Background
Distal renal tubular acidosis (dRTA) is characterized by hyperchloraemic metabolic acidosis, hypokalaemia, hypercalciuria and nephrocalcinosis. It is due to reduced urinary acidification ...by the α-intercalated cells in the collecting duct and can be caused by mutations in genes that encode subunits of the vacuolar H
+
-ATPase (
ATP6V1B1
,
ATP6V0A4
) or the anion exchanger 1 (
SLC4A1
). Treatment with alkali is the mainstay of therapy.
Methods
This study is an analysis of clinical data from a long-term follow-up of 24 children with dRTA in a single centre, including a genetic analysis.
Results
Of the 24 children included in the study, genetic diagnosis was confirmed in 19 patients, with six children having mutations in
ATP6V1B1
, ten in
ATP6V0A4
and three in
SLC4A1
; molecular diagnosis was not available for five children. Five novel mutations were detected (2 in
ATP6V1B1
and 3 in
ATP6V0A4
). Two-thirds of patients presented with features of proximal tubular dysfunction leading to an erroneous diagnosis of renal Fanconi syndrome. The proximal tubulopathy disappeared after resolution of acidosis, indicating the importance of following proximal tubular function to establish the correct diagnosis. Growth retardation with a height below −2 standard deviation score was found in ten patients at presentation, but persisted in only three of these children once established on alkali treatment. Sensorineural hearing loss was found in five of the six patients with an
ATP6V1B1
mutation. Only one patient with an
ATP6V0A4
mutation had sensorineural hearing loss during childhood. Nine children developed medullary cysts, but without apparent clinical consequences. Cyst development in this cohort was not correlated with age at therapy onset, molecular diagnosis, growth parameters or renal function.
Conclusion
In general, the prognosis of dRTA is good in children treated with alkali.
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the ...reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
Purpose
Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). ...Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet.
Methods
In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus
n
= 11 patients, everolimus
n
= 1 patient, flucloxacillin
n
= 11 patients).
Results
The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (
p
= 0.009) and after flucloxacillin treatment (
p
= 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed.
Conclusions
Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.
Background
Cystinosis is a rare, inherited autosomal recessive disease caused by the accumulation of free cystine in lysosomes. It is treated by the administration of cysteamine, which should be ...monitored by trough white blood cell (WBC) cystine measurements to ensure effective treatment.
Case-Diagnosis/Treatment
The index case had an older brother who had previously been diagnosed with cystinosis, allowing early diagnosis of the index case at the age of 5 months. Cysteamine therapy was started at the age of 3 years; however, monitoring of WBC cystine levels did not occur on a regular basis during most of his life. Growth retardation improved after correction of electrolyte disturbances, the initiation of cysteamine therapy and treatment with recombinant human growth hormone. Renal replacement therapy was started at the age of 11 years, and renal transplantation was performed at the age of 12 years. Extra-renal cystine accumulation caused multiple endocrinopathies (including adrenal insufficiency, hypothyroidism and primary hypogonadism), neurological symptoms, pancytopenia owing to splenomegaly and portal hypertension due to nodular regenerative hyperplasia, aggravated by splenic vein thrombosis and partial portal vein thrombosis. The patient died of diffuse intra-abdominal bleeding caused by severe portal hypertension.
Conclusion
Cysteamine treatment should be started as early as possible, and dosage should be monitored and adapted based on trough WBC cystine levels.
Relevant international guideline
Emma F et al. (2014) Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29:iv87–iv94.
Cysteamine Toxicity in Patients with Cystinosis Besouw, Martine T.P., MD; Bowker, Richard, MA, MBBS; Dutertre, Jean-Paul, MD ...
The Journal of pediatrics,
12/2011, Letnik:
159, Številka:
6
Journal Article
Recenzirano
Objective To report new adverse effects of cysteamine. Study design Detailed clinical information was obtained from the patients’ physicians. Results New adverse events were reported in 8 of 550 ...patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m2 /day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. Conclusion Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m2 /day should be prescribed with great caution, but underdosing is not advocated.
While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against ...the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio 95% confidence interval 0.25, 0.10-0.62). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, 0.14-0.91). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio 95% confidence interval 1.16, 1.08-1.24). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.
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Background
Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). The objective of this study is to evaluate fibroblast growth factor 23 (FGF23) and calcium‐phosphate ...metabolism in relation to cardiovascular risk factors in adults with and without T1D.
Methods
A case–control study was conducted using data from patients with T1D and age‐ and sex matched controls without T1D from the Lifelines Cohort Study.
Results
We included 302 adults in the T1D group and 302 adults in the control group. Median age was 42 years. Median glycosylated hemoglobin (HbA1c) in the T1D group was 7.8%. FGF23 of all patients with T1D was not significantly different from controls. Females with T1D had significantly higher FGF23 than males with T1D (83.3 vs 69.3 U/mL, p = 0.002), this was not observed in controls. Serum phosphate, calcium, and alkaline phosphatase were higher and parathyroid hormone was lower in patients with T1D, compared to controls (all p < .001), all within normal range. In the T1D group, FGF23 was positively correlated with serum phosphate (p < .001), alkaline phosphatase (p = .01), and calcium (p = .030), these correlations were not observed in controls. Median FGF23 was significantly higher in current smokers than in nonsmokers with T1D (84.9 vs 73.5 U/mL, p < .05).
Conclusions
Serum calcium, phosphate, and alkaline phosphatase were higher in patients with T1D than in controls and were positively correlated to FGF23 in patients with T1D. Current smokers with T1D had higher FGF23 than nonsmokers with T1D. These findings may contribute to the increased risk of CVD in patients with T1D.
Highlights
Serum calcium, phosphate, calcium‐phosphate product and alkaline phosphatase levels were significantly higher in adult patients with type 1 diabetes (T1D) than in controls and were positively correlated to fibroblast growth factor 23 (FGF23) in patients with T1D. FGF23 was higher in current smokers than in nonsmokers with T1D. These findings may be related to the increased risk of cardiovascular disease in individuals with T1D.
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.
Background
Cystinosis is an autosomal recessive disorder characterized by intralysosomal cystine accumulation. Growth retardation is more pronounced in cystinosis than in other chronic kidney ...diseases and is mostly not corrected by cysteamine.
Methods
Growth was evaluated in nine cystinosis patients, all treated with cysteamine, both after cysteamine and recombinant human growth hormone (rhGH) therapy initiation. Growth hormone (GH) secretion was studied by nocturnal GH measurements in four of nine patients and by glucagon test in four of nine patients.
Results
RhGH was administered to seven of nine patients. At rhGH initiation, height was below −2 SDS in five of seven patients, final height was above −2 SDS in six of seven. In two patients not treated with rhGH, final height remained below −4 SDS despite cysteamine treatment being started at the age of 6.1 and 8.1 years, respectively. Nocturnal GH secretion was normal in all patients. Glucagon tests revealed GH deficiency in one patient; two of four patients had abnormal GH peak timing.
Conclusions
We present the first reported case of GH deficiency in cystinosis. Although no overt GH deficiency was detected in other patients, abnormal GH peak timing can indicate a subclinical GH secretion problem. RhGH significantly improved growth in cystinosis patients and should be initiated early in life.
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