Long-term complications of primary distal renal tubular acidosis.

The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout life. This review focuses on the complications of distal tubular acidosis that occur or remain long-term such as nephrocalcinosis and urolithiasis, growth impairment, bone mineralization, severe hypokalemia, kidney cysts, and progressive kidney failure, as well as other persistent manifestations that occur independent of acidosis but are associated with some inherited forms of the disease. The pathogenic factors responsible for kidney failure are discussed in particular because it is a complication to which different publications have recently drawn attention and which affects a high percentage of adults with primary distal renal tubular acidosis. The need to maintain optimal metabolic control of the disease and scheduled clinical follow-up throughout life and the importance of organizing protocols for the transition of patients to adult nephrology services are emphasized.

The emerging roles and therapeutic potential of cyclin M/CorC family of Mg2+ transporters.

Cyclin M (CNNM) and its prokaryotic ortholog CorC belong to a family of proteins that function as Mg2+-extruding transporters by stimulating Na+/Mg2+ exchange, and thereby control intracellular Mg2+ levels. The Mg2+-extruding function of CNNM is inhibited by the direct binding of an oncogenic protein, phosphatase of regenerating liver (PRL), and this inhibition is responsible for the PRL-driven malignant progression of cancers. Studies with mouse strains deficient for the CNNM gene family revealed the importance of CNNM4 and CNNM2 in maintaining organismal Mg2+ homeostasis by participating in intestinal Mg2+ absorption and renal reabsorption, respectively. Moreover, CNNM proteins are involved in various diseases, and gene mutations in CNNM2 and CNNM4 cause dominant familial hypomagnesemia and Jalili syndrome, respectively. Genome wide association studies have also revealed the importance of CNNM2 in multiple major diseases, such as hypertension and schizophrenia. Collectively, the molecular and biological characterizations of CNNM/CorC show that they are an intriguing therapeutic target; the current status of drug development targeting these proteins is also discussed.

Nephrocalcinosis in adolescent girl with medullary sponge kidney and mild hemihypertrophy: A case report.

RATIONALE: Medullary sponge kidney (MSK) is a rare congenital abnormality characterized by cystic dilatation of the medullary collecting tubules. The disorder is likely to be complicated by nephrocalcinosis, urolithiasis, tubular dysfunctions, and urinary tract infections. In addition, it may be rarely associated with extrarenal anomalies. PATIENT CONCERN: We present a case of 17-year old girl who was referred for metabolic evaluation of bilateral nephrocalcinosis. Physical examination showed signs of mild, left-sided hemihypertrophy involving the lower limb, buttock, trunk, face, and tongue. The imaging studies of kidneys including intravenous urography and contrast computed tomography showed numerous medullary calcification and a typical picture of MSK-"paint brush"/"bouquet of flowers" appearance of the dilated tubules within the renal medulla. Laboratory evaluation revealed sterile pyuria, hypercalciuria, and hypocitraturia. INTERVENTION: The patient was subsequently treated with potassium citrate, hydrochlorothiazide, low sodium and low oxalate diet accompanied by high fluid intake. OUTCOMES: After a 1-year therapy the normalization of calciuria and citraturia occurred and no progression of nephrocalcinosis was observed. LESSONS: We conclude that MSK should always be considered as a cause of nephrocalcinosis. Since the final diagnosis requires specific imaging techniques, the concomitant extrarenal abnormalities such as hemihypertrophy may facilitate diagnostic decisions.

An initial evaluation of hypokalemia turned out distal renal tubular acidosis secondary to parathyroid adenoma.

Primary hyperparathyroidism (PHPT) usually presents with hypercalcemia related symptoms and signs. Kidneys play an important role in calcium homeostasis. PHPT has been reported to be associated with hyperchloremia, defective urinary acidification, and renal tubular acidosis (RTA). The dysfunction of distal renal tubules is proposed to be secondary to calcium deposition in distal tubules. This case report highlights an initial presentation of parathyroid adenoma as hypokalemia due to distal RTA secondary to medullary nephrocalcinosis.

Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation.

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3-14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S-UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipient's and donor's urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1-year follow-up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature.

Hereditary causes of kidney stones and chronic kidney disease.

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.

[A case of hypomagnesemia linked to refractory hypokalemia and hypocalcemia with short bowel syndrome].

We report a case of a 59-year old Japanese woman with short bowel syndrome, whose hypokalemia and hypocalcemia were successfully treated with magnesium (Mg) supplementation. Two years previously, she underwent Mile's operation for advanced rectal cancer, which could have been the cause of subsequent extensive resection of the small intestine by strangulation. After serial resection, she gradually developed chronic diarrhea and anorexia. Three weeks before admission, she developed general fatigue and tetany, and was hospitalized at another hospital. On admission, her serum K and Ca were 2.5 mEq/L and 4.3 mg/dL, respectively, hence regular fluid therapy containing potassium (K) and calcium (Ca) was provided following admission. However, her hypokalemia and hypocalcemia persisted, and she also displayed renal dysfunction and thereafter was transferred to our department for further evaluation and treatment. Since the laboratory tests revealed severe hypomagnesemia (0.4 mg/dL), we started intravenous Mg supplementation together with fluid therapy containing K and Ca. After the combination therapy, her clinical symptoms and electrolyte disorders were remarkably improved within a week. As Mg is essential for PTH secretion in response to hypocalcemia and to inhibit the K channel activity that controls urinary K excretion, hypomagnesemia can cause hypocalcemia and hypokalemia, which is refractory to repletion therapy unless Mg is administered. Therefore, for patients who present with signs of Mg deficiency, early and accurate diagnosis of Mg deficiency should be made and corrected.

Primary hyperoxaluria in an adult presenting with end-stage renal failure together with hypercalcemia and hypothyroidism.

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by overproduction of oxalate due to specific enzyme deficiencies in glyoxylate metabolism. The primary clinical presentation is in the form of recurrent urolithiasis, progressive nephrocalcinosis, end-stage renal disease, and systemic oxalosis. Herein, we present a case of PH who was diagnosed at 47 years of age after 6 years on hemodialysis. He presented with fatigue, anorexia, weight loss, and was found to have cachexia, diffuse edema, hepatomegaly, ascites, hypercalcemia, hyperphosphatemia, hypoalbuminemia, low parathyroid hormone levels, lytic and resorptive areas in the vertebrae, diffusely increased echogenity of the liver, multiple renal stones, and bilateral nephrocalcinosis. Bone marrow biopsy showed calcium oxalate crystals and crystal granulomas. The liver biopsy could not be performed. The absence of an identifiable reason for secondary forms, the severity of the clinical presentation, and pathological findings led to the diagnosis of PH2. He died while waiting for a potential liver and kidney donor. The presented case is consistent with the literature as he had renal stone disease in the third decade and end-stage renal disease in the fifth decade. Hypercalcemia was thought to be due to osteoclast-stimulating activity of macrophages constituting the granuloma. Erythropoietin-resistant anemia and hypothyroidism were thought to be due to accumulation of oxalate in the bone marrow and thyroid gland, respectively. It is very important to keep in mind the possibility of PH when faced with a patient with nephrocalcinosis and oxalate stone disease.

Riesgos de la preparación colónica con fosfato sódico / Risks of sodium phosphate colonic cleansing

Introducción. La difusión de la colonoscopía incrementó el uso del fosfato sódico oral (NaP). Se han notificado complicaciones como deshidratación, hipotensión, insuficiencia renal aguda e insuficiencia renal crónica con nefrocalcinosis, y hasta casos fatales de hiperfosfatemia severa. Basado en la evidencia científica actual, en el presente trabajo se presentan los riesgos y contraindicaciones de la utilización de laxantes de fosfato sódico y cómo evitarlos. Material y métodos. Se realizó un análisis bibliográfico sobre el tema en PubMed y Google Advanced Search, de publicaciones en español e inglés, en el que se incluyen ensayos clínicos, revisiones bibliográficas, cartas, editoriales, guías prácticas, meta análisis y revisiones Cochrane. Resultados. Las complicaciones por NaP se relacionan con patologías que incrementan la absorción del fosfato, con hiperparatiroidismo y con disfunción renal. También se asocian con dosis mayores a 60 g y con intervalos entre las tomas menores a 5 h, y son facilitadas por la deshidratación. Se reportaron algunos casos en los que no se respetaron estas condiciones. La insuficiencia renal por nefrocalcinosis es irreversible. Conclusión. Se debe realizar una selección adecuada de los pacientes para evitar el uso de NaP en aquellos que presenten riesgo de desarrollar hiperfosfatemia o insuficiencia renal; además, es necesario efectuar una correcta hidratación oral, no administrar más de 60 g de NaP y evitar que los intervalos entre las dosis sean menores a 5 h.

Introduction. The spread of colonoscopy has increased the use of oral sodium phosphate (OSP). Complications such as dehydration, hypotension, acute renal failure and chronic kidney disease with nephrocalcinosis and even fatal cases of severe hyperphosphatemia have been reported. The risk and contraindications of OSP use and the ways to avoid them are shown in this paper according to the scientific evidence. Material and methods. Bibliographic analysis on this subject is carried in PubMed and Google Advanced Search, publications in Spanish and English, including clinical trials, bibliographic revisions, letters, editorials, practical guidelines, meta analyses and Cochrane reviews. Results. OSP complications are related to pathologies that increase its absorption, with hyperparathyroidism and with kidney impairment. They are also associated with OSP doses >60 g and with dose intervals <5 h and are facilitated by dehydration. Some cases have been reported in patients without those conditions. Nephrocalcinosis kidney disease is irreversible. Conclusion. Adequate patient selection is mandatory to avoid OSP in patients with risk of developing hyperphosphatemia or renal impairment; proper oral hydration is also essential as is not administering more than 60 g OSP, and avoiding dose intervals <5 h.

Introdução. A difusão da colonoscopia aumentou o uso de fosfato de sódio oral (NaP). Têm sido relatadas complicações como desidratação, hipotensão, insuficiência renal aguda e insuficiência renal crônica com nefrocalcinose, e até casos fatais de hiperfosfatemia severa. Com base na evidência científica atual, são apresentados os riscos e contraindicações da utilização de laxantes de fosfato de sódio e a forma de evitá-los. Material e métodos. Foi feita uma análise bibliográfica sobre o tema (publicações em espanhol e inglês) em PubMed e Google Advanced Search que abrange ensaios clínicos, revisões bibliográficas, cartas, editoriais, guias práticos, meta-análise e revisões Cochrane. Resultados. As complicações por NaP se associam a patologias que aumentam a absorção de fosfato, a hiperparatiroidismo e a disfunção renal. Também se associam a doses maiores que 60 g e intervalos entre as tomadas menores que 5 h, e são facilitadas pela desidratação. São relatados casos em estas condições não foram respeitadas. A insuficiência renal por nefrocalcinose é irreversível. Conclusão. Deve ser feita uma seleção adequada dos pacientes para evitar o uso de NaP naqueles com risco de desenvolver hiperfosfatemia ou insuficiência renal; além disso, é necessário realizar uma correta hidratação oral, não administrar mais do que 60 g de NaP e evitar intervalos entre as doses menores que 5 h.

[Hypercalcemia in sarcoidosis--case report, prevalence, pathophysiology and therapeutic options]. / Die Hyperkalzämie im Verlauf der Sarkoidose--Fallbeispiel, Prävalenz, Pathophysiologie und Therapiemöglichkeiten.

Hypercalcemia is a highly prevalent complication of sarcoidosis. A medical history of a patient with sarcoidosis is shown as case report. Depending on the population studied about 2-63% of sarcoidosis patients show hypercalcemia. The major difference in the prevalence of hypercalcemia may be in part due to the undulating course of subacute sarcoidosis, so hypercalcemia may be missed when serum calcium is not frequently measured. Hypercalciuria appears to be twice as prevalent then hypercalcemia and should be looked for in every sarcoidosis patient. Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to an increased absorption of calcium in the intestine and to an increased resorption of calcium in the bone. Immunoregulatory properties have been ascribed to 1,25-dihydroxyvitamin D3. It is an important inhibitor of interleukin-2 and of interferon-gamma-synthesis, two cytokines that are important in granuloma formation in sarcoidosis. It is thought that 1,25-dihydroxyvitamin D3 counterregulates uncontrolled granuloma formation. Treatment of hypercalcemia depends on the serum level of hypercalcemia and its persistence. Generally sarcoidotic patients should be advised to avoid sun exposition to reduce vitamin D3 synthesis in the skin, to omit fish oils that are rich of vitamin D and to produce more than two liters urine a day by adapting fluid intake. Although severe hypercalcemia seems to be rare, glucocorticosteroid treatment should be started if corrected total calcium level rises beyond 3 mmol/l. If hypercalcemia is symptomatic, treatment should be started even at lower levels. Glucocorticosteroids act by inhibition of the overly 1alpha-hydroxylase activity of macrophages. Alternatively, treatment with chloroquine or ketoconazole can be established. If isolated hypercalciuria without hypercalcemia is present with evidence for recurrent nephrolithiasis, patients can be treated with a thiazide diuretic.

Nefrocalcinose associada provavelmente com abuso de furosemida: relato de caso e revisão de literatura / Nephrocalcinosis probably associated with furosemide abuse: case report and review

Introdução: Nefrocalcinose tem sido descrita em neonatos e crianças que fazem uso de furosemida em altas doses por longo período de tempo. Relatamos aqui um caso de nefrocalcinose em uma mulher adulta após o uso de furosemida por dez anos. Relato de caso: Paciente de 27 anos, sexo feminino, admitida com queixa de edema, tendo feito uso de furosemida 40 a 120mg por dez anos. Ultra-sonografia diagnosticou nefrocalcinose, mostrando aumento difuso da ecogenicidade das pirâmides renais. Tratada com suspensão do furosemida. Evolução mostrou regressão do edema e nefrocalcinose persistente. Conclusão: Nefrocalcinose medular associada com abuso de furosemida por tempo prolongado em adulto é relatada e feita revisão de literatura sobre oassunto.

Introduction: Nephrocalcinosis has been described in neonates and infants who used furosemide in high doses for extended periods of time. We report here a case of nephrocalcinosis in an adult female after taking furosemide for ten years. Case report: A 27 year-old, female, admitted for edema took 40to 120 mg of furosemide per day for ten years. Nephrocalcinosis was diagnosed by ultrasonography, which showed a diffuse increase in echogenicity pyramids. Treatment was a furosemide suspension. Evolution showed regression of edema and persistent nephrocalcinosis. Conclusion: A case of medullary nephrocalcinosis associated with long-term furosemide abuse in adults is described and a review of the literature is presented.

Nefrocalsinosis en niños / Nefrocalcinosis in children

Con el advenimiento de estudios de imagen altamente sensibles, como el ultrasonido y la tomografía computada, la nefrocalcinosis (NC) se diagnostica más frecuentemente. Mientras que en muchos casos la NC puede manifestarse de forma leve y reversible, en otros casos puede ser progresiva, causando inicialmente daño tubular y posteriormente daño glomerular. Por lo tanto, el diagnóstico temprano e intervención apropiada son de crucial importancia. Esta revisión abarcará aspectos de la NC en niños, incluyendo etiología, patogénesis, prevención y tratamiento

Endourologic treatment of nephrocalcinosis.

Calcifications of the kidney may be located free within the collecting system, attached to a papilla, trapped beneath the urothelium, or sequestered in the renal parenchyma. Extracorporeal shock wave lithotripsy has failed to render patients who presented with nephrocalcinosis stone free because of the submucosal location of some of the calculi. We report a unique case of symptomatic nephrocalcinosis in which the patient was rendered stone free using flexible ureteroscopy and intrarenal laser and electrohydraulic lithotripsy to treat both the attached and submucosal papillary calculi.

Long-term outcome of paediatric patients with hereditary tubular disorders.

BACKGROUND: An increasing number of children with hereditary tubular disorders (HTD) reach adult life due to diagnostic and therapeutic advances which results in growing need to manage these patients by adult centres. Data on the prevalence and the late clinical problems of these patients are limited. METHODS: We observed 177 paediatric patients with isolated or complex HTD between 1969 and 1994. The median age at the time of diagnosis was 3 (range 0-18) years and the median observation period 10 (range 1-43) years. The long-term outcomes with respect to renal function, bone disease, and body growth were analyzed. RESULTS: The prevalence of HTD was 3.2% of all patients observed in our renal unit and 14% of those patients with chronic renal failure and/ or end-stage renal disease. The three most frequent disorders observed were nephropathic cystinosis (n = 34), X-linked hypophosphataemic rickets (n = 26), and idiopathic hypercalciuria (n = 17). At the last observation, 12% of the patients with isolated HTD and 30% of those with complex HTD had developed preterminal chronic renal failure; end-stage renal disease was observed in 5 and 25%, respectively (p < 0.001). Progressive disease occurred mainly in patients having cystinosis, primary hyperoxaluria, the syndrome of hypomagnesaemia/hypercalciuria, primary Fanconi syndrome, Fanconi-Bickel syndrome, and methylmalonic aciduria. Nephrocalcinosis was found in 42%, urolithiasis in 14%, bone deformities and/or fractures in 28%, and other extrarenal alterations in 29% of all patients. The median body height at last observation was 2.0 SD below the normal mean (range from -10.4 to +2. 6), and the adult height was subnormal in 48% of 67 grown-up patients. Growth retardation was more severe in complex than in isolated HTD. The mortality decreased from 17% in 1969-1981 to 12% in 1982-1994. CONCLUSION: Although HTD are rare nephropathies, their frequently progressive course associated with extrarenal complications requires the attention of nephrologists beyond the paediatric age.

Effects of mineral composition of drinking water on risk for stone formation and bone metabolism in idiopathic calcium nephrolithiasis.

1. To assess whether the mineral content of drinking water influences both risk of stone formation and bone metabolism in idiopathic calcium nephrolithiasis, 21 patients were switched from their usual home diets to a 10 mmol calcium, low-oxalate, protein-controlled diet, supplemented with 21 of three different types of mineral water. Drinking water added 1, 6 and 20 mmol of calcium and 0.5, 10 and 50 mmol of bicarbonate respectively to the controlled diet. 2. The three controlled study periods lasted 1 month each and were separated by a 20 day washout interval. Blood and urine chemistries, including intact parathyroid hormone, calcitriol and two markers of bone resorption, were performed at the end of each study period. The stone-forming risk was assessed by calculating urine saturation with calcium oxalate (beta CaOx), calcium phosphate (beta bsh) and uric acid (beta UA). 3. The addition of any mineral water produced the expected increase in urine output and was associated with similar decreases in beta CaOx and beta UA, whereas beta bsh varied marginally. These equal decreases in beta CaOx, however, resulted from peculiar changes in calcium, oxalate and citrate excretion during each study period. The increase in overall calcium intake due to different drinking water induced modest increases in calcium excretion, whereas oxalate excretion tended to decrease. The changes in oxalate excretion during any one study period compared with another were significantly related to those in calcium intake. Citrate excretion was significantly higher with the high-calcium, alkaline water. 4. Parathyroid hormone, calcitriol and markers of bone resorption increased when patients were changed from the high-calcium, alkaline to the low-calcium drinking water. 5. We suggest that overall calcium intake may be tailored by supplying calcium in drinking water. Adverse effects on bone turnover with low-calcium diets can be prevented by giving high-calcium, alkaline drinking water, and the stone-forming risk can be decreased as effectively as with low-calcium drinking water.

Diagnóstico, prevención y tratamiento de la litiasis renal y de vías urinarias / Diagnosis, prevention and treatment of renal lythiasis and the urinary tract

La litasis de riñón y vías urinarias representa un grave problema de salud pública, por tanto, merece un abordaje sistematizado para evitar su recurrencia mediante métodos de diagnóstico precisos que orientan terapia eficaz. En este trabajo se revisan los resultados de un protocolo que se diseñó para establecer las causas metabólicas responsables de litogenicidad en 626 pacientes estudiados en dos etapas: I (1979-1987) 185 casos. En la etapa I el protocolo incluyó determinaciones en suero y orina de 24 hs de electrolitos, iones divalentes, fosforo, ácido úrico, cistina, filtración glomerular, evaluación del funcionamiento paratiroideo con hormona paratiroidea, Tm fosfato y a partir de 1982 (Ia) con AMP cíclico antes y después de una carga oral de calcio. En la etapa II se añadieron determinaciones de inhibidores de la nucleación de cristales (magnesio y citrato) y de promotores de la misma (oxalato). En 185 casos de la etapa I se desmostró en el 88.2 por ciento de los pacientes alguna variedad de trastorno metabólico, en la etapa II se detectó alguna alteración metabólica en el 96.2 por ciento de los casos. El 55 por ciento de los casos acudieron dos años al seguimiento y el 39 por ciento acudieron hasta cuatro años. El número de cálculos expulsados por paciente por año antes del estudio fue de 2.8 y durante el tratamiento se redujo a 0.8. La elevada eficiencia diagnóstica y la vigilancia sistematizada del tratamiento durante los tres años que siguieron al diagnóstico, resultaron en un abatimiento significativo de la producción de cálculos en este nutrido grupo de pacientes, lo cual justifica la integración de este protocolo a la Clínica de Litiasis Renal y de Vías Urinarias