[Show abstract][Hide abstract] ABSTRACT: Background/purpose:
Peritoneal dialysis (PD) is a common method of renal replacement therapy for children. However, placement of PD catheters has risk, and some are never used.
We conducted a retrospective chart review of children with a PD catheter placed between 2000 and 2014. Logistic regression analyses were used to identify covariates associated with complications.
We identified 175 children with PD catheters. 110 complications developed in 80 children (45.7%). Complications including unexpected return to the operating room and peritonitis increased as the length of time a catheter was in place increased. Children who weighed <12.4kg had 3.2 times greater odds of developing a leak (95% CI 1.21-8.63, p=0.02). Twelve children never used their PD catheters, 9 with acute kidney injury (AKI) who recovered from their disease more quickly than expected. No covariate was associated with nonuse.
Complications with PD catheters are common and increase the longer catheters are in place. Lower weight children are at greater risk of PD catheter leak. Decreased initial volumes of dialysate in smaller children may mitigate this risk. Nonuse may be reduced if dialysis is permitted the day of placement for children with AKI.
Full-text · Article · Oct 2015 · Journal of Pediatric Surgery
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD is progressive cystic dilatation of renal tubules with kidney enlargement and progression to end-stage renal disease in approximately half of cases by 60 years of age. Although previously considered a condition of adults, it is clear that children and young adults are subject to the complications of ADPKD.
It has been increasingly recognized that interventions early in life are necessary in order to confer the best long-term outcome in this common condition. Therefore, it is imperative for pediatricians to recognize the manifestations and complications of this disease. Until recently ADPKD management focused on general principles of chronic kidney disease. However, several recent clinical trials in children and adults with ADPKD have focused on disease-specific therapies.
This review will highlight the clinical manifestations, diagnosis, and appropriate management of ADPKD in childhood and will review recent relevant clinical trials in children and adults with this condition.
No preview · Article · Jan 2015 · Current Opinion in Pediatrics
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT A study ADPKD patients (early disease group with eGFR>60mL/min/1.73m(2)) were compared with samples from 49 patients from HALT study B group with moderately advanced disease (eGFR 25-60mL/min/1.73m(2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60mL/min/1.73m(2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine and S-adenosylhomocysteine (SAH) as compared to the healthy controls. Upon adjustments for age, sex, systolic blood pressure and creatinine, SDMA, homocysteine and SAH remained negatively correlated with eGFR. Resulting cellular methylation power (SAM (S-adenosylmethionine):SAH-ratio) correlated with the reduction of renal function and increase of TKV. Concentrations of prostaglandins (PG), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD2 and PGE2, were markedly elevated in patients with ADPKD as compared to healthy controls. Upon adjustments for age, sex, systolic blood pressure and creatinine, increased PGD2 and PGF2α were associated with reduced eGFR, whereas 8-isoprostane and again PGF2α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.
Full-text · Article · Sep 2014 · American journal of physiology. Renal physiology
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.
Preview · Article · Jun 2014 · Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD.
There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a ≥20% change in HtTKV, LVMI, or UAE over the study period.
Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23%±3% versus 31%±3%; P=0.02).
Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.
No preview · Article · Apr 2014 · Clinical Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: Inflammatory activity is evident in patients with chronic kidney disease with limited data available in ADPKD. We hypothesized that inflammation is an upstream event in the pathogenesis of ADPKD and may be a contributing factor in the disease severity and progression. Serum samples from 61 HALT study A group patients (early disease group with eGFR>60mL/min/1.73m2) were compared with samples from 49 patients from HALT study B group with moderately advanced disease (eGFR 25-60mL/min/1.73m2). Targeted mass spectrometry analysis of bioactive lipid mediators as markers of inflammation was performed and correlated with eGFR and total kidney volume (TKV) normalized to the body surface area (BSA) to assess if these markers are predictive of ADPKD severity. ADPKD patients with eGFR >60mL/min/1.73m2 showed higher levels of 5- and 12/15-lipoxygenase (LOX) and cycloxygenase (COX) generated hydroxy-octadecadienoic acids 9-HODE and 13-HODE and hydroxy-eicosatetraenoic acids 8-HETE, 11-HETE, 12-HETE and 15-HETE as compared to healthy subjects. Linear regression of 9-HODE and 13-HODE revealed significant relationship with eGFR and TKV, while 15-HETE significantly correlated with TKV/BSA. Production of 20-HETE, a P450-produced metabolite of arachidonic acid, was higher in ADPKD patients as compared to healthy subjects and significantly correlated with eGFR and TKV/BSA. Perturbation in fatty acid metabolism is evident early in ADPKD patients, even in those with preserved kidney function. Identified lipoxygenase pathways may be potential therapeutic targets for slowing down ADPKD progression.
No preview · Article · Dec 2013 · The Journal of Lipid Research
[Show abstract][Hide abstract] ABSTRACT: As judged by the American College of Radiology Appropriateness Criteria, renal Doppler ultrasonography is the most appropriate imaging test in the evaluation of AKI and has the highest level of recommendation. Unfortunately, nephrologists are rarely specifically trained in ultrasonography technique and interpretation, and important clinical information obtained from renal ultrasonography may not be appreciated. In this review, the strengths and limitations of grayscale ultrasonography in the evaluation of patients with AKI will be discussed with attention to its use for (1) assessment of intrinsic causes of AKI, (2) distinguishing acute from chronic kidney diseases, and (3) detection of obstruction. The use of Doppler imaging and the resistive index in patients with AKI will be reviewed with attention to its use for (1) predicting the development of AKI, (2) predicting the prognosis of AKI, and (3) distinguishing prerenal azotemia from intrinsic AKI. Finally, pediatric considerations in the use of ultrasonography in AKI will be reviewed.
Preview · Article · Nov 2013 · Clinical Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: Nephrotic syndrome is an important clinical condition affecting both children and adults. Studies suggest that the pathogenesis of edema in individual patients may occur via widely variable mechanisms, i.e., intravascular volume underfilling versus overfilling. Managing edema should therefore be directed to the underlying pathophysiology. Nephrotic syndrome is also associated with clinically important complications related to urinary loss of proteins other than albumin. This educational review focuses on the pathophysiology and management of edema and secondary complications in patients with nephrotic syndrome.
Full-text · Article · Aug 2013 · Pediatric Nephrology
[Show abstract][Hide abstract] ABSTRACT: In adults with end-stage renal disease (ESRD), the preservation of residual renal function (RRF) has been shown to be associated with decreased mortality and improved control of complications of chronic kidney disease. However, less is known on the benefits of RRF in the pediatric dialysis population. The purpose of this article is to review the clinical significance of RRF and to discuss strategies for the preservation of RRF in children with ESRD.
No preview · Article · Jul 2013 · Pediatric Nephrology
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1 in 1000 individuals. Previously termed "adult polycystic kidney disease", ADPKD is now known to have important clinical manifestations beginning early in life and even in utero. Hypertension is an important risk factor for progressive renal and cardiovascular disease in children with ADPKD and may signify irremediable organ injury. The purpose of this article is to review current knowledge and treatment strategies in hypertension associated with pediatric ADPKD.
No preview · Article · Feb 2013 · Current Hypertension Reviews
[Show abstract][Hide abstract] ABSTRACT: Hemolytic uremic syndrome is a thrombotic microangiopathy. Clopidogrel, a recently developed platelet aggregation inhibitor, has not been previously reported as a treatment for this illness. Our study's objective was to explore the efficacy and safety of clopidogrel in children with diarrhea associated hemolytic uremic syndrome.
We performed a retrospective chart review of all children (≤ 18 years) hospitalized with diarrhea associated hemolytic uremic syndrome. Outcomes in clopidogrel treated children were described. In subgroup analysis, outcomes were compared to those untreated with platelet aggregation inhibitors.
Of 72 children with diarrhea associated hemolytic uremic syndrome, 88% were treated with platelet aggregation inhibitors (clopidogrel 56%, sulfinpyrazone 19%, dipyridamole 13%). The median age of clopidogrel treated children was 5 years; 40% were male. Initial median hemoglobin, platelet count, and serum creatinine were 10.1g/dL, 53 × 10(3)/μL, and 2.3mg/dL respectively. Clopidogrel (median dose 1mg/kg/d) was given for a median of 4 days (range 1-15). Other therapies included erythropoietin (98%), red blood cell transfusions (80%), diuretics (58%), anti-hypertensive agents (45%), and dialysis (33%). The median hospital length of stay was 9 days (range 3-26). Three children had bleeding complications (epistaxis/hematemesis). The risk of chronic kidney disease was 5% and death 2.5%. In subgroup analysis, median duration of dialysis was 11 days in thirteen clopidogrel treated children compared to 21 days in five untreated patients (P=0.04).
Children with diarrhea associated hemolytic uremic syndrome treated with clopidogrel have outcomes comparable to untreated patients. Bleeding complications may occur.
No preview · Article · Jun 2012 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a novel disease caused by a gain-of-function mutation in the V2 vasopressin receptor (V2R), which results in water overload and hyponatremia. We report the effect of water loading in a 3-year old boy with NSIAD, diagnosed in infancy, to assess urine aquaporin-2 (AQP2) excretion as a marker for V2R activation, and to evaluate the progression of the disease since diagnosis. The patient is one of the first known NSIAD patients and the only patient with a R137L mutation. Patient underwent a standard water loading test in which serum and urine sodium and osmolality, serum AVP, and urine AQP2 excretion were measured. The patient was also evaluated for ad lib fluid intake before and after the test. This patient demonstrated persistent inability to excrete free water. Only 39% of the water load (20 ml/kg) was excreted during a 4-hour period (normal ≥ 80-90%). Concurrently, the patient developed hyponatremia and serum hypoosmolality. Serum AVP levels were detectable at baseline and decreased one hour after water loading; however, urine AQP2 levels were elevated and did not suppress normally during the water load. The patient remained eunatremic but relatively hypodipsic during ad lib intake. In conclusion, this is the first demonstration in a patient with NSIAD caused by a R137L mutation in the V2R that urine AQP2 excretion is inappropriately elevated and does not suppress normally with water loading. In addition, this is the first longitudinal report of a pediatric patient with NSIAD diagnosed in infancy who demonstrates the ability to maintain eunatremia during ad lib dietary intake.
Preview · Article · Feb 2012 · International Journal of Pediatric Endocrinology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children.
One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ≥140 ml/min per 1.73 m(2).
Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (β: rate of change = +19.3 ± 10.8 cm(3)/year) over 5 years compared with those without GH at baseline (β = -4.3 ± 7.7 cm(3)/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (β = -5.0 ± 0.8 ml/min per 1.73 m(2) per year) compared with those without GH at baseline (β = +1.0 ± 0.4 ml/min per 1.73 m(2) per year), P < 0.0001.
This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.
Full-text · Article · Sep 2011 · Clinical Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8-22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population.
Preview · Article · May 2011 · Contemporary clinical trials
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and has important clinical manifestations in childhood. Numerous studies have documented the superiority of magnetic resonance imaging (MRI) for serial monitoring of kidney and cyst volume in this condition in adults. However, no studies have examined the utility of MRI for serial assessment of kidney and cyst volume in children with ADPKD.
Subjects 4 to 21 years of age with ADPKD underwent abdominal MRI on an annual basis for 5 years. Subjects were grouped according to BP as hypertensive (HBP; BP≥95th percentile for age, height, and gender) or as normotensive (NBP; BP<95th percentile). Total kidney volume (TKV), cyst volume, and cyst number were assessed by stereology.
MRI studies (n=302) were obtained in 77 children with ADPKD. TKV and cyst volume were significantly increased in HBP versus NBP subjects. HBP subjects demonstrated a greater increase in fractional cyst volume over time versus NBP subjects. Cyst number increased more rapidly in HBP ADPKD children.
This is the first large-scale clinical study examining the utility of MRI for serial assessment of TKV, cyst volume, and cyst number in children with ADPKD. These results demonstrate that MRI is an acceptable means to follow these parameters in children with ADPKD. Because of the embryonic occurrence of cysts, interventional trials are needed in ADPKD children and MRI may be the preferred renal imaging approach.
No preview · Article · Feb 2011 · Clinical Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: Interleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6.
Urine was collected in 25 consecutive pediatric patients undergoing cardiac bypass surgery (CPB). AKI was defined as a 50% increase in serum creatinine at 24 hours (RIFLE (Risk, Injury, Failure, Loss, End stage), R). Mouse models of AKI and freshly isolated proximal tubules were also studied.
Urine IL-6 increased at six hours in patients with AKI versus no AKI (X2 = 8.1750; P < 0.0042). Urine IL-6 > 75 pg/mg identified AKI with a sensitivity of 88%. To assess whether increased urine IL-6 occurs in functional versus structural renal failure, mouse models of pre-renal azotemia after furosemide injection (no tubular injury), ischemic AKI (tubular injury) and cisplatin AKI (tubular injury) were studied. Urine IL-6 did not significantly increase in pre-renal azotemia but did increase in ischemic and cisplatin AKI. To determine if circulating IL-6 appears in the urine in AKI, recombinant human (h)IL-6 was injected intravenously and urine collected for one hour; urine hIL-6 increased in ischemic AKI, but not pre-renal azotemia. To determine the effect of AKI on circulating IL-6, serum hIL-6 was determined one hour post-intravenous injection and was increased in ischemic AKI, but not pre-renal azotemia. To directly examine IL-6 metabolism, hIL-6 was added to the media of normal and hypoxic isolated proximal tubules; hIL-6 was reduced in the media of normal versus injured hypoxic proximal tubules.
Urine IL-6 increases early in patients with AKI. Animal studies demonstrate that failure of proximal tubule metabolism of IL-6 results in increased serum and urine IL-6. Impaired IL-6 metabolism leading to increased serum IL-6 may contribute to the deleterious systemic effects and increased mortality associated with AKI.
Full-text · Article · Oct 2010 · Critical care (London, England)
[Show abstract][Hide abstract] ABSTRACT: Renal cysts, pain, and hematuria are common presentations of autosomal dominant polycystic kidney disease (ADPKD) in children. Renal function, however, is typically preserved in these patients despite increased renal volume. Since angiogenesis has been implicated in promotion of renal cyst growth in ADPKD, we measured the serum level of various angiogenic factors and early renal structural changes and cardiovascular parameters in 71 patients with ADPKD, with a mean age of 16 years. Renal structure and left ventricular mass index were measured by magnetic resonance imaging or by echocardiogram. Renal function was assessed by creatinine clearance and urinary protein excretion. Serum growth factor levels were measured by enzyme-linked immunosorbent assay. Because of skewed distributions, the various parameters are reported as log(10). Serum log(10) vascular endothelial growth factor was positively correlated with renal and cardiac structure, but negatively with creatinine clearance. Serum angiopoietin 1 levels significantly correlated with structural change in both the kidney and the heart and with urinary protein. Thus, the correlation between angiogenic growth factors with both renal and cardiac disease severity is compatible with a possible role for angiogenesis in the early progression of disease in ADPKD.
No preview · Article · Sep 2010 · Kidney International