Danniele G. Holanda

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.

Case Report: Eculizumab Rescue of Severe Accelerated Antibody-Mediated Rejection After ABO-Incompatible Kidney Transplant

ABO-incompatible (ABOI) living donor kidney transplantation has become a well-accepted practice with standard protocols using perioperative antibody-depleting therapies to lower blood group titers to an acceptable threshold for transplantation. However, a subset of patients will experience accelerated antibody-mediated rejection (AMR) after ABOI kidney transplantation and require aggressive intervention to prevent allograft loss. Here in we report the successful use of terminal complement inhibition with eculizumab to rescue an ABOI kidney allograft with accelerated AMR refractory to salvage splenectomy and daily plasmapheresis. This case emphasizes the fact that, despite close postoperative surveillance and aggressive intervention, graft loss from accelerated AMR after ABOI kidney transplantation remains a very real risk. Eculizumab may offer a graft-saving therapeutic option for isolated cases of severe AMR after ABOI kidney transplantation refractory to standard treatment.

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.

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.

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.

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.

Lenalidomide-induced acute interstitial nephritis

The first case of biopsy-proven lenalidomide-induced acute interstitial nephritis is presented.

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 γ 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.

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.

An unexpected surge in plasma BKPyV viral load heralds the development of BKPyV associated metastatic bladder cancer in a lung transplant recipient with BKPyV nephropathy

We report a lung transplant recipient who developed BK polyoma virus (BKPyV) DNAemia and BKPyV nephropathy. With careful management of his immunosuppression he achieved significant reduction in BKPyV DNAemia and stabilization of his kidney function. He later developed a high‐grade bladder cancer and shortly thereafter he experienced a major upsurge in the level of BKPyV DNAemia that coincided with the discovery of hepatic metastasis. Retrospectively, the bladder cancer and the hepatic secondary tumor stained uniformly for SV40 large T antigen, and the BKPyV DNA sequences identified in plasma corresponded to BKPyV DNA within hepatic tissue, indicating that the spike in BKPyV load was likely derived from the circulating tumor cells or cell‐free tumor DNA following metastases of a BKV‐associated cancer. To the best of our knowledge, this is the first description of a surge in BKPyV load in a patient with controlled BKPyVN that heralded the appearance of a metastatic urothelial malignancy. This report discusses the literature on BKPyV‐associated malignancies and the possibility that unexplained increases in BKPyV DNAemia may be a biomarker for metastatic BKPyV‐related urothelial cancer.