Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN developed in parallel with increasing glomerular deposition of a noninfectious form of HEV open reading frame 2 (ORF2, capsid) protein secreted in excess. HEV particles or RNA, however, were not detectable. Patients with acute hepatitis E displayed similar but less pronounced deposits. Our results elucidate an immunologic mechanism by which this hepatotropic virus causes variable renal manifestations and establish a link between the HEV ORF2 protein and hepatitis E-associated GN. They directly provide a tool for etiology-based diagnosis of HEV-associated GN as a distinct entity and suggest therapeutic implications.

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of “stroke-like” episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.

To present a man with cystinosis-related cerebral lesions including a literature review focused on longitudinal clinical, imaging and pathology data.

We present a severe case of hypocomplementemic urticarial vasculitis syndrome (HUVS) and its diagnostic and therapeutic challenges. A 56-year-old male presenting with fever and impaired kidney function was diagnosed with HUVS. Before the initiated treatment was effective, he developed severe colon ischemia, and a subtotal colectomy was required. We discuss other affected organs, such as kidneys, lungs, the heart, and the skin. Pathophysiology is briefly reviewed and the difficulty of overlapping autoimmune diseases is discussed. Treatment continues to be challenging, as there is no consensus about the optimal immunosuppressive therapy.

Acute kidney injury has been recognized as a frequent complication of severe COVID-19 early in the pandemic1 with histology mostly revealing acute tubular injury.2 Later, collapsing glomerulopathy was identified as a peculiar manifestation of SARS-CoV-2 and termed COVID-19 associated nephropathy (COVAN).3–5 COVAN is morphologically indistinguishable from HIV-associated nephropathy and affects, with few exceptions, persons of African ancestry with high-risk APOL1 genotype.6 In addition to these two well-recognized renal manifestations of COVID-19, numerous case reports and case series have described a variety of other renal diseases, mostly glomerulopathies, manifesting in temporal association with SARS-CoV-2 infection.

Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations.

Abstract Background and Aims Biopsy-based transcripts associated with antibody-mediated rejection (AMR) hold promise as substitutes for C4d positivity, according to the Banff Meeting Report of 2022. However, incorporating histologic and molecular features of disease activity and chronicity is crucial to potentially guide patient management. Method We analyzed 365 kidney allograft biopsies by histology and the Molecular Microscope Diagnostic System (MMDx) at the University Hospital Zurich from July 2021 to November 2023. Histologic findings were classified according to Banff 2022 into (1) active AMR (n = 24), (2) chronic active AMR (MVI, n = 47), and (3) chronic AMR (n = 30). The corresponding histologic subgroups with DSA negativity were used for comparison. Results Fourteen out of 24 cases (58%) with active AMR, 28 of 47 cases (60%) with chronic active AMR, but only 1 of 30 cases (3%) with chronic AMR showed molecular AMR. Among cases with molecular AMR the sum of the fully-developed AMR-related (R5) and late-stage AMR-related (R6) phenotype scores was significantly higher in chronic active AMR compared to active AMR cases (p = 0.0017). This finding was even more pronounced in chronic active AMR cases with double contours (cg)>1 (p = 0.00062). Similarly, in the cases without molecular AMR the sum of the fully-developed AMR-related (R5) and late-stage AMR-related (R6) phenotype scores was higher in chronic active AMR compared to active AMR cases (p = 0.039) and more pronounced in cases with cg>1 (p = 0.008). However, rejection phenotype scores (R1-R6) among chronic AMR cases did not differ from DSA-positive or DSA-negative cases without microvascular inflammation (p = 0.705 for R5+R6). Conclusion Incorporating molecular rejection phenotype patterns may further differentiate disease activity and chronicity in cases with active and chronic active AMR by histology. However, molecular subthreshold findings do not appear relevant in chronic AMR cases.

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications. It's poorly understood how renal manifestations develop in HEV infection in patients. Here, the authors observe glomerular accumulation of the viral protein ORF2 in complex with host IgG in immunocompromised patients with chronic or acute HEV infection who developed glomerulonephritis.

Abstract Background and Aims According to the 2018 Banff classification, the Molecular Microscope Diagnostic System (MMDx) is indicated in cases when histology is insufficient to diagnose antibody-mediated rejection (ABMR) due to an absence of diagnostic criteria groups 2 and/or 3. The impact of isolated glomerulitis (g>0, ptc0) on the likelihood of ABMR diagnosis by the MMDx appears critical to the implementation of this new biomarker. Method We analyzed 251 kidney allograft biopsies by histology and molecular diagnostics at the University Hospital Zurich from October 2018 to November 2022. Histologic findings were classified concerning the absence of (1) diagnostic criteria groups 2 and 3 (n = 18), (2) diagnostic criteria group 2 only (n = 18), and (3) diagnostic criteria group 3 only (n = 28). In addition, cases with histologically proven ABMR were used for comparison (n = 65). High-resolution re-typing was performed from the kidney allograft biopsies if necessary. Results The MMDx diagnosed ABMR in 1 of 18 cases (6%) with absent diagnostic criteria groups 2 and 3, 4 of 18 cases (22%) with absent diagnostic criteria groups 2, and 19 of 28 cases (68%) with absent diagnostic criteria groups 3. On the contrary, MMDx confirmed the diagnosis of ABMR in 42 of 65 cases (65%) with histologically proven ABMR but did not in 23 of 65 cases (35%). Among 28 cases with absent diagnostic criteria group 3, only 2 of 19 cases (11%) with ABMR by MMDx but 6 of 9 cases (67%) with no ABMR by MMDx showed isolated glomerulitis (p = 0.0048). Among 65 cases with histologically proven ABMR, only 7 of 42 cases (17%) with ABMR by MMDx but 14 of 23 cases (61%) with no ABMR by MMDx showed isolated glomerulitis (p<0.001). Overall, 14 of 65 cases (21%) with isolated glomerulitis showed ABMR diagnosis by MMDx. Conclusion Isolated glomerulitis is strongly associated with the absence of ABMR by MMDx not only when diagnostic criteria group 2 is missing but also when diagnostic criteria 3 is missing or ABMR is proven by histology. Our results may help to guide the indication for MMDx in clinical practice. However, the clinical significance of these results needs further investigation.

Background. The Molecular Microscope Diagnostic System (MMDx) may overcome histology shortcomings. Previous studies have simply examined discrepant findings but have not attempted to determine clinical endpoints. To measure performance, clinical outcomes are strongly required. Methods. This single-center cohort study described discrepancies between MMDx and histology from 51 kidney transplant recipients (KTRs) and analyzed 72 indication biopsies, including 21 follow-up biopsies. Clinical performance was assessed by a combined endpoint of graft failure, rejection on follow-up biopsy, de novo donor-specific antibody, and improvement of kidney allograft function upon antirejection treatment. Results. MMDx agreed in 33 (65%) and differed in 18 (35%) of 51 KTRs. Most discrepancies occurred in biopsies called no rejection by MMDx and rejection by histology (15/24, 63%). In contrast, in biopsies called rejection by MMDx, 3 were classified as no rejection by histology (3/27, 11%). Discrepant findings between MMDx and histology occurred following delayed graft function and MMDx from biopsies with a low percentage of cortex. Among 15 biopsies classified as no rejection by MMDx but rejection by histology, the clinical course suggested no rejection in 9 cases. Six KTRs reached the endpoint, showing predominant t ≥ 2 lesions. Conclusions. The most often occurring discrepancy is rejection by histology but no rejection by MMDx. As more KTRs do not meet the combined endpoint for rejection, MMDx might be clinically useful in these discrepant cases. Although strong histological findings have priority in indicating the treatment, clinical implementation of MMDx could strengthen treatment strategies.

Abstract Background and Aims The Molecular Microscope Diagnostic System (MMDx) may resolve inconclusive histology findings, as preserved biopsy material can be examined after histology findings have been obtained. The extent to which this proposed approach can be implemented in clinical practice remains an open question. Method We prospectively analyzed 104 consecutive indication kidney allograft biopsies by histology and molecular diagnostics at the University Hospital Zurich from April 2022 to December 2022. Pathologists and clinicians with experience in molecular diagnostics assessed the need for MMDx by questionnaire when the histology report was available. Clinicians then assessed the added value of the molecular diagnostics by questionnaire when the MMDx report was available. Results 29 of 104 cases (28%) showed rejection by histology, 42 of 104 cases (40%) showed no rejection by histology, and 33 of 104 cases (32%) showed histologic findings insufficient to diagnose ABMR due to an absence of diagnostic criteria groups 2 and/or 3. Pathologists considered molecular diagnostics indicated in 42 of 104 cases (40%), 9 cases to give extra confidence, and 33 cases for diagnostic clarification concerning rejection. Clinicians considered molecular diagnostics indicated in 54 of 104 (52%) cases, 5 cases to give extra confidence, and 49 for diagnostic clarification concerning rejection. In 33 cases with histologic findings insufficient to diagnose ABMR, molecular diagnostics were considered indicated by pathologists and clinicians. Molecular diagnostics allowed the diagnosis of ABMR in 8 of 33 cases (24%). In addition, 11 of 104 cases (11%) showed a discrepancy between the histologic findings and the molecular diagnosis. Clinicians considered adjustment of treatment based on the MMDx report in 3 of 11 discrepant cases. Pathologists and clinicians considered molecular diagnostics indicated in 2 of 11 and 3 of 11 discrepant cases, respectively. Conclusion The need for molecular diagnostics goes beyond the recommendation of the 2018 Banff classification for histologic findings insufficient to diagnose ABMR. However, the added value of molecular diagnostics appears to be largely limited to these cases.

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9–20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. We studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease and membranous nephropathy. The observed incidence during the vaccination campaign (Jan to Aug 2021) was not different from the expected incidence based on the years 2015 to 2019 (incidence rate ratio 0.86, 95%-credible interval 0.73–1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients aged >18 years with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was 0.97 (95% CI 0.66–1.42, P =0.95) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within 4 weeks after vaccine did not differ clinically from the rest of the cohort. Results were consistent across all types of glomerulonephritis with the possible exception of minimal change disease. In conclusion, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies. Most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis are likely coincidental.### Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at [www.icmje.org/disclosure-of-interest/][1]. I. F. reports holding stocks from Pfizer. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.### Funding StatementThis study did not receive external funding.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics Committee of Eastern Switzerland gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will be made available on reasonable request to the corresponding author, after approval by the local ethics committee. [1]: http://www.icmje.org/disclosure-of-interest/

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic “type 1 versus type 2” classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.