Piotr Skrzypczyk

Long-term outcomes in idiopathic nephrotic syndrome: from childhood to adulthood.

BACKGROUND The aim of the study was to assess idiopathic nephrotic syndrome (INS) relapse rate, co-morbidities, and social status of adults diagnosed with INS in childhood. MATERIAL AND METHODS A written questionnaire was sent to 118 adults treated for INS in childhood. In 61 (51.7%) responders (aged 26.0 ± 6.2 years, range 18 - 51.5 years), we used available medical records to evaluate age at the onset of INS, number of INS relapses below 18 years of age, response to corticosteroids (CS), renal biopsy findings, and immunosuppressive treatment as well as questionnaire to evaluate the number and treatment of INS relapses above 18 years of age, co-morbidities, age at menarche, marital status, offspring, educational status, and occupation. RESULTS In the group of 61 responders, median age at the onset of INS was 3 (range 1.3 - 14.0) years, median number of INS relapses at < 18 years of age was 5 (1 - 20). Steroid-sensitive nephrotic syndrome (SSNS) was diagnosed in 37 (60.7%) patients, steroid-dependent nephrotic syndrome SDNS in 18 (29.5%) patients, and steroid-resistant nephrotic syndrome (SRNS) in 6 (9.8%) patients. Mesangial proliferation was the most common pattern in renal biopsy (35.7%). All patients received CS, 15 were treated with methylprednisolone pulses, 13 with cyclophosphamide, 11 with chlorambucil, 2 with cyclosporine, and 21 with levamisole. All patients achieved remission and had normal renal function at the age of 18. In adulthood, INS relapsed in 10 (16.4%) patients, including 5 (13.5%) patients with SSNS, 4 (22.2%) with SDNS, and 1 (16.7%) with SRNS (p = 0.72). Median number of relapses was 2 (range 1 - 11). Patients with relapses at > 18 years of age had more (p < 0.005) relapses at < 18 years of age. Hypertension was diagnosed in 8 (16.1%), overweight in 14 (23.0%), obesity in 3 (4.9%), and bone fractures in 12 (19.7%) patients. Five patients had height < 3rd percentile, including 4 with INS onset at < 3 years of age. One patient had growth retardation before the treatment. No myocardial infarctions, strokes, severe infections, or malignancies were reported. Mean age at menarche was 12.9 ± 1.4 years, 37 (60.7%) patients were in a steady relationship/ married, 1/18 (5.6%) patients treated with cytostatic agents and 12/43 (24/7%) patients not treated with cytostatic agents had offspring (p < 0.05). Elementary education was reported by 4 (6.6%), secondary education by 32 (52.5%), and higher education by 25 (40.9%) patients, and 34 (55.7%) patients were professionally active. None of the 6 patients with SRNS developed end-stage renal disease. CONCLUSIONS 1. High number of INS relapses in childhood is a risk factor for recurrences in adulthood. 2. INS relapses in childhood do not preclude active professional life in adulthood.

Markers of Bone Metabolism in Children with Nephrotic Syndrome Treated with Corticosteroids

The aim of the study was to assess bone mineral density, bone metabolism markers, and vitamin D level in children with idiopathic nephrotic syndrome in the course of 1-year observation. Twenty five children with nephrotic syndrome aged 5-17 years were enrolled into the study. The median number of relapses was 6 (range 1-22). All patients were treated with prednisone and vitamin D (800 IU/day). Bone mineral density of total body (TB-BMD) and lumbar spine (L-BMD), evaluated by dual energy X-ray absorptiometry (DXA) expressed as Z-score, and serum calcium, phosphorus, parathormone (iPTH), alkaline phosphatase (ALP), bone alkaline phosphatase (BAP), osteocalcin (OC), albumin, creatinine, 25(OH)D3, 1,25(OH)2D3 and urine calcium/creatinine ratio (uCa/Cr) were evaluated at the enrollment visit and after 1 year of therapy. After 1 year significant decreases of TB-BMD Z-score (from -0.24±1.34 to -0.74±1.31, p<0.05) and 25(OH)D3 serum level (from 31.7±16.3 to 23.7±9.3; p<0.05) were observed. No other appreciable differences were found. At the study onset, negative correlations were found between L-BMD Z-score and serum ALP, BAP, and phosphorus and between TB-BMD Z-score and urine uCa/Cr. After 1 year, L-BMD Z-score correlated negatively with serum BAP and OC, and positively with serum 25(OH)D3. Multivariate analysis showed that BAP was the strongest predictor of L-BMD Z-score (beta=-0.49; p<0.05). We conclude that children with nephrotic syndrome treated with corticosteroids are at risk of bone mass loss. Serum BAP concentration seems to be a good indicator of spongy bone metabolism in these children, who should be supplemented with vitamin D in an adjustable dose, possibly higher than 800 IU/24 h to prevent osteopenia.

Methods to evaluate arterial structure and function in children – State-of-the art knowledge

BACKGROUND With increasing rates of hypertension, obesity, and diabetes in the pediatric population, wide available, and reproducible methods are necessary to evaluate arterial structure and function in children and adolescents. METHODS MEDLINE/Pubmed was searched for articles published in years 2012-2017 on methodology of, current knowledge on, and limitations of the most commonly used methods to evaluate central, proximal and coronary arteries, as well as endothelial function in pediatric patients. RESULTS Among 1528 records screened (including 1475 records from years 2012 to 2017) 139 papers were found suitable for the review. Following methods were discussed in this review article: ultrasound measurements of the intima-media thickness, coronary calcium scoring using computed tomography, arterial stiffness measurements (pulse wave velocity and pulse wave analysis, carotid artery distensibility, pulse pressure, and ambulatory arterial stiffness index), ankle-brachial index, and methods to evaluate vascular endothelial function (flow-mediated vasodilation, peripheral arterial tonometry, Doppler laser flowmetry, and cellular and soluble markers of endothelial dysfunction). CONCLUSIONS Ultrasonographic measurement of carotid intima-media thickness and measurement of pulse wave velocity (by oscillometry or applanation tonometry) are highly reproducible methods applicable for both research and clinical practice with proved applicability for children aged ≥6 years or with height ≥120cm. Evaluation of ambulatory arterial stiffness index by ambulatory blood pressure monitoring is another promising option in pediatric high-risk patients. Clearly, further studies are necessary to evaluate usefulness of these and other methods for the detection of subclinical arterial damage in children.

Levamisole therapy in children with frequently relapsing and steroid-dependent nephrotic syndrome: a single-center experience

Introduction Numerous studies suggest that levamisole, an antihelmintic agent with an immunomodulatory effect, reduces the number of relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome (FRNS/SDNS). The aim of the study was to present a single center’s experience in treatment of FRNS and SDNS with levamisole. Material and methods Among 72 children with FRNS/SDNS treated in our department with levamisole in the years 1984-2011 we studied in detail 53 patients (mean age: 6.5 ±3.0 years), in whom the medication was administered for at least 6 months. In these 53 patients we evaluated: the course of the disease before levamisole, the renal biopsy result, medications used, prednisone dose on levamisole initiation, duration of levamisole treatment, time to first relapse and number of relapses on levamisole, and levamisole side effects. Results The duration of nephrotic syndrome was 3.4 ±2.9 years, and the number of relapses before levamisole treatment was 6.0 ±3.4. The dose of prednisone on initiation of levamisole treatment was 1.2 ±0.6 mg/kg/24 h, and the duration of levamisole treatment was 15.0 ±7.3 months. During levamisole treatment proteinuria relapsed in 34/53 (64.2%) children, and the time to first relapse was 8.8 ±8.1 months. During levamisole therapy relapses of the disease decreased significantly (2.7 ±2.0 vs. 1.8 ±2.1 relapses/year, p = 0.02). Time to first relapse correlated with total number of relapses (R = –0.59, p < 0.001) and number of relapses in one year during levamisole treatment (R = –0.60, p < 0.001). Conclusions Levamisole is effective in reducing the number of relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome. Early relapse of proteinuria on levamisole treatment in children with FRNS/SDNS suggests low efficacy of further treatment.

Effect of hypertension and antihypertensive medications on residual renal function in children treated with chronic peritoneal dialysis

PURPOSE To evaluate the effect of hypertension (HTN) and antihypertensive medications (AHM) on residual renal function (RRF) in children on CAPD and APD. MATERIAL/METHODS We retrospectively evaluated underlying kidney disease, systolic and diastolic blood pressure (SBP/DBP), presence and control of HTN (SBP/DBP≥95th percentile), AHM, RRF (daily diuresis, residual glomerular filtration rate [rGFR]), biochemical parameters, BMI Z-score, and dialysis parameters during 12-month follow-up in 87 children (38 CAPD, 49 APD) aged 10.22±4.31 years. The rate of RRF loss was expressed as absolute and relative [%] reduction. RESULTS At baseline, HTN was found in 74.7% patients (CAPD/APD: 84.2%/67.3%, P=0.06), most commonly in HUS and least frequently in CAKUT. The proportion of CAPD/APD patients with poorly controlled HTN was 70.0%/63.3% (P=0.50). Relative daily diuresis loss in children with uncontrolled HTN was higher (P=0.017) compared to children with SBP/DBP <95th percentile. No effect of AHM on the rate of RRF loss was found. In multivariate analysis, absolute daily diuresis loss was related to baseline diuresis (β=-0.30, P<0.001) and proteinuria (β=-0.31, P=0.004); absolute rGFR loss to baseline rGFR (β=-0.73, P<0.001) and glucose load after 12 months (β=-0.36, P=0.02); relative daily diuresis loss to mean BMI Z-score (β=-0.44, P=0.04); and relative rGFR to baseline rGFR (β=-0.37, P<0.001) and SBP percentile (β=-0.21, P=0.045).

Hypertension in children with end-stage renal disease.

This review summarizes current data on the epidemiology, pathophysiology, and treatment of hypertension (HTN) in children with end-stage renal disease (ESRD). Worldwide prevalence of ESRD ranges from 5.0 to 84.4 per million age-related population. HTN is present in 27-79% of children with ESRD, depending on the modality of renal replacement therapy and the exact definition of hypertension. Ambulatory BP monitoring has been recommended for the detection of HTN and evaluation of treatment effectiveness. HTN in dialyzed patients is mostly related to hypervolemia, sodium overload, activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, impaired nitric oxide synthesis, reduced vitamin D levels, and effects of microRNA. In children undergoing chronic dialysis therapy, important factors include optimization of renal replacement therapy and preservation of residual renal function, allowing reduction of volume- and sodium-overload, along with appropriate drug treatment, particularly with calcium channel blockers, RAAS inhibitors, and loop diuretics.

Residual renal function in children treated with chronic peritoneal dialysis.

Residual renal function (RRF) in patients with end-stage renal disease (ESRD) receiving renal replacement therapy is defined as the ability of native kidneys to eliminate water and uremic toxins. Preserved RRF improves survival and quality of life in adult ESRD patients treated with peritoneal dialysis. In children, RRF was shown not only to help preserve adequacy of renal replacement therapy but also to accelerate growth rate, improve nutrition and blood pressure control, reduce the risk of adverse myocardial changes, facilitate treatment of anemia and calcium-phosphorus balance abnormalities, and result in reduced serum and dialysate fluid levels of advanced glycation end-products. Factors contributing to RRF loss in children treated with peritoneal dialysis include the underlying renal disease such as hemolytic-uremic syndrome and hereditary nephropathy, small urine volume, severe proteinuria at the initiation of renal replacement therapy, and hypertension. Several approaches can be suggested to decrease the rate of RRF loss in pediatric patients treated with chronic peritoneal dialysis: potentially nephrotoxic drugs (e.g., aminoglycosides), episodes of hypotension, and uncontrolled hypertension should be avoided, urinary tract infections should be treated promptly, and loop diuretics may be used to increase salt and water excretion.

Tuberculosis infection in children with proteinuria/nephrotic syndrome

Children with nephrotic syndrome (NS) are at greater risk of infections than the general population, due to immunodeficiency in the course of the disease and the treatment. In this study we present 4 children (2 girls, 2 boys), mean age 7.6 ±5.1 years, with NS/proteinuria and latent tuberculosis in 3 children and lymph node tuberculosis in 1 child. The reasons for testing these children for tuberculosis (TB) were the evaluation of the epidemiological status before treatment with corticosteroids (GCS), leukopenia and the relapse of NS, and non-nephrotic proteinuria. The diagnosis of TB infection was based on positive IGRA (Interferon-Gamma Release Assay). Chest X-ray was normal in all the children. Chest CT scan revealed an enlargement of lymph nodes in 1 child. The children were treated with isoniazid (3 children) and isoniazid, rifampicin and pyrazinamide (1 child). Three children with idiopathic nephrotic syndrome were treated with prednisone. The child with non-nephrotic proteinuria was treated with enalapril. Proteinuria disappeared in all children during anti-TB treatment.

Risk Factors for Decline of Residual Renal Function in Children Treated With Peritoneal Dialysis

♦ Background: The aim of the study was to assess risk factors for residual renal function (RRF) decline in children during the first/second year of chronic peritoneal dialysis (PD). ♦ Methods: The study group included 56 children with end-stage renal disease (ESRD) (age 10.13 ± 4.86 years), including 18 on continuous ambulatory PD (CAPD) and 38 on automated PD (APD), in whom we evaluated RRF (daily diuresis [mL/m2/24 h], residual glomerular filtration rate (rGFR) [mL/min/1.73 m2]), etiology of ESRD, PD fluid volume (mL/m2/24 h), glucose load (g/m2/24 h), ultrafiltration (mL/m2/24 h), peritoneal permeability (D/PCrea 4h, D/D0 Glu 4h), dialysis adequacy (twKt/V, twCCr [L/week/1.73 m2]), blood pressure (BP), biochemical parameters, and medications used. Duration of follow-up was 24 months. ♦ Results: Mean diuresis before initiation of PD was 1,394.93 ± 698.37 (mL/m2/24 h), and mean rGFR was 7.41 ± 3.96 (mL/min/1.73 m2). The rate of daily diuresis decline was −529.34 ± 546.28 in the first year and −107.10 ± 291.54 (mL/m2/24 h) in the second year (p = 0.005), and the rate of rGFR decline was −3.35 ± 3.73 in the first year and −1.63 ± 1.85 (mL/min/1.73 m2) in the second year (p = 0.118). Eleven (19.64%) patients became anuric. In univariate analysis, the rate of daily diuresis decline in the first year was related to baseline diuresis (r = −0.29, p = 0.031), proteinuria (r = −0.43, p = 0.001), and systolic BP (r = −0.31, p = 0.020); 12-month changes (Δ0 – 12) in PD fluid volume (r = −0.37, p = 0.004), glucose load (r = −0.28, p = 0.035), and ultrafiltration (r = −0.38, p = 0.004); serum calcium-phosphorus product (r = −0.41, p = 0.002); and Δ0 – 12 body mass index (BMI) Z-score (r = 0.30, p = 0.024); while the rate of rGFR decline in the first year was related only to baseline rGFR (r = −0.57, p < 0.001). In multivariate analysis, significant predictors of the rate of daily diuresis decline in the first year were baseline diuresis (β = −0.386, p < 0.001) and proteinuria (β = −0.278, p = 0.017), mean systolic BP Z-score (β = −0.237, p = 0.027), and age at the onset of PD (β = −0.224, p = 0.037), while predictors of the rate of rGFR decline were baseline rGFR (β = −0.607, p < 0.001) and baseline proteinuria (β = −0.225, p = 0.046). In the second year, the only predictors of the rate of rGFR decline were D/D0 Glu 4h (r = 0.44, p = 0.033, univariate analysis) and rGFR at 12 months (β = −0.499, p = 0.044). ♦ Conclusion: The most important risk factors for rapid RRF decline in children during the first year of chronic PD include higher baseline daily diuresis and proteinuria, and additional factors are systolic BP and age at the onset of PD; while high baseline GFR and low peritoneal transport status may be the only important factors during the second year.

Benign acute childhood myositis complicating influenza B infection in a boy with idiopathic nephrotic syndrome

Introduction Benign acute childhood myositis (BACM) is an acute complication of an infection characterized by calf pain, limitation of lower limb mobility, an increase in serum creatine kinase, and a self-limiting course. No reports of BACM in children with idiopathic nephrotic syndrome (INS) can be found in the literature. Case report A 5-year-old boy with steroid-sensitive INS presented with fever, leg pain, and problems with walking. Physical examination showed pharyngeal erythema, preserved movements in all joints, and weakness of leg muscles. Laboratory tests showed white blood cell count 3900/µl, albumin 2.3 g/dl, urea 25 mg/dl, creatinine 0.3 mg/dl, increased transaminases (AspAT 440 U/l, AlAT 100 U/l) and creatine kinase (10 817 U/l), and proteinuria 3500 mg/dl. The boy was diagnosed with an INS bout and BACM. Testing for infective causes of myositis showed evidence of an influenza B virus infection. Treatment included prednisone and oseltamivir. A rapid improvement of motor function was observed, with normalization of serum creatine kinase and transaminases, and resolution of proteinuria. Conclusions 1. As influenza virus infection in a child with INS is a risk factor for complications and a disease bout, these patients should be vaccinated against influenza. 2. Differential diagnosis of leg pain and mobility limitation in a child with INS should include lower limb deep venous thrombosis, arthritis, post-infectious neurological complications (including Guillain-Barré syndrome), and BACM. 3. Serum creatine kinase level should be measured in all cases of motor disturbances in a child with symptoms of respiratory tract infection.