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Background Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review. Design PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein–creatinine ratio > Albustix) was used for NP classification. Results Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRL mutation. TPE was not significantly different between both forms ( p  = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP ( p  = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria. Conclusion More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.

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Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl - /H + exchanger ClC-5, which belongs to the CLC family of Cl - channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP 2 ) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1 , pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3 rd and 5 th decades of life in 30-80% of affected males.

Dent's disease is a rare inherited renal disorder characterized by generalized proximal tubule dysfunction with low molecular weight proteinuria, hypercalciuria, and urinary loss of other solutes. The disease is progressive and leads to chronic kidney disease. To study the mechanisms involved in its progression, we generated a knock‐in mouse model displaying a classical Dent's disease type 1 phenotype. Currently, no targeted therapy exists for Dent's disease; treatment strategies primarily aim to slow the progression of specific clinical aspects. Accordingly, empagliflozin [a sodium–glucose cotransporter 2 (SGLT2) inhibitor] known to exert nephroprotective effects and to slow down the decrease of the glomerular filtration rate in diabetic and non‐diabetic patients with chronic kidney disease, was administered to the knock‐in mice. We demonstrated that empagliflozin administration reduces renal and urinary levels of the marker of tubular damage, Lipocalin‐2 (LCN2). However, we observed that this preventive treatment does not alleviate low molecular weight proteinuria, hypercalciuria, inflammation, renal fibrosis or the decline of the glomerular filtration rate. Overall, our findings suggest that SGLT2 inhibition with empagliflozin does not prevent the progression of Dent's disease type 1 towards chronic kidney disease. What is the central question of the study? Can empagliflozin prevent the progression of Dent's disease type 1, a rare inherited renal disorder that frequently leads to chronic kidney disease? What is the main finding and its importance? Administration of empagliflozin to a model of Dent's disease type 1 reduced the expression of LCN2, which might be involved in the development of fibrosis. Surprisingly, fibrosis was not reduced, suggesting that it might be involved in other mechanisms of the disease progression. Furthermore, administration of empagliflozin for 8 months did not seem to reduce the major clinical features of Dent's disease type 1.

This study aims to elucidate the genetic and phenotypic characteristics of pediatric patients with potential Dent disease (DD). High-throughput sequencing was conducted on 11 pediatric patients with potential cases of DD. We also analyzed clinical phenotype and treatment regimens. Variants in and were identified in nine patients, including three novel variants. The predominant clinical manifestations among these patients with a definitive diagnosis of DD included low molecular weight proteinuria (LMWP) (100%), hypercalciuria (66.7%), abnormal renal function (55.6%), nephrocalcinosis (44.4%), and hypophosphatemia (44.4%). Patients with or variants exhibited significantly elevated levels of both β2-microglobulin and α1-microglobulin, exceeding the normal threshold by more than tenfold. In contrast, the potential cases of DD without identified genetic mutations showed a moderate increase in β2-microglobulin (5-10 times the normal level), while α1-microglobulin levels remained below this range. Seven DD patients were treated with nonsteroidal angiotensin-converting enzyme inhibitors. By the end of this study, five DD patients were diagnosed with stage 2 chronic kidney disease (CKD2), while four were classified as having CKD1. This study provides insight into the clinical and genetic profiles of DD patients. Notably, integrating genetic analysis with the detection of markedly elevated levels of LMWP, particularly α1-microglobulin,can substantially reduce the misdiagnosis of this disease.

Dent disease is a rare disease with proximal renal tubular dysfunction, and is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease. Renal failure slowly progresses and end-stage renal disease may develop in the late decades of life. We report a case of a 15-year-old boy who was diagnosed with Dent disease 1 with a CLCN5 truncating mutation. The patient presented with arthralgia and rickets at the onset of Dent disease and he was diagnosed with end-stage renal disease at the age of 15 years. His only symptoms were arthralgia and rickets during the disease course. The findings in this case suggest that patients with arthralgia and rickets could have a rare cause such as Dent disease.