Sequential genetic testing of living-related donors for inherited renal disease to promote informed choice and enhance safety of living donation.

Living kidney donors (LKDs) with a family history of renal disease are at risk of kidney disease as compared to LKDs without such history suggesting that some LKDs may be pre-symptomatic for monogenic kidney disease. LKDs with related transplant candidates whose kidney disease was considered genetic in origin were selected for genetic testing. In each case, the transplant candidate was first tested to verify the genetic diagnosis. A genetic diagnosis was confirmed in 12 of 24 transplant candidates (ADPKD-PKD1: 6, ALPORT-COL4A3: 2, ALPORT-COL4A5: 1: nephronophthisis-SDCCAG8: 1; CAKUT-HNF1B and ADTKD-MUC1: 1 each) and 2 had variants of unknown significance (VUS) in phenotype-relevant genes. Focused genetic testing was then done in 20 of 34 LKDs. 12 LKDs screened negative for the familial variant and were permitted to donate; seven screened positive and were counseled against donation. One, the heterozygous carrier of a recessive disorder was also cleared. Six of seven LKDs with a family history of ADPKD were under 30 years and in 5, by excluding ADPKD, allowed donation to safely proceed. The inclusion of genetic testing clarified the diagnosis in recipient candidates, improving safety or informed decision-making in LKDs.

Zebra-like bodies in COVID-19: is phospholipidosis evidence of hydroxychloroquine induced acute kidney injury?

COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.

Soluble CR1 therapy improves complement regulation in C3 glomerulopathy.

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Short-term use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN.

TNXB mutations can cause vesicoureteral reflux.

Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.

Atypical presentation of atypical amyloid.

Amyloidosis is a group of diseases categorized by precipitation of a group of protein aggregates (amyloid) in tissues, including the kidney, and proteinuria is usually the commonest, though not exclusive, hallmark of clinical presentation. AL and AA are the most commonly recognized forms of amyloidosis involving the kidney, but other forms have been described. We present a case of renal amyloidosis due to a novel amyloidogenic protein, leucocyte cell-derived chemotaxin 2, without proteinuria at presentation or on subsequent follow-up.

Patient with a PRKAG2 mutation who developed Immunoglobulin A nephropathy: a case report.

BACKGROUND: PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant inherited disease caused by mutations in PRKAG2, the gene encoding the regulatory γ2 subunit of adenosine monophosphate-activated protein kinase. PRKAG2 syndrome is associated with many cardiac manifestations, including pre-excitation, arrhythmias, left ventricular hypertrophy, and chronotropic incompetence frequently leading to early pacemaker placement. A meta-analysis of genome-wide association data in subjects with chronic kidney disease (CKD) identified a susceptibility locus in an intron of PRKAG2, which has been replicated in other studies. However, CKD has not been reported in patients with PS or mutations in PRKAG2. CASE SUMMARY: We report a case of a woman diagnosed at age 27 with PS when she presented with atrial fibrillation and pre-excitation on electrocardiogram. By age 35, she had developed mild renal insufficiency and a biopsy demonstrated IgA nephropathy (IGAN). DISCUSSION: This is the first reported case of IGAN in a patient with PS. We discuss both PS and IGAN and the potential mechanisms by which they could be related.

Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease.

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II-IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.

C1q Donor-Specific Antibody Associates with Post-transplant Biopsy Findings in Highly- Sensitized Kidney Transplant Recipients.

Donor-specific anti-human leukocyte antigen antibodies (DSA) are associated with antibody-mediated rejection (AMR) in kidney transplantation, but the spectrum of graft injury seen in patients with DSA ranges from no damage to florid rejection. Since immunoglobulin G (IgG) antibodies with cytotoxic potential can be distinguished by their binding complement fraction C1q, the level of C1q-binding IgG (C1q+) DSA may be useful for stratifying risk or diagnosing AMR. We therefore investigated the value of IgG and C1q+ DSA in predicting pathologic features of AMR on kidney biopsies. We tested the associations between DSA at different cut-off levels and pathologic features of AMR on biopsy in a cohort of consecutive, highly-sensitized patients transplanted after December 2014 who had 1-, 3-, and 6-month protocol kidney biopsies and monitoring for IgG and C1q+ DSA. Eight patients with cPRA >90% and negative flow crossmatch underwent kidney transplant and completed six months of follow-up contributing 23 pairs of biopsy/ serum samples for analysis. C1q+ DSA was significantly associated with C4d finding on biopsy at mean fluorescence intensity (MFI) cut-offs of >100 (p=0.046) and >300 (p=0.008) and showed superior positive and negative predictive value in comparison to conventional IgG DSA. C1q+ DSA also showed significant association and good predictive value for any AMR feature on biopsy (p=0.003, for >100 MFI; p=0.005 for >300 MFI), while IgG DSA showed no association. In a small cohort of high cPRA transplant recipients, C1q+ DSA outperformed IgG DSA as an indicator of AMR biopsy findings. Including C1q+ DSA testing in post-transplant DSA monitoring of highly-sensitized patients may aid the timely diagnosis of AMR.

BK polyoma virus infection and renal disease in non-renal solid organ transplantation.

BK virus (BKV) is a non-enveloped DNA virus of the polyomaviridae family that causes an interstitial nephritis in immunosuppressed patients. BKV nephropathy is now a leading cause of chronic kidney disease and early allograft failure following kidney transplantation. It is also known to cause renal disease with a progressive decline in kidney function in non-renal solid organ transplant (NRSOT) recipients, although the disease may not be recognized nor its impact appreciated in this patient population. In this report, we review the existing literature to highlight our current understanding of its incidence in NRSOT populations, the approaches to diagnosis and the potential treatment options.

Characterization of renal cell carcinoma, oncocytoma, and lipid-poor angiomyolipoma by unenhanced, nephrographic, and delayed phase contrast-enhanced computed tomography.

The purpose of this study was to assess the characterization of renal cell carcinoma (RCC) and benign renal tumors by unenhanced, nephrographic, and delayed phase computed tomography (CT). The study group consisted of 129 renal tumors including 79 clear cell RCCs, 17 papillary RCCs, 6 chromophobe RCCs, 21 oncocytoma, and 6 lipid-poor angiomyolipomas (AMLs). CT studies were retrospectively reviewed. Our results suggested that it was possible to discriminate clear cell RCC from papillary RCC, chromophobe RCC, and lipid-poor AML. CT findings of oncocytoma overlapped with both clear cell and non-clear cell RCCs, although oncocytoma more commonly became homogeneous in the delayed phase.

Tumor grade of clear cell renal cell carcinoma assessed by contrast-enhanced computed tomography.

The purpose of this study was to clarify the association between CT findings and Fuhrman grade of clear cell renal cell carcinoma (ccRCC). The study group consisted of 214 surgically proven ccRCC in 214 patients. Contrast-enhanced CT studies were retrospectively assessed for tumor size, cystic versus solid, calcification, heterogeneity of lesions, percentage of non-enhancing (necrotic) areas, and growth pattern. CT findings and Fuhrman grade were compared. Nineteen of 22 (86.4%) cystic ccRCC were low grade (Fuhrman grades 1-2). There was no significant correlation between tumor size and grade in cystic ccRCC (P = 0.43). In predominantly solid ccRCC, there was significant correlation between tumor size and grade (P < 0.0001). Thirty-eight of 43 (88.4%) infiltrative ccRCC were high grade (Fuhrman grades 3-4). Logistic regression showed tumor size and infiltrative growth were significantly associated with grades 3-4 (P = 0.00083 and P = 0.0059). Cystic ccRCC tends to be low grade. Infiltrative growth and larger tumor size may increase the likelihood of high grade ccRCC.

Primary gastric T cell lymphoma mimicking marginal zone B cell lymphoma of mucosa-associated lymphoid tissue.

Primary gastric T cell lymphoma is rare and mostly of large cell type. In this paper, we present a case of gastric T cell lymphoma morphologically similar to the gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Morphologically, the cells are small with abundant clear cytoplasm. Lymphoepithelial lesions are readily identified with diffuse destruction of gastric glands. Immunohistochemically, the neoplastic cells are CD3+/CD4+/CD8-/Granzyme B-. Molecular studies revealed monoclonal T cell receptor gamma gene rearrangement. Clinically, the patient responded initially to four cycles of R-CHOP, but then progressed. Because peripheral T cell lymphoma is usually associated with a poor prognosis, whereas marginal zone B cell lymphoma is an indolent lymphoproliferative disorder, this morphologic mimicry should be recognized and completely investigated when atypical small lymphoid infiltrates with lymphoepithelial lesions are encountered in the stomach.