Severe Nephrocalcinosis Research Articles

АУТОСОМНО-ДОМИНАНТНАЯ ГИПОКАЛЬЦИЕМИЯ: ОПИСАНИЕ СЕМЕЙНОГО НАБЛЮДЕНИЯ

Autosomal dominant hypocalcemia (ADH), or familial hypocalciuric hypercalcemia (FHH) is a rare hereditary disease manifested by hypocalcemia and hypercalciuria due to a malfunction of the calcium-sensitive receptor (mutations in the CASR or GNA11 genes). A familial clinical case of ADH is presented: the disease was diagnosed in a 36 y/o female and her two male children of 11 and 1.5 y/o. The disease was detected in an older child aged 7 years on the basis of convulsive syndrome, decreased blood calcium and parathyroid hormone, increased calciuria and detection of a mutation in the CASR gene (c.344-358del TTGCTCAAAACAAAA/ p.116 120delAQNKI). The initial manifestations of the disease in the form of a convulsive syndrome were observed in a child starting his 2nd day of life and were regarded as a manifestation of epilepsy, which was then followed by a long non-convulsive period. The patient needs constant therapy with alfacalcidol and has nephrocalcinosis. Based on the diagnosis made, the disease was also confirmed in his mother as the asymptomatic hypocalcemia and a mutation in the CASR gene were found. The woman does not need drug therapy, does not have nephrocalcinosis. In the youngest child, the diagnosis was suspected at birth on the basis of convulsions, hypocalcemia and was subsequently confirmed then by the detection of a mutation in the CASR gene. The course of the disease in the youngest child is severe, aggravated by the presence of perinatal CNS lesions and epilepsy. The patient has been receiving therapy with alfacalcidol since birth, has manifestations of severe nephrocalcinosis with a decrease in the filtration function of the kidneys. To stop the convulsive syndrome the patient needs to maintain a higher level of blood calcium, which is complicated due to hypercalciuria and causes chronic kidney disease. Conclusion: the observed familial case demonstrates the polymorphism of the course of the disease, and, given the rarity of the disease and the nonspecificity of manifestations, the description of this case will improve the awareness of medical practitioners of various specialties about the disease for its timely diagnosis.

Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD.

Nephron loss dramatically increases tubular phosphate to concentrations that exceed supersaturation. Osteopontin (OPN) is a matricellular protein that enhances mineral solubility in solution; however, the role of OPN in maintaining urinary phosphate solubility in CKD remains undefined. Here, we examined (1) the expression patterns and timing of kidney/urine OPN changes in CKD mice, (2) if tubular injury is necessary for kidney OPN expression in CKD, (3) how OPN deletion alters kidney mineral deposition in CKD mice, (4) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineral deposition in phosphaturic mice, and (5) the in vitro effect of phosphate-based nanocrystals on tubular epithelial cell OPN expression. Tubular OPN expression was dramatically increased in all studied CKD murine models. Kidney OPN gene expression and urinary OPN/Cr ratios increased before changes in traditional biochemical markers of kidney function. Moreover, a reduction of nephron numbers alone (by unilateral nephrectomy) was sufficient to induce OPN expression in residual nephrons and induction of CKD in OPN-null mice fed excess phosphate resulted in severe nephrocalcinosis. Neutralization of the ASARM motif of OPN in phosphaturic mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice. Lastly, in vitro experiments revealed calcium-phosphate nanocrystals to induce OPN expression by tubular epithelial cells directly. Kidney OPN expression increases in early CKD and serves a critical role in maintaining tubular mineral solubility when tubular phosphate concentrations are exceedingly high, as in late-stage CKD. Calcium-phosphate nanocrystals may be a proximal stimulus for tubular OPN production.

Gene expression patterns in Atlantic salmon (Salmo salar) with severe nephrocalcinosis.

Nephrocalcinosis is a common disorder in farmed Atlantic salmon, but the consequences for the fish physiology are not well understood. We performed a transcriptome study in kidneys of Atlantic salmon (Salmo salar) smolts without and with severe chronic nephrocalcinosis (NC). The study revealed that numerous genes are differentially expressed in fish with NC compared with healthy salmon. The most evident changes in gene expression patterns in the NC group were a massive downregulation of metabolism and energy production, upregulation of signalling pathways important for tissue repair and function maintenance and upregulation of inflammatory responses. Overall, the extensive tissue damage and the gene regulation responses that affect salmon with severe nephrocalcinosis are highly likely to have dramatic consequences on fish survival.

Idiopathic infantile hypercalcemia with severe nephrocalcinosis, associated with CYP24A1 mutations: a case report

Nephrocalcinosis often occurs in infants and is caused by excessive calcium or vitamin D supplementation, neonatal primary hyperparathyroidism, and genetic disorders. Idiopathic infantile hypercalcemia (IIH), a rare cause of nephrocalcinosis, results from genetic defects in CYP24A1 or SLC34A1. Mutations in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, disrupt active vitamin D degradation. IIH clinically manifests as failure to thrive and hypercalcemia within the first year of life and usually remits spontaneously. Herein, we present a case of IIH wih CYP24A1 mutations.An 11-month-old girl visited our hospital with incidental hypercalcemia. She showed failure to thrive, and her oral intake had decreased over time since the age of 6 months. Her initial serum parathyroid hormone level was low, 25-OH vitamin D and 1,25-OH vitamin D levels were normal, and renal ultrasonography showed bilateral nephrocalcinosis. Whole-exome sequencing revealed compound heterozygous variants in CYP24A1 (NM_000782.4:c.376C>T [p.Pro126Ser] and c.1310C>A [p.Pro437His]). Although her hypercalcemia and poor oral intake spontaneously resolved in approximately 8 months, we suggested that her nephrocalcinosis and renal function be regularly checked in consideration of potential asymptomatic renal damage. Hypercalcemia caused by IIH should be suspected in infants with severe nephrocalcinosis, especially when presenting with failure to thrive.

Oxalobacter formigenes treatment confers protective effects in a rat model of primary hyperoxaluria by preventing renal calcium oxalate deposition.

In primary hyperoxaluria, increased hepatic oxalate production sometimes leads to severe nephrocalcinosis and early end-stage kidney disease. Oral administration of Oxalobacter formigenes (O. formigenes), an oxalate-degrading bacterium, is thought to derive oxalate from systemic sources by inducing net enteric oxalate secretion. Here, the impact of O. formigenes on nephrocalcinosis was investigated in an ethylene glycol rat model mimicking hepatic oxalate overproduction in primary hyperoxaluria. Eighteen rats were administered ethylene glycol (0.75% in drinking water) for 6weeks, of which 9 were treated by oral gavage with O. formigenes and 9 received vehicle. Five control rats did not receive ethylene glycol or O. formigenes. Plasma and urinary oxalate levels, calcium oxalate crystalluria, urinary volume, fluid intake, and serum creatinine were monitored during the study. On killing, nephrocalcinosis was quantified. Ethylene glycol intake induced pronounced hyperoxalemia, hyperoxaluria, calcium oxalate crystalluria and nephrocalcinosis. Concomitant O. formigenes treatment partially prevented the ethylene glycol-induced increase in plasma oxalate and completely prevented nephrocalcinosis. Urinary oxalate excretion was not reduced by O. formigenes treatment. Nevertheless, absence of crystals in renal tissue of O. formigenes-treated ethylene glycol animals indicates that the propensity for oxalate to crystallize in the kidneys was reduced compared to non-treated animals. This is supported by the lower plasma oxalate concentrations in O. formigenes-treated animals. This study shows a beneficial effect of O. formigenes treatment on ethylene glycol-induced hyperoxalemia and nephrocalcinosis, and thus supports a possible beneficial effect of O. formigenes in primary hyperoxaluria.

Frequency of Ectopic Calcifications Among Patients With Hypophosphatasia in the Global HPP Registry

Abstract Ectopic calcifications have been observed in patients with hypophosphatasia (HPP)—a rare, inherited, metabolic disorder characterized by reduced enzymatic activity of tissue nonspecific alkaline phosphatase. The natural history of these calcifications is poorly understood. Using data from the Global HPP Registry, a cross-sectional, observational analysis was conducted to better understand the prevalence of nephrocalcinosis and eye calcifications in patients with HPP in the absence of treatment with the enzyme replacement therapy, asfotase alfa. The association between hypercalcemia (serum calcium ≤10.3 mg/dL [normal]; 10.4–11.9 mg/dL [mild hypercalcemia]; ≥12.0 mg/dL [moderate to severe hypercalcemia]) and ectopic calcification was also evaluated. Of the patients in the study population with renal ultrasound data (n=327), 11.0% had nephrocalcinosis; no patients had severe nephrocalcinosis. In children (aged <18 years; n=174), 13.2% had nephrocalcinosis, and the median age at the first diagnosis of nephrocalcinosis was 4 years (range: 0–17 years). In adults (aged ≥18 years; n=153), 8.5% had nephrocalcinosis, and the median age at the first diagnosis of nephrocalcinosis was 52 years (range: 27–72 years). Data on serum calcium levels were available for 318 patients with renal ultrasounds. Of these patients, 73 patients (23.0%) had a history of hypercalcemia, of whom 10 (13.7%; children: n=9; adults: n=1) also had nephrocalcinosis. In patients with moderate to severe hypercalcemia (n=7), 6 patients (85.7%) were diagnosed with nephrocalcinosis; the majority (68.8%) of patients with nephrocalcinosis did not have a documented history of hypercalcemia. Of the patients who had ophthalmological assessments (n=137), 6 patients (4.4%) had eye calcifications; no patients had moderate or severe eye calcifications. The median age at the first diagnosis of eye calcifications was 16 years (range: 15–16 years) in children and 51 years (range: 30–57 years) in adults. Data on serum calcium levels were available for 80 patients with ophthalmological assessments. Coexistence of eye calcifications and reported hypercalcemia was observed in only 3 of these patients, all of whom had mild hypercalcemia; the remaining 3 patients with eye calcifications exhibited no hypercalcemia. No patients in this analysis presented with both nephrocalcinosis and eye calcifications. These results indicate that the prevalence of ectopic calcifications in patients with HPP is low during the natural course of the disease, with nephrocalcinosis being more common than eye calcifications. In addition, the higher prevalence of nephrocalcinosis in patients with moderate to severe hypercalcemia suggests that very high serum calcium may be a risk factor in some patients. Future studies are needed to assess the impact of treatment with asfotase alfa on ectopic calcifications in patients with HPP.

Coexistent CYP24A1 and PHEX Gene Mutations With Hypervitaminosis D Plus Hypercalcemia Treated With Fluconazole

Background: CYP24A1 and PHEX gene mutations are rare and can cause hypercalcemia, hypervitaminosis D and elevated FGF23 levels. Fluconazole, an antifungal medication, has shown therapeutic benefit in achieving normocalcemia plus normalisation of vitamin D levels in this case report. Clinical Case: A 42 year old man was referred to the endocrine clinic with a history of severe nephrocalcinosis and recurrent nephrolithiasis requiring surgical intervention and gradual decline in kidney function over 20 years. Biochemical investigations revealed hypercalcaemia with adjusted calcium levels of 2.83 mmol/L (R 2.2–2.6 nmol/L) and suppressed PTH 1.1 pmol/L(R 1.6–6.9 pmol/L). Twenty-four hour urine calcium/creatinine clearance ratio was above 0.0578 mmol/mmol indicating hypercalciuria. Vitamin D metabolites 25 OH Vitamin D was elevated at 201 nmol/L, (R 50–120 nmol/L) along with intermittently elevated 1,25 OH Vitamin D 147 pmol/L(R 55–139 pml/L). 24,25 Vitamin D was low at 2.0 nmol/L producing a 25:24,25 dihydroxyvitamin D ratio of 80 (n<25). This biochemical data was highly suggestive of a loss of function mutation in the CYP24A1 gene that codes for the enzyme 24-hydroxylase, which is responsible for conversion of 1,25 vitamin D to 24,25 vitamin D. A pathogenic variant (heterozygous c.756G>A) was confirmed on genetic testing.Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n<100 RU/mL) but a full body octreotide scan did not reveal malignancy or other paraneoplastic syndromes such as oncogenic osteomalacia. A pathogenic variant in his PHEX gene (homozygous c.1874A>T) was also identified that has been associated with increased levels of FGF23 plus hypophosphataemia. Fluconazole at 50 mg once daily was initiated. Azoles inhibit cytochrome P450 enzymes and have been used in sarcoidosis to block vitamin D-synthesizing enzymes such as 25-hydroxylases and 1-α-hydroxylase that are P450 dependent. Few cases of CYP24A1 gene defects have been treated with fluconazole, which has a favourable side effect profile and yields good results. Adjusted calcium reduced to 2.62 nmol/L, 25 OH Vitamin D normalised to 111 nmol/L and 24:24,25 dihydroxyvitamin D ratio is now 17. Patient’s liver functions and full blood count has been monitored regularly during the course of treatment and the drug was well tolerated. Conclusion: Genetic causes of hypercalcemia can be left undiagnosed for long periods and there is a lack of proven or definitive therapeutic agents for correction of elevated calcium. Here fluconazole has been shown to reduce the hypercalcaemic burden and effectively lowered the Vitamin D levels in this case of a CYP24A1 mutation. This study augments fluconazole use in these cases but further studies are needed to elucidate the long term safe usage.

Nephrectomy in a Patient with Medullary Sponge Kidney Associated with Severe Nephrocalcinosis and Nephrolithiasis: A Rare Condition

Background: Medullary sponge kidney (MSK) is a disturbance of renal development characterized by cystic dilation and diffuse precalyceal duct ectasia. The disease affects both genders in equal proportions and is generally diagnosed in adulthood, as a result of recurrent calcium nephrolithiasis and nephrocalcinosis. The most frequently encountered manifestations being renal colic, microscopic or macroscopic hematuria, and fever. The intravenous pyelogram is standard for diagnosis and metabolic workup is required to identify the underlying cause. The main goal of treatment is to prevent recurrence and disease progression. Though considered a benign condition, a nephrectomy may often be required in patients presenting late with irreversible complications and end-stage renal disease. Aim: To highlight and discuss the presentation and management of a rare case of nephrocalcinosis and nephrolithiasis secondary to the medullary sponge kidney. Case presentation: We report herein the case of a 56-year-old male with long-standing hematuria in whom a diagnosis of medullary sponge kidney disease was made and he underwent a left total nephrectomy. The postoperative course was uneventful. Conclusion: Nephrocalcinosis and nephrolithiasis are complications of MSK and can result in irreversible renal damage. A high index of suspicion is necessary for patients presenting with renal colic, recurrent urinary tract infections, or hematuria for prompt diagnosis and management.

CRISPR/Cas9–mediated metabolic pathway reprogramming in a novel humanized rat model ameliorates primary hyperoxaluria type 1

Primary hyperoxaluria type I is caused by mutations in the alanine glyoxylate aminotransferase gene (AGXT), leading to accumulation of glyoxylate and subsequent production of oxalate and urolithiasis. Here, we generated a novel rat model of primary hyperoxaluria type I that carries a D205N mutation in the partially humanized Agxt gene through the CRISPR/Cas9 system. The AgxtD205N mutant rats showed undetectable alanine glyoxylate aminotransferase protein expression, developed hyperoxaluria at 1 month of age and exhibited severe renal calcium oxalate deposition after ethylene glycol challenge. This suggests our novel model is more relevant to the human disease than existing animal models. To test whether this model could be used for the development of innovative therapeutics, SaCas9 targeting hydroxyacid oxidase 1, responsible for metabolizing glycolate into glyoxylate, was delivered via adeno-associated viral vectors into newborn rats with primary hyperoxaluria type 1. This approach generated nearly 30% indels in the Hao1 gene in the liver, leading to 42% lower urine oxalate levels in the treated group than in the control group and preventing the rats with primary hyperoxaluria type 1 from undergoing severe nephrocalcinosis for at least 12 months. Thus, our results demonstrate that this partially humanized AgxtD205N rat strain is a high-performing model of primary hyperoxaluria type 1 for understanding pathology, and the development of novel therapeutics, such as reprogramming of the metabolic pathway through genome editing.

Generation of a Primary Hyperoxaluria Type 1 Disease Model Via CRISPR/Cas9 System in Rats.

Primary hyperoxaluria type 1 (PH1) is an inherited disease caused by mutations in alanine-glyoxylate aminotransferase (AGXT). It is characterized by abnormal metabolism of glyoxylic acid in the liver leading to endogenous oxalate overproduction and deposition of oxalate in multiple organs, mainly the kidney. Patients of PH1 often suffer from recurrent urinary tract stones, and finally renal failure. There is no effective treatment other than combined liver-kidney transplantation. Microinjection was administered to PH1 rats. Urine samples were collected for urine analysis. Kidney tissues were for Western blotting, quantitative PCR, AGT assays and histological evaluation. In this study, we generated a novel PH1 disease model through CRISPR/Cas9 mediated disruption of mitochondrial localized Agxt gene isoform in rats. Agxt-deficient rats excreted more oxalate in the urine than WT animals. Meanwhile, mutant rats exhibited crystalluria and showed a slight dilatation of renal tubules with mild fibrosis in the kidney. When supplied with 0.4% ethylene glycol (EG) in drinking water, mutant rats excreted greater abundance of oxalate and developed severe nephrocalcinosis in contrast to WT animals. Significantly elevated expression of inflammation- and fibrosisrelated genes was also detected in mutants. These data suggest that Agxt-deficiency in mitochondria impairs glyoxylic acid metabolism and leads to PH1 in rats. This rat strain would not only be a useful model for the study of the pathogenesis and pathology of PH1 but also a valuable tool for the development and evaluation of innovative drugs and therapeutics.

Delayed Presentation of Short Bowel Syndrome Complicated with Severe Degree of Nutritional Deficiencies, Nephrocalcinosis and Distal Renal Tubular Acidosis

Background: Short bowel syndrome (SBS) is a malabsorptive state due to functional or anatomic loss of extensive segments of small intestine which can lead to nutritional deficiencies and metabolic disarrangements. Here we describe a young patient with short bowel presenting with severe nutritional deficiencies, nephrocalcinosis and distal renal tubular acidosis. Nephrocalcinosis and distal renal tubular acidosis are closely associated and each can lead to the other. There are only rare case reports of short bowel syndrome complicated with nephrocalcinosis and distal RTA and severe degree of metabolic derangement with nutritional deficiencies. And this case highlights the importance of early management of short bowel syndrome in order to prevent long-term complications. Case presentation: A forty two-year-old Sri Lankan male patient who had undergone appendectomy at the age of nineteen years, which was complicated by bowel gangrene and about 240 cm of small bowel was resected. Later he presented with recurrent urolithiasis and urinary tract infections and ten years after the surgery imaging revealed bilateral nephrocalcinosis and obstructive uropathy. Distal Renal tubular acidosis (RTA) was diagnosed at the same time. He also had osteomalacia, proximal myopathy, multiple vitamin deficiencies, mixed deficiency anemia. He was started on calcium, iron supplements, parenteral B12, vitamin D injections and alkali therapy to achieve a normal serum bicarbonate concentration. His calcium and Vitamin D supplementation is currently being monitored with serum calcium, 25-hydroxyvitamin D, serum alkaline phosphatase, serum PTH and urinary calcium/creatinine ratio. Conclusion: Patients with extensive small bowel resection are at risk for nutrient, mineral, and vitamin deficiencies because of the loss of absorptive surface. It can also be complicated with nephrocalcinosis and distal RTA which is rare in short bowel syndrome. It is therefore important to identify patients at risk of short bowel syndrome and institute an early management, follow up plan to prevent complications.

HumanSLC26A1Gene Variants: A Pilot Study

Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

Distal Renal Tubular Acidosis in Adolescence with Severe Growth Retardation and Nephrocalcinosis

Chronic acidosis is an important, often overlooked cause of growth retardation. Here we present the case of a girl with distal renal tubular acidosis who had visited multiple hospitals before the diagnosis was made. She presented to us in adolescence with non anion gap metabolic acidosis, hypokalemia, severe growth retardation and nephrocalcinosis. In 18 months follow up with alkali therapy, she had good weight gain and growth velocity.

Impact of a high-phosphorus diet on the sonographic and CT appearance of kidneys in degus, and possible concurrence with dental problems

The main aim of this study was to investigate the impact of pelleted diet of different mineral composition on the sonographic and CT appearance of kidneys in degus (Octodon degus)....

A case of Rabson-Mendenhall syndrome with a novel mutation in the tyrosine kinase domain of the insulin receptor gene complicated by medullary sponge kidney

Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.

Hydroxyproline metabolism in mouse models of primary hyperoxaluria.

Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in glyoxylate reductase/hydroxypyruvate reductase (GRHPR KO) developed severe nephrocalcinosis in contrast to animals deficient in alanine-glyoxylate aminotransferase (AGXT KO) where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney.

Diagnosis, treatment and follow-up in a patient with Nephrocalcinosis due to distal renal tubular acidosis

AbstractTen years ago, a 73 year-old patient presented at our unit with a right nephritic colic and elevated serum creatinine (2.1 mg/dl). This was the first time that the patient had consulted for a urology workup. An abdominal X-ray was performed in which we observed a severe bilateral nephrocalcinosis with right ureteral lithiasis. One of the causes of nephrocalcinosis is distal renal tubular acidosis (dRTA), in that sense the patient presented metabolic acidosis (pH 7.25) together with normopotassaemia (4.4 meq/L) and normochlorine (105 mEq/L). A 24-hour urine test detected citrate (55 mg/dl), calcium (12 mg/dl) and pH of 6.5. A diuretic renogram showed the right relative renal function as 91.2% and left relative renal function as 8.8%. A test with bicarbonate and acetazolamide was performed, confirming a diagnosis of dRTA because the urinary CO2 pressure was 32 mmHg (normal, greater than 70 mmHg). Treatment with potassium citrate and increased intake of liquids was prescribed. Consequently, the patient’s serum creatinine normalized, her blood pH rose to 7.35 and urinary citrate increased to 154 mg/dl. After 10 years of treatment with potassium citrate the patient remains stable. We believe that in these patients it is crucial to carry out an alkalizing treatment: patients with dRTA cannot acidify the urine because a defect in the permeability of the tubule membrane prevents secretion of H+. It is important to administer potassium citrate continuously to improve blood pH, increase urinary citrate and reduce the risk of calcium phosphate crystallization.

Son Dönem Böbrek Hastalığı Olan Bir Süt Çocuğunda Eritropoietine Dirençli Anemi

renal disease (ESRD) in infancy. Bartter syndrome and the primary hyperoxalurias (PH) are the main causes of severe nephrocalcinosis with ESRD in infancy period. Bartter syndrome was ruled out because of the absence of hyponatremic hypokalemic metabolic alkalosis and recurrent dehydration attacks in our patient. Urinary chloride level was normal. Furthermore, SLC12A1 and CLCNKB gene analyses showed no mutation. Therefore, the most likely etiology in this infant with ESRD was the primary hyperoxalurias. The primary hyperoxalurias are autosomal recessive and rare metabolic disorders resulting from deficiencies of the hepatic peroxisomal enzyme alanine-glyoxlate aminotransferase (PH-1) and the enzyme glyoxylate reductase/hydroxypyruvate reductase (PH-2) which cause excessive oxalate formation and calcium oxalate deposition in various organs.1,2 The most common type of primary hyperoxaluria is type 1. Diagnosis relies on detection of increased levels of oxalate in urine (N: < 0.5 mmol/l/1.73m2 per day) and either assay enzyme activity from liver biopsy or molecular genetic testing of associated gene. Liver biopsy is still considered as the gold standard, but it is an invasive process and bears some risks. Genetic analysis provides some additional non-diagnostic information.1,2 However, the diagnosis of PH-1 was mainly established on the basis of clinical and radiologic findings in our case. Urine oxalate level could not be measured on admission due to financial problems of the family, and then urine output abruptly decreased.

ANTENATAL BARTTER SYNDROME: Analysis of Two Cases with Placental Findings

The prenatal diagnosis of Bartter syndrome can be based on the high chloride level in the amniotic fluid. Microscopic examination of the placenta in untreated cases showed extensive mineralization in the chorionic villi in previous studies. Two cases were presented at 26–29 weeks of gestation with severe polyhydramnios. The mothers were treated with Indomethacin, KCl, and serial amniocentesis in order to reduce the amniotic fluid volume and prevent fetal hypokalemia. The microscopic examination of the placenta revealed focal calcification and acute atherosis in placental vessels. The treatment with Indomethacin in the antenatal period can prevent severe nephrocalcinosis.

Acidose tubulaire rénale distale primitive

Renal tubular acidosis are forms of metabolic acidosis characterized by an impairment of urinary acidification due to a lack of urine excretion of protons or loss of bicarbonates. Primary distal renal acidosis (dRTA) is characterized by hyperchloremic metabolic acidosis due to failure in proton excretion, variably severe nephrocalcinosis and/or nephrolithiasis associated with hypercalciuria and hypocitraturia. When the metabolic acidosis is compensated, dRTA can be diagnosed by the failure of urinary acidification after oral ammonium chloride or furosemide administration. dRTA is inherited as either an autosomal dominant or autosomal recessive trait. An autosomal dominant form results from a SLC4A1 gene mutation leading to dysfunction of the anionic exchanger type 1 (AE1). Otherwise, recessive forms are due to mutations of ATP6V1B1 gene encoding the B1-subunit of H+-ATPase expressed in the apical membrane of the alpha intercalated cells in collecting duct and in the cochlea. Those mutations lead to dRTA accompanied by sensorineural deafness. Also, mutations in ATP6V0A4 gene encode the accessory subunit a4 of the H+ATPase, leading to recessive forms of dRTA with preserved hearing or delayed signs of deafness. Molecular approach can identify mutations which are responsible for this pathology. The medical treatment is simple and involves an alkali load which allows curing the metabolic acidosis. Long-term outcome is usually good unless the patient's compliance is low or alkalizing treatment is insufficient.