Fibronectin glomerulopathy (FGP), also known as fibronectin deposition glomerulopathy (GFND), is a rare hereditary autosomal dominant glomerular disease. Its clinical manifestations are proteinuria, hematuria, hypertension, and hyperkalemic distal renal tubular acidosis, which often progresses slowly to end-stage renal disease. We report a 21-year-old woman with fibronectin glomerulopathy who underwent renal puncture at the age of 10. The pathology was considered to be thrombotic microangiopathy, and it was not treated regularly. This time, renal puncture was performed again due to proteinuria combined with elevated serum creatinine. Light microscopy showed severe mesangial matrix hyperplasia of glomeruli with dense deposition and foam cell aggregation in capillary loops. Fibrinogen immunostaining was positive. Electron microscope showed severe hyperplasia of mesangial matrix, and a large amount of electron-dense matter deposited in mesangial area. Perfect genetic testing suggested that the FN1 gene was heterozygous for NM_212482.4 (c.2918A>G), that is, Y973C mutation. Therefore, she was diagnosed with fibronectin glomerulopathy and was given sacubitril valsartan sodium tablets 200 mg b.i.d. orally. We report a case of a patient with fibronectin glomerulopathy and review the literature of this disease. The disease often has insidious onset, and fibronectin deposition is a typical pathological change that can result. The disease slowly progresses to end-stage renal disease. At present, there is no specific treatment. It is advocated to use reninangiotensin-aldosterone system blockers to strictly control blood pressure and proteinuria, and the overall prognosis is poor. Genetic testing techniques may be helpful in early diagnosis of the disease.

Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) enables more accurate evaluation of underlying etiologies. The existing clinical evidence regarding genetic testing in adults with NL comprises only a few cohort studies. We retrospectively analyzed 49 adult patients diagnosed with NL and/or NC from a single center, on whom we performed a genetic test using a nephrolithiasis panel. We reviewed the phenotype of the patients and compared the cases with positive and negative molecular diagnosis. In total, 49 adult patients with NL and/or NC underwent genetic testing. Of the tested patients, 29 (59.2%) patients had 24 abnormal variants in 14 genes. Mendelian diseases were diagnosed in 14 (28.6%) cases: cystinuria (SLC3A1, SLC7A9; n = 4), hereditary distal renal tubular acidosis (SLC4A1; n = 3), Dent disease (CLCN5; n = 2), familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (CLDN16; n = 1), infantile hypercalcemia type 1 (CYP24A1; n = 1), primary hyperoxaluria type 1 (AGXT; n = 1), Bartter syndrome type 2 (KCNJ1; n = 1), and autosomal dominant tubulointerstitial kidney disease (UMOD; n = 1). Eight (16.3%) patients had pathogenic or likely pathogenic monoallelic variants as predisposing factors for NL and/or NC, and seven (14.3%) had biallelic or monoallelic variants of uncertain significance. Patients with positive genetic tests had a lower estimated glomerular filtration rate (p = 0.03) and more frequent NL associated with NC (p = 0.007) and were unlikely to have arterial hypertension (p = 0.03) when compared with patients with negative tests. Our study shows an increased effectiveness of molecular diagnosis and highlights the benefits of genetic testing. NL associated with NC and the presence of chronic kidney disease are the characteristics that should prompt the clinician to suspect an inherited form of NL and/or NC. Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-related dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of hereditary dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired kidney function. Additional manifestations include bone demineralization (rickets, osteomalacia), sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-related dRTA), hereditary hemolytic anemia (in some individuals with SLC4A1-related dRTA), and amelogenesis imperfecta (in WDR72-related dRTA). The diagnosis of hereditary dRTA is established in a proband with dRTA and biallelic pathogenic variants in ATP6V0A4, ATP6V1B1, FOXI1, or WDR72, a heterozygous or biallelic pathogenic variants in SLC4A1, or specific heterozygous pathogenic variants in ATP6V1B1 (affecting codon p.Arg394) identified by molecular genetic testing. Targeted therapies: Oral alkaline therapy to correct metabolic acidosis and hypokalemia with additional potassium chloride as needed. ADV7103 is a combination controlled-release potassium bicarbonate and potassium citrate medication approved in Europe that allows less frequent dosing. Supportive care: Standard treatments for other possible manifestations including sensorineural hearing, hemolytic anemia, and amelogenesis imperfecta. Surveillance: Fasting venous blood gas or total CO2 prior to alkali dose in rapidly growing infants and children at least every three to four months, and at least every six months in older individuals. Serum creatinine, urea, sodium, potassium, chloride, calcium, phosphate, alkaline phosphatase, and albumin in rapidly growing infants and young children at least every three to four months, and at least every six to 12 months in stable older children and adults. Urinalysis and urine creatinine, sodium, potassium, calcium, and citrate annually and more frequently when adjusting treatment. Annual renal ultrasound to evaluate for nephrocalcinosis, urolithiasis, and cysts in asymptomatic individuals. Growth assessment with calculation of body mass index in infants at least every three months, and in older children at least every six months until achievement of final height. Bone densitometry as needed. Audiometry annually in at-risk individuals. Assessment for hemolytic anemia and dental assessment as needed in at-risk individuals. Agents/circumstances to avoid: Potassium-sparing diuretics should be used with caution or avoided. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Pregnancy management: Women with hereditary dRTA may develop severe metabolic acidosis and hypokalemia during pregnancy, especially when complicated by hyperemesis gravidarum. Close monitoring of women with hereditary dRTA during pregnancy is necessary. Hereditary distal renal tubular acidosis caused by loss-of-function variants in ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, or WDR72 is inherited in an autosomal recessive manner. Hereditary dRTA caused by dominant-negative variants in SLC4A1 or heterozygous pathogenic variants in ATP6V1B1 affecting the specific amino acid p.Arg394 are inherited in an autosomal dominant manner. Autosomal recessive inheritance: If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Autosomal dominant inheritance: Each child of an individual with autosomal dominant dRTA has a 50% chance of inheriting the pathogenic variant. Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

ATP6V1B1 encodes a subunit of the vacuolar H+-ATPase and pathogenic variants are associated with autosomal recessive distal renal tubular acidosis (dRTA) with deafness. Heterozygous variants predicted to affect a specific amino acid, Arg394, have been recurrently reported in dRTA but their significance has been unclear. We hypothesized that these variants are associated with a dominant disease mechanism. We conducted a retrospective analysis of cases identified in our genetic laboratories and through European nephrology organizations. Data regarding demographics, clinical presentation, laboratory findings, hearing and imaging studies of kidneys were collected from the index patient and, if available, from other family members. The potential disease mechanism was investigated through structural modelling in silico. Twenty index patients in total were included, of which 19 carried the variant c.1181G>A; p.(Arg394Gln) and one c.1180C>G; p.(Arg394Gly). In seven families, more than one member was affected and the variant segregated with the disease in those with available information (15 affected, 6 unaffected), except for the unaffected mother of 2 affected children, who was mosaic. In no patient was a second causative variant in trans identified. In eight sporadic patients and one affected parent, the variant was confirmed to be de novo. Both variants are absent in gnomAD. Sensorineural hearing loss was reported in 8 of the 22 patients with available information. Structural modelling supports a crucial role for Arg394 in nucleotide binding. We provide strong evidence for the pathogenicity of heterozygous variants affecting Arg394 and thus a novel inheritance modus for ATP6V1B1-associated dRTA. Clinically, this form differs from the recessive one by the lower prevalence of hearing loss. The prominent position of Arg394 in the nucleotide binding fold of the H+-ATPase structure is consistent with a dominant negative mechanism. Our findings inform the diagnosis and management of patients with dRTA and variants of Arg394.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Genetic variants in SEC61A1 are associated with autosomal dominant tubulointerstitial kidney disease. SEC61A1 is a translocon in the endoplasmic reticulum membrane and variants affect biosynthesis of renin and uromodulin. A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis. Genetic evaluation was performed by whole genome sequencing. The patient has a novel de novo heterozygous SEC61A1 variant, Phe458Val. Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low. Kidney biopsy at 2 years exhibited subtle changes suggestive of tubular dysgenesis without tubulocystic or glomerulocystic lesions and with renin staining of the juxtaglomerular cells. The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being. Blood pressure and potassium normalized. Biopsy at 9 years showed extensive glomerulosclerosis and mild tubulointerstitial fibrosis, as well as tubular mitochondrial abnormalities, without specific diagnostic changes. Her GFR improved to 54 ml/min/1.73m2. As the renin-angiotensin system promotes aldosterone release, and the patient had repeatedly undetectable aldosterone levels, the SEC61A1 variant presumably contributed to severe hypotension. Treatment with a mineralocorticoid had a beneficial effect and corrected the electrolyte and acid-base disorder. We suggest that the increased blood pressure hemodynamically improved the patient's kidney function.