Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.

Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis.

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known: • Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate. • Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New: • The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome. • Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

Practice variations in the management of childhood nephrotic syndrome in the Netherlands.

Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome.Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known: • National and international guidelines are available to guide the management of childhood nephrotic syndrome. • Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians. What is New: • Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS. • The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists.

Pharmacokinetics in children with chronic kidney disease.

In children, the main causes of chronic kidney disease (CKD) are congenital diseases and glomerular disorders. CKD is associated with multiple physiological changes and may therefore influence various pharmacokinetic (PK) parameters. A well-known consequence of CKD on pharmacokinetics is a reduction in renal clearance due to a decrease in the glomerular filtration rate. The impact of renal impairment on pharmacokinetics is, however, not limited to a decreased elimination of drugs excreted by the kidney. In fact, renal dysfunction may lead to modifications in absorption, distribution, transport, and metabolism as well. Currently, insufficient evidence is available to guide dosing decisions on many commonly used drugs. Moreover, the impact of maturation on drug disposition and action should be taken into account when selecting and dosing drugs in the pediatric population. Clinicians should take PK changes into consideration when selecting and dosing drugs in pediatric CKD patients in order to avoid toxicity and increase efficiency of drugs in this population. The aim of this review is to summarize known PK changes in relation to CKD and to extrapolate available knowledge to the pediatric CKD population to provide guidance for clinical practice.

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome.

Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients.

BACKGROUND: Tacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients. METHODS: Data were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated. RESULTS: In total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations. CONCLUSION: A critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.

Unusual severe case of hemolytic uremic syndrome due to Shiga toxin 2d-producing E. coli O80:H2.

BACKGROUND: Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children, with the majority of cases caused by an infection with Shiga toxin-producing Escherichia coli (STEC). Whereas O157 is still the predominant STEC serotype, non-O157 serotypes are increasingly associated with STEC-HUS. However, little is known about this emerging and highly diverse group of non-O157 serotypes. With supportive therapy, STEC-HUS is often self-limiting, with occurrence of chronic sequelae in just a small proportion of patients. CASE DIAGNOSIS/TREATMENT: In this case report, we describe a 16-month-old boy with a highly severe and atypical presentation of STEC-HUS. Despite the presentation with multi-organ failure and extensive involvement of central nervous system due to extensive thrombotic microangiopathy (suggestive of atypical HUS), fecal diagnostics revealed an infection with the rare serotype: shiga toxin 2d-producing STEC O80:H2. CONCLUSIONS: This report underlines the importance of STEC diagnostic tests in all children with HUS, including those with an atypical presentation, and emphasizes the importance of molecular and serotyping assays to estimate the virulence of an STEC strain.

Therapeutic drug monitoring of mycophenolate mofetil in pediatric patients: novel techniques and current opinion.

Introduction: Mycophenolate mofetil (MMF) is an ester prodrug of the immunosuppressant mycophenolic acid (MPA) and is recommended and widely used for maintenance immunosuppressive therapy in solid organ and stem-cell transplantation as well as in immunological kidney diseases. MPA is a potent, reversible, noncompetitive inhibitor of the inosine monophosphate dehydrogenase (IMPDH), a crucial enzyme in the de novo purine synthesis in T- and B-lymphocytes, thereby inhibiting cell-mediated immunity and antibody formation. The use of therapeutic drug monitoring (TDM) of MMF is still controversial as outcome data of clinical trials are equivocal. Areas covered: This review covers in great depth the existing literature on TDM of MMF in the field of pediatric (kidney) transplantation. In addition, the relevance of TDM in immunological kidney diseases, in particular childhood nephrotic syndrome is highlighted. Expert opinion: TDM of MMF has the potential to optimize therapy in pediatric transplantation as well as in nephrotic syndrome. Limited sampling strategies to estimate MPA exposure increase its feasibility. Future perspectives rather encompass approaches reflecting total immunosuppressive load than single drug TDM.

Mitochondrial Disease and the Kidney With a Special Focus on CoQ10 Deficiency.

Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Most mitochondrial cytopathies that cause kidney symptoms are characterized by tubular defects, but glomerular, tubulointerstitial, and cystic diseases have also been described. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Early recognition of defects in the coenzyme Q10 (CoQ10) biosynthesis is important, as patients with primary CoQ10 deficiency may be responsive to treatment with oral CoQ10 supplementation, in contrast to most mitochondrial diseases. A literature search was conducted to investigate kidney involvement in genetic mitochondrial cytopathies and to identify mitochondrial and nuclear DNA mutations involved in mitochondrial kidney disease. Furthermore, we identified all reported cases to date with a CoQ10 deficiency with glomerular involvement, including 3 patients with variable renal phenotypes in our clinic. To date, 144 patients from 95 families with a primary CoQ10 deficiency and glomerular involvement have been described based on mutations in PDSS1, PDSS2, COQ2, COQ6, and COQ8B/ADCK4. This review provides an overview of kidney involvement in genetic mitochondrial cytopathies with a special focus on CoQ10 deficiency.