Abstract
Background and Aims
Hepatocyte nuclear factor 1 gene (HNF1B) encodes for HNF-1ß, a transcription factor that is expressed early in embryonic development and plays a key role for ...tissue-specific regulations of gene expression in various organs such as the kidneys, urogenital tract, liver, biliary ducts and pancreas. HNF1B disease (MIM 137920) is recognized to represent an autosomal dominant syndromal disorder comprising variable phenotype with renal and extrarenal manifestations. Renal phenotype in HNF1B nephropathy is highly heterogeneous. The aim of the study was to evaluate the clinical characteristics of renal involvement in children with genetically proven HNF1B nephropathy.
Method
Five children (2M/3F) from unrelated families with heterozygous HNF1β mutations and kidney disorders were examined. We evaluated serum levels of electrolytes, magnesium (Mg), phosphorus (P), uric acid, acid-base composition; urinary excretion of Ca, P, creatinine (Cr); fractional excretion (FE) of Mg, urate (Ur), Na, K; tubular maximum phosphate reabsorption per GFR (TmP/GFR), and urinary β-2 microglobulin. Molecular genetic analysis was performed using by next generation sequencing.
Results
Cortical or medullary bilateral renal cysts were detected in all five children with HNF1B nephropathy. Kidney hypoplasia, medullary nephrocalcinosis, and low-grade proteinuria (<0.5 g/m2/d) revealed in 2\5 (40%) of cases. One child had vesicoureteral reflux. All patients with HNF1B nephropathy had normal serum level of uric acid and all electrolytes, including Mg. Increased FE of Mg and urinary excretion of β-2 microglobulin was found in all cases. Increased FE of Ur, Na and K revealed in 4\5 (80%) of subjects. Decreased TmP/GFR had 3\5 (60%) of cases. At the first examination of patients aged 1.0 (IQR: 1.0; 2.0) years all of them already had decreased eGFR to CKD stage 2-3.
Conclusion
The present study demonstrates that patients with HNF1B-associated disease had wide spectrum of renal involvement. The most prevalent features of HNF1B nephropathy in our children were bilateral renal cysts, defects of proximal tubular function with wasting of electrolytes and progression to CKD stage 2-3 at early age.
Cystinosis is an autosomal recessive lysosomal storage disorder characterized by accumulation of cystine in lysosomes throughout the body. Cystinosis is caused by mutations in the CTNS gene that ...encodes the lysosomal cystine carrier protein cystinosin. CTNS mutations result in either complete absence or reduced cystine transporting function of the protein. The diagnosis of nephropathic cystinosis is generally based on measuring leukocyte cystine level, demonstration of corneal cystine crystals by the slit lamp examination and confirmed by genetic analysis of the CTNS gene.
A boy born to consanguineous Caucasian parents had the characteristic clinical features of the infantile nephropathic cystinosis including renal Fanconi syndrome (polydipsia/polyuria, metabolic acidosis, hypokalemia, hypophosphatemia, low molecular weight proteinuria, glycosuria, cystine crystals in the cornea) and elevated WBC cystine levels. Initially we performed RFLP analysis of the common in the Northern European population 57-kb deletion of proband's DNA, then a direct Sanger sequencing which revealed no mutations in the coding part of the CTNS gene. To confirm the diagnosis we performed RT-PCR analysis of total RNA obtained from patient-derived fibroblasts in combination with cDNA sequencing. This revealed the skipping of exon 4 and exon 5 in the CTNS in our patient. Therefore, we detected a novel 9-kb homozygous deletion in the CTNS gene at genomic DNA level, spanning region from intron 3 to intron 5. In order to identify the inheritance pattern of the deletion we analyzed DNA of proband's mother and father. Both parents were found to be heterozygous carriers of the CTNS mutation.
Analysis of CTNS gene transcript allowed to identify a large homozygous deletion in the patient with infantile nephropathic cystinosis. Mutational detection at RNA level may be an efficient tool to establish the genetic defect in some cystinosis patients.
Abstract
Background and Aims
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH; MIM #241530) is an autosomal recessive renal phosphate-wasting disorder caused by mutations in the ...SLC34A3/NPT2c gene. HHRH characterized by increased urinary phosphate excretion leading to hypophosphatemic rickets, short stature and elevated serum 1,25(OH)2D levels which result in hypercalciuria leads to nephrocalcinosis/urolithiasis due to enhanced intestinal calcium absorption and reduced PTH-dependent calcium reabsorption in the distal renal tubules.
Treatment of HHRH involves administration of oral phosphate supplements alone to normalize of serum phosphate, alkaline phosphatase activity (ALP), PTH levels, urine calcium excretion for prevention of renal calcifications and progression of rickets. Currently there is no consensus on the optimal dose of oral phosphate in patients with HHRH. The aim of the study was to evaluate the efficacy of oral phosphate supplements in Russian cohort of children with HHRH.
Method
9 children (7M/2F) with homozygous (n=6) and compound heterozygous (n=3) SLC34A3 mutations from unrelated families were examined. Treatment with oral phosphate supplements was started at the median age of patients 12.0 (IQR: 9.0; 13.0) years. The median dosage of oral phosphate supplements was 14.1 (IQR: 13.8; 14.8) mg/kg/day based on elemental phosphorus. The duration of follow-up was 36.0 (IQR: 16; 49) months. Blood electrolytes levels, ALP, PTH and 24-hour-urine excretion of calcium were evaluated in all children. ALP Z-scores were calculated using age- and sex-specific mean/standard deviation (SD) lab reference data. Bone mineral density with Z-score were measured in lumbar spine and whole body for all patients using a dual energy X-ray absorptiometry device. Molecular genetic analysis was performed in all children using by next generation sequencing.
Results
The median SD score of height at the first and last follow-up was -1.35 (IQR: -1.8; -0.87) and -1.51 (IQR: -2.0; -0.66) (p=0.6), respectively, short stature had 33.3% (3/9) of patients at first and 44.4% (4/9) at last follow-up (p=0.7). Treatment with low doses of oral phosphate supplements did not led to normalization of serum phosphorus:1.05 (IQR: 0.97; 1.39) vs. 0.93 (IQR: 0.81; 1.27) mmol/l (p=0.13), PTH: 8.3 (IQR: 5.8; 13.8) vs. 12.9 (IQR: 12.0; 16.0) pg/ml (p=0.34), Z-score in lumbar spine: -1.2 (IQR: -2.7; -0.1) vs. -1.8 (IQR: -2.8; -1.1) (p=0.48) and Z-score in total body: -2.1 (IQR -2.6; -1.5) vs. -2.4 (IQR: -3.0; -2.0) (p=0.37). Hypercalciuria had 88.8% (8/9) of children (0.15 (IQR: 0.12; 0.19) mmol/kg/day) at first follow-up and 44.4% (4/9) (0.09 (IQR: 0.08; 0.16) mmol/kg/day) in last examination (p=0.13). ALP blood levels were elevated in all patients (9/9) at first and most recent visit, but ALP Z-score were significant lower at last follow-up: 3.9 (IQR: 1.2; 5.1) vs. 0.57 (IQR: -0.36; 2.1) (p=0.04). There were significant correlations between doses of oral phosphate supplements and ALP Z-score (r=-0.68; p=0.04) and total body Z-score (r=0.78; p=0.03). There was no significant correlations between ALP Z-score and total body Z-score (r=-0.3) or lumbar spine Z-score (r=-0.1).
Conclusion
The present study demonstrated that treatment of HHRH with low doses (<20 mg/kg/day) of oral phosphorus supplements led to decreasing of ALP Z-score in 7/9 (77.8%) and hypercalciuria in 5/9 (55.6%) of patients. However, that therapy didn’t improve significantly height and severity of rickets, as well didn’t led to normalization of serum phosphorus in children with HHRH. It is therefore conceivable that higher daily doses of phosphate supplements are needed to normalize all clinical and radiological features of disease.
Lack of association between ALP Z-score and bone mineral density severity on radiographs limits the value of serum ALP as the indicator of rickets activity.
Abstract
Background and Aims
Monogenic causes of steroid-resistant nephrotic syndrome (SRNS) have been reported for up to one-third of children depending on age of the disease onset. ...Immunosuppressive treatment of genetic SRNS with calcineurin inhibitors (CNIs) is still controversial. The aim of the study was to investigate the efficacy of CNIs with focus on inducing remission and long-term kidney function in children with monogenic SRNS.
Method
Retrospective analysis of efficacy CNIs in five children (2M/3F) with monogenic SRNS was performed. Kidney biopsy prior CNIs revealed FSGS (n=4) and MCD (n=1). The initial cyclosporine (CsA) dose was 5 mg/kg/24h to keep a target level of 80-150 ng/ml and tacrolimus (TAC) - 0.1 mg/kg/24h to achieve a target level of 5-10 ng/ml. CsA took all 5 patients with subsequent switching to TAC in 2 children due to cosmetic side effects. The median follow-up period was 165.0 (IQR: 59.0; 185.5) months. Next generation sequencing (NGS) was used for identification of pathogenic variants in all patients.
Results
The median age at onset of monogenic SRNS was 33.0 (IQR: 16.5; 63.0) months. 2/5 (40%) patients presented with acute SRNS, 1/5 (20%) child with infantile NS, 1/5 (20%) - with isolated nephrotic range proteinuria with hypoalbuminemia and 1/5 (20%) - with NS and extrarenal features of Nail-Patella syndrome. NGS identified previously described pathogenic variants in all 5 children, including NPHS2 homozygous c.28dup (p.Glu87Ter) (n=1), NPHS2 compound heterozygous c.868G>A (p.Val290Met) in combination with c.686G>A (p.Arg229Gln) (n=1), LMX1B heterozygous c.788T>G (p.Val263Gly) (n=1), LMX1B heterozygous c.737G>A (p.Arg246Gln) (n=1), and COL4A3 heterozygous c.2962G>A (p.Gly988Arg) variant (n=1). The median time from diagnosis to initiation of CNIs treatment was 72.0 (IQR: 33.0; 93.0) months. CNIs induced complete remission in 2/5 (40%) patients, presented with acute SRNS, including one girl with MCD due to NPHS2 compound heterozygous variants with mutation-dependent pathogenicity of one (p.R229Q) of them and one boy with FSGS due to COL4A3 heterozygous variant (n=1). Partial remission was induced by CNIs in 2/5 (40%) girls with FSGS due to LMX1B heterozygous variants with isolated SRNS (n=1) and Nail-Patella syndrome (n=1). The median duration of CNIs treatment to obtain complete or partial remission was 13.5 (IQR: 6.8; 15.8) months. Acute CNIs-associated nephrotoxicity had 2 patients with LMX1B variants. At the last follow up full and partial responders to CNIs treatment aged of 16.5 (IQR: 11.8; 17.5) years had CKD-1 (n=3) and CKD-2 (n=1). 1/5 (20%) boy with NPHS2-associated infantile NS was CNI resistant and developed CKD-5 at the age of 6.5 years with subsequent living related kidney transplantation.
Conclusion
We found that 4/5 (80%) children with monogenic SRNS demonstrated partial or full response to CNIs treatment with stable long-term kidney function. We assume that CNIs might improve podocyte function by stabilization of their cytoskeleton disrupted in patients with monogenic SRNS.
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