Rare Genetic Kidney Diseases: Windows of Precision Nephrology / 罕见病研究

As an important category of rare diseases, rare genetic kidney diseases have many types. In recent years, their diagnosis, treatment, research and management strategies have made great progress. Continuously more new genes and mechanisms have been discovered, giving rise to new technologies and drugs for precision medicine and clinical applications. This article systematically analyzes rare diseases involving the urinary system listed in the catalog of rare diseases in China, gives examples to illustrate the research and management methods for the diagnosis and treatment of rare genetic kidney diseases, promotes clinical applications of new drugs by expanding physiological mechanisms, introduces the application of special blood purification in the field of critical rare diseases, and provides an outlook forward to the future prospects of precise diagnosis and treatment of rare kidney diseases in China.

Alterações urinárias em cães com diabetes mellitus / Urinary alterations in dogs with diabetes mellitus / Alteraciones urinarias en perros con diabetes mellitus

A diabetes mellitus (DM) é uma doença comum na rotina veterinária, de caráter multifatorial, gerando graves consequências na saúde dos pacientes acometidos. O diagnóstico é possível por meio de manifestações clínicas apresentadas e da realização de exames laboratoriais complementares. Entre esses exames, estão a dosagem da glicose sérica e a urinálise, as quais trazem ao clínico diversas informações, que podem ser correlacionadas aos demais achados, tornando possível o diagnóstico conclusivo de DM. Dessa forma, o presente trabalho teve como objetivo avaliar as alterações urinárias e de glicemia em cães com DM. Para isto, foram analisados laudos de amostras urinárias e de glicose sérica de 15 animais, onde o diagnóstico foi conclusivo para DM. Verificou-se presença de glicosúria em 100% dos casos, sendo observado em 66,67% das amostras glicosúria maior que 1000 mg/dL e, em 33,33% amostras, de 500 mg/dL; a cetonúria esteve presente em 66,67 %; proteinúria em 66,67% e bacteriúria presente em 73,33 dos dados analisados. Já a hiperglicemia foi constatada em 13 pacientes (86,67%). Assim, conclui-se que a urinálise é um exame de suma importância para o estabelecimento do diagnóstico, da melhor terapêutica para cada caso e do prognóstico dos pacientes.(AU)

Diabetes mellitus (DM) is a common disease on the veterinary routine. It has a multifactorial character generating severe consequences on the health of the patient. It can be diagnosed by clinical manifestations and by making additional laboratory tests. These tests include the measurement of serum glucose and urinalysis, which provides the physician with additional information to be correlated with other findings, in order to reach a conclusive diagnosis of DM. Therefore, this study aimed at evaluating urinary and glycemic alterations in dogs with DM. It analyzed reports of urine and serum glucose samples from 15 animals with a conclusive diagnosis for DM. Glycosuria was present in 100% of the cases. In addition, it was also observed that in 66.67% of the samples, glycosuria was higher than 1000 mg/dL, and in 33.33%, it was 500 mg/dL. Ketonuria was present in 66.67% of the samples, while proteinuria was observed in 66.67%. Bacteriuria was present in 73.33% of the samples on the analyzed data. Hyperglycemia was observed in 13 of these patients (86.67%), and thus, it can be concluded that urinalysis is an extremely important test for diagnosis, to choose the best therapy for each case and prognosis of the patients.(AU)

Diabetes mellitus (DM) es una enfermedad común en la rutina veterinaria, con un carácter multifactorial, que genera graves consecuencias en la salud de los pacientes afectados. El diagnóstico es posible a través de las manifestaciones clínicas presentadas y mediante realización de pruebas de laboratorio complementarias. Entre esas pruebas, están la medición de la glucosa en suero y el análisis de orina, que brindan al médico informaciones diversas que pueden ser correlacionadas a otros hallazgos, lo que permite hacer un diagnóstico concluyente de DM. Por lo tanto, el presente estudio tuvo como objetivo evaluar las alteraciones urinarias y glucémicas en perros con DM. Para esto, se analizaron informes de muestras de glucosa en suero y orina de 15 animales, donde el diagnóstico fue concluyente para DM. La glucosuria estuvo presente en el 100% de los casos, observándose en el 66,67% de las muestras glucosuria mayor de 1000 mg / dL y, en el 33,33% de las muestras, de 500 mg / dL; la cetonuria estuvo presente en 66.67%; proteinuria en 66.67% y bacteriuria presente en 73.33 de los datos analizados. Se observó hiperglucemia en 13 de esos pacientes (86,67%). Por lo tanto, se concluye que el análisis de orina es una prueba extremadamente importante para establecer el diagnóstico, el mejor tratamiento para cada caso y el pronóstico de los pacientes.(AU)

Mutation analysis of SLC5A2 gene and determination of the renal threshold for glucose excretion in Chinese patients with familial renal glucosuria / 中华肾脏病杂志

Objective To analyze and identify the mutations in SGLT2 gene of nine Chinese families with FRG, and determine the renal threshold for glucose excretion (RTG), so as to explore the association of genotype and RTG. Methods All coding regions of SGLT2 gene, including intron exon boundaries, were analyzed using PCR followed by direct sequence analysis. Quantitative test for 24?hour urine glucose and RTG were measured among 9 probands (21 patients) and their family members from 9 pedigrees (total 25 subjects). The differences in renal glucose thresholds between patients with different genotypes (heterozygotes and compound heterozygotes; c.886(-10_-31) del heterozygotes and other heterozygotes) were compared. Results Twelve mutations were identified by SGLT2 gene analysis, including 10 novel ones that were not included in HGMD:c.331T>C, p.W111R;c.374T>C, p.M125T; c.394C>T, p.R132C; c.612G>C, p.Q204H; c.829C>T, p.P277S; c.880G>A, p.D294N;c.1129G>A, p.G377S; c.1194C>A, p.F398L; c.1540C>T, p.P514S; c.1573C>T, p.H525Y. In thisstudy, the mutation c.886(-10_-31)del that is specific to Chinese population accounted for about 28％of the total alleles (5/18). The RTG values of patients with compound heterozygous mutations were much lower than those with simple heterozygous mutations [(1.28 ±0.10) vs (5.14±0.77) mmol/L; P<0.001];and c.886(-10_-31)del heterozygotes had significant lower RTG values than others [(4.43 ± 0.37) vs (5.70 ± 0.51) mmol/L, P<0.001]. Conclusions Ten novel mutations which may be related to FRG are found in this study, and c.886(-10-31)del may be a hot?spot mutation in Chinese patients. Compound heterozygotes had much lower RTG values than simple heterozygotes.

Urinary Glucose Screening for Early Detection of Asymptomatic Type 2 Diabetes in Jeonbuk Province Korean Schoolchildren

This study aimed to investigate the prevalence of glucosuria and the characteristics of diabetes in schoolchildren as detected by a school urine glucose screening program implemented from 2010 to 2013 in the Jeonbuk province area of Korea. A total of 110 children without known diabetes were analyzed. They were checked with an oral glucose tolerance test (OGTT) with other laboratory tests and their clinical data were collected. A total of 707,238 schoolchildren from a school population of 1,064,999 were screened for glucosuria. In total, over a 4-year period, 545 schoolchildren (0.077%) were positive for glucosuria on the second urine test. The prevalence of glucosuria was more common among middle and high schoolchildren than among elementary schoolchildren. Among 110 students who completed the OGTT to confirm diabetes, 40 were diagnosed with diabetes mellitus (DM); 39 children, type 2 diabetes mellitus (T2DM) and 1 child, slowly progressive insulin dependent diabetes mellitus (SPIDDM). The mean annual incidence of diabetes was 5.6 per 100,000 schoolchildren and adolescents. The subjects with diabetes diagnosed through the urine screening test showed minimal or no symptoms of diabetes. The students with diabetes were more likely to be woman and obese, and they have a higher body mass index, higher cholesterol, triglyceride, insulin, C-peptide, and fasting glucosuria values than the students with normal glucose tolerance. We identified 40 new cases of diabetes in the Korean schoolchildren with asymptomatic glucosuria on urine glucose screening. This finding shows that school urine glucose screening is a feasible and simple method for early detection of asymptomatic T2DM.

The clinical manifestation and gene mutation of primary renal glucosuria in a child / 临床儿科杂志

Objective To explore the clinical manifestation and gene mutation of primary renal glucosuria (PRG). Methods The clinical data and gene detection results of a child with PRG were analyzed. Results A girl aged 2 years and 10 mouths had glucose ++++ by urine dipstick analysis and 22.4 g of the 24 h urine glucose. Her father was urine glucose positive. Genome DNA was extracted from peripheral blood of the girl and her parents, SLC5A2 gene were amplified by PCR for sequencing, including exons and splicing areas. The results showed a homozygous point mutation (c.127-16C>A) in girl, and both of her patents had the same heterozygous mutation. This mutation had been classified to pathogenic mutations by ClinVar data base. Conclusions The diagnosis of PRG is confirmed in this child and SLC5A2 gene mutation is the cause.

Analysis on the mutation of SLC5A2 gene in Chinese patients with familial renal glucosuria and investigation on the association of genotype and phenotype / 中华肾脏病杂志

Objective To describe and analyze the clinical characters of patients with FRG from 7 Chinese families.Then analyze and identify their mutations in SGLT2 gene,and explore the association of genotype and phenotype.Methods Quantitative test for 24-hour urine glucose and other laboratory tests were carried out among 7 probands (14 patients in all) and their family members from 7 pedigrees (totaling 23 subjects).All coding regions,including intron-exon boundaries,were analyzed using PCR followed by direct sequence analysis.Results Five novel mutations in SLC5A2 gene were identified in this investigation,including four missense mutations (A Serine to Glycine at position 335 (c.1003A＞G,p.S335G),a Glutamine to Arginine at position 448 (c.1343A ＞ G,p.Q448R),an alanine to proline at position 474 (p.A474P,c.1420G ＞ C) and a glycine to aspartic acid at position 580 (c.1739G ＞ A,p.G580D) and a deletion in intron 7 (c.886(-10_-31)del).By the minigene studies using the pSPL3 plasmids,we confirmed the deletion c.886(-10_-31)del as a splicing mutation.In this study,the mutation c.886(-10_-31)del accounted for about 43％ of the total alleles (12/28).These patients with compound heterozygous or homozygous mutations manifested middle degree or severe glycosuria (Quantitative test for 24-hour urine glucose:10.56-50.68 g/1.73 m2),however those with heterozygous variants presented with mild to moderate glycosuria (Quantitative test for 24-hour urine glucose ≤ 2.45 g/1.73 m2).This fits co-dominant inheritance pattern.Conclusions Five novel mutations which may be related to FRG are found in this study,and c.886(-10-31) del may be a high frequency mutation in Chinese patients.

A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.

Establishment of Na+-glucose cotransporter 2 heterologous expression system in HEK293 cells / 中华肾脏病杂志

Objective To establish heterologous expression system of Na+-glucose cotransporter 2 (SGLT2) gene.Methods Human SGLT2 cDNA from normal kidney, generated by RT-PCR,was subclonedintoPEXL-GFP vector andtransfectedinto HEK293cells. After 24hours of incubation, the expression of SGLT2-GFP fusion protein was detected by Western blotting and laser confocal microscopy.Transport activity of SGLT2-GFP fusion proteins in cultured human HEK293 cells was evaluated with the uptake test of glucose analogue.ResultsSGLT2-GFP fusion protein was expressed in cultured human HEK293 cells.Furthermore, confocal microscopy using green fluorescent protein(GFP) revealed a punctate membrane pattern of SGLT2.Glucose analogue uptake increased in HEK293 cells transfected with SGLT2-GFP at least by 3.5 folds compared with HEK293 cells transfected with GFP vector only(P＜0.01).Conclusion Heterologous expression of SGLT2 gene in HEK293 cells is successfully established, which provides valuable approach for the functional and pathological study of SGLT2 gene.

Diabetes survey among children

3238 school children with ages ranging from 7 to 13 years were screened for post-prandial glucosuria using the glucose oxidase method (TESTAPE). None of them were found to have a positive urine sugar test. To show a clearer picture of the status of diabetes mellitus among our children, more extensive surveys using both urine sugar and blood sugar testings must be done

Prevalence of asymptomatic hematuria, proteinemia and glucosuria in primary school children in Chonju area

No abstract available.