2-Step Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

Background: The decision to accept or discard the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and 1-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium.

Methods: The training set was n = 620 for DGF and n = 711 for 1y-tl, with validation sets n = 158 and n = 162, respectively.

Combined Therapy with Intravenous Immunoglobulins, Letermovir and (Val-)Ganciclovir in Complicated Courses of CMV-Infection in Transplant Recipients.

The treatment options for cytomegalovirus (CMV) infections in immunosuppressed patients are limited, mainly consisting of (val-)ganciclovir (VGC/GCV) as the first-line treatment. We report on three transplant recipients, one stem cell transplant (allo-HSCT) patient and two kidney transplant (KTx) recipients, with prolonged CMV viremia treated with a combined therapy based on letermovir (LMV), CMV-specific intravenous immunoglobulins (IVIg), and VGC/GCV, which led to the sustained control of CMV viremia in all patients.

Fabry disease-what cardiologists can learn from the nephrologist: a narrative review.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder resulting in decreased or absent activity of the lysosomal enzyme alpha-galactosidase A. Subsequent accumulation of storage material can occur in virtually all cells of the body. Organs and structures affected by storage material deposition include the heart, the kidney, the central and peripheral nervous system and the cornea of the eyes.

The proteomic landscape of small urinary extracellular vesicles during kidney transplantation.

Kidney transplantation is the preferred renal replacement therapy available. Yet, long-term transplant survival is unsatisfactory, partially due to insufficient possibilities of longitudinal monitoring and understanding of the biological processes after transplantation. Small urinary extracellular vesicles (suEVs) - as a non-invasive source of information - were collected from 22 living donors and recipients.

Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling.

Background/aims: Fabry disease (FD) is a lysosomal storage disorder characterized by impaired alpha-galactosidase A (α-Gal A) enzyme activity due to mutations in the GLA gene. While virtually all tissues are affected, renal damage is particularly critical for the patients' outcome. Currently, powerful diagnostic tools and in vivo research models to study FD in the kidney are lacking, which is a major obstacle for further improvements in diagnosis and therapy.

Urine-derived cells: a promising diagnostic tool in Fabry disease patients.

Fabry disease is a lysosomal storage disorder resulting from impaired alpha-galactosidase A (α-Gal A) enzyme activity due to mutations in the GLA gene. Currently, powerful diagnostic tools and in vivo research models to study Fabry disease are missing, which is a major obstacle for further improvements in diagnosis and therapy. Here, we explore the utility of urine-derived primary cells of Fabry disease patients.

Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier.

Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein.

Altered lipid metabolism in the aging kidney identified by three layered omic analysis.

Aging-associated diseases and their comorbidities affect the life of a constantly growing proportion of the population in developed countries. At the center of these comorbidities are changes of kidney structure and function as age-related chronic kidney disease predisposes to the development of cardiovascular diseases such as stroke, myocardial infarction or heart failure. To detect molecular mechanisms involved in kidney aging, we analyzed gene expression profiles of kidneys from adult and aged wild-type mice by transcriptomic, proteomic and targeted lipidomic methodologies.

Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure.

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling.

An approach to cystic kidney diseases: the clinician's view.

Advances in molecular genetics have led to the identification of more than 70 different genes involved in the development of cystic kidney diseases. Most of these diseases are rare, and interpreting the resultant plethora of disease-causing mutations requires a methodical and meticulous approach to differential diagnosis. In this Review we discuss a clinical approach to the diagnosis of cystic kidney diseases in adults, for use by nephrologists.

Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: a systematic review.

Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remain a therapeutic challenge, since steroids and other immunosuppressive agents exhibit an unfavorable adverse event spectrum. The aim of this review was to systematically summarize and analyze data from preexisting studies reporting the outcome of rituximab (RTX) treatment in these patients.

Methods: Study data on adult patients with either steroid-dependent or frequently relapsing MCD/FSGS were identified by a PubMed and Embase search.

Protection of human podocytes from shiga toxin 2-induced phosphorylation of mitogen-activated protein kinases and apoptosis by human serum amyloid P component.

Hemolytic uremic syndrome (HUS) is mainly induced by Shiga toxin 2 (Stx2)-producing Escherichia coli. Proteinuria can occur in the early phase of the disease, and its persistence determines the renal prognosis. Stx2 may injure podocytes and induce proteinuria.

Monoclonal gammopathy-associated pauci-immune extracapillary-proliferative glomerulonephritis successfully treated with bortezomib.

Extracapillary-proliferative glomerulonephritis is a rare complication of multiple myeloma. Partial remission of kidney involvement with cyclophosphamide therapy has previously been described. We report the case of a 60-year-old male patient diagnosed with rapidly progressive glomerulonephritis associated with IgG kappa monoclonal gammopathy.

Transcriptional profiling reveals progeroid Ercc1(-/Δ) mice as a model system for glomerular aging.

Background: Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes.

Dysregulated autophagy contributes to podocyte damage in Fabry's disease.

Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase α-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally α-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood.

Survival and distribution of injected haematopoietic stem cells in acute kidney injury.

Background: Endogenous bone marrow-derived cells are known to incorporate into renal epithelium at a low rate. Haematopoietic stem cells (HSCs) rather than mesenchymal stem cells (MSC) are responsible for this phenomenon. MSCs have the potential to ameliorate kidney function after acute kidney injury (AKI) without directly repopulating the tubules.

Indicators of acute and persistent renal damage in adult thrombotic microangiopathy.

Background: Thrombotic microangiopathies (TMA) in adults such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are life-threatening disorders if untreated. Clinical presentation is highly variable and prognostic factors for clinical course and outcome are not well established.

Methods: We performed a retrospective observational study of 62 patients with TMA, 22 males and 40 females aged 16 to 76 years, treated with plasma exchange at one center to identify clinical risk factors for the development of renal insufficiency.

Rituximab treatment for adults with refractory nephrotic syndrome: a single-center experience and review of the literature.

Background/aims: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are common causes of nephrotic syndrome (NS) in adults. However, induction of remission and sustained control of proteinuria is often difficult. Recently, B cell-directed therapy using the anti-CD20 antibody rituximab has been suggested as induction regimen in pediatric FSGS and MCD patients.

Putative re-entrant loop 1 of AE2 transmembrane domain has a major role in acute regulation of anion exchange by pH.

Normal pH sensitivity of the SLC4A2/AE2 anion exchanger requires transmembrane domain (TMD) amino acid (aa) residues not conserved in the homologous but relatively pH-insensitive SLC4A1/AE1 polypeptide. We tested the hypothesis that the nonconserved aa cluster 1075DKPK1078 within the first putative re-entrant loop (RL1) of AE2 TMD contributes to pH sensor function by studying anion exchange function of AE2 mutants in which these and other RL1 aa were systematically substituted with corresponding RL1 aa from AE1. Regulation of Cl-/Cl- and Cl-/HCO(-)3 exchange by intracellular pH (pHi) or extracellular pH (pHo) was measured as 4,4'-di-isothiocyanatostilbene-2,2' disulfonic acid-sensitive 36Cl- efflux from Xenopus oocytes.

Mouse strain-specific coding polymorphism in the Slc4a2/Ae2 gene encodes Ae2c2 variants differing in isoform-specific dominant negative activity.

The Slc4a2/Ae2 gene encodes multiple polypeptides arising from alternate promoter usage. The Ae2c promoter gives rise to only one Ae2c transcript from the human Ae2 gene, but to two, alternatively spliced, Ae2c1 and Ae2c2 transcripts from the mouse and rat genes. Unlike in the rat, the mouse Ae2c2 transcript encodes a novel Ae2c2 polypeptide.

Zebrafish ae2.2 encodes a second slc4a2 anion exchanger.

The genome of zebrafish (Danio rerio) encodes two unlinked genes equally closely related to the SLC4A2/AE2 anion exchanger genes of mammals. One of these is the recently reported zebrafish ae2 gene (Shmukler BE, Kurschat CE, Ackermann GE, Jiang L, Zhou Y, Barut B, Stuart-Tilley AK, Zhao J, Zon LI, Drummond IA, Vandorpe DH, Paw BH, Alper SL. Am J Physiol Renal Physiol Renal Physiol 289: F835-F849, 2005), now called ae2.

Alkaline-shifted pHo sensitivity of AE2c1-mediated anion exchange reveals novel regulatory determinants in the AE2 N-terminal cytoplasmic domain.

The mouse anion exchanger AE2/SLC4A2 Cl(-)/HCO(-)(3) exchanger is essential to post-weaning life. AE2 polypeptides regulate pH(i), chloride concentration, cell volume, and transepithelial ion transport in many tissues. Although the AE2a isoform has been extensively studied, the function and regulation of the other AE2 N-terminal variant mRNAs of mouse (AE2b1, AE2b2, AE2c1, and AE2c2) have not been examined.

Zebrafish slc4a2/ae2 anion exchanger: cDNA cloning, mapping, functional characterization, and localization.

Although the zebrafish has been used increasingly for the study of pronephric kidney development, studies of renal ion transporters and channels of the zebrafish remain few. We report the cDNA cloning and characterization of the AE2 anion exchanger ortholog from zebrafish kidney, slc4a2/ae2. The ae2 gene in linkage group 2 encodes a polypeptide of 1,228 aa exhibiting 64% aa identity with mouse AE2a.