Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease? / Inibidores de cotransportadores sódio-glicose-2 (SGLT2) na nefrolitíase - devemos "gliflozinar" os litiásicos?

ABSTRACT The prevalence of nephrolithiasis is increasing worldwide. Despite advances in understanding the pathogenesis of lithiasis, few studies have demonstrated that specific clinical interventions reduce the recurrence of nephrolithiasis. The aim of this review is to analyze the current data and potential effects of iSGLT2 in lithogenesis and try to answer the question: Should we also "gliflozin" our patients with kidney stone disease?

RESUMO A prevalência da nefrolitíase está aumentando em todo o mundo. Apesar dos avanços na compreensão da patogênese da doença litiásica, poucos estudos demonstraram que intervenções clínicas específicas diminuem a recorrência da nefrolitíase. O objetivo desta revisão é analisar os dados atuais e efeitos potenciais dos iSGLT2 na doença litiásica e tentar responder à pergunta: devemos também "gliflozinar" os litiásicos?

Sodium-glucose cotranspor ter 2 (SGLT2) inhibitors in nephrolithiasis: should we "gliflozin" patients with kidney stone disease?

The prevalence of nephrolithiasis is increasing worldwide. Despite advances in understanding the pathogenesis of lithiasis, few studies have demonstrated that specific clinical interventions reduce the recurrence of nephrolithiasis. The aim of this review is to analyze the current data and potential effects of iSGLT2 in lithogenesis and try to answer the question: Should we also "gliflozin" our patients with kidney stone disease?

Pre-Transplant Hyperparathyroidism and Graft or Patient Outcomes After Kidney Transplantation.

The impact of pre-transplant parathyroid hormone (PTH) levels on early or long-term kidney function after kidney transplantation is subject of debate. We assessed whether severe hyperparathyroidism is associated with delayed graft function (DGF), death-censored graft failure (DCGF), or all-cause mortality. In this single-center cohort study, we studied the relationship between PTH and other parameters related to bone and mineral metabolism, including serum alkaline phosphatase (ALP) at time of transplantation with the subsequent risk of DGF, DCGF and all-cause mortality using multivariable logistic and Cox regression analyses. In 1,576 kidney transplant recipients (51.6 ± 14.0 years, 57.3% male), severe hyperparathyroidism characterized by pre-transplant PTH ≥771 pg/mL (>9 times the upper limit) was present in 121 patients. During 5.2 [0.2-30.0] years follow-up, 278 (15.7%) patients developed DGF, 150 (9.9%) DCGF and 432 (28.6%) died. A higher pre-transplant PTH was not associated with DGF (HR 1.06 [0.90-1.25]), DCGF (HR 0.98 [0.87-1.13]), or all-cause mortality (HR 1.02 [0.93-1.11]). Results were consistent in sensitivity analyses. The same applied to other parameters related to bone and mineral metabolism, including ALP. Severe pre-transplant hyperparathyroidism was not associated with an increased risk of DGF, DCGF or all-cause mortality, not supporting the need of correction before kidney transplantation to improve graft or patient survival.

Adipose Tissue Denervation Blunted the Decrease in Bone Formation Promoted by Obesity in Rats.

The impact of obesity upon bone metabolism is controversial since both beneficial or harmful effects have been reported. Bone remodeling is modulated by the central nervous system through cytokines, hormones and neuromodulators. The present study aimed to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation (Dnx) upon bone mineral metabolism and remodeling in an experimental model of obesity in rats. Male Wistar rats were fed during 18 weeks with high-fat diet (HFD) or standard diet (SD) as controls, and rWAT Dnx or Sham surgery was performed at the 14th week. Biochemical and hormonal parameters, bone histomorphometry, rWAT and hypothalamus protein and gene expression were analyzed. The HFD group presented decreased bone formation parameters, increased serum and bone leptin and FGF23, increased serum and hypothalamic neuropeptide Y (NPY) and decreased serum 1,25-dihydroxyvitamin D3 and PTH. After rWAT Dnx, bone markers and histomorphometry showed restoration of bone formation, and serum and hypothalamic NPY decreased, without alteration in leptin levels. The present study shows that the denervation of rWAT improved bone formation in obese rats mediated by a preferential reduction in neurohormonal actions of NPY, emphasizing the relevance of the adipose tissue-brain-bone axis in the control of bone metabolism in obesity.

Urinary Calcium Is Associated with Serum Sclerostin among Stone Formers.

BACKGROUND: Sclerostin plays an important role in bone metabolism and adipose tissue. Animal studies suggest that sclerostin influences urinary calcium (UCa), but this relationship has not been evaluated in stone formers (SFs). We aimed to investigate the association of UCa with serum sclerostin, bone mineral density (BMD), and body composition among SFs. METHODS: Clinical and laboratorial data were retrieved from medical records. Determinants of UCa were studied using linear regression. RESULTS: A total of 107 SFs (35.8 ± 9.3 years, 54% male) with eGFR 99.8 ± 14.5 mL/min/1.73 were studied. Subjects were split by sex and grouped into tertiles of UCa levels. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin, lower lean mass, and a trend towards higher fat mass. Women in the highest tertile had higher BMI and a trend towards higher serum sclerostin. Hypertension and metabolic syndrome, but not lower BMD, were more prevalent in the highest UCa tertile for both sexes. Sclerostin was positively correlated with fat mass and inversely correlated with lean mass among men, but not among women. BMD corrected for BMI at lumbar spine was inversely associated with UCa in a univariate analysis, but only serum sclerostin, hypertension, and NaCl intake were independent determinants of UCa in the multivariate model. CONCLUSION: The present findings disclose that in addition to hypertension and salt intake, serum sclerostin is associated with urinary calcium in stone formers, suggesting that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further investigation.

Bone density, microarchitecture and estimated strength in stone formers: a cross-sectional HR-pQCT study.

BACKGROUND: Low areal bone mineral density (BMD), increased fracture risk and altered bone remodeling have been described among stone formers (SFs), but the magnitude of these findings differs by age, sex, menopausal status and urinary calcium (uCa). This study aimed to investigate volumetric BMD (vBMD), bone microarchitecture and biomechanical properties by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA) in young SFs, irrespective of calciuria, further distinguishing trabecular from cortical compartments. METHODS: HR-pQCT/FEA was performed at the distal tibia (DT) and distal radius (DR) in 106 SFs (57 males and 49 premenopausal females; median age 37 years) and compared with 106 non-SFs (NSFs) retrieved from an existing database, matched for age, sex and body mass index (BMI). Biochemical/hormonal serum and urinary parameters were obtained from SFs. RESULTS: SFs exhibited significantly lower trabecular number (TbN) and higher trabecular separation (TbSp) than NSFs at both anatomical sites and lower cortical porosity in the DR. In a subgroup analysis separated by sex, female SFs presented significantly lower TbvBMD, relative bone volume fraction (BV/TV) and TbN and higher TbSp than NSFs at both sites, while male SFs showed significantly lower stiffness and failure load. Multivariate analysis showed TbN to be independently associated with sex and BMI at both sites and with uCa at the DR. CONCLUSIONS: The present findings suggest that bone disease represents an early event among SFs, associated at least in part with calcium excretion and mainly characterized by trabecular bone microarchitecture impairment, especially among women, but with reduced bone strength parameters in men.

Echocardiographic Abnormalities in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patients.

Cardiovascular abnormalities, such as left ventricular hypertrophy and valvular disorders, particularly mitral valve prolapse, have been described as highly prevalent among adult patients with autosomal dominant polycystic kidney disease (ADPKD). The present study aimed to assess echocardiographic parameters in a large sample of both normotensive and hypertensive ADPKD patients, regardless of kidney function level, and evaluate their association with clinical and laboratorial parameters. A retrospective study consisted of the analysis of clinical, laboratorial, and transthoracic echocardiograms data retrieved from the medical records of young adult ADPKD outpatients. A total of 294 patients (120 M/174 F, 41.0 ± 13.8 years old, 199 hypertensive and 95 normotensive) with a median estimated glomerular filtration rate (eGFR) of 75.5 mL/min/1.73 m2 were included. The hypertensive group (67.6%) was significantly older and exhibited significantly lower eGFR than the normotensive one. Increased left ventricular mass index (LVMI) was seen in 2.0%, mitral valve prolapse was observed in 3.4%, mitral valve regurgitation in 15.3%, tricuspid valve regurgitation in 16.0%, and aortic valve regurgitation in 4.8% of the whole sample. The present study suggested that the prevalence of mitral valve prolapse was much lower than previously reported, and increased LVMI was not seen in most adult ADPKD patients.

Vascular Calcification Is Associated with Fetuin-A and Cortical Bone Porosity in Stone Formers.

Background: Nephrolithiasis has been associated with bone loss and vascular calcification (VC), reflecting abnormal extraosseous calcium deposition. Fetuin-A (Fet-A) acts as a potent inhibitor of ectopic mineralization. The aim of the present study was to evaluate the prevalence of VC in stone formers (SF) and non-stone formers (NSF) and to investigate potential determinants of VC among SF, including circulating levels of Fet-A and bone microarchitecture parameters. Methods: Abdominal aortic calcification (AAC) was assessed using available computed tomography in SF and in age-, sex-, and BMI-matched NSF (potential living kidney donors). Serum Fet-A was measured in stored blood samples from SF. Bone microarchitecture parameters were obtained as a post hoc analysis of a cross-sectional cohort from young SF evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Results: A total of 62 SF (38.0 [28.0−45.3] years old) and 80 NSF (40.0 [37.0−45.8] years old) were included. There was no significant difference in AAC scores between SF and NSF. However, when dividing SF according to mean AAC score, below <5.8% (n = 33) or above ≥5.8% (n = 29), SF with higher AAC presented significantly higher BMI and tibial cortical porosity (Ct.Po) and significantly lower serum HDL, klotho, Fet-A, and eGFR. Urinary calcium did not differ between groups, but fractional excretion of phosphate was higher in the former. Upon multivariate regression, BMI, serum Fet-A, and tibial Ct.Po remained independently associated with AAC. Conclusions: This study suggests an association between reduced circulating Fet-A levels and increased bone Ct.Po with VC in SF.

Increased Body Fat and Organic Acid Anions Production Are Associated with Larger Kidney Size in ADPKD.

Background and Objectives: A high body mass index (BMI) is associated with the progression of autosomal dominant polycystic kidney disease (ADPKD). However, body fat (BF), which is another adiposity marker, has not yet been studied. Excessive weight may promote elevation in the endogenous synthesis of organic acid (OA) anions. Accordingly, we aimed to investigate the possible association of the aforementioned markers with kidney volume and renal function in patients with ADPKD. Materials and Methods: We conducted a retrospective cohort study of adult ADPKD outpatients involving clinical, serum, and urinary laboratorial data and body composition assessments retrieved from their medical records. BF was estimated by skinfold thickness (mm) on the non-dominant arm and was considered as normal or high for each sex. Total kidney volume (TKV) and height-adjusted volume (htTKV) were measured by magnetic resonance imaging. The annual estimated glomerular filtration rate (eGFR) slope was analyzed during a median follow-up time of 6 (5.0-7.0) years to calculate rapid progression (decline in renal function ≥2.5 mL/min/year over 5 years). Results: A total of 104 patients were included (41.9 ± 11.9 years old, 38.5% men), with 62.5% of the patients classified as high BF. The High BF group presented higher levels of OA, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), 24 h urinary sodium (UNa), and htTKV, and lower eGFR than those with a normal BF. In the multivariate linear regression, the associated variables with TKV were high BF, OA and BMI (std. ß 0.47, p < 0.05; std. ß 0.36, p = 0.001; std. ß 0.25, p = 0.01, respectively). In the binary logistic regression, when adjusted for potential confounders, UNa was the only parameter associated with an increased risk of eGFR decline ≥2.5 mL/min/year (OR 1.02, 95% CI 1.01-1.03, p = 0.02). Conclusions: Increased body fat and endogenous production of organic acid anions are associated with larger kidney size in ADPKD but not with a decline in renal function.

COVID-19: The impact on urolithiasis treatment in Brazil

ABSTRACT Introduction: It has been more than a year since the first case of Covid-19 was diagnosed in Brazil, and its most problematic feature is the oversaturation of the healthcare system capacity. Urolithiasis is a disease that requires timely and appropriate management. The present study aimed to evaluate the impact of the pandemic in hospital admissions for urolithiasis in the Brazilian public healthcare system. Materials and Methods: In this cross-sectional study, hospital admissions were obtained from the Brazilian Public Health Information system. All hospital admissions associated with urolithiasis diagnosis (ICD-10 N20) between March 2017 and February 2021 were analyzed. Results: During the COVID-19 outbreak, there was a significant decrease in hospital admissions (p<0.0001). More than 20.000 patients probably did not have the opportunity to undergo their surgeries. The impact of the COVID-19 outbreak on women's admissions was significantly more intense than for men, reducing from 48.91% to 48.36% of the total (p=0.0281). The extremes of age seemed to be more affected, with patients younger than 20 years and older than 60 years having a significant reduction in access to hospital services (p=0.033). Conclusions: In conclusion, we have noticed a considerable reduction in overall admissions for the treatment of urolithiasis in the Brazilian public healthcare system during the first year of the Covid-19 pandemic. Women and individuals older than 60 years were especially affected. In contrast, we noted a rise in urgent procedures, comparing with the average of the corresponding period of the three previous years. Recovery plans will be needed while returning to activities to handle the impounded surgical volume.

Urinary Citrate Is Associated with Kidney Outcomes in Early Polycystic Kidney Disease.

Low urinary citrate and crystal deposition accelerated cystogenesis in an experimental model of polycystic kidney disease (PKD).Hypocitraturia, frequently observed in patients with autosomal dominant PKD (ADPKD) could contribute to disease progression.Present findings suggest lower urinary citrate in early PKD was associated with faster eGFR decline and worse kidney survival.

COVID-19: The impact on urolithiasis treatment in Brazil.

INTRODUCTION: It has been more than a year since the first case of Covid-19 was diagnosed in Brazil, and its most problematic feature is the oversaturation of the healthcare system capacity. Urolithiasis is a disease that requires timely and appropriate management. The present study aimed to evaluate the impact of the pandemic in hospital admissions for urolithiasis in the Brazilian public healthcare system. MATERIALS AND METHODS: In this cross-sectional study, hospital admissions were obtained from the Brazilian Public Health Information system. All hospital admissions associated with urolithiasis diagnosis (ICD-10 N20) between March 2017 and February 2021 were analyzed. RESULTS: During the COVID-19 outbreak, there was a significant decrease in hospital admissions (p<0.0001). More than 20.000 patients probably did not have the opportunity to undergo their surgeries. The impact of the COVID-19 outbreak on women's admissions was significantly more intense than for men, reducing from 48.91% to 48.36% of the total (p=0.0281). The extremes of age seemed to be more affected, with patients younger than 20 years and older than 60 years having a significant reduction in access to hospital services (p=0.033). CONCLUSIONS: In conclusion, we have noticed a considerable reduction in overall admissions for the treatment of urolithiasis in the Brazilian public healthcare system during the first year of the Covid-19 pandemic. Women and individuals older than 60 years were especially affected. In contrast, we noted a rise in urgent procedures, comparing with the average of the corresponding period of the three previous years. Recovery plans will be needed while returning to activities to handle the impounded surgical volume.

Kidney organoids generated from erythroid progenitors cells of patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Kidney organoids have been broadly obtained from commercially available induced pluripotent stem cells (iPSCs); however, it has been a great challenge to efficiently produce renal organoid models from patients with autosomal dominant polycystic kidney disease (ADPKD) that recapitulate both embryogenesis and the mechanisms of cystogenesis. METHODS: Blood erythroid progenitors (EPs) from two ADPKD patients and one healthy donor (HC) was used as a comparative control to normalize the many technical steps for reprogramming EPs and for the organoids generation. EPs were reprogrammed by an episomal vector into iPSCs, which were differentiated into renal tubular organoids and then stimulated by forskolin to induce cysts formation. RESULTS: iPSCs derived from EPs exhibited all characteristics of pluripotency and were able to differentiate into all three germ layers. 3D tubular organoids were generated from single cells after 28 days in Matrigel. HC and ADPKD organoids did not spontaneously form cysts, but upon forskolin stimulation, cysts-like structures were observed in the ADPKD organoids but not in the HC-derived organoids. CONCLUSION: The findings of this study showed that kidney organoids were successfully generated from the blood EP cells of ADPKD patients and a healthy control donor. This approach should contribute as a powerful tool for embryonic kidney development model, which is able to recapitulate the very early pathophysiological mechanisms involved in cytogenesis.

Thiazide and thiazide-like diuretics in nephrolithiasis / Diuréticos tiazídicos e tiazídicos-like na nefrolitíase

Abstract Thiazide and thiazide-like diuretics are widely used for the management of hypercalciuria among stone-forming patients. Although the effects of different thiazides should be relatively similar in terms of prevention of stone recurrence, their potency and side effects may differ. However, there is scarce data concerning the metabolic and bone effects of these agents among recurrent nephrolithiasis patients with hypercalciuria. The aim of this update article was to compare our experience in the use of thiazide and thiazide- like diuretics with that of the current literature, concerning their anticalciuric properties and consequent reduction of recurrent stone formation. Their impact on bone mass and potential side effects were also discussed.

Resumo Diuréticos tiazídicos e tiazídicos-like são amplamente usados para o tratamento da hipercalciúria em pacientes com formação de cálculos. Embora os efeitos dos diferentes tiazídicos devam ser relativamente semelhantes em termos de prevenção da recorrência do cálculo, sua potência e efeitos colaterais podem ser diferentes. No entanto, há poucos dados sobre os efeitos metabólicos e ósseos desses agentes em pacientes com nefrolitíase recorrente com hipercalciúria. O objetivo deste artigo de atualização foi comparar nossa experiência quanto ao uso de tiazídicos e tiazídicos-like com a publicada na literatura atual, no que diz respeito às suas propriedades anticalciúricas e consequente redução da formação de cálculos recorrentes. Discutimos também seu impacto na massa óssea e potenciais efeitos colaterais.

Thiazide and thiazide-like diuretics in nephrolithiasis.

Thiazide and thiazide-like diuretics are widely used for the management of hypercalciuria among stone-forming patients. Although the effects of different thiazides should be relatively similar in terms of prevention of stone recurrence, their potency and side effects may differ. However, there is scarce data concerning the metabolic and bone effects of these agents among recurrent nephrolithiasis patients with hypercalciuria. The aim of this update article was to compare our experience in the use of thiazide and thiazide- like diuretics with that of the current literature, concerning their anticalciuric properties and consequent reduction of recurrent stone formation. Their impact on bone mass and potential side effects were also discussed.

Dietary pattern analysis among stone formers: resemblance to a DASH-style diet / Análise do padrão alimentar de pacientes litiásicos: similaridades com o padrão de dieta DASH

Abstract Recent epidemiological studies have shown that dietary patterns may have a more persistent impact on the risk of stone formation than single nutrients of the diet. Dietary Approaches to Stop Hypertension (DASH), a low-sodium and fruits/vegetables-rich diet, has been associated with a lower risk of nephrolithiasis, due to altered urinary biochemistry. This observational study aimed to investigate whether the dietary pattern of stone formers (SF) resembled a DASH-diet and its influence on urinary lithogenic parameters. Anthropometric data, fasting serum sample, 24-h urine samples, and a 3-day food intake record under an unrestricted diet were obtained from 222 SF and compared with 136 non-SF subjects (controls). The DASH-diet food portions were determined from the food records whereas intakes of sodium chloride (NaCl) and protein (protein equivalent of nitrogen appearance, PNA) were estimated from 24-hr urinary sodium and urea. A dietary profile close to a DASH-diet was not observed in any of the groups. NaCl intake and PNA were significantly higher in SF versus non-SF (12.0 ± 5.2 v.s. 10.1 ± 3.4 g/day, p = 0.01 and 1.8 ± 0.1 v.s. 1.4 ± 0.1 g/kg/day, p = 0.03). SF exhibited a positive correlation of NaCl intake and PNA with urinary calcium, oxalate and uric acid, and of PNA with urinary sodium. SF consumed more vegetables and legumes, but less fruits and low-fat dairy items than non-SF. The present series presented a dietary profile characterized by low calcium and high salt and protein contents, not reflecting an ideal DASH-style diet pattern.

Resumo Estudos epidemiológicos recentes mostraram que os padrões alimentares podem ter um impacto mais persistente sobre o risco de formação de cálculos do que apenas os nutrientes da dieta. A dieta DASH (Dietary Approaches to Stop Hypertension), uma dieta pobre em sódio e rica em frutas/vegetais, tem sido associada a um menor risco de nefrolitíase, devido às alterações metabólicas urinárias. Este estudo observacional teve como objetivo investigar se o padrão alimentar de pacientes litiásicos (Lit) se assemelhava a uma dieta estilo DASH e sua influência nos parâmetros litogênicos urinários. Dados antropométricos, amostra de soro em jejum, amostras de urina de 24 horas e um registro de ingestão alimentar de 3 dias sob dieta irrestrita foram obtidos de 222 Lit e comparados com 136 indivíduos não-Lit (controles). As porções de alimentos do padrão de dieta DASH foram determinadas a partir dos registros alimentares, enquanto a ingestão de cloreto de sódio (NaCl) e proteína (Equivalente Protéico do Aparecimento de Nitrogênio Urinário, PNA) foram estimadas a partir da uréia e sódio urinários de 24 horas. Um perfil alimentar próximo a uma dieta estilo DASH não foi observado em nenhum dos grupos. A ingestão de NaCl e PNA foram significativamente maiores nos Lit versus não-Lit (12,0 ± 5,2 v.s. 10,1 ± 3,4 g/dia, p = 0,01 e 1,8 ± 0,1 v.s. 1,4 ± 0,1 g/kg/dia, p = 0,03). Os Lit exibiram uma correlação positiva entre a ingestão de NaCl e PNA com cálcio, oxalato e ácido urinários, e de PNA com sódio urinário. Os Lit consumiram mais vegetais e leguminosas, mas menos frutas e lácteos com teor reduzido de gordura do que os não-Lit. A presente série apresentou um padrão alimentar caracterizado por reduzido consumo de cálcio e elevado em sal e proteínas, não refletindo um padrão ideal de dieta DASH.

Influence of socioeconomic disparities, temperature and humidity in kidney stone composition.

INTRODUCTION: Large variations in demographic, economic and environmental factors might influence the worldwide distribution of urolithiasis, but scarce data are available concerning their associations with stone composition. We aimed to evaluate the frequency and composition of kidney stones and their associations with temperature, humidity, and human development index (HDI). MATERIALS AND METHODS: A total of 1,158 stones from distinct patients (47±14 years old, male/female 2:1) were included. The mean annual temperature and relative humidity of each town were considered separately. RESULTS: Calcium oxalate monohydrate (COM) was disclosed in 38.8% of patients, calcium oxalate dihydrate (COD) in 22.1%, mixed COD/apatite in 9.4%, pure apatite in 1.9%, brushite in 1.8%, struvite in 8.3%, pure uric acid in 11.1%, mixed uric acid/COM in 5.6%, and cystine/rare types in 0.8%. Mean HDI of all pooled cities was 0.780±0.03. However, people living in HDI<0.800 regions had twice the odds of having a struvite stone versus those living in HDI>0.800 (OR=2.14, 95% CI 1.11-4.11). Furthermore, a progressive increase in the struvite stones frequency from 4.5 to 22.8% was detected from HDI>0.800 through HDI<0.700. No significant difference for other stone types was disclosed. Separate logistic regression models assessed the association of each stone composition with gender, temperature, humidity and HDI as covariates. CONCLUSION: Patients living in low HDI areas are more prone to develop struvite stones, possibly due to lower access to healthcare. Temperature and humidity did not represent a specific risk factor for any stone type in the present sample.

Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease caused by mutations in the CLDN16 or CLDN19 gene; however, few cases develop classical amelogenesis imperfecta. Herein, we report the case of a boy with early clinical renal manifestations that started at 1 year of age and presenting with dental hypoplasia and growth delay. The patient presented with vomiting, polyuria, and polydipsia. Apart from recurrent sterile leukocyturia, erroneously treated as infectious, he was normal, except for short stature and amelogenesis imperfecta with gradually discolored teeth. Laboratory tests revealed hyperparathyroidism, hypomagnesemia, severe hypercalciuria, and hypermagnesuria on 24-h urine testing. Helical computed tomography confirmed nephrocalcinosis. We performed whole-exome sequencing (WES) to test the hypothesis of FHHNC and oligogenic inheritance of amelogenesis. Analysis of the WES binary sequence alignment/map file revealed the presence of exon 1 of the CLDN16 and absence of the other exons [c.325_c918*? (E2_E5del)]. We confirmed a CLDN16 E2_E5 homozygous deletion by multiplex ligation-dependent probe amplification and polymerase chain reaction assays. Although most mutations causing FHHNC are missense and nonsense mutations in the CLDN16 or CLDN19 gene, large deletions occur and may be misled by WES, which is generally used for genetic screening of oligogenic disorders. The patient received cholecalciferol, magnesium oxide and potassium citrate. Later, the combination with hydrochlorothiazide plus amiloride was prescribed, with a good response during follow-up. Our report broadens the phenotype of FHHNC, including severe early-onset amelogenesis and short stature, and reinforces the phenotype-genotype correlation of the large deletion found in CLDN16.