therapy, 57% with hypertension, 31% with diabetes, 27% with hepatitis C and 6% with hepatitis B co-infections. Race, known in 308 patients, included 58% black, 25% white and 17% Hispanic. Pathologic diagnoses were surprisingly diverse. Immune complex glomerulonephritis (ICGN) and diabetic nephropathy each outnumbered HIV-associated nephropathy, followed by tenofovir nephrotoxicity, FSGS- not otherwise specified (NOS) and global sclerosis (NOS). HIV-associated nephropathy was the most common disease in patients not on anti-retroviral therapy, and 94% were black. The association of FSGS (NOS) with black race (68%) and anti-retroviral therapy use (77%) suggests some cases may represent attenuated HIV-associated nephropathy. The most common ICGNs were IgA nephropathy and membranous glomerulopathy, both associating with anti-retroviral therapy (over 90%), followed by hepatitis C-associated proliferative ICGN. Among the 16 cases of uncharacterized ICGN lacking identifiable etiology, 69% were not on anti-retroviral therapy, possibly representing true HIV-associated immune complex kidney disease. Dual diseases occurred in 17% of patients, underscoring lesion complexity. Thus, anti-retroviral therapy has shifted the landscape of HIV-associated kidney disease toward diverse ICGN, diabetic nephropathy, and non-collapsing glomerulosclerosis, but has not eradicated HIV-associated nephropathy.
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