Clinicopathological features and prognosis of IgA vasculitis nephritis with nephrotic-range proteinuria in children.

BACKGROUND: To investigate the clinical features, kidney pathology, treatment regimens, and clinical outcomes of IgA vasculitis nephritis (IgAVN) with nephrotic-range proteinuria in children. METHODS: A retrospective review of children diagnosed with IgAVN between January 2019 and December 2022 was conducted. Participants were divided into two groups based on their urine protein/creatinine (UPCR) levels. Biodata, clinical characteristics, laboratory findings, pathologic features, treatment regimens, and outcomes were abstracted from case records and analyzed. RESULTS: A total of 255 children were identified, 94 with nephrotic-range proteinuria (UPCR ≥ 200 mg/mmol) and 161 with non-nephrotic proteinuria (UPCR < 200 mg/mmol). Patients in the nephrotic-range proteinuria group were significantly younger and had worse grades of glomerular and acute tubulointerstitial injury compared to those in the non-nephrotic proteinuria group. Higher levels of blood urea nitrogen (BUN), D-dimer (DD), and fibrin degradation products (FDP), and lower levels of total protein (TP), albumin (ALB), urine creatinine (Cr), prothrombin time (PT), activated partial thromboplastin time (APTT), IgG, CD3 + cells, and CD4 + cells were found in patients in the nephrotic-range proteinuria group. Clinical outcome of patients with nephrotic-range proteinuria was significantly associated with ISKDC grading, proportion of glomerular crescents and severity of acute tubulointerstitial injury. CONCLUSIONS: Children with nephrotic-range proteinuria exhibit more severe disordered immunologic function, hypercoagulability, glomerular and tubulointerstitial pathological damage, and have worse outcomes than those with lower proteinuria levels. Clinicians should pay great attention to the kidney injury and more extensive studies are required to identify optimal treatment regimens to improve outcomes in patients.

Renal involvement in solid cancers: epidemiological, clinical and histological characteristics study of 154 onconephrology patients.

BACKGROUND: Onconephrology is a growing discipline that aims to improve the management of patients with cancer and kidney disease. If kidney histology is an essential key, the anatomopathological data remain weak although essential to this complex management. METHODS: Patients with active cancer who had a kidney biopsy (KB) between 2014 and 2020 were included, and their clinicobiological and histological data were analyzed retrospectively. RESULTS: Our cohort consisted of 154 patients (83 women) with a mean age of 58 years. One hundred twelve patients presented with proteinuria, 95 with acute kidney injury, and 59 with arterial hypertension. Histologically, interstitial fibrosis was found in 74% of KBs, tubular atrophy in 55.1%, arteriolar hyalinosis in 58.4%, and fibrous endarteritis in 54.4%. Regarding the main acute lesions, thrombotic microangiopathy (TMA) was found in 29.9% of biopsies, acute tubular necrosis (ATN) in 51.3%, and acute interstitial nephritis in 24.8%. The etiological diagnosis most often made was the nephrotoxicity of anticancer drugs (87 patients), followed by a pre-renal (15 patients) and kidney disease unrelated to cancer (13 patients). Sixty-seven patients presented with at least 2 associated diagnoses reflecting the complexity of kidney damage in cancer. Different clusters were found, highlighting that immunotherapy and anti-VEGF were the most commonly involved drugs. CONCLUSIONS: During onconephrology practice, kidney toxicity of treatments is the most common etiology. Several mechanisms can be involved, underscoring the importance of kidney biopsy and the complexity of its management. Chronic histological lesions were very common.

Deep learning-based segmentation and quantification of podocyte foot process morphology suggests differential patterns of foot process effacement across kidney pathologies.

Morphological alterations at the kidney filtration barrier increase intrinsic capillary wall permeability resulting in albuminuria. However, automated, quantitative assessment of these morphological changes has not been possible with electron or light microscopy. Here we present a deep learning-based approach for segmentation and quantitative analysis of foot processes in images acquired with confocal and super-resolution fluorescence microscopy. Our method, Automatic Morphological Analysis of Podocytes (AMAP), accurately segments podocyte foot processes and quantifies their morphology. AMAP applied to a set of kidney diseases in patient biopsies and a mouse model of focal segmental glomerulosclerosis allowed for accurate and comprehensive quantification of various morphometric features. With the use of AMAP, detailed morphology of podocyte foot process effacement was found to differ between categories of kidney pathologies, showed detailed variability between diverse patients with the same clinical diagnosis, and correlated with levels of proteinuria. AMAP could potentially complement other readouts such as various omics, standard histologic/electron microscopy and blood/urine assays for future personalized diagnosis and treatment of kidney disease. Thus, our novel finding could have implications to afford an understanding of early phases of kidney disease progression and may provide supplemental information in precision diagnostics.

Proliferative Glomerulonephritis With Hidden Monotypic IgG3κ Deposits: A Case Report.

Rare cases of immunoglobulin G (IgG)-dominant immune complex-mediated glomerulonephritis demonstrate immunoglobulin subclass restriction without light chain restriction. Some of these cases may represent proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) in which monotypic immunoglobulin is obscured by coexisting polytypic immunoglobulin. However, rigorous demonstration of this possibility is lacking to date. Here, we describe a case of IgG3-restricted immune complex-mediated glomerulonephritis without light chain restriction that apparently "transformed" into IgG3κ-PGNMID in a subsequent biopsy. We demonstrate, using several ancillary techniques, including use of the newly described antibodies directed against the conformational epitope at the junctions of heavy and light chains (HLC-IF), that the first biopsy likely represents IgG3κ-PGNMID in which monotypic IgG3κ was hidden by polytypic IgM. This case underscores the need to consider PGNMID in a differential diagnosis of IgG-dominant immune complex-mediated glomerulonephritis without light chain restriction and highlights the potential utility of IgG subclass staining and HLC-IF in such cases to detect monotypic immunoglobulin that may be obscured by coexisting IgM and/or IgA deposits.

Automated scoring of total inflammation in renal allograft biopsies.

BACKGROUND: Computer-assisted scoring is gaining prominence in the evaluation of renal histology; however, much of the focus has been on identifying larger objects such as glomeruli. Total inflammation impacts graft outcome, and its quantification requires tools to identify objects at the cellular level or smaller. The goal of the current study was to use CD45 stained slides coupled with image analysis tools to quantify the amount of non-glomerular inflammation within the cortex. METHODS: Sixty renal transplant whole slide images were used for digital image analysis. Multiple thresholding methods using pixel intensity and object size were used to identify inflammation in the cortex. Additionally, convolutional neural networks were used to separate glomeruli from other objects in the cortex. This combined measure of inflammation was then correlated with rescored Banff total inflammation classification and outcomes. RESULTS: Identification of glomeruli on biopsies had high fidelity (mean pixelwise dice coefficient of .858). Continuous total inflammation scores correlated well with Banff rescoring (maximum Pearson correlation .824). A separate set of thresholds resulted in a significant correlation with alloimmune graft loss. CONCLUSIONS: Automated scoring of inflammation showed a high correlation with Banff scoring. Digital image analysis provides a powerful tool for analysis of renal pathology, not only because it is reproducible and can be automated, but also because it provides much more granular data for studies.

Diagnosis and treatment of IgA nephropathy and IgA vasculitis nephritis in Chinese children.

IgA nephropathy (IgAN) and IgA vasculitis-associated nephritis (IgAVN) are among the most frequent childhood glomerular diseases and are characterized by significant variability in clinical manifestations, pathological presentation and long-term outcomes. IgAVN, alternatively called purpura nephritis, is pathologically indistinguishable from kidney-limited IgAN. In Chinese children, the clinical presentations and pathological manifestations of IgAN and IgAVN are variable. The severity of proteinuria and abnormalities in kidney function and blood pressure of children in China are comparable to those of children in Europe, the USA, and Japan. Compared to Caucasian children and Japanese children, crescents were more common in Chinese children with IgAN or IgAVN. Approximately 10-20% of childhood IgAN or IgAVN progresses to impaired kidney function in China. Since 2007, a series of guidelines on the diagnosis and treatment of pediatric kidney diseases has been published following the principles of evidence-based medicine. However, a large difference exists between the Chinese evidence-based guidelines and the guidelines developed by Kidney Disease: Improving Global Outcomes (KDIGO) in 2021. Chinese children with IgAN or IgAVN were more likely to be treated with steroids or immunosuppressive agents. Further studies exploring the optimal treatment regimen for childhood IgAN or IgAVN are needed in the future.

Digital spatial profiling of collapsing glomerulopathy.

Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

CD163 and CD206 expression define distinct macrophage subsets involved in active ANCA-associated glomerulonephritis.

INTRODUCTION: Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study. MATERIAL AND METHODS: Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data. RESULTS: In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality. CONCLUSIONS: Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.

Opisthorchis viverrini Infection Induces Metabolic and Fecal Microbial Disturbances in Association with Liver and Kidney Pathologies in Hamsters.

Opisthorchis viverrini (Ov) infection causes hepatobiliary diseases and is a major risk factor for cholangiocarcinoma. While several omics approaches have been employed to understand the pathogenesis of opisthorchiasis, effects of Ov infection on the host systemic metabolism and fecal microbiota have not been fully explored. Here, we used a 1H NMR spectroscopy-based metabolic phenotyping approach to investigate Ov infection-induced metabolic disturbances at both the acute (1 month postinfection, 1 mpi) and chronic (4 mpi) stages in hamsters. A total of 22, 3, and 4 metabolites were found to be significantly different in the liver, serum, and urine, respectively, between Ov+ and Ov- groups. Elevated levels of hepatic amino acids and tricarboxylic acid (TCA)-cycle intermediates (fumarate and malate) were co-observed with liver injury in acute infection, whereas fibrosis-associated metabolites (e.g., glycine and glutamate) increased at the chronic infection stage. Lower levels of lipid signals ((CH2)n and CH2CH2CO) and higher levels of lysine and scyllo-inositol were observed in serum from Ov+ hamsters at 1 mpi compared to Ov- controls. Urinary levels of phenylacetylglycine (a host-bacterial cometabolite) and tauro-ß-muricholic acid were higher in the Ov+ group, which coexisted with hepatic and mild kidney fibrosis. Furthermore, Ov+ animals showed higher relative abundances of fecal Methanobrevibacter (Archaea), Akkermansia, and Burkholderia-Paraburkholderia compared to the noninfected controls. In conclusion, along with liver and kidney pathologies, O. viverrini infection resulted in hepatic and mild renal pathologies, disturbed hepatic amino acid metabolism and the TCA cycle, and induced changes in the fecal microbial composition and urinary host-microbial cometabolism. This study provides the initial step toward an understanding of local and systemic metabolic responses of the host to O. viverrini infection.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings.

BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.

Characteristics of disease distribution for the 1 370 renal biopsy cases in two hospitals from Guilin and Jining. / 桂林和济宁两所医院1 370ä¾‹è‚¾æ´»æ£€ç–¾ç— åˆ†å¸ƒç‰¹å¾.

OBJECTIVES: To analyze the constitution and distribution characteristics of renal pathological disease spectrum in the 2 hospitals from Guilin city and Jining city in recent 5 years. METHODS: The pathological results of inpatients with renal biopsy in the 2 hospitals from Guilin city and Jining city from April 1, 2014 to August 15, 2018 were retrospectively analyzed. A total of 1 370 renal biopsy cases were collected, including 706 cases in Affiliated Hospital of Jining Medical College (Jiyi) and 664 cases in Affiliated Hospital of Guilin Medical College (Guiyi). RESULTS: There was no significant difference in gender, age, seasonal distribution and the total proportion of primary and secondary glomerular diseases between the 2 hospitals (all P>0.05). The ratio of male to female in the 2 hospitals was 1.18 (Jiyi) and 0.98 (Guiyi). IgA nephropathy (IgAN) was the major disease in 14-30 years old patients, and membranous nephropathy (MN) was the most common in 40-50 years old patients. There are 15 kinds of same diseases and 10 kinds of different diseases in the 2 hospitals. Among them, three pathological diseases (3 cases) including obesity-related nephropathy, primary Sjogren's syndrome renal damage, and pregnancy-induced hypertensive renal damage only appeared in Jiyi, while 7 diseases (55 cases) including focal segmental glomerulosclerosis (FSGS), focal proliferative glomerulonephritis (FGN), proliferative sclerosing glomerulonephritis (PSGN), endocapillary proliferative glomerulonephritis (EPGN), multiple myeloma renal damage, eosinophilic tumor renal damage and angiomyolipoma renal damage only appeared in Guiyi. Primary glomerular diseases (82% in Jiyi/79% in Guiyi) were higher than secondary nephropathy. The top two diseases in biopsy rate were MN and IgAN. The incidence rate of some diseases in Jiyi was higher than that in Guiyi, and these diseases included MN (48.87%, 31.78%), minimal change disease (MCD) (11.47%, 2.71%), allergic purpura nephritis (Henoch-Schlein purpura nephritis, HSPN) (3.97%, 1.51%), hypertensive renal damage (3.12%, 0.15%), diabetic nephropathy (DN) (2.97%, 1.36%). The incidence rate of other diseases in Guiyi were higher than that in Jiyi, and these diseases included IgAN (22.59%, 19.14%), mesangial proliferative glomerulonephritis (MsPGN) (11.45%, 0.99%), lupus nephritis (LN) (8.58%, 4.67%), hepatitis B virus associated nephritis (HBVGN) (7.53%, 1.84%), there were significant difference between the 2 hospitals in the above diseases (all P<0.05). CONCLUSIONS: The disease distribution of renal biopsy cases in the 2 hospitals displays both similarities and characteristics. Primary glomerular disease is still the main disease. MN has surpassed IgAN and jumped to the first place. The high incidence age of MN is 40-50 years old, and IgAN is 14-30 years old. The incidence rates of MN, MCD, HSPN, hypertensive renal damage, DN and other related diseases of air quality and lifestyle in Jiyi are higher than those in Guiyi. IgAN, MsPGN, LN, HBVGN and other diseases related to infection and tumor factors were higher in Guiyi than those in Jiyi. The prevention and control strategies in the 2 regions need to be adapted to local conditions. More attention should be paid to the impact of environment and lifestyle on kidney health in East China. We should pay attention to the damage to kidney caused by infectious diseases in Southern China, especially in female patients.

Heterotrimeric Gα12/13 proteins in kidney injury and disease.

Gα12 and Gα13 are ubiquitous members of the heterotrimeric guanine nucleotide-binding protein (G protein) family that play central and integrative roles in the regulation of signal transduction cascades within various cell types in the kidney. Gα12/Gα13 proteins enable the kidney to adapt to an ever-changing environment by transducing stimuli from cell surface receptors and accessory proteins to effector systems. Therefore, perturbations in Gα12/Gα13 levels or their activity can contribute to the pathogenesis of various renal diseases, including renal cancer. This review will highlight and discuss the complex and expanding roles of Gα12/Gα13 proteins on distinct renal pathologies, with emphasis on more recently reported findings. Deciphering how the different Gα12/Gα13 interaction networks participate in the onset and development of renal diseases may lead to the discovery of new therapeutic strategies.

Symmetric nephromegaly.

We report a lady with bilateral symmetrical xanthogranulomatous pyelonephritis (XPGN) presented with acute kidney injury and sepsis, in which both CT and MRI mimicked an infiltrative disease, except that the infiltration was not very homogenous. Eventually, the pathological diagnosis turned out to be XPGN. Most XPGN were unilateral, and there have been a few publications of bilateral involvement. Moreover, this case lacked typical manifestations, such as renal calculus, contracted renal pelvis, or obstructive nephropathy. This image reminds us that bilateral renal infiltrative disease could not completely exclude the possibility of XPGN, in which the inhomogeneity of the infiltration pattern on CT/MRI may be a clue.

Podocyte Infolding Glomerulopathy (PIG) in a Patient With Undifferentiated Connective Tissue Disease: A Case Report.

Podocyte infolding glomerulopathy (PIG) is a recently described pathologic entity characterized by diffuse podocyte infolding into the glomerular basement membrane (GBM) associated with ultrastructurally demonstrable microspherular aggregates. The clinical features, significance, and pathogenesis of this condition are still not well delineated because only a few cases have been documented to date, all from Japan. We report a case of PIG associated with undifferentiated connective tissue disease in an Indian woman who presented with nephrotic syndrome while undergoing treatment for an autoimmune disorder. Ultrastructural analysis of the kidney biopsy specimen revealed unusual subepithelial aggregates of microspherules admixed with few microtubules alongside extensive infolding of podocyte foot processes into the underlying GBMs. Characteristic clustering of these microparticles near the invaginated tips of podocyte foot processes in the GBM was observed on transmission electron microscopy. The patient's clinical condition responded favorably to immunosuppressive therapy. The clinical, light microscopic, and diagnostic electron microscopic features of this condition are highlighted in this report in an attempt to contribute some insights into the possible pathogenetic mechanisms of this obscure entity.

Renal aquaporin-4 associated pathology in TG-26 mice.

Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

Schistosomiasis and hydration status: Schistosoma haematobium, but not Schistosoma mansoni increases urine specific gravity among rural Tanzanian women.

OBJECTIVES: Schistosome infections can damage organs important for water homeostasis, especially the kidneys. Urogenital schistosomiasis (caused by Schistosoma haematobium) increases protein and blood in urine and intestinal schistosomiasis (caused by S. mansoni) affects total body water. However, no data exist on how different schistosome species affect urine specific gravity (USG), a hydration biomarker. Therefore, we assessed the relationship between S. haematobium- and S. mansoni-infected and uninfected women and USG in rural Tanzania. MATERIALS AND METHODS: Surveys were conducted and stool and urine samples were collected among 211 nonpregnant women aged 18-50. S. haematobium eggs were detected using the urine filtration method. S. mansoni eggs were detected using the Kato Katz method. USG was measured using a refractometer and analyzed as both a continuous and dichotomous variable. Regression (linear/logistic) models were estimated to test the relationship between infection and hydration status. RESULTS: The prevalence of S. haematobium was 5.9% and S. mansoni was 5.4% with no coinfections. In regression models, S. haematobium-infected women had significantly higher USG (Beta = 0.007 g mL-1 ; standard error = 0.002; p = 0.001) and odds (Odds ratio: 7.76, 95% CI: 1.21-49.5) of elevated USG (>1.020 g mL-1 ) than uninfected women, whereas S. mansoni-infected women did not. DISCUSSION: Schistosoma haematobium, but not S. mansoni, infection is associated with higher USG and risk of inadequate hydration. Future work should determine whether findings are attributable to parasite-induced debris in urine or urinary tract pathologies and signs of renal damage. Human and non-human primate studies using USG in schistosome-endemic areas should account for schistosomiasis.

The Renal Connexome and Possible Roles of Connexins in Kidney Diseases.

Connexins are membrane-spanning proteins that allow for the formation of cell-to-cell channels and cell-to-extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment.

Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct diagnosis.

BACKGROUND AND OBJECTIVES: Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A modified Delphi procedure was conducted to reach consensus among 11 FD experts. A systematic review was performed to identify possible criteria that could confirm or exclude FD nephropathy. RESULTS: The gold standard for FD nephropathy was defined as characteristic storage on electron microscopy (EM) in a kidney biopsy in the absence of medication that may induce similar storage. The suggested criteria to confirm FD nephropathy are as follows: 'renal cysts', 'Maltese cross sign', 'immunohistochemical staining of Gb3 in urine' and 'high urinary Gb3'; and to exclude FD nephropathy: 'absence of renal cysts', 'small kidneys' and 'high protein excretion' were rejected because of low or uncertain specificity. Urinary Gb3 may be increased in other kidney diseases and there was no agreement on this criterion, although a third of the panel indicated that it is sufficient to diagnose FD nephropathy. The 'Maltese cross sign' and 'high urinary Gb3' were selected as red flags to suggest the possibility of FD nephropathy, but are not sufficient for a definite diagnosis of FD nephropathy. CONCLUSIONS: In adults with chronic kidney disease, an α-galactosidase A gene variant and an uncertain diagnosis of FD, a kidney biopsy with EM analysis should be performed to confirm or reject the diagnosis of FD nephropathy. Other criteria currently cannot substitute for a biopsy in these cases.