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Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β2 also serves as a potentially novel cell-adhesive ligand for integrin α4β1. Our findings define biochemical functions of laminin β2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.

Background: Castleman's disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment., Case Presentation: An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function., Conclusions: Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure.

Purpose: Congenital urinary tract obstruction is a leading cause of renal maldevelopment and pediatric kidney disease. Nonetheless, few groups have examined its molecular pathogenesis in humans. We evaluated the role of BMP-7, a protein required for renal injury repair and nephrogenesis, in disease progression in patients with obstructive uropathy., Materials and Methods: Whole kidney and cell specific BMP-7 expression was examined in a murine model of unilateral ureteral obstruction and in patients with congenital ureteropelvic junction obstruction. Findings were correlated with molecular markers of renal injury and clinical parameters., Results: Unilateral ureteral obstruction led to a dramatic decrease in BMP-7 expression in the proximal and distal tubules before the onset of significant loss of renal architecture and fibrosis, suggesting that this is a critical molecular event that drives early stage disease progression. Loss of BMP-7 expression then extended to the collecting ducts and glomeruli in end stage kidney disease. When translating these findings to patients with ureteropelvic junction obstruction, global loss of BMP-7 expression correlated with a decreased number of nephrons, loss of renal architecture, severe renal fibrosis and loss of kidney function., Conclusions: Given that BMP-7 has a critical role in renal injury repair and nephrogenesis, these findings show that cell specific changes in BMP-7 expression contribute to the onset of irreversible renal injury and impaired kidney development secondary to congenital urinary tract obstruction. Accordingly therapies that target these cell populations to restore BMP-7 activity may limit disease progression in patients with obstructive uropathy., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Electron microscopy (EM) has been an indispensable tool for kidney research since its inception more than half a century ago. Much of the substantial advances were propelled by the need to find methods to best visualize and analyze the kidney's structure deduced from the fundamental principle that has structure and function intimately related. The result of 3 decades of experimental kidney work between 1950 and 1980 coincided with remarkable advances in nephrology that marked a renaissance era for renal pathology and resulted in the morphologic classification of medical kidney diseases. In the era of genetics and molecular medicine TEM continues to contribute significant clinical and pathogenetic insights in kidney disease. The basic principles as applied to kidney disease experimental models are discussed with emphasis on crescent formation in Col4A3-deficient mice and a mouse model of experimental oxalosis (CaOx).

Renal biopsy was introduced in the 1950s. By 1980 the pathologic diagnostic criteria for the majority of medical kidney diseases known today, including pediatric diseases, were established using light, electron microscopy and immunohistochemistry. However, it has become clear that there are limitations in the morphologic evaluation, mainly because a given pattern of injury can be caused by different aetiologies and, conversely, a single aetiology may present with more than one histological pattern. An explosion in kidney disease research in the last 20-30 years has brought new knowledge from bench to bedside rapidly and resulted in new molecular and genetic tools that enhance the diagnostic and prognostic power of the renal biopsy. Genomic technologies such as polymerase chain reaction (PCR), in situ hybridization and oligonucleotide microarrays, collectively known as genomics, detect single or multiple genes underscoring the pathologic changes and revealing specific causes of injury that may require different treatment. The aims of this review are to (1) summarize current recommendations for diagnostic renal biopsies encompassing light microscopy, immunofluorescence or immunohistochemistry and electron microscopy; (2) address the limitations of morphology; (3) show current contributions of genomic technologies adjunct to the renal biopsy, and provide examples of how these may transform pathologic interpretation into molecular disease phenotypes.

Introduction: Laparoscopic partial nephrectomy has emerged as a standard of care for small renal masses. Nevertheless, there remains concern over the potential for irreversible insult to the kidney as a result of exposure to warm ischemia. We aim to investigate the utility of selective segmental arterial clamping as a means to reduce the potential for ischemic damage to a solitary kidney during laparoscopic partial nephrectomy utilizing a porcine model., Materials and Methods: A total of 20 domestic swine were randomized into four equal groups. Each subject underwent laparoscopic radical nephrectomy to create the condition of a solitary kidney. On the contralateral side, a laparoscopic lower pole partial nephrectomy was performed, employing either selective or nonselective vascular clamping for either 60 or 90 minutes. Postoperatively, clinical status and serial serum studies were closely monitored for 1 week., Results: There were no intraoperative complications. The 90-minute nonselective clamping produced devastating effects, resulting in rapid deterioration into florid renal failure within 72 hours. The 60-minute nonselective clamping group experienced modest but significant rises in both blood urea nitrogen and creatinine. Both 60- and 90-minute selective clamping groups performed well, with no significant rises in creatinine over a 7-day period, and no instances of renal failure., Conclusions: Selective arterial clamping is a safe and feasible means of vascular control during laparoscopic partial nephrectomy. In the porcine model, selective clamping appears to improve functional outcomes during prolonged periods of warm ischemic insult. Prospective evaluation of the technique in humans is necessary to determine if selective arterial control confers long-term functional benefits in patients with limited renal reserve.

Light-chain deposition disease (LCDD) of the kidney is defined as deposition of monotypic light chains (LC) within glomerular (GBM) and tubular (TBM) basement membranes. The morphologic features of pure renal LCDD have been presented only in case reports or small series. The aim of this study was to perform a comprehensive evaluation of the light (LM), immunofluorescence (IF), and electron microscopic (EM) features of pure renal LCDD in a large series of biopsies. Out of 46 cases assembled, 42 had multiple myeloma, 2 had monoclonal gammopathy of unknown significance, and in 2 patients no lymphoproliferative disease was identified. The most common LM lesion of LCDD, nodular glomerulosclerosis, was present in only 14 (30%) cases. GBM and/or TBM thickening was found in 3 (6%), mild to moderate mesangial matrix increase in 12 (23%), and unremarkable glomeruli and tubules were seen in 15 (32%) cases. Forty-two had IF and 40 (92%) showed characteristic linear LC immunoreactivity (24 kappa, 16 lambda) along GBM and/or TBM. Among 39 cases in which IF and EM was available, 25 (64%) were positive by both. Two (6%) were negative by IF, but had deposits by EM. In 12 (30%) with immunoreactivity to LC (4 kappa, 8 lambda), no deposits were identified ultrastructurally. This study shows heterogeneous LM lesions in pure LCDD cases. LM alone may be suspicious but not diagnostic of LCDD. Immunofluorescence is more sensitive than EM for detection of LC for the definitive diagnosis of LCDD. This study supports the importance of utilizing kappa and lambda stains in the routine IF panel for diagnosis of LCDD.

There are few data on morphology of light-chain deposition disease (LCDD) of kidney with coexistent light-chain cast nephropathy (LCCN). Here, the authors report the morphology in 23 cases of LCDD and LCCN. They retrospectively evaluated 23 renal biopsies with light (LM), immunofluorescence (IF), and electron microscopy (EM). Twenty-one patients had myeloma, 1 had a monoclonal gammopathy, and in 1 no illness was found. Nodular glomerulosclerosis, the LM lesion suggestive of LCDD, was noted in only 3 of 23 cases. Glomeruli were unremarkable in 16 (69%) cases. The diagnostic casts of LCCN were seen in all biopsies. Linear light chain (LC) immunoreactivity was observed in 23 (100%) cases (18 kappa, 5 lambda); GBM + TBM in 13, TBM only in 7, GBM only in 1, TBM and interstitium in 1, GBM, TBM and mesangium in 1. Casts were positive with same LC in all cases (100%). Fifteen cases (65%) showed granular electron-dense deposits; GBM only in 5, TBM only in 5, GBM and TBM in 4, mesangium in 1. In 8 patients without EM deposits, the diagnosis of LCDD was rendered by IF. Fifteen (65%) had deposits detectable by IF and EM, 8 (37%) had deposits with IF only. LCCN dominated the LM findings in all patients. There were minimal or no glomerular changes by LM. This study shows the lack of characteristic LM findings of LCDD in combined cases of LCDD and LCCN and emphasizes the difficulty for-definitive diagnosis-without IF and EM.

Electron microscopy defined classic patterns of hereditary glomerular disease long before genetics revealed an underlying specific mutation. Genetic analysis is now easier to perform in clinical practice but an earlier optimism that genetics would predict disease severity and phenotype is challenged. The classic paradigm is Alport nephritis in which only a subset of mutations may predict glomerular abnormalities and disease severity. Interpretation of ultrastructural pathology of monogenetic diseases like Alport nephritis is complicated when the proband is the first family member to be diagnosed or there is discrepancy between clinical presentation and ultrastructural changes. In this review the authors have selected a dozen cases representative of common monogenetic glomerular diseases as a platform to discuss the utility of diagnostic electron microscopy in the era of molecular genetics. The emphasis is on genotype/glomerular phenotype correlations.

Membranoproliferative glomerulonephritis, with or without cryoglobulinemia, and membranous glomerulonephritis are the best characterized glomerulonephropathies associated with hepatitis C virus (HCV) infection. Other more unusual patterns of glomerular injury, including IgA nephropathy, focal segmental glomerulosclerosis, crescentic glomerulonephritis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, and thrombotic microangiopathy, have also been associated with HCV infection, but primarily on an anecdotal basis. It remains uncertain whether the patterns of glomerular injury seen in HCV infected patients, particularly the unusual patterns, represent a disease process specifically related to HCV infection or whether they represent nonspecific patterns of injury due to other causes that happen to occur in HCV-infected patients. We examine this issue by reviewing the epidemiological and pathological evidence in the literature that either supports or refutes a specific relationship between HCV and the pattern of glomerular injury. We also include our experience with 31 HCV-infected patients. In addition, the pathogenesis of HCV-associated glomerulonephropathies is discussed with an emphasis on the significance of detecting HCV in renal biopsies by reverse transcriptase-polymerase chain reaction.