Pathological and sonographic review of early isolated severe lower urinary tract obstruction and implications for prenatal treatment.

OBJECTIVE: To identify favorable renal histology in fetuses with early severe lower urinary tract obstruction (LUTO) and determine the best timing and selection criteria for prenatal surgery. METHODS: This multicenter, retrospective study included male fetuses with severe LUTO which died before 24 weeks of gestation during the period January 2000 to December 2018. Age-matched controls were used as reference standard for renal histology. Prenatal ultrasound features and fetal serum and/or urine ß2microglobulin level were retrieved and kidney histology slides (hematein-eosin-safran and α-smooth-muscle-actin (αSMA) immunostaining) were prepared and reviewed. αSMA-positive staining of the blastema is due to its aberrant differentiation into myofibroblastic cells. Cases were sorted into histopathologic groups (favorable or unfavorable) according to the blastema's morphology and αSMA labeling and the data of these groups were compared. RESULTS: Included in the study were 74 fetuses with a median gestational age at outcome of 17 + 6 (range, 13 + 0 to 23 + 5) weeks. Parenchymal organization was preserved in 48% of the kidneys. A blastema was present in 90% of the kidneys, but it was morphologically normal in only 9% and αSMA-negative in only 1% of them. Most (82%) fetuses had an unfavorable prognosis, and 36% of fetuses died ≤ 18 weeks and had severe renal lesions detected on histology (early unfavorable prognosis). A favorable renal prognosis was associated with an earlier gestational age (P = 0.001). Fetuses with LUTO had a significantly lower number of mature glomeruli (P < 0.001) compared with controls. However, there was no significant difference in the number of glomeruli generations between the early-unfavorable-prognosis group (≤ 18 weeks) and the group with a favorable prognosis (P = 0.19). A comparison of prenatal ultrasound features and biochemical markers between groups could not identify any prenatal selection criteria. CONCLUSIONS: Before 18 weeks, around 30% of fetuses with severe LUTO still have potential for kidney development. Identification of these cases would enable them to be targeted for prenatal therapy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

[Renal lesions in patients with Fabry's disease]. / Lésions rénales dans la maladie de Fabry.

Kidney involvement is one of the main manifestations of Fabry's disease. In the absence of enzyme replacement therapy, hemizygous males and some heterozygous females progress to end stage renal failure. In hemizygous males, diffuse glycolipid accumulation is observed in all glomerular and vascular cells whereas distal tubular cells are focally involved. In heterozygous females, the glycolipid storage is irregular in glomeruli and vessels, some cells being massively involved, others being normal. In both sexes, degenerative changes occur, linked to the necrosis of overloaded mesangial and vascular smooth muscle cells. Their progression leads to unspecific arteriopathy and glomerulosclerosis not prone to reverse under enzymotherapy. Kidney biopsy is useful for confirming the diagnosis if clinical presentation of Fabry's disease is atypical. Moreover, histological analysis of renal tissue allows to assess the severity of degenerative changes and to evaluate the beneficial impact of enzyme replacement therapy.

Very early twin-to-twin transfusion syndrome and discordant activation of the renin-angiotensin system.

We present evidence of a first-trimester discordant renin-angiotensin system (RAS) response and structural abnormalities of the kidneys in twins with twin-to-twin transfusion syndrome (TTTS). A dark red fetus and a pale fetus were spontaneously delivered at 13.5 weeks of gestation following a double intra-uterine death. Pathological examination confirmed the placentation as monochorionic, with arteriovenous anastomoses on the chorionic plate. The donor twin had a normal heart and mildly hypoplastic kidneys, and the recipient twin had cardiomegaly and hypertrophic kidneys. Immunohistochemical analysis of the kidneys showed secretion of renin occurring in the donor but not in the recipient twin, more intense expression of angiotensin II receptor type 1 in the donor, and modifications of renal architectures in both twins. Renin protein appeared qualitatively higher in the placental territory of the recipient compared to that of donor. These findings indicate that hemodynamic discordance caused by vascular anastomoses may lead to serious physiologic and organic consequences as early as the first trimester. To our knowledge, this case presents the earliest first-trimester TTTS confirmed by a complete anatomopathological examination and is the first TTTS case to show a first-trimester discordant RAS response confirmed by immunohistochemistry.

A missense mutation in podocin leads to early and severe renal disease in mice.

Mutations in the NPHS2 gene, encoding podocin, are responsible for familial autosomal recessive and sporadic cases of steroid-resistant nephrotic syndrome. We have successfully generated a mouse model in which the common p.R138Q mutation found in nephrotic patients is expressed in the kidney. Homozygous mice express the mutant protein, which is mislocated to the cytoplasm, along with a portion of the nephrin pool. These mice die within the first month of life, but their survival depends on the genetic background. Albuminuria manifests early and leads to progressive renal insufficiency, characterized histologically by diffuse mesangiolysis and mesangial sclerosis, endothelial lesions along with podocyte abnormalities such as widespread foot process effacement. Gene expression profiling revealed marked differences between these and the podocin-null mice, including significant perturbations of podocyte-expressed genes such as Cd2ap, Vegfa and the transcription factors Lmx1b and Zhx2. Upregulation of Serpine1 and Tgfb1 implicates these as potential mediators of disease progression in these mice. This mouse model of nephrotic syndrome may serve as a valuable tool in studies of in vivo intracellular protein trafficking of podocyte proteins, as well as testing therapeutic modalities aimed at correcting the targeting of mutant proteins.

[Renal tubular dysgenesis and mutation in the renin gene]. / Dysgénésie tubulaire proximale et mutation du gène de la rénine.

Renal tubular dysgenesis is a severe and rare disorder of the renal development characterized by fetal anuria, oligohydramnios and early death from pulmonary hypoplasia and refractory arterial hypotension. We report on a female patient who presented with anuria in the neonatal period, requiring peritoneal dialysis until 5 months of age with unexpected diuresis recovery at 2 months of age. Clinical, histological and pathophysiological issues are discussed for this disease related to a mutation in the renin gene.

[Autosomal recessive renal tubular dysgenesis: morphologic and genetic study of 2 cases]. / Dysgénésie tubulaire rénale autosomique récessive: étude morphologique et génétique de 2 nouveaux cas.

Renal tubular dysgenesis (RTD) is a rare and severe nephropathy characterized by persistent fetal anuria leading to oligohydramnios with the Potter sequence, and perinatal death. The diagnosis is based on the histological finding of absence or paucity of proximal tubules. A consanguineous family is described in which 2 siblings, born after pregnancies complicated by oligohydramnios were affected with RTD. Patients were small for gestational age at birth. The first patient died after a few hours, the second after a few days of life, with persistent anuria unresponsive to treatment. Histologically, there was marked reduction in the number of proximal tubule sections and no renin was detected by immunohistochemistry. An homozygous mutation of the gene encoding renin was identified in both patients. This study underlines the interest of the histological examination of the kidney for the diagnostic of RTD in anuric fetuses and newborns, and the possibility of mutation analysis of RAS genes for genetic counselling and early prenatal diagnosis.

Autosomal dominant Alport's syndrome: study of a large Tunisian family.

Alport's syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in early adult life. It is a clinically and genetically heterogeneous nephropathy. Alport's syndrome is often associated with sensorineural deafness and/or ocular abnormalities. In contrast with the well-known X-linked phenotype, very little is known about the autosomal dominant form caused by mutations in COL4A3 and COL4A4 in the chromosome region 2q35-q37. We describe a Tunisian family with autosomal dominant Alport's syndrome in which males and females were equally affected. Two members reached ESRD at age 40 and 53 years, respectively. Three members experienced isolated microhematuria and one member experienced sensorineural deafness. No eye abnormalities were observed. Immunohistochemical studies showed a normal distribution of the alpha5 (type IV collagen) chain in the epidermal basement membrane. Genetic analysis demonstrated that a common haplotype co-segregated with the disease in the heterozygous state in all affected patients, thereby, confirming an autosomal dominant mode of inheritance. The same haplotype was observed in two asymptomatic children. We conclude that autosomal dominant Alport's syndrome, follows a rare mode of inheritance and exhibits a milder phenotype than usually observed in classic X-linked Alport's syndrome. The frequency of this mode of inheritance should be confirmed by a larger study.

Meckel-Grüber syndrome: sonography and pathology.

OBJECTIVE: To define a specific sonographic pattern for the appearance of the kidneys in fetuses affected by Meckel-Grüber syndrome (MGS). METHODS: This was a retrospective analysis of 30 cases, collected from five centers, with ultrasound features suggestive of MGS. Only fetuses with a confirmed diagnosis of MGS were finally included. Analysis included a detailed evaluation of the sonographic findings and comparison with pathological follow-up. RESULTS: Seventeen cases met the pathological criteria for a diagnosis of MGS and were included in the study. In all cases, a typical sonographic pattern was seen: the kidneys were enlarged (mean, + 4.8 SD) and showed unusual corticomedullary differentiation, occurring as early as the first trimester. In most cases, the medullary areas appeared excessively large and mottled due to the presence of multiple small cysts. CONCLUSIONS: The kidneys of fetuses with MGS are enlarged, cystic and have unusual corticomedullary differentiation. These features can be observed as early as the first and early second trimesters.

[Immunohistochemistry contribution in Alport syndrome diagnosis]. / Apport de l'immunohistochimie dans le diagnostic du syndrome d'Alport.

UNLABELLED: Alport syndrome (AS) is an hereditary disease characterised by the association of progressive hematuria nephritis. The diagnosis is based on clinical genetic and ultrastructural findings. Nowadays, immunohistochemical technique is of great interest. It enables us to analyze the distribution of the different chains of the type IV collagen in renal basement membrane (RBM) and epidermal basement membrane (EBM) which appeared to be abnormal in 70% of cases. METHODS: We report a prospective study of five families affected with AS. Six patients were investigated by immunohistochemical studies of kidney (3 cases) and skin (6 cases) frozen specimens. Monoclonal antibodies recognizing the collagenous domain of alpha1 (MAB1), alpha3 (MAB3) and alpha5 (MAB5) chains of type IV collagen were used. Two methods were performed: direct immunofluorescence and immunohistochemical (ultravision) analysis. RESULTS: The different chains distribution of type IV collagen in the EBM and RBM was normal in four cases (4 men), abnormal in two patients (1 man and woman). Based on the clinical, genetical and immunohistochemical findings we established three transmission modes: autosomal recessive in two families, dominant X linked in two other familiales, and autosomal dominant in one family. CONCLUSION: Immunohistochemical studies is a simple technique of an easy interpretation accomplished on kidney frozen specimen, or even on a simple cutaneous biopsy. It could be very useful for the diagnosis and enables us in addition to determine the mode of transmission of AS.

Sonographic findings in Beckwith-Wiedemann syndrome related to H19 hypermethylation.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with congenital malformations and tumour predisposition. BWS results from variable mutations or epigenetic modifications of imprinted genes in the 11p15 chromosomal region. We present a fetus with mild general overgrowth and bilateral enlarged echogenic kidneys with loss of the corticomedullary differentiation in which prenatal diagnosis of BWS was suspected. The rest of the fetal anatomy and the amniotic fluid volume appeared normal. After termination of the pregnancy, molecular analysis confirmed the diagnosis of BWS by showing an isolated hypermethylation of the H19 gene.

Prenatal diagnosis of bilateral isolated fetal hyperechogenic kidneys. Is it possible to predict long term outcome?

OBJECTIVE: To study perinatal and long term outcome following prenatal diagnosis of hyperechogenic kidneys. DESIGN: Prospective observational cohort study. SETTING: The Maternité Port-Royal Hôpital Cochin and at the Departments of Obstetrics and Paediatric Nephrology, Necker Enfants Malades in Paris, France. POPULATION: Forty-three fetuses with isolated bilateral hyperechogenic kidneys. METHODS: All patients referred with isolated bilateral hyperechogenic fetal kidneys were followed up prospectively up to 34-132 months. The following prenatal items were analysed: fetal kidney size, amniotic fluid volume, gestational age at diagnosis, family history and renal ultrasound in parents. Postmortem examination was carried out in cases with perinatal death. Postnatal follow up of survivors included postnatal ultrasound, blood pressure, serum creatinine, proteinuria, need for restricted diet, weight and height and renal biopsy when available. MAIN OUTCOME MEASURES: Aetiology of hyperechogenicity, perinatal mortality and renal function in survivors. RESULTS: The aetiology could be established by family history, postmortem or postnatal data, but not by prenatal ultrasound. There were 20 autosomal recessive, 8 autosomal dominant polycystic kidney diseases, 9 other renal disorders and 6 symptom-free survivors without aetiological diagnosis. There were 19 terminations of pregnancy, 5 neonatal deaths and 19 survivors, of whom 14 had normal renal function three had mild and two had end stage renal failure. None of those with severe oligohydramnios and fetal kidneys > 4 SD survived (n = 14, 10 terminations and 4 neonatal deaths), whereas of the 17 with normal amniotic fluid volume and kidneys < 4 SD, 14 survived, of whom 9 were symptom-free. CONCLUSION: Aetiology could not be established prenatally in the absence of familial data. Kidney size and amniotic fluid volume were the best prenatal predictors of outcome.

[Contribution of genetics to knowledge and management of hereditary kidney diseases progressing to renal failure]. / Apport de la génétique à la connaissance et à la prise en charge des maladies rénales héréditaires progressant vers l'insuffisance rénale.

Genes of most of the hereditary renal diseases progressing to renal insufficiency are now identified. In the first part of this paper we describe their multi-faceted genetics. Genetic heterogeneity has been demonstrated in many of these diseases, such as Alport's syndrome and nephronophtisis. In some of them an allelic heterogeneity is present as in the X-linked form of Alport's syndrome (more than 300 different mutations have been described along the COL4A5 gene). Besides these classical mendelian diseases, mendelian subentities have been isolated within common diseases such as cortico-resistant nephrosis. Many diseases also demonstrate a variability of their phenotype resulting from allelic and/or genetic heterogeneity, or from modifier genes. In the second part of the paper we discuss the consequences of this explosion of knowledge with respect to epidemiology, genetic diagnosis, prenatal diagnosis and treatment.

Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation.

Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.

Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis.

UNLABELLED: Diffuse mesangial sclerosis, isolated (IDMS) or observed in the context of Denys-Drash syndrome (DDS) due to WT1 mutation, is characterized by early onset nephrotic syndrome progressing to renal failure. A striking morphological feature is the rapid development of glomerulosclerosis. THE AIMS OF OUR STUDY WERE: (1) to analyze the glomerular distribution of extracellular matrix (ECM) antigens at the early stage of DMS, (2) to determine the composition of the ECM accumulated within the mesangial areas and leading to glomerular sclerosis, and (3) to analyze the expression of growth factors, transforming growth factor-beta 1 (TGF beta 1) and platelet-derived growth factor A (PDGFA). In glomeruli of patients with IDMS and DDS, the glomerular basement membrane (GBM) expression of the heparan sulfate chain of heparan sulfate proteoglycan (HSPG) was decreased from the early stage of DMS, at a time when ECM proteins retained a normal distribution. In fully developed lesions, mesangial and subendothelial accumulation of collagenous and noncollagenous glycoproteins normally expressed in the mesangial area (types IV [alpha 1(IV)2 alpha 2(IV)] and VI collagen, beta 1 laminin, fibronectin, tenascin, and perlecan) increased with progression of mesangial sclerosis. This was associated with mesangial expression of proteins normally restricted to the GBM (agrin, alpha 1/alpha 5, beta 2, and gamma 1 laminin chains) and with accumulation of chondroitin sulfate proteoglycan. The distribution of the alpha 3-alpha 5 chains of type IV collagen was normal. Focal accumulation of types I, III, and V collagen was seen only in severely sclerotic glomeruli. Expression of growth factors TGF beta 1 and PDGFA was increased in 9 of 10 and 5 of 10 patients, respectively. Early decreased GBM expression of the heparan sulfate chain of HSPG could play a role in the proteinuria of DMS patients. Changes in the composition of the ECM accumulated within the mesangial areas are not specific. We speculate that deregulation of the expression of growth factors normally downregulated by WT1, is one of the factors responsible for the rapid and massive mesangial deposition of basement membrane material in DDS.

Pathogenesis of twin-twin transfusion syndrome: the renin-angiotensin system hypothesis.

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as '2 kidneys-1 clip' with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.

Detection of apoptosis in kidney biopsies of patients with D+ hemolytic uremic syndrome.

In this study we have investigated the presence of apoptotic cells in renal biopsy material of seven patients with hemolytic uremic syndrome (HUS) by using an improved and stringent terminal deoxynucleotidyl nick-end labeling (TUNEL) technique. Renal biopsy material was taken in the second or third week after onset of the disease. Renal biopsy material of patients with minimal lesions nephrotic syndrome or thin basement syndrome were used as control. It has been reported that nonapoptotic cells can be labeled nonspecifically due to proteinase K pretreatment or a delay in fixation when only TUNEL technique is used. In post mortem material this delay in fixation is seen. Moreover, it has been described that mainly nonapoptotic cells that shows signs of active gene transcription can be labeled in this nonspecific way. For this reason we used the TUNEL technique in combination with a label for RNA synthesis and splicing factor (SC-35). Indeed, we found nonspecific labeling of nonapoptotic nuclei in biopsy material of HUS patients, but not in control biopsy material. By using co-labeling with RNA synthesis factor SC-35, we were able to identify true apoptotic cells. There was a significant increase (p < 0.05) in the presence of apoptotic cells in biopsy material of HUS patients compared with material of controls. About 80 % of apoptotic cells were detected in tubuli and only 20 % in glomeruli of the renal biopsies of HUS patients. Furthermore, most apoptotic cells were detected in those patients that had received peritoneal dialysis suggesting that there is a relationship between severity of the disease and amount of apoptotic cells. The finding of apoptotic cells suggest that apoptosis plays a role in HUS.

PAX2 mutations in oligomeganephronia.

BACKGROUND: Oligomeganephronia (OMN) is a rare congenital and usually sporadic anomaly. It is characterized by bilateral renal hypoplasia, with a reduced number of enlarged nephrons. The mechanisms involved in this deficient nephrogenesis are unknown. The paired box transcription factor PAX2 plays a fundamental role in renal development. Heterozygous Pax2 mutants in mice are characterized by renal hypoplasia and retinal defects, and in humans, PAX2 mutations have been described in the renal-coloboma syndrome. METHODS: To assess whether OMN could be related to PAX2, we searched for PAX2 mutations in nine patients presenting with sporadic and apparently isolated OMN. RESULTS: Heterozygous PAX2 mutations were found in three patients. A limited optic nerve coloboma was secondarily detected in two cases and a very mild optic disk dysplasia in one patient. None of these patients had visual impairment. CONCLUSIONS: Ocular anomaly and PAX2 mutations should be sought in all patients with OMN.

Congenital erythropoietic porphyria: prenatal diagnosis and autopsy findings in two sibling fetuses.

Congenital erythropoietic porphyria is an autosomal recessive disease characterized by a deficiency of uroporphyrinogen III cosynthetase activity, with diffuse tissue accumulation of specific type I porphyrins. The diagnosis of this disease was made in two fetuses, who were siblings, and from a Caucasian nonconsanguinous family. The first fetus died in utero with hydrops fetalis and anemia, but without an etiopathogenic diagnosis. In the second case, the diagnosis was based on pink fluorescence of the amniotic fluid examined fortuitously in sunlight. DNA analysis showed that the fetus was heteroallelic for the mutation C73R. The autopsy showed brown skin, and at histological examination, porphyrin pigment was deposited in many tissues. Retrospectively, similar deposits were found in the tissues of the first fetus.