A Case of Dent Disease in Children Presenting with Massive Proteinuria / 罕见病研究

This article reported the diagnosis and treatment of a boy with Dent disease presenting with massive proteinuria.He was 3 years old and found to have massive proteinuria during routine physical examination without hypoalbuminemia, urine protein electrophoresis indicated mainly low molecular weight proteins, with hypercalciuria, and metabolic acidosis, no diabetes, no amino acid urine, and renal ultrasound showed no renal calcium deposition, He had no mental and physical developmental delay and no abnormal family history. Gene detection revealed one missense mutation in exon 15 of the OCRL1 gene, c.1477C > T (p.Arg493Trp). After the diagnosis was confirmed, restrictions in dietary intake of calcium, sodium, and oxalate was restricted and oral potassium citrate and hydrochlorothiazide was prescribed. During two months of follow-up, we observed a decrease in urinary calcium levels and normal renal function. This article aims to improve the understanding of this disease among physicians and provide reference for the diagnosis and treatment of this disease through typical case report and review of previous literatures.

Proteinuria en la infancia: a propósito de un caso de enfermedad de Dent

Introducción: la proteinuria en la edad pediátrica es una entidad relativamente frecuente, la cual puede ser fisiológica o patológica. La segunda, por una alteración a nivel glomerular con pérdida de proteínas de gran tamaño o a nivel tubular, caracterizada por pérdida de proteínas de bajo peso molecular y alteraciones en la excreción de iones. Entre las enfermedades hereditarias que cursan con proteinuria tubular, se ha descrito la enfermedad de Dent, una patología ligada al cromosoma X. Esta enfermedad se manifiesta principalmente en varones, pero las mujeres pueden ser portadoras y tener manifestaciones clínicas leves de la enfermedad. La primera descripción de esta enfermedad fue hecha por Dent y Friedman en 1964. La mayoría de los casos recientemente reportados han sido en China y Alemania. Objetivo: realizar una revisión general de la enfermedad de Dent y del enfoque diagnóstico de la proteinuria en la infancia con base en nuestro caso, para así, sospechar de esta enfermedad. Descripción del caso: se presenta el caso de un paciente masculino sin antecedentes prenatales ni personales de importancia, quien presenta proteinuria persistente desde los primeros meses de vida y a quien, a los 7 años de edad, se le documenta la presencia de una variante ya conocida en el gen CLCN5, causante de la enfermedad de Dent tipo 1. Discusión: la proteinuria persistente patológica en la infancia debe ser estudiada debido a su posible relación con patologías que pueden afectar la función renal. Además de la diferenciación de la proteinuria persistente, de origen glomerular y tubular, la evaluación de alteraciones en la excreción de electrolitos, puede guiarnos hacia la realización de estudios genéticos y, por ende, al diagnóstico de patologías infrecuentes como la enfermedad de Dent. Conclusión: el enfoque diagnóstico de causas poco frecuentes de proteinuria tubular en la infancia, como la enfermedad de Dent, requiere de la valoración conjunta entre nefrología pediátrica y genética clínica.

Background: In pediatric patients, proteinuria is a relatively frequent entity that can be physiological or pathological. The second one, due to an alteration at the glomerular level with the loss of large proteins or at the tubular level, characterized mainly by the loss of low molecular weight proteins and changes in the excretion of ions. Among the hereditary diseases that present with tubular proteinuria, Dent disease is a disease linked to the X chromosome. Therefore, it manifests essentially in males, but women can be carriers and have minor clinical manifestations of the disease. Dent and Friedman made the first description of this disease in 1964. Recently, most of the cases have been reported in China and Germany. Objective: To perform a revision of Dent disease, as well as the diagnostic approach of childhood proteinuria based in our case in order to suspect this disease. Case description: This is the case of a masculine patient, without relevant prenatal and personal antecedents, the son of a father with polycystic renal disease, who presents persistent proteinuria from the first months of life, and who, at seven years old, the presence of a variant in the CLCN5 gene -causing of type 1 Dent disease- was documented. Discussion: The persistent pathological proteinuria in childhood must be studied due to its possible relation with pathologies that could affect renal function. Moreover, the differentiation among glomerular and tubular proteinuria can guide us to perform additional studies, including genetic tests to diagnose infrequent pathologies like Dent disease. Conclusion: The diagnostic approach to rare causes of tubular proteinuria in childhood, such as Dent's disease, requires joint assessment between pediatric nephrology and clinical genetics.

Una nueva mutación de la enfermedad de Dent en un niño de 11 años con nefrolitiasis y nefrocalcinosis / A novel mutation of Dent's disease in an 11-year-old male with nephrolithiasis and nephrocalcinosis

La enfermedad de Dent es una tubulopatía recesiva ligada al cromosoma X caracterizada por proteinuria de bajo peso molecular (bpm), hipercalciuria, nefrocalcinosis o nefrolitiasis, disfunción tubular proximal e insuficiencia renal en la adultez. Las mujeres son portadoras y, en general, padecen una forma leve de la enfermedad. La progresión hacia la insuficiencia renal en estadio terminal se da entre los 30 y los 50 años de edad en el 30-80% de los varones afectados. A falta de un tratamiento dirigido al defecto molecular, en la actualidad, los pacientes con enfermedad de Dent reciben tratamientos complementarios orientados a prevenir la nefrolitiasis y la nefrocalcinosis. El caso que presentamos es el de un niño de 11 años con nefrocalcinosis y nefrolitiasis, en quien se detectó una nueva mutación en el gen CLCN5.

Dent's disease is a rare X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrolcalcinosis or nephrolithiasis, proximal tubular dysfunction and renal failure in adulthood. Females are carriers and usually mildly affected. Progression to endstage renal failure are at the 3rd-5th decades of life in 30-80% of affected males. In the absence of therapy targeting for the molecular defect, the current care of patients with Dent's disease is supportive, focusing on the prevention of nephrolithiasis and nephrocalcinosis. We present an 11-year-old child with nephrocalcinosis and nephrolithiasis caused by a new mutation at CLCN5 gene.

Clinical features and genetic variants of Dent disease in 10 children / 中华儿科杂志

Objective@#To summarize the clinical features and genetic analysis results of 10 children with Dent disease.@*Methods@#The clinical data and gene test results of 10 boys aged from 8 months to 12 years with Dent disease diagnosed in Children's Hospital of Nanjing Medical University from January 2014 to July 2017 were analyzed retrospectively.@*Results@#All patients had insidious onset, 5 cases were found to have proteinuria on routine urine examination after hospitalization duo to other diseases, 4 cases were admitted to hospital because increased foams in the urine, and 1 case was found to have proteinuria on health checkup. All cases presented with low molecular weight proteinuria, urine protein electrophoresis showed that the proportion of low molecular weight protein was greater than 50%, 7 cases had nephrotic-range proteinuria, but none had hypoproteinemia. Six cases had hypercalciuria, 3 cases had nephrocalcinosis, 1 case had nephrolithiasis, 2 cases had glomerular microscopic hematuria, in 1 case urine glucose wa weakly positive but blood glucose was normal. All patients had normal renal function, normal serum calcium, no hypophosphoremia and none had rickets. Genetic analysis results showed that 7 patients with variants in the CLCN5 gene, including 2 nonsense variants (p.R637X, p.Y143X), 3 missense variants (p.A540D, p.G135E, p.G703V), 1 deletion variant (exons 9, 10, 11, 12, 13, 1 missing), and 1 frameshift variant (p.T260Tfs*10). Three cases had missense variants of OCRL gene (p.I274T, p.I371T, p.F399S). Except for p.R637X and p.I274T, the other 8 cases had newly discovered variants. Five patients underwent a renal biopsy, the biopsy revealed focal global glomerulosclerosis in 3 patients, mild mesangial proliferative glomerulonephritis in 1 patient and renal minimal change in 1 patient. Mild focal tubular atrophy and interstitial fibrosis were noted in three cases. Mild segmental foot process effacement was noted under electron microscope in all five cases.@*Conclusions@#All the children with Dent disease had insidious onset, low molecular weight proteinuria is the main clinical manifestation, most cases presented with nephrotic-range proteinuria, but there was no hypoalbuminemia, some cases were not associated with hypercalciuria. The pathogenic genes in most cases were CLCN5 and a few were OCRL. The types of genetic variation include missense variant, nonsense variant, deletion variant and frameshift variant. Although Dent disease is a renal tubular disease, renal biopsy suggests that most cases are associated with glomerular lesions.

Dent disease in childhood and associated clinical problems / 中华实用儿科临床杂志

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria (LMWP),hypercalciuria,nephrocalcinosis and/or nephrolithiasis,renal dysfunction and variable manifestations of other proximal tubule dysfunctions.The gene of Dent disease is now known that Dent disease Ⅰ is caused by mutations of the CLCN5 gene,coding for the ClC-5;and Dent disease Ⅱ by mutations of the OCRL gene,coding for the inositol polyphosphate 5-phosphatase OCRL-1.The pathological manifestations of Dent's kidney are often focal segmental sclerosis(FSGS),mesangial proliferative glomerulonephritis(MsPGN) and minimal change(MCD).Dent disease could progresses to chronic renal failure over 3 to 4 decades.As key point,the LMWP of Dent disease in childhood often express as nephrotic-range proteinuria with normal serum albumin,the differentiation with nephrotic syndrome in clinic.When a boy accompany with LMWP and hypercalciuria or nephrocalcinosis,he should be examined for CLCN5 and OCRL1 gene tests to avoid misdiagnosis and missed diagnosis of Dent disease.

Dent disease combined with renal failure:two case report and literature review / 临床儿科杂志

Objective To explore the etiology and prognosis of Dent disease combined with renal failure in children. Methods The clinical data of 2 children with Dent disease combined with renal failure from January 2014 to December 2016 were analyzed and the related literature was reviewed. Results Both of them were male, with the age of 8 and 10 years old respectively. Their renal functions were normal, and no renal calcification. Both of them had the history of upper respiratory tract virus infections within 1 week before the onset of renal failure. In case 1, acute phase (10 days) renal biopsy showed combined with acute tubulointerstitial nephritis, and his renal function recovered completely after glucocorticoids treatment. In case 2, renal biopsy at 6 months in course of disease showed the combined with subacute tubulointerstitial nephritis, and his renal function was improved partly after glucocorticoids treatment. Conclusions For children with Dent disease combined with acute renal failure, especially with upper respiratory tract virus infections and other inducement, renal biopsy should be early performed to exclude the possibility of acute tubulointerstitial nephritis, so that the treatment can be timely conducted and the prognosis can be improved.

Diagnosis and treatment of 6 cases of Dent’s disease / 临床儿科杂志

Objective To explore the diagnosis and treatment of Dent’s disease.MethodsThe clinical characteristics, treatment process and disease-causing gene mutation were retrospectively analyzed in 6 pediatric patients with Dent’s disease misdiagnosed of nephritic syndrome from January 2014 to August 2015.ResultsIn these 6 male patients aged 4.5-9.8 years old, the main clinical manifestations were nephropathy-level of proteinuria and transient low serum albumin (26-30 g/L) without obvious edema or high serum cholesterol. In 4 patients who had renal biopsy, 2 cases showed mesangial proliferative glomerulonephritis and other 2 cases showed focal segmental glomerulosclerosis. All of 6 patients were treated with at least one immunosuppressive agent after resistance to full dose of hormone and no changes in proteinuria were observed. After admission, the indexes of early renal damage and urinary protein electrophoresis pointed to low-molecular proteinuria. The ratio of alpha 1 micro albumin (α1-MG) / micro albumin (MA) (the early renal damage index) was?>?1, there was hypercalciuria, and renal function was normal. The B ultrasonography showed renal calciifcation in 2 patients. The ifndings in all the patients were in accord with the clinical diagnosis of Dent’s disease. Further genetic analysis conifrmed the presence ofCLCN5 gene mutation in these 6 patients.ConclusionAs a type of rare inherited renal tubular disorder, Dent’s disease is easily misdiagnosed, to which pediatricians need to pay attention. The early renal damage index, α1-MG/MA?>?1, can be regarded as one of the diagnostic criteria of renal tubular proteinuria.

Clinical efficacy of medicinal treatment in 15 children with Dent disease / 中华实用儿科临床杂志

Objective To investigate the drug effect of children with Dent disease who received therapy of po-tassium citrate and thiazide diuretics and angiotensin -converting enzyme inhibitors(ACEI),and to provide the refe-rence for the clinical treatment.Methods Dent disease patient who were followed -up in Bayi Children′s Hospital Af-filiated to Beijing Military Region General Hospital during the period of July 2006 and March 201 4 were selected.The patients were administered a therapy of potassium citrate associated with thiazide diuretics and ACEI according to the level of proteinuria and calciuria and serum potassium.The underlying changes before and after the treatment were com-pared and analyzed.Results In 1 5 children with Dent disease,they were all male cases,onset age ranged from 3 months to 1 1 years old[(2.62 ±3.1 1 )years old],and the disease duration ranged from 0.50 to 9.50 years old [(2.81 ±2.34)years].The patients were followed up for 0.50 to 7.50 years[(3.61 ±2.62)years].There was a sig-nificantly statistical difference in calcium/creatinine and daily Ca -creat ratio in contrast to before treatment[(0.41 ± 0.1 9)mg/mg vs(0.26 ±0.1 2)mg/mg,t =2.603,P =0.021 ;(6.76 ±2.0)mg/kg vs (4.34 ±1 .97)mg/kg,t =5.265,P =0.000],there was no significantly statistical difference in 24 -hour urinary protein quantity in contrast to before treatment[(0.96 ±0.62)g/24 h vs (0.87 ±0.44)g/24 h,t =1 .01 6,P =0.327].One case with kidney stone and 5 cases with nephrocalcinosis had a negative result of renal ultrasound after treatment.Conclusions Treatment of potassium citrate combination with thiazide diuretics and ACEI can significantly decrease urinary calcium excretion, make a disappearance of kidney stone and nephrocalcinosi,and it may have a role in protecting renal function.Treat-ment of benazepril can not significantly decrease the proteinuria and has no substantial improvement in low molecular weight protein urine.

Chloride channels and kidney diseases / 临床儿科杂志

Chloride ion is an important anion in organisms, managing various physiological events. A particular gene mu-tation leads to involved channel deifciency and to develop channelopathy. In kidney, different chloride channels distribute along certain fractions of the renal tubule, located at apical and basolateral membranes of tubular epithelial cells. Previous studies dis-covered that voltage-sensitive chloride channels in kidney are associated with Bartter syndrome and Dent’s disease. In addition, the kidney can be involved by cystic ifbrosis resulting from dysfunction of cystic ifbrosis transmembrane conductance regulator. In this review, the function and mechanism of chloride channels in maintenance of normal renal function, and the renal diseases caused by related gene defects were discussed.

Progress of the renal chloride channel CLC-5 and Dent disease / 国际儿科学杂志

Chloride channel CLC-5 is a voltage-dependent gated channel.The voltage-gated characteristic of CLC-5 is not only regulated by glutamate E211 and E268,but also by lysine K210.In proximal renal tubule,CLC-5 can interact with megalin protein,and adjust the reabsorption of albumin together.CLC-5 can also affect the activities of the sodium hydrogen exchanger isoform 3 in proximal renal tubule.CLCN5 gene mutations can lead to Dent disease,and recent studies have found some new pathogenic mutants of CLC-5,VS05G,L266V and G446A,and so on.CLCN5 can also mutate together with ORCL1,and then result in Dent disease.However,the regulatory mechanism of the voltage-gated channel,physiological functions and molecular mechanism,and Dent disease are still not entirely clear.In this paper,we will review these problems of CLC-5.

Origin of Proteinuria as Observed from Qualitative and Quantitative Analysis of Serum and Urinary Proteins

It is well known that proteins present in the primary urine are reabsorbed in the renal proximal tubules, and that this reabsorption is mediated via the megalincubilin complex and the neonatal Fcgamma receptor. However, the reabsorption is also thought to be influenced by an electrostatic interaction between protein molecules and the microvilli of the renal proximal tubules. By analyzing the charge diversity of urinary IgG, we showed that this reabsorption process occurs in a cationic charge-preferential manner. The charge-selective molecular sieving function of the glomerular capillary walls has long been a target of research since Brenner et al. demonstrated the existence of this function by a differential clearance study by using the anionic dextran sulfate polymer. However, conclusive evidence was not obtained when the study was performed using differential clearance of serum proteins. We noted that immunoglobulin (Ig) A and IgG have similar molecular sizes but distinct molecular isoelectric points. Therefore, we studied the differential clearance of these serum proteins (clearance IgA/ clearance IgG) in podocyte diseases and glomerulonephritis. In addition, we studied this differential clearance in patients with Dent disease rather than in normal subjects because the glomerular sieving function is considered to be normal in subjects with Dent disease. Our results clearly showed that the charge-selective barrier is operational in Dent disease, impaired in podocyte disease, and lacking in glomerulonephritis.

Uso a longo prazo de enalapril e hidroclorotiazida em dois pacientes com novas mutações com doença de Dent tipo 1 / The long-term use of enalapril and hydrochlorothiazide in two novel mutations patients with Dent's disease type 1

A doença de Dent é uma tubulopatia ligada ao X causada por mutações no gene que codifica o canal de cloro CLCN-5 e é caracterizada por proteinúria de baixo peso molecular, hipercalciúria, nefrocalcinose e insuficiência renal. Vários casos têm sido descritos, nos quais o único sintoma na apresentação foi proteinúria assintomática e glomerulosclerose global ou segmentar. A insuficiência renal nesses pacientes pode ser causada pela hipercalciúria e proteinúria persistente. Portanto, o inibidor da enzima de conversão da angiotensina e os tiazídicos poderiam ser úteis. O objetivo desta pesquisa é relatar os efeitos destas drogas em dois pacientes com doença de Dent tipo 1 com mutações novas. Neste relato não foram observadas correlações significativas entre dose de hidroclorotiazida e calciúria e entre enalapril e proteinúria. Este achado é importante, pois, sendo pacientes poliúricos, o uso destas drogas poderia prejudicar a função renal.

Dent's disease type 1 is an X-linked tubular disease caused by mutations in the renal chloride channel CLCN-5, and it is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal failure. Several cases have been described in which the only presenting symptoms were asymptomatic proteinuria, and focal segmental or global glomerulosclerosis. The renal failure in these patients may be caused by hypercalciuria and persistent proteinuria. Therefore, angiotensin converse enzyme inhibitor and thiazides could be useful. Our aim is to report the effects of these drugs in two novel mutations patients with Dent's disease type 1. In this report, no significant correlations between dosage of hydrochlorothiazide and calciuria and no significant correlations between proteinuria and dosage of enalapril were detected. This is important since these are polyuric patients and these drugs could be dangerous to their renal function.

Progress of renal voltage-gated chloride channel / 国际儿科学杂志

Voltage-gated chloride channel (ClC) is a class of very important chloride ion channels in vivo,participating in the chloride ion transporter,cell volume regulation,cell control acidification and many pathological physiological process.The studies have found that ClC-K was related to dent disease,and ClC-5 was associated with bartter syndrome.This article mainly reviews ClC-type chloride ion channel classification,structure,regulation and distribution in the kidney,and summarizes the related diseases.

Progress on Dent's disease / 国际儿科学杂志

There are many causes of proteinuria in children.Because proteinuria is mainly caused by glomerular diseases,renal tubulopathies are often ignored.Dent's disease is an hereditary renal tubulopathy characterized by low-molecular-weigh proteinuria,hypercalciuria,nephrocalcinosis,nephrolithiasis,and progressive renal failure.Dent's disease is mainly caused by mutations in CLCN5 and OCRL1 genes.Current treatments of the disease are still mainly symptomatic and supportive therapy,including reducing urinary calcium excretion,lightening nephrocalcinosis,and delaying the occurrence of renal insufficiency.

Proteinuria in a Boy with Infectious Mononucleosis, C1q Nephropathy, and Dent's Disease

C1q nephropathy is a proliferative glomerulopathy with extensive mesangial deposition of C1q. A three-year old boy presented with a nephrotic-range proteinuria during an acute phase of Epstein-Barr virus (EBV) infection, and he had a family history of Dent's disease. The renal biopsy findings were compatible with C1q nephropathy. However, EBV in situ hybridization was negative. The CLCN5 gene analysis revealed an R637X hemizygous mutation, which was the same as that detected in his maternal cousin, the proband of the family. The causal relationship between EBV infection and C1q nephropathy remains to be determined. Moreover, the effects of underlying Dent's disease in the process of C1q nephropathy has to be considered.