Matthias Wolf - Academia.edu (original) (raw)
Papers by Matthias Wolf
The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency
Pediatric Nephrology
Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the ... more Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years. A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels. We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients.
Autosomal Dominant Tubulointerstitial Kidney Disease
Advances in Chronic Kidney Disease
There are 3 major forms of autosomal dominant tubulointerstitial kidney disease (ADTKD): ADTKD du... more There are 3 major forms of autosomal dominant tubulointerstitial kidney disease (ADTKD): ADTKD due to UMOD mutations, MUC1 mutations, and mutations in the REN gene encoding renin. Lack of knowledge about these conditions contributes to frequent nondiagnosis, but with even limited knowledge, nephrologists can easily obtain a diagnosis and improve patient care. There are 3 cardinal features of these disorders: (1) the conditions are inherited in an autosomal dominant manner and should be considered whenever both a parent and child suffer from kidney disease; the presence of even more affected family members provides further support. (2) These conditions are associated with a bland urinary sediment, ruling out glomerular disorders. (3) There is a variable rate of decline in kidney function. The mean age of ESRD is approximately 45, but the range is from 17 to >75. ADTKD-UMOD is often but not always associated with gout in the teenage years. ADKTKD-REN is associated with signs of hyporeninemia: mild hypotension, mild hyperkalemia, anemia in childhood, and hyperuricemia and gout in the teenage years. The only clinical manifestation of ADTKD-MUC1 is slowly progressive CKD. Diagnosis should be made by genetic testing, and kidney biopsy should be avoided.
Journal of the American Society of Nephrology : JASN, 2016
Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin... more Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encodingMucin-1(MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused byUMODmutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collec...
Journal of medical genetics, 2011
Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic... more Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.
Renal Tubular Acidosis in Children
American Journal of Nephrology, 1986
To delineate the spectrum of clinical expressions of distal, type 1 renal tubular acidosis in chi... more To delineate the spectrum of clinical expressions of distal, type 1 renal tubular acidosis in children and to update progress in diagnosis, therapy, and prognosis, the medical records of 14 girls and 10 boys, seen over a 7 year period, who met the following criteria, were examined: persistent urinary pH more than 6, net acid excretion less than 70 μEq/min/1.73
The Journal of biological chemistry, Jan 23, 2018
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated wit... more Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. -knockout ( ) mice excreted more urinary magnesium than wild-type (WT) and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical ...
Pediatric Medicine
While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertens... more While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertension is well known, the significance and contribution of low renin hypertension is often overlooked. RAAS stimulation results in more tubular absorption of sodium and water along the nephron, contributing to a higher circulating vascular volume. In addition, members of the RAAS system, such as angiotensin II, have direct effects on vascular vasoconstriction, the heart, aldosterone synthesis in the adrenal glands, the sympathetic nervous system, and the CNS. This has resulted in a line of antihypertensive therapeutics targeting RAAS with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors, which prevent conversion of angiotensinogen to angiotensin. While general practitioners and nephrologists are well aware of the causes and the long-term consequences of elevated renin and aldosterone levels, the opposite situation with low renin and/or low aldosterone levels is frequently underappreciated. The low renin and aldosterone levels may be indicators of inherited (especially when associated with hypokalemia), monogenic forms of hypertension stimulating excessive tubular sodium and water absorption which subsequently results in plasma volume expansion and hypertension. In this review article we will outline the different forms of hypertension characterized by low renin/low aldosterone and low renin/high aldosterone levels, how to diagnose these forms of hypertension, and how to treat them.
Uromodulin in mineral metabolism
Current Opinion in Nephrology and Hypertension
Scientific reports, Jan 8, 2018
Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubu... more Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study ...
Nature Genetics, Aug 1, 2003
Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most comm... more Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults 1. NPHP may be associated with Leber congenital amaurosis, tapetoretinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis 2-6. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped 7-10. NPHP1 and NPHP4 have been identified 11-13 , and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown 13. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype 14. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone 15-17 , suggesting therapeutic strategies for treating individuals with NPHP3.
Aniride - Molekulare Analyse des PAX6 - Gens und Versuch einer Genotyp - Phänotyp - Korrelation [microform] /
ABSTRACT
Hereditäre Nierenerkrankungen
Medizinische Therapie 2005|2006, 2005
Page 1. 927 11.6 Hereditäre Nierenerkrankungen 11 Gault MM, Barrett BJ (1998) Analgesic nephropat... more Page 1. 927 11.6 Hereditäre Nierenerkrankungen 11 Gault MM, Barrett BJ (1998) Analgesic nephropathy. In depth review. Am J Kidney Dis 32:351360 Markowitz GS, Radhakrsihnan J, Kambham N, Valeri AM, Hines WH, D ...
Nephronophthisis and related syndromes
Current opinion in pediatrics, 2015
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most co... more Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in children and adolescents. NPHP is a genetically heterogenous disorder with 20 identified genes. NPHP occurs as an isolated kidney disease, but approximately 15% of NPHP patients have additional extrarenal symptoms affecting other organs [e.g. eyes, liver, bones and central nervous system (CNS)]. The pleiotropy in NPHP is explained by the finding that almost all NPHP gene products share expression in primary cilia, a sensory organelle present in most mammalian cells. If extrarenal symptoms are present in addition to NPHP, these disorders are classified as NPHP-related ciliopathies (NPHP-RC). This review provides an update about recent advances in the field of NPHP-RC. The identification of novel disease-causing genes has improved our understanding of the pathomechanisms contributing to NPHP-RC. Multiple interactions between ...
The Journal of biological chemistry, Jan 26, 2014
The anti-aging protein Klotho is a type 1 membrane protein produced predominantly in the distal c... more The anti-aging protein Klotho is a type 1 membrane protein produced predominantly in the distal convoluted tubule. The ectodomain of Klotho is cleaved and secreted into the urine to regulate several ion channels and transporters. Secreted Klotho (sKL) up-regulates the TRPV5 calcium channel from the cell exterior by removing sialic acids from N-glycan of the channel and inhibiting its endocytosis. Because TRPV5 and Klotho coexpress in the distal convoluted tubule, we investigated whether Klotho regulates TRPV5 action from inside the cell. Whole-cell TRPV5-mediated channel activity was recorded in HEK cells coexpressing TRPV5 and sKL or membranous Klotho (mKL). Transfection of sKL, but not mKL, produced detectable Klotho protein in cell culture media. As for sKL, mKL increased TRPV5 current density. The role of sialidase activity of mKL acting inside is supported by findings that mutations of putative sialidase activity sites in sKL and mKL abrogated the regulation of TRPV5 but that t...
Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—A KDIGO consensus report
Kidney International, 2015
Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes enc... more Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.Kidney International advance online publication, 4…
Nature Genetics, 2003
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal fai... more Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.
Nephronophthisis
Pediatric Nephrology, 2011
Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene
Pediatric Nephrology, 2002
Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessiv... more Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.
Pediatric Nephrology, 2009
Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD... more Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD). UMOD transcription is activated by the transcription factor HNF1B. Mutations in HNF1B cause a phenotype similar to FJHN/GCKD but also congenital anomalies of the kidney and the urinary tract (CAKUT). Moreover, we recently detected UMOD mutations in 2 patients with CAKUT. As HNF1B and UMOD act in the same pathway and cause similar phenotypes we here examined, whether UMOD mutations would be found in patients with CAKUT. Mutation analysis of UMOD was performed in 96 individuals with CAKUT by direct sequencing of exons 4 and 5 and by heteroduplex analysis following CEL I digestion assay of the exons 3 and 6-12. The mean age of patients was 11.4 years and in 36.4% of patients the family history was positive for CAKUT. In the CEL I assay 12 aberrant bands were detected in 103 of 960 PCR products and were sequenced. Two previously known and eight new SNPs were detected. As no UMOD mutations were identified in these 96 patients with CAKUT, UMOD mutations do not seem to be a significant cause of CAKUT in this cohort.
Nephrology Dialysis Transplantation, 2005
Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and envir... more Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and environmental interaction. The pathogenesis of nephrolithiasis is far from being understood. So far, no gene locus for autosomal dominant nephrolithiasis only has been described. We here identified a new suggestive gene locus for autosomal dominant nephrolithiasis by a genome-wide search for linkage in a Spanish kindred with nephrolithiasis. Methods. Clinical data, blood and urine samples of 18 individuals from a Spanish kindred with nephrolithiasis were collected. We performed a genome-wide search for linkage using 380 polymorphic microsatellite markers. Results. Nephrolithiasis segregated in this Spanish kindred in a pattern compatible with autosomal dominant inheritance. The total genome search yielded the highest two-point LOD score of Z max ¼ 1.99 (y ¼ 0) for marker D9S159 on chromosome 9q33.2-q34.2. Multipoint analysis of 24 polymorphic markers used for further fine mapping resulted in a LOD score of Z max ¼ 2.7 (y ¼ 0) for markers D9S1881-D9S164, thereby identifiying a new gene locus for autosomal dominant nephrolithiasis (NPL1). Two recombination events define D9S1850 as the centromeric flanking marker and D9S1818 as the telomeric flanking marker, restricting the NPL1 locus to a 14 Mb interval. Conclusion. We here identified a new suggestive gene locus (NPL1) for autosomal dominant nephrolithiasis. It is localized on chromosome 9q33.2-q34.2. The identification of the responsible gene will provide new insights into the molecular basis of nephrolithiasis.
The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency
Pediatric Nephrology
Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the ... more Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years. A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels. We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients.
Autosomal Dominant Tubulointerstitial Kidney Disease
Advances in Chronic Kidney Disease
There are 3 major forms of autosomal dominant tubulointerstitial kidney disease (ADTKD): ADTKD du... more There are 3 major forms of autosomal dominant tubulointerstitial kidney disease (ADTKD): ADTKD due to UMOD mutations, MUC1 mutations, and mutations in the REN gene encoding renin. Lack of knowledge about these conditions contributes to frequent nondiagnosis, but with even limited knowledge, nephrologists can easily obtain a diagnosis and improve patient care. There are 3 cardinal features of these disorders: (1) the conditions are inherited in an autosomal dominant manner and should be considered whenever both a parent and child suffer from kidney disease; the presence of even more affected family members provides further support. (2) These conditions are associated with a bland urinary sediment, ruling out glomerular disorders. (3) There is a variable rate of decline in kidney function. The mean age of ESRD is approximately 45, but the range is from 17 to >75. ADTKD-UMOD is often but not always associated with gout in the teenage years. ADKTKD-REN is associated with signs of hyporeninemia: mild hypotension, mild hyperkalemia, anemia in childhood, and hyperuricemia and gout in the teenage years. The only clinical manifestation of ADTKD-MUC1 is slowly progressive CKD. Diagnosis should be made by genetic testing, and kidney biopsy should be avoided.
Journal of the American Society of Nephrology : JASN, 2016
Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin... more Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encodingMucin-1(MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused byUMODmutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collec...
Journal of medical genetics, 2011
Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic... more Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.
Renal Tubular Acidosis in Children
American Journal of Nephrology, 1986
To delineate the spectrum of clinical expressions of distal, type 1 renal tubular acidosis in chi... more To delineate the spectrum of clinical expressions of distal, type 1 renal tubular acidosis in children and to update progress in diagnosis, therapy, and prognosis, the medical records of 14 girls and 10 boys, seen over a 7 year period, who met the following criteria, were examined: persistent urinary pH more than 6, net acid excretion less than 70 μEq/min/1.73
The Journal of biological chemistry, Jan 23, 2018
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated wit... more Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. -knockout ( ) mice excreted more urinary magnesium than wild-type (WT) and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical ...
Pediatric Medicine
While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertens... more While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertension is well known, the significance and contribution of low renin hypertension is often overlooked. RAAS stimulation results in more tubular absorption of sodium and water along the nephron, contributing to a higher circulating vascular volume. In addition, members of the RAAS system, such as angiotensin II, have direct effects on vascular vasoconstriction, the heart, aldosterone synthesis in the adrenal glands, the sympathetic nervous system, and the CNS. This has resulted in a line of antihypertensive therapeutics targeting RAAS with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors, which prevent conversion of angiotensinogen to angiotensin. While general practitioners and nephrologists are well aware of the causes and the long-term consequences of elevated renin and aldosterone levels, the opposite situation with low renin and/or low aldosterone levels is frequently underappreciated. The low renin and aldosterone levels may be indicators of inherited (especially when associated with hypokalemia), monogenic forms of hypertension stimulating excessive tubular sodium and water absorption which subsequently results in plasma volume expansion and hypertension. In this review article we will outline the different forms of hypertension characterized by low renin/low aldosterone and low renin/high aldosterone levels, how to diagnose these forms of hypertension, and how to treat them.
Uromodulin in mineral metabolism
Current Opinion in Nephrology and Hypertension
Scientific reports, Jan 8, 2018
Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubu... more Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study ...
Nature Genetics, Aug 1, 2003
Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most comm... more Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults 1. NPHP may be associated with Leber congenital amaurosis, tapetoretinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis 2-6. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped 7-10. NPHP1 and NPHP4 have been identified 11-13 , and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown 13. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype 14. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone 15-17 , suggesting therapeutic strategies for treating individuals with NPHP3.
Aniride - Molekulare Analyse des PAX6 - Gens und Versuch einer Genotyp - Phänotyp - Korrelation [microform] /
ABSTRACT
Hereditäre Nierenerkrankungen
Medizinische Therapie 2005|2006, 2005
Page 1. 927 11.6 Hereditäre Nierenerkrankungen 11 Gault MM, Barrett BJ (1998) Analgesic nephropat... more Page 1. 927 11.6 Hereditäre Nierenerkrankungen 11 Gault MM, Barrett BJ (1998) Analgesic nephropathy. In depth review. Am J Kidney Dis 32:351360 Markowitz GS, Radhakrsihnan J, Kambham N, Valeri AM, Hines WH, D ...
Nephronophthisis and related syndromes
Current opinion in pediatrics, 2015
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most co... more Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in children and adolescents. NPHP is a genetically heterogenous disorder with 20 identified genes. NPHP occurs as an isolated kidney disease, but approximately 15% of NPHP patients have additional extrarenal symptoms affecting other organs [e.g. eyes, liver, bones and central nervous system (CNS)]. The pleiotropy in NPHP is explained by the finding that almost all NPHP gene products share expression in primary cilia, a sensory organelle present in most mammalian cells. If extrarenal symptoms are present in addition to NPHP, these disorders are classified as NPHP-related ciliopathies (NPHP-RC). This review provides an update about recent advances in the field of NPHP-RC. The identification of novel disease-causing genes has improved our understanding of the pathomechanisms contributing to NPHP-RC. Multiple interactions between ...
The Journal of biological chemistry, Jan 26, 2014
The anti-aging protein Klotho is a type 1 membrane protein produced predominantly in the distal c... more The anti-aging protein Klotho is a type 1 membrane protein produced predominantly in the distal convoluted tubule. The ectodomain of Klotho is cleaved and secreted into the urine to regulate several ion channels and transporters. Secreted Klotho (sKL) up-regulates the TRPV5 calcium channel from the cell exterior by removing sialic acids from N-glycan of the channel and inhibiting its endocytosis. Because TRPV5 and Klotho coexpress in the distal convoluted tubule, we investigated whether Klotho regulates TRPV5 action from inside the cell. Whole-cell TRPV5-mediated channel activity was recorded in HEK cells coexpressing TRPV5 and sKL or membranous Klotho (mKL). Transfection of sKL, but not mKL, produced detectable Klotho protein in cell culture media. As for sKL, mKL increased TRPV5 current density. The role of sialidase activity of mKL acting inside is supported by findings that mutations of putative sialidase activity sites in sKL and mKL abrogated the regulation of TRPV5 but that t...
Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—A KDIGO consensus report
Kidney International, 2015
Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes enc... more Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.Kidney International advance online publication, 4…
Nature Genetics, 2003
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal fai... more Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.
Nephronophthisis
Pediatric Nephrology, 2011
Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene
Pediatric Nephrology, 2002
Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessiv... more Familial hypomagnesemia, hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive inherited disorder that has recently been attributed to a defect in the paracellin-1 ( PCLN-1)gene, encoding for a protein responsible for the tubular reabsorption of magnesium and calcium. Limited information is available on clinical course, therapy and prognosis. We provide information on five patients with FHHNC and their follow-up at our institution. Polyuria, nephrocalcinosis and hyperuricemia were the main clinical findings of a diagnosis at a median age of 4.4 years. The clinical course of PCLN-1 mutations as presented in this study is highly variable, ranging from compensated renal failure to end-stage renal failure - as happened in two of our patients. The progression to renal failure cannot be deduced from the initial presentation. Medical treatment does not appear to influence the progression of the disease. Despite calcium and magnesium substitution, normal values could not be achieved in these patients. Early treatment with vitamin D and calcium was essential to maintain growth. Adequate treatment allows for a normal height and pubertal development.
Pediatric Nephrology, 2009
Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD... more Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD). UMOD transcription is activated by the transcription factor HNF1B. Mutations in HNF1B cause a phenotype similar to FJHN/GCKD but also congenital anomalies of the kidney and the urinary tract (CAKUT). Moreover, we recently detected UMOD mutations in 2 patients with CAKUT. As HNF1B and UMOD act in the same pathway and cause similar phenotypes we here examined, whether UMOD mutations would be found in patients with CAKUT. Mutation analysis of UMOD was performed in 96 individuals with CAKUT by direct sequencing of exons 4 and 5 and by heteroduplex analysis following CEL I digestion assay of the exons 3 and 6-12. The mean age of patients was 11.4 years and in 36.4% of patients the family history was positive for CAKUT. In the CEL I assay 12 aberrant bands were detected in 103 of 960 PCR products and were sequenced. Two previously known and eight new SNPs were detected. As no UMOD mutations were identified in these 96 patients with CAKUT, UMOD mutations do not seem to be a significant cause of CAKUT in this cohort.
Nephrology Dialysis Transplantation, 2005
Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and envir... more Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and environmental interaction. The pathogenesis of nephrolithiasis is far from being understood. So far, no gene locus for autosomal dominant nephrolithiasis only has been described. We here identified a new suggestive gene locus for autosomal dominant nephrolithiasis by a genome-wide search for linkage in a Spanish kindred with nephrolithiasis. Methods. Clinical data, blood and urine samples of 18 individuals from a Spanish kindred with nephrolithiasis were collected. We performed a genome-wide search for linkage using 380 polymorphic microsatellite markers. Results. Nephrolithiasis segregated in this Spanish kindred in a pattern compatible with autosomal dominant inheritance. The total genome search yielded the highest two-point LOD score of Z max ¼ 1.99 (y ¼ 0) for marker D9S159 on chromosome 9q33.2-q34.2. Multipoint analysis of 24 polymorphic markers used for further fine mapping resulted in a LOD score of Z max ¼ 2.7 (y ¼ 0) for markers D9S1881-D9S164, thereby identifiying a new gene locus for autosomal dominant nephrolithiasis (NPL1). Two recombination events define D9S1850 as the centromeric flanking marker and D9S1818 as the telomeric flanking marker, restricting the NPL1 locus to a 14 Mb interval. Conclusion. We here identified a new suggestive gene locus (NPL1) for autosomal dominant nephrolithiasis. It is localized on chromosome 9q33.2-q34.2. The identification of the responsible gene will provide new insights into the molecular basis of nephrolithiasis.