Clinical Analysis And Literature Review Of Hereditary Nephrogenic Diabetes Insipidus

ObjectiveBy analyzing the clinical features of the patients with Hereditary Nephrogenic Diabetes Insipidus(HNDI)and reviewing the relevant literature,this paper summarizes the experience of diagnosis,treatment and follow-up,with which to improve the clinicians’ s understanding of this disease as well as to reduce missed diagnosis or misdiagnosis.At the same time,this study evaluate the efficacy and safety of drug therapy for patients with HNDI in what way to improve the quality of life and clinical prognosis of patients and provide help for genetic counseling and prenatal diagnosis.Methods 1.Clinical data,laboratory data of proband and their families who meet the inclusion criteria were collected as well as the result of genetic test of who agreed to get the test.2.Patients who meet the inclusion criteria were given oral hydrochlorothiazide or add the indomethacin with informed consent of the patients and their family members.3.The patients were followed up to measure their height and weight,urine volume,drinking water volume,electrolyte and urine routine and other indicators to evaluate the efficacy of drug treatment and side effect.4.The data were analyzed by Excel and SPSS25.0software,counting data was used for cases and percentages,measurement data was used for average±standard.T test was used for the comparison between means,Chi-square test was used to compare between groups,and simple linear correlation was expressed by Pearson correlation coefficient.The difference was statistically significant with P value<0.05.5.With the consult of Wanfang,CNKI,VIP,Pub Med database,collected the related literature of HNDI for review,so as to analyze and summarize the clinical characteristics of misdiagnosis and treatment experience of this disease.Results1.A total of 8 HNDI patients were enrolled and all of them were male(100%),the first reason to see a doctor included(occur separated/combined):repeated fever with 7 patients(87.5%),growth retardation with 5 patients(62.5%),polydipsia and polyuria with 4 patients(50%),and repeated electrolyte disturbance with 2 patients(25%).2.Among the 8 HNDI patients,the first diagnosis included: fever of unknown origin for 3 patients(37.5%),hephrogenic diabetes insipidus for 2patients(25%),nutritional disease for 2 patients(25%),and repeated electrolyte disturbance for 1 patients(12.5%).3.Polydipsia,polyuria,thirst and permanent low specific density urine can be seen in all of these 8 HNDI patients,with whose parents’ volume of urine and water intake were all in the normal range and no consanguineous marriage were found.4.Among the 8 HNDI patients,the middle age of first time to see a doctor was 24.5 months,middle height was 74.5cm,middle weight was7.65 kg,middle volume of urine was 2625 ml/d,middle volume of water intake was 3025 ml/d.Growth retardation was found in all patients before the treatment to varying degrees,in which 5 patients’ height and weight were both lower than-2SD(standard deviation)compared to the normal children,4patients who get the bone age test were all found a developmental retardation,and 2 patients found abnormal kidney(Pyelic separation,hydronephrosis).5.Among the 8 HNDI patients,7 patients get a test of water deprivation-vasopressin test and all of them showed a result that the urine osmotic pressure had no significant change before and after the test,1 patient get a simple test of water deprivation as well as a empiric therapy due to his age and the result showed a significant change before and after the test.6.Among the 8 HNDI patients,patient 3 did not get the genetic test due to the economic reason,patient 1 can not definite his gene mutation type,patient 2 and 5 and 7 were caused by the mutation of AQP2(Aquaporin 2),patient 4 and 6 and 7 were caused by the mutation of AVPR2(Arginine vasopressin receptor type 2).7.Among the 7 patients who get the genetic test,patient 1 used the AVPR2 single genetic testing technology,patient 2 and 4 and 6 used the hereditary nephropathy panel testing technology,patient 5 used the genetic metabolic disease panel testing technology,and patient 7 and 8used the whole exome sequencing panel testing technology.8.Among the 6 patients who get the positive genetic test,patient 2found a homozygosis mutation in AQP2 gene with c.427 del G(p.Leu143 Serfs Ter22),patient 5 and 7 found a homozygosis mutation in AQP2 gene with c.3G>T(p.Met1Ile),patient 4 found a hemizygote mutation in AVPR2 gene with c.541C>T(p.R181C),patient 6 found a hemizygote mutation in AVPR2 gene with c.733 del G(p.Arg247 Alafs Ter24),and patient 8 found a hemizygote mutation in AVPR2 gene with the deletion of 1-3 exome.9.The clinical symptoms were all improve after the treatment in the 8HNDI patients,middle height was 100 cm,middle weight was 14.35 kg,middle volume of urine was 2042 ml/d,middle volume of water intake was 1646 ml/d,there were a significant improvement after the treatment(P < 0.05);The standard deviation of height and weight get the improvement compared to the prior treatment,the number of patients who’s height and weight lower than-2SD compared to the normal children were reduced from 5 to 1 after the treatment;All of these patients get a increase of BMI(Body mass inde)after the treatment and the difference had a statistical significance(P<0.05).10.There were no side effect such as rash or body fluid retention found in these 8 HNDI patients during the treatment of hydrochlorothiazide.Patient 7found a slight increase of ALT and AST after the add of indometacin for 2months,and reexamination was normal deal with the glutathione for 8 months.Patient 1 and 4 and 5 found a slight electrolyte disturbance(low sodium,low potassium,low chloride)during the treatment,it returned to normal after the measure of redecue the dose of hydrochlorothiazide and the supple of sodium and potassium.All the other patients found no abnormal of liver function or blood glucose or electrolyte during the treatment.11.There were 86 pieces of domestic and overseas literatures retrospectively analyzed which clinical data were completed from 2000 to 2021.(1)A total of 464 HNDI patients were identified,402 patients of them were male(87%),while 62 patients were female(13%).423 patients provided a genetic test results,there were 363 patients with the mutation of AVPR2 gene(86%),60 patients with the mutation of AQP2gene(14%).The middle age was 24.4 months when they get the first diagnosis in 464 patients,in which 324 patients’ height(70%)and 330patients’ weight(71%)were low than-2SD compared to the normal children.(2)More than 250 types of HNDI-related AVPR2 mutations have been identified for the moment,with missense mutations being the most common type(about 56%).More than 60 types of HNDI-related mutations of AQP2 have been identified,with autosomal recessive inheritance being the dominant mode(about 90%).(3)The reasons for the first time to see a doctor were provided in149 patients,which mainly included(occur separated/combined):polydipsia and polyuria for 140 patients(94%),growth retardation for72 patients(48%),repeated fever for 36 patients(24%),repeated vomiting and nausea for 35 patients(24%),non-urinary tract infection for 33 patients(22%),repeated electrolyte disturbance for 20 patients(13%),thirst for 17 patients(11%),repeated constipation for 13 patients(9%),psychomotor retardation for 7 patients(5%),repeated urinary incontinence for 5 patients(3%),repeated urinary tract infections for 4patients(3%),HNDI positive family history for 4 patients(3%)and repeated nocturnal enuresis for 3 patients(2%).(4)The diagnosis for the first time were provided in 149 patients,which mainly included: nephrogenic diabetes insipidus for 112 patients(75%),central diabetes insipidus for 12 patients(8%),infectious diseases for 11 patients(7%),digestive diseases for 8 patients(5%),nutritional disease for 4 patients(3%),the other disease for 2 patients(1%).In the same time,8 patients(5%)were identified only after receiving the wrong treatment.(5)Routine treatment for HNDI patients included thiazide diuretics,NSAIDs,potase-conserving diuretics,rehydration therapy and a low-salt diet.315 patients provided information on treatment regimens,268 patients(85%)had used thiazide diuretics and/or NSAIDs,211 patients(67%)used thiazide diuretics,110 patients(35%)used potassium-preserving diuretics,97 patients(31%)used nonsteroidal anti-inflammatory drugs,59 patients(19%)had used nasogastric tubes,and 22 patients(7%)had a history of gastrostomy.(6)53 patients provided the information of the treatment effect,before the treatment,the height of 32 patients(60%)and weight of 37(70%)were lower than-2SD compared to the normal children;After the treatment,the height of 20 patients(38%)and weight of 18 patients(34%)were still lower than-2SD.(7)315 patients provided the information of the complications,141 patients(45%)had urinary tract disease,107 patients(34%)had hydronephrosis,72 patients(23%)had bladder dysfunction,95 patients(30%)had primary nocturia who were over 6 years old,64 patients(64/178)had psychological problems,28 patients(28/178)had attention deficit hyperactivity disorder,16 patients(16/178)had intellectual disability,53 patients(53/199)had stage II renal impairment,and 9 patients(9/199)had stage II or more renal impairment.Conclusions1.HNDI has a low incidence,most of the patients are male,there are lots of reasons for the patients with HNDI when the first time to see a doctor,in which way can easy to miss diagnosis or get a misdiagnosis.For the patients who are familiar to this disease especially the male as well as the infants with repeated fever,vomiting or growth retardation should always pay attention to HNDI.2.The water deprivation test-vasopressin test plays an important role in the differential diagnosis of patients with HNDI.Empiric therapy with a simple water test is also an option for those who are difficult to test.3.HNDI can occur in the early age,it usually occur soon after the birth,the inefficacy of vasopressin treatment are important differentiating points,and diagnosis can be confirmed by genetic testing.4.All patients with HNDI have different degrees of growth retardation,early intervention therapy can improve the clinical symptoms and growth and development.5.Indolomethacin and hydrochlorothiazide have a low incidence of side effects in patients with HNDI,no serious side effects have been found.The safety of long-term application still needs to be discussed.