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Nephropathic cystinosis is a rare lysosomal storage disease whose basic defect, impaired transport of cystine out of lysosomes, results in intracellular cystine storage. Affected individuals exhibit renal Fanconi Syndrome in infancy, end-stage kidney disease at approximately 10 years of age, and many other systemic complications. Oral cysteamine therapy mitigates the detrimental effects on glomerular function and prevents most of the late complications of the disease but has not shown benefit with respect to the early tubular damage of cystinosis. This is because cystinosis is generally diagnosed in the second year of life, after the damage to kidney tubular function has already occurred. We longitudinally evaluated 6 infants diagnosed and treated with cysteamine from before 2 months of age. The 4 infants with good compliance with cysteamine and consistently low leucocyte cystine levels maintained normal eGFR values, exhibited only minor degrees of renal Fanconi Syndrome, and maintained normal serum levels of potassium, bicarbonate, phosphate, and calcium without electrolyte or mineral supplementation through 2, 4, 10 and 16 years of age. Thus, renal Fanconi syndrome can be attenuated by early administration of cysteamine and renew the call for molecular-based newborn screening for cystinosis.

Inherited and acquired disorders that affect proximal tubule endocytosis and lysosomal processing manifest with improper loss of solutes and proteins. The zebrafish pronephros is conserved with humans and is used to model numerous renal conditions, but has few quantitative measures for proximal tubule function. Here, Chen et al. developed a high-throughput assay to quantify proteinuria and lysosomal processing in transgenic zebrafish by labeling vitamin D protein, allowing for precise reporting of proximal tubule function.

Fanconi syndrome, also known as the DeToni, Debré, Fanconi syndrome is a global dysfunction of the proximal tubule characterized by glucosuria, phosphaturia, generalized aminoaciduria, and type II renal tubular acidosis. Often there is hypokalemia, sodium wasting, and dehydration. In children, it typically is caused by inborn errors of metabolism, principally cystinosis. In adults, it is mainly caused by medications, exogenous toxins, and heavy metals. Treatment consists of treating the underlying cause and replacing the lost electrolytes and volume.

Background The leading cause of death in patients with Fukuyama congenital muscular dystrophy (FCMD) is congestive heart failure or respiratory dysfunction, which is same as that in Duchenne muscular dystrophy (DMD). Recent studies reported that renal dysfunction is a common complication and an increasing cause of death in advanced DMD. It can be attributable to circulatory instability or inappropriate use of drugs for treating cardiac dysfunction. Methods We retrospectively evaluated renal function in 38 genetically diagnosed patients with FCMD (range, 1.3–32.9 years; mean age, 13.7 ± 6.9 years) using cystatin C. We examined possible relationships of cystatin C with blood natriuretic peptide and creatinine levels along with cardiac echocardiography findings. Results Twenty-five patients were treated for cardiac dysfunction. Elevated cystatin C level was detected only in two, who also showed proteinuria, glycosuria, hematuria, and extremely high β2-microglobulin levels on urine tests, and were thus diagnosed with renal tubular cell damage. Because both patients were treated for intractable epilepsy with various antiepileptic drugs, including valproic acid (VPA), and had low serum carnitine levels, renal tubular cell damage was considered as an adverse effect of VPA. Unlike patients with DMD, no patient with FCMD had renal dysfunction. Such a rare occurrence of renal dysfunction can be attributable to mild cardiac dysfunction, short disease duration, and careful and early fluid management. Conclusion Renal dysfunction is rare in patients with FCMD; however, renal tubular cell damage should be ascertained, particularly in those undergoing VPA treatment for epilepsy.

Proximal renal tubular acidosis (pRTA) is an inherited or acquired clinical syndrome in which there is a decreased bicarbonate reclamation in the proximal tubule resulting in normal anion gap hyperchloremic metabolic acidosis. In children, pRTA may be isolated but is often associated with a general proximal tubular dysfunction known as Fanconi syndrome which frequently heralds an underlying systemic disorder from which it arises. When accompanied by Fanconi syndrome, pRTA is characterized by additional renal wasting of phosphate, glucose, uric acid, and amino acids. The most common cause of inherited Fanconi syndrome in the pediatric age group is cystinosis, a disease with therapeutic implications. In this article, we summarize the clinical presentation and differential diagnosis of pRTA and Fanconi syndrome and provide a practical approach to their evaluation in children.

Tubulointerstitial nephritis (TIN) is an inflammatory disorder in renal tubules and interstitium without the involvement of glomerular lesions.1 TIN is often induced by drugs and infections, but idiopathic or systemic disease−related forms have also been observed.2 Primary biliary cirrhosis (PBC) is an immune-mediated chronic and progressive cholestatic liver disease.3 Laboratory data show increased serum values of alkaline phosphatase, γ-glutamyl transpeptidase, and IgM. The hallmark of the disease is the circulating antimitochondrial antibody (AMA). PBC is often associated with extrahepatic autoimmune disorders, such as Sjogren syndrome, thyroid disorders, systemic sclerosis, and rheumatoid arthritis.4 Although distal renal tubular acidosis (RTA) has been observed in 33% to 60% of PBC patients,5, 6 TIN and subsequent Fanconi syndrome are relatively rare.7 We report herein a case of TIN associated with asymptomatic PBC, which was diagnosed after 4 years of treatment for TIN and Fanconi syndrome.

Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for both naïve and experienced patients with chronic hepatitis B (CHB), although reduced estimated glomerular filtration rate (eGFR), hypophosphatemia, hyperphosphaturia and Fanconi syndrome have been reported in some patients. Entecavir (ETV) could be considered as a rescue therapy for TDF-treated patients developing renal dysfunction, though patients with prior history of treatment with lamivudine (LAM) can develop ETV resistance strains, which can lead to potentially severe hepatitis flares. Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has recently been developed to improve the renal and bone safety profile compared to TDF, while maintaining the same virologic efficacy. The recently published 48-week phase III TAF registration studies confirmed the superior safety profile. Here we describe a case of a 75-year-old woman with HBV mono-infection and compensated cirrhosis who developed ETV resistant strains and grade 3 chronic kidney disease after many years of LAM and adefovir (ADV) treatment and a TDF-induced Fanconi syndrome. The administration of 25mg/day of TAF, granted as part of a compassionate use program, rapidly suppressed viral replication to undetectable levels without worsening renal function or side effects.

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La Presse Medicale - In Press.Proof corrected by the author Available online since mercredi 4 janvier 2017

ARC syndrome (arthrogryposis - renal dysfunction - cholestasis) is a rare lethal multisystemic autosomal recessive disease. A newborn of consanguineous parents of Algerian descent presented cholestatic jaundice, dehydration, and Fanconi syndrome at 10 days of life. The blood smear showed a very characteristic gray appearance of platelets. A homozygous mutation was evidenced in the VPS33B gene. This gene codes for a protein involved in trafficking of intracellular vesicles. The mutation (c.604-2A>G) present in the heterozygous state in the parents affects an invariant base of the splice acceptor site and to our knowledge has not been reported yet. This child died at the age of 3 months. Prenatal diagnosis was offered to the family; another pregnancy was carried to completion and a girl was born without the disease. The combination of cholestasis and proximal tubulopathy should suggest the diagnosis in a newborn with orthopedic problems. A blood smear greatly facilitates diagnosis.

Crystalline nephropathy is a rare yet well-known condition associated with multiple myeloma and other light chain–secreting disorders. Paraproteins that are resistant to proteolysis crystallize within proximal tubular cells and cause light-chain proximal tubulopathy, which presents clinically as Fanconi syndrome. Podocytes are rarely affected, and the crystalline inclusions within podocytes are typically precipitated, yielding significant glomerular proteinuria. Here we report a case of extensive crystalline inclusions primarily within podocytes and proximal tubules that presented only with Fanconi syndrome and renal insufficiency. Despite the presence of extensive crystalline inclusions in podocytes and diffuse foot process effacement, the patient had no clinical evidence suggestive of podocyte injury.

ResumenEl síndrome de Lowe es un trastorno raro con afectación multiorgánica y herencia recesiva ligada a X. Presenta repercusión a nivel de sistema nervioso central, riñones y ojos, siendo las manifestaciones más frecuentes el retraso del desarrollo psicomotor, síndrome de Fanconi, cataratas y glaucoma congénito. Los estudios enzimáticos y moleculares son de ayuda en el diagnóstico. El tratamiento incluye: cirugía de catarata, control de glaucoma, terapia física y de lenguaje, medicamentos para manejo de la conducta y la corrección de la acidosis tubular y alteraciones óseas mediante la utilización de bicarbonato, fosfato y potasio. El pronóstico para la función y la vida es malo, presentando una supervivencia alrededor de los 40 años. Presentamos el caso de un síndrome de Lowe con afectación renal, cataratas y glaucoma bilateral que fueron intervenidos quirúrgicamente mediante trabeculectomía con mitomicina C y lensectomía con vitrectomía anterior. Es importante conocer las repercusiones potencialmente mortales de este síndrome para iniciar manejo multidisciplinario de manera oportuna.AbstractLowe syndrome is an infrequent condition that affects several organs including the brain, kidneys and eyes inherited in an X-linked pattern. The most frequent abnormalities found are psychomotor retardation, Fanconi's syndrome and congenital cataracts and glaucoma. Enzymatic and molecular tests are available for confirmation of the diagnosis and for prenatal detection of the disease. The treatment includes: cataract extraction, glaucoma control, physical and speech therapy, use of drugs to address behavioural problems, and correction of the tubular acidosis and the bone disease with the use of bicarbonate, phosphate and potassium. Life span rarely exceeds 40 years. We present a case of Lowe's syndrome with renal abnormalities, bilateral cataracts and glaucoma, which were treated by trabeculectomy with mitomicin-C and lensectomy with anterior vitrectomy. It is important to acknowledge the potentially lethal repercussions to initiate an early multidisciplinary treatment.

Summary: We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing β-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity, mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na+/K+-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells. : Assmann et al. examine the molecular mechanism underlying a recently described Fanconi syndrome. Mistargeting of the peroxisomal protein EHHADH to mitochondria leads to impaired mitochondrial fatty acid β-oxidation and respiration, resulting in decreased ATP production. Diminished transport activity leads to the observed Fanconi syndrome. Keywords: Fanconi syndrome, mitochondriopathy, fatty acid oxidation, supercomplexes

Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to tenofovir disoproxil fumarate (TDF). Although potent and generally well tolerated, TDF therapy has been associated with changes in markers of renal function, decreases in bone mineral density and a rare occurrence of serious renal adverse events, including Fanconi's Syndrome. The renal and bone toxicity observed with TDF is associated with high circulating plasma levels of TFV. TAF was discovered to be a more efficient prodrug able to further refine HIV therapy and better address life-long therapy in an older and increasingly comorbid HIV infected population. By enhancing stability in biological matrices while being rapidly activated in cells, TAF produces higher levels of intracellular TFV diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially reduced oral doses of TFV equivalents. All TFV released in the body is eventually eliminated renally; therefore, lowering the TFV equivalents administered reduces off-target kidney exposure. Effective therapy is thus achieved at approximately 90% lower systemic exposure to TFV, translating to statistically and clinically significant improvement in safety parameters associated with bone mineral density and markers of renal function.

Apremilast is a recently developed phosphodiesterase 4-inhibitory medication approved for use to treat psoriasis and psoriatic arthritis. We report a case of Fanconi syndrome and proximal renal tubular acidosis that was associated with this medication. Our patient was started on treatment with apremilast 2 weeks before his admission. On arrival, laboratory test results were significant for hypokalemia, hyperchloremic metabolic acidosis, low uric acid concentration, positive urine anion gap, and proteinuria, which resolved on discontinuation of the drug. Two months after the hospitalization, he was restarted on apremilast therapy; 17 days after resumption, the patient was admitted for similar laboratory values, which again improved when apremilast treatment was discontinued. After discharge, laboratory values remained normal without long-term electrolyte repletion. Proximal renal tubular acidosis (Fanconi syndrome) with quick correction of electrolyte concentrations on discontinuation of the drug was diagnosed. Our patient lacked evidence of other causes. Our patient fulfilled criteria associated with this disease and responded well off treatment with the offending agent. Literature review did not reveal prior cases associated with this medication.

Inherited metabolic conditions of the kidney are uncommon but require consideration as diagnostic clarity informs specific treatment which improves outcomes considerably and allows children with life limiting disorders to experience greater longevity. This article focuses on four conditions, cystinosis, methylmalonic aciduria (MMA), primary hyperoxaluria and Fabry's disease. These conditions often present with renal impairment, predominantly in childhood, but with appropriate treatments survival well into adult life is becoming more common. Recognition of the genetic mutations, phenotypic variability and specific treatment options can improve long term prognosis.

ResumenIntroducciónLa cistinosis es una enfermedad lisosomal minoritaria de expresión sistémica con especial afectación renal y oftalmológica, en la que los pacientes inician terapia renal sustitutiva en la primera década de la vida en ausencia de tratamiento. El pronóstico de la cistinosis depende del diagnóstico precoz, la pronta instauración del tratamiento con cisteamina y el buen cumplimiento terapéutico. La progresión de la enfermedad renal y de las complicaciones extrarrenales y una menor supervivencia, son más acentuadas en pacientes no adherentes.ObjetivoEl objetivo de este trabajo fue la elaboración de unas recomendaciones para la atención integral de la cistinosis y la transición del adolescente a la medicina del adulto, basadas en la experiencia clínica, con el fin de reducir el impacto de la enfermedad y mejorar la calidad de vida y el pronóstico del paciente.MétodoBúsqueda bibliográfica y reuniones de consenso de un equipo multidisciplinar de expertos en la práctica clínica con pacientes afectos de cistinosis (Grupo T-CiS.bcn), procedentes de 5 hospitales localizados en Barcelona.ResultadosEl documento recoge recomendaciones específicas y necesarias para el diagnóstico, tratamiento y seguimiento multidisciplinar de la cistinosis en las siguientes áreas: nefrología, diálisis, trasplante renal, oftalmología, endocrinología, neurología, laboratorio, consejo genético, enfermería y farmacia.ConclusionesDisponer de un documento de referencia para la atención integral de la cistinosis constituye una herramienta de soporte para los profesionales de la salud que asisten a estos pacientes. Los principales pilares en los que se sustenta son: a) el enfoque multidisciplinar, b) la adecuada monitorización de la enfermedad y control de los niveles de cistina intraleucocitarios, c) la importancia de la adherencia al tratamiento con cisteamina y d) la promoción del autocuidado del paciente mediante programas de educación en la enfermedad. Todo ello conducirá, en una segunda fase, a la elaboración de un modelo de transición coordinado entre los servicios de pediatría y de adultos que contemple las necesidades específicas de la cistinosis.AbstractIntroductionCystinosis is a rare lysosomal systemic disease that mainly affects the kidney and the eye. Patients with cystinosis begin renal replacement therapy during the first decade of life in absence of treatment. Prognosis of cystinosis depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in those patients that do not follow treatment.The objective of this work was to elaborate recommendations for the comprehensive care of cystinosis and the facilitation of patient transition from paediatric to adult treatment, based on clinical experience. The goal is to reduce the impact of the disease, and to improve patient quality of life and prognosis.MethodsBibliographic research and consensus meetings among a multidisciplinary professional team of experts in the clinical practice, with cystinotic patients (T-CiS.bcn group) from 5 hospitals located in Barcelona.ResultsThis document gathers specific recommendations for diagnosis, treatment and multidisciplinary follow-up of cystinotic patients in the following areas: nephrology, dialysis, renal transplant, ophthalmology, endocrinology, neurology, laboratory, genetic counselling, nursing and pharmacy.ConclusionsA reference document for the comprehensive care of cystinosis represents a support tool for health professionals who take care of these patients. It is based on the following main pillars: a) a multi-disciplinary approach, b) appropriate disease monitoring and control of intracellular cystine levels in leukocytes, c) the importance of adherence to treatment with cysteamine, and d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated transition model between paediatric and adult care services which will cover the specific needs of cystinosis.

Introduction Cystinosis is a rare systemic lysosomal storage disease that mainly affects the kidney and the eye. Renal replacement therapy is started in patients with cystinosis during the first decade of life in the absence of treatment. The prognosis of cystinosis depends on early diagnosis and the prompt start of and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in patients who do not adhere to treatment. Objective The aim of this work was to establish recommendations for the comprehensive care of cystinosis and facilitate patient transition from paediatric to adult medicine, based on clinical experience. The goal is to reduce the impact of the disease and improve prognosis and patient quality of life. Methods Bibliographic research and consensus meetings with a multidisciplinary professional team of clinical experts in cystinosis (T-CiS.bcn group) from 5 hospitals in Barcelona. Results This consensus document gathers specific recommendations for the diagnosis, treatment and multidisciplinary care of cystinotic patients in the following areas: nephrology, dialysis, kidney transplantation, ophthalmology, endocrinology, neurology, laboratory, genetic counselling, nursing and pharmacy. Conclusions Guidelines for the comprehensive care of cystinosis provide a support tool for health professionals who look after these patients. They are based on the following main pillars: (a) a multidisciplinary approach; (b) appropriate disease monitoring and control of white blood cell (WBC) cystine levels; (c) the importance of adherence to cysteamine treatment; and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated model of transition from paediatric to adult care services which will cover the specific needs of cystinosis.

Aim: To describe the characteristics of hypophosphatemia in severely disabled individuals with neurological disorders and to identify its causative factors. Method: We retrospectively reviewed clinical data from 82 individuals with motor skills classified as sitting, rollover or bedridden. Age, gender and body mass index were compared in individuals with (n = 19) and without (n = 63) a history of hypophosphatemia (serum phosphate levels

Background Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1. Methods Five HT1 patients (age between 5 and 53 months) with different types of presentation were evaluated before and during the first 2 weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function. Results Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48 h, while the other markers of renal dysfunction showed an improving trend over 2 weeks. Conclusions NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.

Kearns-Sayre syndrome (KSS), resulting from a mitochondrial DNA deletion, is a rare cause of diabetes in children. We report 2 pediatric cases of KSS associated with diabetes that presented with hyperosmolar hyperglycemia with minimal ketosis. Both patients were treated initially with isotonic fluid resuscitation followed by intravenous insulin infusion. The first case was a boy of Blackfoot Aboriginal ancestry who presented with failure to thrive, developmental delay and Fanconi syndrome and was diagnosed with KSS at 3 years of age. At 4 years he presented with a cough and left upper lobe lung infiltrate as well as a hyperosmolar hyperglycemic episode. He subsequently required multiple daily insulin injections. This patient developed cardiomyopathy and died at the age of 10 years. The second case was a 6-year-old boy of Asian ancestry who presented with ataxia exacerbated by intercurrent illnesses, decreased exercise tolerance, gross motor and fine motor delays, anorexia and recurrent episodes of vomiting associated with dehydration, and he was subsequently diagnosed with KSS. At 11 years of age, the patient developed hyperosmolar hyperglycemia, and after treatment for it, he required multiple daily insulin injections. He died of end stage congestive heart failure secondary to cardiomyopathy at 13 years of age. These 2 cases are presented to describe the possible pathophysiology of mitochondrial diabetes and to emphasize the need to monitor for the development of diabetes in patients with known mitochondrial disease and also to be aware of possible mitochondrial disease in pediatric patients who present with hyperglycemia in the context of multisystem involvement.

Lymphoplasmacytic neoplasms cause a wide range of injuries to the kidney exemplified by light chain cast nephropathy and amyloidosis. Filtered paraproteins can also accumulate within kidney cells and cause direct cytotoxic injury. Rarely, paraproteins that are resistant to proteolysis can crystallize within proximal tubules and cause acute tubular injury. In contrast, accumulation of crystallized paraproteins in other kidney cells, especially podocytes, is exceptional. Here, we report the finding of crystalline inclusions within podocytes and proximal tubules in a patient who presented with a combined nephrotic syndrome and Fanconi syndrome. Further workup revealed previously unsuspected multiple myeloma and elevated serum free light chains, highlighting the protean presentation of paraprotein-mediated injuries to the kidney.

Introduction Carboplatin is a congener of cisplatin used in the treatment of ovarian, head and neck and small-cell lung cancer. However, the clinical efficacy of carboplatin is marred by the development of ROS-dependent nephrotoxicity. The pathophysiological damage inflicted upon the kidney by carboplatin closely resembles to that of Fanconi syndrome. Aims and objectives The present study aimed at inducing Fanconi-like syndrome in rats by administration of carboplatin. Objectives of the study involved evaluation of biochemical parameters coherent to Fanconi-like syndrome. Further, an attempt was made to evaluate the potential therapeutic effect of pentoxifylline in this condition. Results The results of the study demonstrated that the urinary excretion profile of carboplatin treated rats closely resembled to that of patients suffering from Fanconi-like condition. Pentoxifylline was able to ameliorate this nephrotoxic condition as suggested by the change in levels of membrane bound ATPases, MDA and GSH. The urinary levels of tyrosine and cysteine correlate well with that of Fanconi-like condition in animals and humans. Conclusion In lieu of these observations, our study suggested that carboplatin-induced renovascular damage resembles to Fanconi-like condition which can be mitigated by pentoxifylline.

Multiple myeloma is a malignant plasma cell disorder characterized by the overproduction of monoclonal proteins. The kidney is 1 of the major target organs of multiple myeloma. Most often, this is the result of the monoclonal proteins, which can injure the kidney via several mechanisms. In some cases, direct invasion by myeloma cells and/or bone marrow cells can also result in kidney injury. A kidney biopsy can help distinguish the various myeloma-related kidney diseases and aid in the treatment plan.

The HNF4A p.R76W mutation causes congenital hyperinsulinism with Fanconi syndrome. Here, we report two cases who also presented with increased urinary calcium excretion and one had a transient hepatic dysfunction with hepatomegaly. Clinical variations including transient liver dysfunction is a likely mutation-specific clinical characteristic.

La Presse Medicale - In Press.Proof corrected by the author Available online since mardi 23 decembre 2014

Item does not contain fulltext OBJECTIVES: To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN: Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS: All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION: Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.

ResumenIntroducciónEl tenofovir (TDF) es un inhibidor de la transcriptasa reversa análogo de nucleótidos, aunque tiene buena tolerabilidad y alta actividad antirretroviral, su efecto sobre el riñón ha sido un motivo de preocupación.ObjetivoDescribir el caso de una niña infectada por VIH que presenta síntomas y hallazgos de laboratorio compatibles con un síndrome de Fanconi durante el tratamiento con TDF como parte de su terapia antirretroviral.Caso clínicoNiña infectada por el VIH-1, que después de 18 meses con el tratamiento con TDF presentó pérdida de fuerza y dolor de las extremidades inferiores con deterioro funcional. Los hallazgos de laboratorio fueron compatibles con el síndrome de Fanconi. Las radiografías mostraron fractura bilateral de cadera y muñecas. El síndrome de Fanconi se recuperó por completo cuatro meses después del cambio de terapia antirretroviral.ConclusionesLos médicos que prescriben TDF deben estar preparados para detectar signos y síntomas indicativos de disfunción renal y considerar de inmediato el cambio del fármaco a otro antirretroviral.AbstractIntroductionTenofovir (TDF) is an inhibitor of reverse transcriptase nucleotide analogue, although it has good tolerability and high anti-retroviral activity, its effect on the kidney has been a concern.ObjectiveTo describe a girl infected with HIV who presented Fanconi syndrome during antiretroviral therapy with TDF.Clinical caseWe describe a HIV-1-infected girl, who after 18 months treatment with TDF presented loss of strength and pain of the lower extremities with functional impairment. Laboratory findings were consistent with Fanconi syndrome. Radiographs showed bilateral hip fracture and wrists. Full recovery of Fanconi syndrome was achieved four months after changing antiretroviral therapy.ConclusionsTDF-prescribing physicians must be prepared to detect signs and symptoms of renal dysfunction and immediately consider switching to another antiviral drug.

In cystinosis, renal proximal tubule (RPT) function is compromised, due to mutations in ctns, which encodes for the transporter cystinosin, which removes cystine from lysosomes. Altered RPT function in cystinosis has been attributed to decreased ATP, as well as increased apoptosis. In this report, the role of AMPK was examined. AMPK was activated in primary rabbit RPT cells with a cystinosin knockdown, using cystinosin siRNA. The activation of AMPK was associated with a 50% decrease in ATP and a 1.7-fold increase in the ADP/ATP level. Cisplatin-induced apoptosis also increased in primary RPT cells with a cystinosin knockdown. The role of AMPK in the increased sensitivity to cisplatin was examined. The increased sensitivity to cisplatin was prevented in primary RPT cells with a cystinosin knockdown by the AMPK inhibitor Compound C. The effect of siRNAs against AMPKα1 and AMPKα2 was also studied. The siRNAs knocked down AMPKα, and prevented AMPKα activation by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR). The siRNAs against AMPKα1 and AMPKα2 also prevented the increased sensitivity to cisplatin in the primary RPT cells with a cystinosin knockdown. These results suggest that signaling through AMPK plays a role in the enhanced apoptosis in the RPT in cystinosis.

Acute kidney injury in myeloma, a serious complication associated with poor prognosis, is generally mediated by the toxic and inflammatory effects of monoclonal free light chains (FLCs) on kidney proximal tubule cells and by the formation of intratubular casts through interaction with Tamm-Horsfall proteins. Production of excessive quantities of FLCs is seen in most cases of FLC-associated kidney injury, although a direct relation between quantity and nephrotoxicity does not exist, indicating variable toxicity among light chain species. Toxic effects of FLCs include inhibition of transport functions, Fanconi syndrome, generation of reactive oxygen species, cytoskeletal abnormalities, and apoptosis and necrosis in proximal tubule cells. Excessive endocytosis of FLCs in proximal tubule cells also induces cell stress responses that result in stimulation of inflammatory pathways through activation of nuclear transcription factors κB and mitogen-activated protein kinases, induction of proinflammatory cytokines, and epithelial to mesenchymal transition. The mechanisms of nephrotoxicity of FLC described here explain the basis of acute kidney injury seen in patients with multiple myeloma and provide the rationale for eliminating or reducing the FLC burden in myeloma patients with renal involvement. The inflammatory pathways that are activated as a result of FLC toxicity also show clearly how severe chronic tubulointerstitial nephritis can occur in patients with myeloma kidney and identify several attractive opportunities for novel therapeutic interventions.

Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.

Nephropathic cystinosis is an autosomal recessive disorder caused by mutations in the CTNS gene [1] , which encodes for a transporter (cystinosin) responsible for cystine efflux from lysosomes. In cystinotic renal proximal tubules (RPTs), the defect in cystinosin function results in reduced reabsorption of solutes by apical Na+/solute cotransport systems, including the Na+/phosphate (Pi) cotransport system [2] . However the underlying molecular mechanisms are unknown, given the lack of an appropriate cellular model. To obtain such a model system, we have knocked down cystinosin with siRNA in primary RPT cell cultures. An 80% reduction in cystinosin strongly inhibited Na+ dependent Pi uptake (70%). Although this finding could be explained by a direct effect on transporters as well as by altered energetics (the ATP level dropped by 52%), our results demonstrate a lack of involvement of Na, K-ATPase, and a reduction in the number of NaPi2a transporters.

Nephropathic cystinosis results from lysosomal cystine storage and, if untreated with cysteamine, results in end-stage renal disease by 10 years of age. The renal Fanconi syndrome occurs in the first year of life and is accompanied by a characteristic "swan neck" deformity of the proximal renal tubule. The linkage between cystine storage, Fanconi syndrome, and renal failure has not been understood. This study reports the presence of substantial numbers of atubular glomeruli (ATG) in end-stage cystinotic renal tissue. Compared to normal renal tissue, cystinotic kidneys at end stage had 69% atubular glomeruli and 30% atrophic glomeruli. Normal renal tissue had 4% ATG and 0% atrophic glomeruli (p

Ig-related renal diseases occurring in lymphoplasmacytic disorders (LPD) cover a wide spectrum of renal lesions. Except for cast nephropathy, which is almost specific for multiple myeloma, similar renal lesions caused by deposition or precipitation of monoclonal Ig-related material may occur in the various types of LPD. Because the secreted Ig provides the link between the LPD and the kidney disease, the renal outcome is linked to efficacy of chemotherapy. In the past 10 years, considerable advances have occurred in chemotherapy regimens with the advent of new classes of drugs, which already result in markedly improved renal and vital survival.

The oculocerebrorenal syndrome of Lowe, an X-linked multisystem disorder, was diagnosed in a male patient who presented with typical abnormalities of the eyes, kidneys and nervous system. Besides congenital cataracts, renal tubular dysfunction and psychomotor retardation, the patient had also suffered from profound failure to thrive, growth hormone deficiency, severe osteoporosis with hypophosphatemic rickets, and progressive renal dysfunction since early childhood, which were attributed to the metabolic derangements following Fanconi syndrome. Direct sequencing of the OCRL1 gene (responsible for the oculocerebrorenal syndrome of Lowe) revealed a de novo c.2282_2283insT in exon 20, which resulted in premature termination of translation (D762X). After monthly intravenous administration of pamidronate since the age of 17.8 years, his urine creatinine clearance and tubular resorption of phosphate increased slightly and bone mineral density was much improved (Z score increased from −7.3 to −3.3) without deterioration of renal function. Simultaneous growth hormone therapy enhanced the positive response. The beneficial osseous and renal effects of the bisphosphonate, along with growth hormone treatment in Lowe syndrome with hypophosphatemia, may be related to reduced renal calcium and phosphate excretion.

The multiple and complex functions of the renal tubule in regulating water, electrolyte, and mineral homeostasis make it prone to numerous genetic abnormalities resulting in malfunction. The phenotypic expression depends on the mode of interference with the normal physiology of the segment affected, and whether the abnormality is caused by loss of function or, less commonly, gain of function. In this review we address the current knowledge about the association between the genetics and clinical manifestations and treatment of representative disorders affecting the length of the nephron.

CASE PRESENTATION A 6-year-old Korean-American boy was found to have asymptomatic proteinuria and glycosuria during routine urinary screening. His birth was complicated by polyhydramnios. His 4-year-old brother was also found to have glycosuria and proteinuria on routine urinalysis (Table 1). There was no history of hematuria, renal failure, hearing loss, or nephrolithiasis. He was taking no medications. There was no other family history of renal disease or renal calculi. Physical examination revealed a healthy-appearing young boy with a normal blood pressure of 90/60 mm Hg and no edema. Physical examination was normal, and there was no evidence of cataracts, rickets, or mental retardation. Height and weight were in the 25th percentiles. Renal ultrasound showed 7.5 cm kidneys with echogenic medullary regions and one echogenic focus suggestive of a calculus. Laboratory examination showed a hematocrit of 34.4% (normal 37–45%), white blood cell count 10.7 10/L (normal 4.5–13.5 10/L) with normal differential, platelet count 527 10/L (normal 150–450 10/L), blood urea nitrogen 15 mg/dL (5.4 mmol/L) (normal 7–18 mg/dL (2.5–6.4 mmol/L)), serum creatinine 0.3 mg/dL, total serum protein 7.6 g/dL (76 g/L) (normal 6–8.2 g/dL (60–82 g/L)), serum albumin 4.3 g/dL (43 g/L) (normal 3.4–5.0 g/dL (34–50 g/L)). The serum electrolytes, including calcium, magnesium, and phosphorus were normal. TCO2 was 25.7 mM (normal 22–32 mM). Serologic testing for antinuclear antibody was negative and the serum complement levels, including C3 and C4, were within normal range. Urinalysis revealed a specific gravity of 1030, pH 5, protein 4300 mg/dL, glucose 100 mg/dL, heme moderate, and leukocyte esterase negative. The urine protein/creatinine ratio was 4.3 and the urine calcium/creatinine ratio was 0.339 (normal o0.200). Urine protein electrophoresis revealed 354 mg/dL of protein of which 26% was albumin with a large fraction of low molecular weight proteins and a markedly elevated b2-microglobulin of 159 000mg/dL (normal 0–300mg/dL). The urinary amino-acid profile showed no abnormality. Urinary uric acid was 633.6 mg/dL (normal 250–750 mg/dL), magnesium 54 mg/24 h (normal 12–293 mg/24 h), phosphorus 880 mg/24 h (normal 400–1300 mg/24 h), and copper 32mg/24 h (normal 3–25mg/24 h). The clinical differential diagnosis included conditions, both inherited and acquired, that impair proximal tubular function producing a partial Fanconi syndrome (glycosuria and low molecular weight proteinuria (LMWP), without proximal renal tubular acidosis, aminoaciduria, or hyperphosphaturia). Acquired conditions to be considered in this age group include heavy metal toxicity, anti-tubular basement membrane nephritis, and other forms of interstitial nephritis. The family history of two affected brothers strongly suggested an inherited disorder, possibly X-linked or autosomal recessive. Inherited forms of Fanconi syndrome to be considered include Dent disease, Lowe syndrome, cystinosis, and a mitochondriopathy. In addition, causes of hypercalciuria such as hyperparathyroidism or excessive calcium intake were considered, although the absence of hypercalcemia and the presence of proteinuria argued against that possibility. Among causes of inherited Fanconi syndrome, Dent disease is the only form that typically manifests marked hypercalciuria. A renal biopsy was performed to determine the cause of the subnephrotic proteinuria and glycosuria. t h e r e n a l c o n s u l t http://www.kidney-international.org

Chronic kidney disease in patients with HIV is being recognized as one of the most frequent comorbidities of this disease and consequently much research is currently being performed in this area. The possible manifestations are highly varied and consequently a high index of suspicion is required. Appropriate investigations should be performed from the moment patients first seek care to rule out renal disease and to prevent worsening, with the diagnostic or therapeutic measures that may subsequently be required. One of the most common problems is nephrotoxicity caused by some drugs and cases associated with tenofovir are becoming more frequently described. However, there is wide clinical experience with this drug and renal toxicity associated with its use is uncommon both in clinical trials and in clinical practice. Familiarity with what may happen, the associated factors and appropriate patient management are essential.

We describe the case of a 17-year-old girl who was admitted to our clinic for drug poisoning. Twelve hours after the ingestion of 25 tablets of aspirin (12.5 g of acetylsalicylic acid), the patient had a generalized proximal tubular dysfunction characterized by glucosuria (in the face of normal serum glucose levels), proteinuria, and uric acid wasting. Further characterization of the tubular dysfunction using high-resolution proton nuclear magnetic resonance spectroscopy of the urine showed a pattern consistent with proximal tubular injury. An important characteristic of the salicylate-induced proximal tubular dysfunction in our patient was its rapid reversibility. A trend toward normalization of fractional excretion values of electrolytes was observed 2 days after ingestion. Determination of serum and urine metabolites and spectroscopy of urine 15 days later showed no evidence of tubular dysfunction. The mechanisms potentially implicated in the pathogenesis of salicylate-induced Fanconi syndrome are discussed and a brief review of the relevant literature is provided. Am J Kidney Dis

The objective is to describe a case of probable aminoglycoside-induced Fanconi syndrome and make clinicians aware of the existence of this underrecognized and underdiagnosed complication in patients treated with a prolonged course of high-dose aminoglycosides. A 53-year-old man admitted for recurrent infective exacerbations of chronic bronchiectasis already colonized with Pseudomonas aeruginosa was treated intermittently with intravenous gentamicin (320 to 560 mg/d) for a total of 4 months to a total cumulative dose of 9.4 g. The patient developed profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria. Electrolyte disturbances persisted until gentamicin therapy was stopped, recurred with rechallenge, and did not correct with calcium and phosphate supplementation. This case shows that prolonged exposure to high-dose aminoglycoside therapy can be associated with Fanconi syndrome, which is a manifestation of proximal tubular dysfunction. There are only a few case reports to date of Fanconi syndrome as a probable complication of high-dose aminoglycoside therapy. The Naranjo Adverse Drug Reaction probability scale score indicated that this was a probable adverse reaction associated with administration of high-dose aminoglycosides. The differential diagnosis of electrolyte disturbances as a manifestation of proximal tubule dysfunction and type 2 renal tubular acidosis is vast; however, Fanconi syndrome needs to be considered in patients treated with high doses of aminoglycosides for longer than 6 days, after more common causes of hypophosphatemia are excluded.

To describe a unique example of renal tubular acidosis type 2 (RTA 2) in conjunction with Fanconi's syndrome and osteomalacia consequent to vitamin D and calcium deficiency in an adult without underlying gastrointestinal disease.We review the clinical, hormonal, histomorphometric, and micro-computed tomographic findings and the response to therapy with vitamin D and calcium in our patient.On admission, a 33-year-old African American woman had the following laboratory findings: serum ionized calcium 3.8 mg/dL (0.95 mmol/L), venous pH 7.26, bicarbonate 20 mEq/L, chloride 111 mEq/L, alkaline phosphatase 1,192 U/L (20.26 microkat/L) (normal, 40 to 136 U/L), 25-hydroxyvitamin D5 ng/mL (12 nmol/L) (normal, 10 to 60 ng/mL), parathyroid hormone 1,620 pg/mL (165.2 pmol/L) (normal, 10 to 60 pg/mL), aldosterone 68.4 ng/dL (1,894.7 pmol/L) (normal, 4.5 to 35.4 ng/dL), supine plasma renin activity 19.8 ng/mL per hour (5.35 ng/L per second) (normal, 0.5 to 1.8 ng/mL per hour), and aminoaciduria. A lumbar spine bone density T-score was -4.6, and a femoral neck T-score was -4.9. An undecalcified tetracycline-labeled bone biopsy specimen showed severe osteomalacia, severe osteoporosis, and peritrabecular fibrosis. A small intestinal biopsy revealed normal findings. Results of an ammonium chloride loading test and a bicarbonate infusion test were consistent with RTA 2. After 24 months of vitamin D and calcium therapy, results of serum and urine chemistry studies and bicarbonate infusion normalized. The lumbar spine T-score improved to -2.0, and the femoral neck T-score improved to -2.7. Bone biopsy specimens demonstrated resolution of the osteomalacia.Nutritional vitamin D and calcium deficiency may cause RTA 2, Fanconi's syndrome, and osteomalacia in adults as well as in children.