Article

Increased risk for kidney sequelae surrogates in survivors of Wilms tumor

Article

Increased risk for kidney sequelae surrogates in survivors of Wilms tumor

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Abstract

Background: There is evidence of increased risk of hypertension, albuminuria, and development of chronic kidney disease (CKD) in long-term follow-up of survivors of Wilms tumor (WT). However, most studies were conducted in heterogeneous groups, including patients with solitary kidney. In addition, little is known about tubular dysfunction. This study aimed to investigate kidney sequelae, including CKD development, hypertension, and glomerular and tubular damage in WT survivors. Methods: This cross-sectional, single-center study included 61 patients treated for WT. Surrogates for kidney sequelae were defined as presence of at least one of the following: decrease in GFR for CKD, hypertension detected by ambulatory blood pressure monitoring, albuminuria (albumin-to-creatinine ratio [ACR] > 30 mg/g), or increase in at least one tubular biomarker (beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, kidney injury marker-1, and liver fatty acid-binding protein) in 24-h urine. Results: Median age of patients was 11.7 years, with median follow-up of 8.8 years. Thirty-eight patients (62%) had at least one surrogate for kidney sequelae. Twenty-four patients (39%) had CKD, 14 patients (23%) had albuminuria, 12 patients (21%) had hypertension, and 11 patients (18%) had tubular damage. Urine ACR was significantly higher in patients with advanced tumor stage and patients with nephrotoxic therapy than their counterparts (p < 0.05), but neither eGFR nor tubular biomarkers showed any association with tumor- or treatment-related factors. Conclusions: A considerable number of patients with WT have kidney sequelae, especially early-stage CKD with a high prevalence. Albuminuria emerges as a marker associated with tumor stages and nephrotoxic treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

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Supported by a Pilot Grant from the Children’s Hospital of Philadelphia Center for Pediatric Clinical Effectiveness (to D.C.). D.C. is also supported by the NIH/NIDDK (K23 DK125670). G.T. was supported by the NIH/NIDDK (K23 DK106428). Ja.G. was supported by NIH/NIDDK (K08 DK110536). M.D. was supported by the NIH/NIDDK (K23 DK093556). The NIH and NIDDK had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the official view of the NIDDK nor NIH. G.T. serves on the scientific advisory boards for Allena Pharmaceuticals, Novome Biotechnology, and Dicerna Pharmaceuticals and serves as a consultant for Alnylam Pharmaceuticals, all of which are unrelated to this work. M.D. receives research funding from Mallinckrodt unrelated to this work. The other authors declare no conflicts of interest. Portions of this study were presented at the Pediatric Academic Society annual meeting, May 5-8, 2020, Toronto, Canada. Objective To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT). Study design This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with pre-existing hypertension, prior dialysis or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for KIM-1, IL-18, EGF, albumin, and creatinine. Estimated glomerular filtration rate (eGFR) was calculated using the bedside CKiD equation. Recent kidney ultrasounds and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy (LVH), respectively. Clinical follow-up data was collected for approximately 2 years following study enrollment. Results Thirty-two participants (median age 13.6 [IQR: 10.5-16.3] years; 75% ≥Stage 3 WT) were evaluated at a median of 8.7 years (IQR: 6.5-10.8) post-therapy; 29 participants underwent unilateral radical nephrectomy, two bilateral partial nephrectomy, and one radical and contralateral partial nephrectomy. 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 ml/min/1.73m² (IQR: 84.6-114.0; 11 (34%) had an eGFR <90). Abnormal ABPM results were found in 22/29 participants (76%), masked hypertension in 10/29 (34%), and microalbuminuria in 2/32 (6%). 22/32 (69%) participants had abnormal EGF; few had abnormal KIM-1 or IL-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had LVH. Conclusion In survivors of WT, adverse kidney outcomes were common and should be closely monitored.
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Article
Purpose: Partial nephrectomy is being considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. We evaluated the prevalence of hypertension and impaired renal function in long-term survivors of non-syndromic UWT treated without nephrotoxic chemotherapy or ionizing radiation. Patients and Methods: Eligibility included: age ≤15 years at diagnosis of non-syndromic UWT, treatment prior to 2002 and maintenance of remission following unilateral nephrectomy without abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients on anti-hypertensive medication or with blood pressure >140/90mmHg were defined as hypertensive. Results: Seventy-five patients with median age at diagnosis of 3.2 (range: 0.2-12.1) years met eligibility criteria. The median length of follow-up was 19.6 (range: 10.0-32.8) years. All but one patient had stage 1/2 disease. Sixty-eight (90.7%) patients had favorable histology WT; seven had anaplastic histology. Sixteen (21.3%) patients had an eGFR <90 ml/min/1.73m2, two of whom also had proteinuria (12.5%). No patient had an eGFR<60 ml/min/1.73m2. Five (6.7%) patients had hypertension, three of whom were taking anti-hypertensive medications. No patient has developed end-stage renal disease. Conclusions: Patients with UWT treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation are at low risk for significant long-term renal dysfunction. For this patient population, routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and so might be at increased risk for adverse cardiovascular sequelae.
Article
Objective The present study is designed to assess the long-term renal function of children who underwent radical nephrectomy for unifocal Wilms tumor. Methods A single institution retrospective cohort study of non-syndromic children treated with radical nephrectomy for unifocal Wilms tumor between 1995 and 2011 was performed to identify risk factors for decreased glomerular filtration rate (GFR). The primary endpoint was decrease in age-adjusted GFR below normal published ranges. The secondary endpoint was progression to chronic renal insufficiency (CRI). Results A total of 55 patients were identified in the cohort. Eight (15%) patients exhibited decreased age-adjusted GFR during the follow-up period, with 2 (4%) progressing to CRI. Increasing time between surgery and the last known GFR follow-up was associated with decreased GFR, with the normal GFR group having median follow-up of 7.32 years versus 11.47 years (p = 0.019) in the decreased GFR group. Conclusions A trend toward decline in GFR was detected with longer follow-up. Longer follow-up may reveal that clinically significant decline in renal function occurs years following nephrectomy among a subset of Wilms tumor survivors, even among those who do not progress to end stage renal disease.
Article
Ambulatory blood pressure monitoring (ABPM) has established roles in the evaluation and management of hypertension in adults but has only been applied to children and adolescents more recently.1 In 2008, the American Heart Association (AHA) issued the first set of consensus recommendations for performance and interpretation of ABPM in pediatrics. Since then, ABPM has found increasing use in children and adolescents, as recently summarized.2 The present document updates the 2008 AHA statement on the use of ABPM in the pediatric population3 with additional data published since the release of that report and also presents a revised interpretation schema. Because no outcome studies are yet available relating ABPM levels in children to outcomes such as myocardial infarction or stroke, these guidelines are largely driven by expert opinion, although they are also informed by available pediatric data on ABPM and surrogate markers of cardiovascular disease. ### Epidemiology of Hypertension High blood pressure (BP) is the leading risk factor–related cause of death throughout the world, accounting for 12.8% of all deaths, including 51% of stroke deaths and 45% of coronary heart disease deaths.4 In the United States, 33.0% of adults >20 years of age have hypertension.5 As our population continues to age, this will only increase, because 90% of people with normal BP at age 55 years will go on to develop hypertension in their lifetimes.6 The prevalence of hypertension in youths is also on the rise. US National Health and Nutrition Examination Survey (NHANES) data from 1963 to 2002 showed a 2.3% increase in prehypertension and a 1% increase in hypertension from 1988 to 1999, with higher rates in non-Hispanic blacks and Mexican Americans.7 In fact, the entire distribution of childhood BP has shifted upward in the United States by 1.4 mm Hg for systolic BP (SBP) and 3.3 …
Article
Background and objectives: AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period. Design, setting, participants, & measurements: This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis. Results: KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinase-associated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2. Conclusions: Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.
Article
The correlations between ambulatory blood pressure measurements (ABPM) and serum cystatin C (Cys C), serum creatinine (Cr), microalbumin (MA), and β2-microglobulin (β2-MG) levels in 24 h (24-h) urine were analyzed in children with solitary kidney (SK) and compared to healthy children. Fifty children with normal functioning SK and 25 controls were studied. The ABPM, serum Cys C, serum Cr, MA, and β2-MG levels in 24-h urine were measured in all children. Clinical symptoms and signs, laboratory results, urinary ultrasonography, voiding cystourethrography, and Dimercaptosuccinic acid (DMSA) scintigraphy results were recorded in the SK group. Four patients with Wilms' tumor and two with renal scarring were excluded from the study. The mean ages of the SK group and controls were 9.6 ± 3.6 and 9.3 ± 3.3 years, respectively. The serum Cys C and Cr levels, 24-h urinary β2-MG and MA levels were similar in both groups (p > 0.05). However, 24-h urinary MA excretion was higher in patients living with SK more than 5 years (p = 0.01). Standard deviation scores of ABPM parameters showed no significant correlation with serum Cr, serum Cys C, MA, and β2-MG in 24-h urine of both groups. Children with SK have increased 24-h urinary MA excretion in the long term, and need prolonged follow-up to detect early deterioration of renal function and to prevent end-organ damage later in life.
Article
Background: Mild-to-moderate renal function loss may be an independent risk factor for cardiovascular disease and overall mortality. As in adults with renal carcinoma nephrectomy is associated with an high risk for moderate renal function loss, we aimed to assess the renal function adaptation over a long period of time in children with unilateral renal tumor (URT). Procedure: Seventy-two children who underwent surgery for URT were enrolled in this study. Glomerular filtration rate was estimated (eGFR) with the Modification of Diet in Renal Study or the Schwartz equation, as appropriate for the age. Results: Twelve patients treated by nephron-sparing surgery (Group A) and 42 treated by nephrectomy (Group B) had an age between 2 and 30 years; 18 patients treated by nephrectomy had an age between 33 and 51 years (Group C). At cross-sectional follow-up 8% patients of Group A, 42% of Group B and 78% of Group C presented a mild-to-moderate renal function. The longitudinal data stratified by post-operative intervals showed that patients of Group C presented a significant progressive decrease in mean ± standard deviation eGFR (88.1 ± 22.6 during the third decade after surgery vs. 66.6 ± 15.6 ml/min/1.73 m(2) during the fifth decade after surgery; P = 0.02). The longitudinal data stratified by age showed that patients with an age between 45 and 54 years presented a mean eGFR significantly lower than that expected for the physiological renal function decline with aging (P = 0.001). Conclusion: Aging is associated with a mild-to-moderate renal function loss in many adult patients following nephrectomy during childhood for URT.
Article
Background: Urinary liver-type fatty acid-binding protein (L-FABP) is a proximal tubular injury candidate biomarker for early detection of acute kidney injury (AKI), with variable performance characteristics depending on clinical settings. Study design: Meta-analysis of diagnostic test studies assessing the performance of urinary L-FABP in AKI. Setting & population: Literature search in MEDLINE, EMBASE, Scopus, Google Scholar, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov using search terms "liver-type fatty acid-binding protein" and "L-FABP." Selection criteria for studies: Studies of humans investigating the performance characteristics of urinary L-FABP for the early diagnosis of AKI and AKI-related outcomes, including dialysis requirement and mortality. Predictor: Urinary L-FABP. Outcomes: Diagnosis of AKI, dialysis requirement, and in-hospital death. Results: 15 prospective cohort and 2 case-control studies were identified. Only 7 cohort studies could be meta-analyzed. The estimated sensitivity of urinary L-FABP level for the diagnosis of AKI was 74.5% (95% CI, 60.4%-84.8%), and specificity was 77.6% (95% CI, 61.5%-88.2%). The estimated sensitivity of urinary L-FABP level for predicting dialysis requirement was 69.1% (95% CI, 34.6%-90.5%), and specificity was 42.7% (95% CI, 3.1%-94.5%); for in-hospital mortality, sensitivity and specificity were 93.2% (95% CI, 66.2%-99.0%) and 78.8% (95% CI, 27.0%-97.4%), respectively. Limitations: Paucity and low quality of studies, different clinical settings, and variable definitions of AKI. Conclusions: Although urinary L-FABP may be a promising biomarker for early detection of AKI and prediction of dialysis requirement and in-hospital mortality, its potential value needs to be validated in large studies and across a broader spectrum of clinical settings.
Article
Unilateral Wilms tumors associated with predisposing syndromes are treated with preoperative chemotherapy followed by surgical resection. We describe our experience with nephron sparing surgery for Wilms tumor in this population at risk for metachronous lesions. We conducted a retrospective review of all children with a predisposing syndrome who underwent nephrectomy for malignancy during a 10-year period (2000 to 2010). Data collected included age, mode of detection, tumor size, treatment, pathology results, followup time and recurrence episodes. From 2000 to 2010, 13 of 75 (19%) patients treated for Wilms tumor were diagnosed with predisposing syndrome(s). Eight patients with unilateral tumors were treated and had a mean age at diagnosis of 27 months (range 7 months to 9 years). Beckwith-Wiedemann syndrome, isolated hemihyperplasia, WAGR (Wilms tumor, Aniridia, Genitourinary abnormalities, mental Retardation) syndrome and isolated 11p13 deletion were the underlying diagnoses in 3, 2, 2 and 1 patient, respectively. All but 2 patients were diagnosed by screening ultrasound and 5 underwent preoperative chemotherapy. Median tumor size at surgery was 2.5 cm (range 1 to 13). Nephron sparing surgery was performed in 6 of 8 patients. Pathological study showed favorable histology Wilms tumor and nephrogenic rests in 6 and 2 patients, respectively. After a mean followup of 36 months (range 6 to 72) no recurrences were documented and all children had normal creatinine levels. Nephron sparing surgery appears safe for patients with unilateral Wilms tumor associated with predisposing syndrome(s), allowing for the preservation of renal function and good oncologic outcomes for the available followup time. If more studies confirm our observation, current recommendations for the surgical treatment of Wilms tumor may need to reemphasize the value of attempting nephron sparing surgery in this patient population.
Article
We sought to verify the hypothesis that children and young adults with cancer who have completed treatment differ according to the type and degree of renal damage. This study included 144 children and young adults (73 female) who had completed treatment for leukemias and lymphomas (group L, n=45), Wilms tumor (group W, n=52) and other solid tumors (group S, n=47). The following parameters were evaluated: serum concentrations of creatinine, cystatin C, β2-microglobulin, neutrophil gelatinase-associated lipocalin and urine excretion of albumin, and urinalysis with sediment. Glomerular filtration rate (eGFR) was estimated using the classic Schwartz (eGFRSch), Schwartz redux (eGFRSchred), and Filler (eGFRFiller) formulas and with the new Schwartz equation for patients with chronic kidney disease (eGFRSchCKD). Group S had the lowest eGFRSchCKD and eGFRFiller, the highest serum cystatin C and the highest albumin excretion compared with groups L and W. Groups S and W had lower eGFRSch and eGFRSchred and higher serum β2-microglobulin and neutrophil gelatinase-associated lipocalin compared with group L. Group W had lower eGFRSchCKD than group L. Children and young adults with cancer who have completed treatment differ in the type and degree of renal damage they sustain.
Article
To test the hypothesis that Wilms tumour survivors (WTs) experience increased disturbance in renal function, even after prompt treatment, compared to patients with unilateral renal agenesis (URA). To assess the renal function of 30 WTs and 17 individuals with URA, the estimated glomerular filtration rate (eGFR) was calculated using the Schwartz and Filler formulas as well as the new Schwartz equation for chronic kidney disease. To measure kidney damage, serum levels and urine excretion of β(2)-microglobulin (B2M), cystatin C (Cys C), neutrophil gelatinase-associated lipocalin (NGAL) were tested, N-acetyl-β-glucosaminidase (NAG), and albumin urine excretion and urine sediment were examined. Blood pressure was measured. No differences were found between the groups in terms of eGFR, serum Cys C, B2M and NGAL concentrations. The urine excretion of Cys C, NGAL and NAG was similar in both groups. URA patients had higher B2M excretion than WTs. Arterial hypertension was present in 7/30 (23%) WTs and 1/17 (6%) patients with URA. WTs have similar eGFR to individuals with URA and are more likely to have arterial hypertension. The patients with URA have signs of tubular damage. This study demonstrates the need for nephrological monitoring of individuals with a single kidney.
Article
We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease. End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions. The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p<0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend). Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall.
Article
To standardize diagnosis and treatment of childhood Wilms tumor (WT) in Turkey. Between 1998 and 2006, WT patients were registered from 19 centers. Patients <16 years with unilateral WT whose treatment started in first postoperative 3 weeks were included. Treatments were stage I favorable (FH) and unfavorable histology (UH) patients, VCR + Act-D; stage IIA FH, VCR + Act-D; stage IIB FH, VCR + Act-D + radiotherapy (RT); stage III-IV FH, VCR + Act-D + adriamycin (ADR) + RT; stages II-IV UH tumors, VCR + Act-D + ADR + etoposide + RT. 165/254 registered cases were eligible (bilateral, 5.9%) [median age 3.0 years; M/F: 0.99; 50/165 cases < or =2 years]. 9.7% cases had UH tumors. Disease stages were stage I 23.6%; IIA 36.4%; IIB 5.5%; III 22.4%; IV 12.1%. Cases >2 years had significantly more advanced disease. 1/11 cases with recurrent disease died; 2/165 had progressive disease, 2/165 had secondary cancers, and all 4 died. In all cases 4-year OS and EFS were 92.8 and 86.5%, respectively. Both OS and EFS were significantly worse in stage IV. Despite problems in patient management and follow-up, treatment results were encouraging in this first national experience with a multicentric study in pediatric oncology. Revisions and modifications are planned to further improve results and minimize short- and long-term side effects.
Article
Eight patients nephrectomized in childhood were studied with regard to growth and function of the remaining kidney. The age of the patients ranged between 8 1/2 and 31 years and the follow-up period was from 1 to 20 years. In most of the patients, repeated renal size determinations were made on postoperative urograms. Normal values for kidney size in childhood are also presented. The structural hypertrophy continued for at least three years after nephrectomy and was most pronounced in patients nephrectomized before three years of age. When more than three years had passed after nephrectomy the remaining kidney was 35-65% larger than normal. Healthy young adults and children with a previous history of urinary tract infection served as controls for function studies. The balance between glomerular and tubular function was well preserved in nephrectomized patients. The renal surface area showed the same relation to GFR and to reabsorption of bicarbonate in nephrectomized patients as in controls. It is therefore concluded that the increase in kidney function following unilateral nephrectomy is, at least in early life, primarily due to structural enlargement.
Article
We report on 10 children, less than 2 years of age, who presented with a genuine type of glomerulopathy: diffuse mesangial sclerosis. In 5, the nephropathy was associated with male pseudohermaphroditism (MPH) and Wilms' tumor (WT); in 3 with MPH and in 2 with WT. The nephropathy was characterized by its very early onset, between the age of 2 weeks and 18 months. Eight patients presented with a nephrotic syndrome with (7 cases) or without (1 case) hypertension. All, but one, who is in advanced RF at 11 years of age, progressed to chronic or end-stage renal failure (ESRF) within a few months to 2 years from the onset. One additional child presented with advanced renal failure at the age of 8 months and the last one, who was hypertensive, developed an anuria related to thrombosis of renal veins at 1 year of age. Drash syndrome is characterized by the association of a "nephron disorder" with MPH and WT. We propose, on the basis of our histological findings, to extend the concept of Drash syndrome to patients who, in addition to the nephropathy, have either WT or MPH and to consider the distinctive glomerular lesions presented by all these patients as their common denominator. The pathogenesis of this glomerulopathy is obscure. Its early onset, its association with a dysembryoplastic tumor and/or with gonadal dysgenesis both suggest an antenatal dysgenetic process.
Article
Kidney size was determined in a sonographic study of 325 children without kidney pathology. Real-time ultrasound equipment adjusted for the pediatric age group, provided standardized renal biometry. Outer kidney diameters showed a linear correlation to somatic developmental parameters. Renal volume was established by the formula for an ellipsoid and showed good correlation to body weight. Growth charts for kidney length and volume in childhood are constructed and provide the basis for objective intra- and interindividual determination of renal size.
Article
Results of renal function studies in 17 nephrectomized children were compared with those from children with a congenital nondiseased solitary kidney of similar age. An early glomerulotubular balance was demonstrated in all patients, but maximal tubular excretion of PAH was only achieved over 4 years after nephrectomy. Patients with a solitary kidney, congenital or acquired, showed a significant tubular predominance and a significant decrease of renal plasma flow per unit of tubular excretory mass when compared with a series of healthy children with two kidneys (p < 0.05; p < 0.005).Copyright © 1982 S. Karger AG, Basel
Article
This report defines the incidence and determines the etiology of renal failure (RF) in patients undergoing treatment for Wilms' tumor (WT). The database of the National Wilms' Tumor Study (NWTS) was searched to identify all children reported to have developed chronic renal failure. There were 55 patients found to have RF. Of these, 39 patients had bilateral tumors, 15 with unilateral disease and one with a WT in a solitary kidney. The median interval from diagnosis to the onset of renal failure was 21 months. The incidence of RF in bilateral WT was 16.4% for NWTS-1 & -2, 9.9% for NWTS-3, and 3.8% for NWTS-4. The incidence of RF in unilateral WT remained stable. The most common etiologies of RF were: bilateral nephrectomy for persistent or recurrent tumor (24 pts), Drash syndrome (12 pts), progressive tumor in the remaining kidney (5 pts), radiation nephritis (6 pts), and other causes (5 pts). The etiology of renal failure was not reported in three children. Children with unilateral WT and a normal contralateral kidney have a very low incidence of RF, and this review does not support a recommendation for parenchymal sparing procedures in these patients. Children with bilateral WT are at risk for the development of RF, and parenchymal sparing procedures are warranted.
Article
Clinical, biochemical, and sonographic evaluation of the remaining kidney function and size was performed in 34 patients, 12 males and 22 females, ages 2.1-19.6 years, nephrectomized (NP) for Wilms' tumor (WT) at least 2 years before (mean 8.6). All patients had normal blood pressure and serum bicarbonates. Two of them had microhematuria, four proteinuria 4 mg/m2/hr, and 11 microalbuminuria (MA) > 20 mg/24 hr. Only one patient had reduced creatinine clearance and maximum bipolar length (MBL) as well as kidney volume (KV) < 100% of expected. In the other patients, average MBL was 128 +/- 11% (P = 0.0001). MBL, but not KV, was inversely correlated (P = 0.04) to age at NP. KV, but not MBL, was directly correlated (P = 0.009) to MA. Average MA was 48 +/- 94 mg/24 hr and was correlated to the time from NP (P = 0.026). The remaining kidney increases in volume much more than in length. The increase in KV is related to the degree of MA, whereas the increase in MBL is higher in subjects younger at NP. The high prevalence of significant MA, which is in turn related to the time from NP and to the KV, raises some concerns about the long-term renal prognosis of children NP for WT.
Article
The effect of therapy on renal function after unilateral nephrectomy for Wilms' tumour was studied. In the second year following unilateral nephrectomy, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated simultaneously by measuring 125I-iothalamate clearance and 131I-hippurate clearance. Of 41 evaluable patients, 29 received chemotherapy as sole treatment modality following nephrectomy (group 1); 12 patients additionally received radiation therapy to a field that included the remaining kidney (group 2). Results were expressed as standard deviation scores (z-scores). In group 1, mean z-score for GFR was -0.27 (94.6% of normal) and in group 2 mean z-score was -1.51 (72.7% of normal for two kidneys) (P = 0.022, Mann-Whitney U-test). Mean z-score for ERPF was -0.09 (97.0%) in group 1 and -1.53 (73.8%) in group 2 (P = 0.039). It was concluded that the combination of chemotherapy and radiation therapy, in contrast to chemotherapy alone, negatively affects the ability of the remaining kidney to adjust its function after the loss of its counterpart.
Article
Study of genotype/phenotype relationships involving the Wilms' tumor (WT) gene, WT1, in WT patients has provided insights into the function of the WT1 protein, a transcriptional regulator, and has suggested possible mutational mechanisms important in the etiology of WT. For example, the identification of deletion/insertion mutations in the first exon implicates a deletion hotspot consensus sequence in the etiology of these mutations. The disproportionate number of WT/aniridia patients with such mutations further suggest that this genetic mechanism may be enhanced by the hemizygous state. WT1 mutations are observed throughout the gene and, as predicted by the two hit mutational model, germline mutations predominantly occur in patients with congenital genitourinary (GU) anomalies and/or bilateral disease. The presence of hemizygous mutations in tumors from individuals with germline 11p13 deletions encompassing WT1 supports the hypothesis that inactivation of both WT1 alleles is important in tumorigenesis. Analyses of WT1 mutations in individuals with WT-associated Drash syndrome and WT patients with GU anomalies in the absence of Drash syndrome indicate that Drash patients almost invariably carry germline missense mutations in the zinc finger domains whereas WT/GU patients carry germline mutations that delete the WT1 gene or encode truncated proteins. These data suggest a functional difference between mutant WT1 protein carrying a single amino acid substitution versus mutant WT1 protein that is grossly truncated or WT1 haploinsufficiency. These and other genotype/phenotype correlations in WT patients will be discussed in more detail.
Article
To assess the relation of cisplatin-induced nephrotoxicity to its pharmacology. In 22 chemonaive patients (median age, 32 years) receiving 100-150 mg/m2 cisplatin for a total of 54 courses of therapy pharmacokinetics of ultra-filtrable platin were analyzed. Nephrotoxicity was sensitively assessed by nephelometric analyses of urinary marker-proteins. The parameters calculated for ultrafiltrable platin were (two-compartment-model): terminal half-life, 36 hours (coefficient of variation [CV], 22%); AUC, 12852 ng h/ml (33%); volume of distribution, 3531 (44%); total clearance, 285 ml/min (30%); renal clearance, 149 ml/min (23%); maximum concentration, 1720 ng/ml (66%); renal elimination, 57% of applied dose (26%). A pathological urinary excretion of albumin > 20 mg/l and alpha-1-microglobulin > 10 mg/l was detected in 39 out of 54 and 42 out of 54 cycles, respectively. The degree of albuminuria was related with urinary monoaquoplatin concentrations (p = 0.003). Nephrotoxicity of cisplatin appears to depend on the urinary monoaquoplatin concentrations which may be modulated by application of saline.
Article
One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months–11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06–27.5) years. Glomerular filtration rate was measured by 51Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61–150) ml min−1 1.73 m−2. Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities ⩾800 mOsm kg−1, but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment. British Journal of Cancer (2002) 87, 1092–1098. doi:10.1038/sj.bjc.6600608 www.bjcancer.com © 2002 Cancer Research UK
Article
The scarcity of early biomarkers for acute renal failure has hindered our ability to launch preventive and therapeutic measures for this disorder in a timely manner. We tested the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for ischaemic renal injury after cardiopulmonary bypass. We studied 71 children undergoing cardiopulmonary bypass. Serial urine and blood samples were analysed by western blots and ELISA for NGAL expression. The primary outcome measure was acute renal injury, defined as a 50% increase in serum creatinine from baseline. 20 children (28%) developed acute renal injury, but diagnosis with serum creatinine was only possible 1-3 days after cardiopulmonary bypass. By contrast, urine concentrations of NGAL rose from a mean of 1.6 microg/L (SE 0.3) at baseline to 147 microg/L (23) 2 h after cardiopulmonary bypass, and the amount in serum increased from a mean of 3.2 microg/L (SE 0.5) at baseline to 61 microg/L (10) 2 h after the procedure. Univariate analysis showed a significant correlation between acute renal injury and the following: urine and serum concentrations of NGAL at 2 h, and cardiopulmonary bypass time. By multivariate analysis, the amount of NGAL in urine at 2 h after cardiopulmonary bypass was the most powerful independent predictor of acute renal injury. For concentration in urine of NGAL at 2 h, the area under the receiver-operating characteristic curve was 0.998, sensitivity was 1.00, and specificity was 0.98 for a cutoff value of 50 microg/L. Concentrations in urine and serum of NGAL represent sensitive, specific, and highly predictive early biomarkers for acute renal injury after cardiac surgery.
Article
We sought to assess accurately the full spectrum of end stage renal disease (ESRD) in Wilms tumor survivors by combining the unique resources of the National Wilms Tumor Study Group (NWTSG) and the United States Renal Data System (USRDS), and to confirm preliminary reports of an increased incidence of ESRD in patients with the Wilms tumor-aniridia syndrome (WAGR). ESRD was ascertained in 5,910 patients enrolled in NWTSG studies during 1969 to 1994 by record linkage to USRDS and by direct followup. Cumulative ESRD incidence was estimated accounting for intercurrent mortality. Of 115 cases of ESRD 10 (9%) were ascertained by the NWTSG alone, 13 (11%) by USRDS alone and 92 (80%) by both. Cumulative incidence of ESRD at 20 years from diagnosis of unilateral Wilms tumor was 74% for 17 patients with the Denys-Drash syndrome, 36% for 37 patients with WAGR, 7% for 125 male patients with hypospadias or cryptorchidism (genitourinary [GU] anomalies) and 0.6% for 5,347 patients with none of these conditions. The incidence of ESRD after diagnosis of bilateral Wilms tumor was 50% for the Denys-Drash syndrome (6 patients), 90% for WAGR (10), 25% for GU anomaly (25) and 12% for other (409). ESRD in patients with WAGR or GU anomalies tended to occur relatively late, often during or after adolescence. The risk of ESRD is remarkably low for the majority of patients with Wilms tumor. However, those with WAGR or associated GU anomalies are at higher risk and should be screened indefinitely to facilitate prospective treatment of impaired renal function.
Article
Nephron-sparing surgery (NSS) is the treatment of choice for children with bilateral Wilms' tumor (WT), or with WT on a single kidney, or with WT and a disease of the contralateral kidney, or with benign kidney tumor. NSS is a reasonable alternative to nephrectomy in children at risk of metachronous WT, including children with genetic syndromes, children younger than 1 year of age, and children with hyperplastic nephroblastomatosis. The use of NSS in selected children with "low-risk" or stage I "intermediate-risk" WT and a normal contralateral kidney is still controversial. Available data suggest that, in children with WT, NSS does not impair the outcome and has a renal function advantage over nephrectomy.
SEER data submission
  • N Howlader
  • Na
  • M Krapcho
  • D Miller
  • A Brest
  • M Yu
  • J Ruhl
  • Z Tatalovich
  • A Mariotto
  • D R Lewis
  • H S Chen
  • E J Feuer
  • K A Cronin
Denburg MR (2021) kidney outcomes and hypertension in survivors of Wilms tumor: A prospective cohort study
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  • A M Ehlayel
  • J P Ginsberg
  • K E Meyers
  • M Benton
  • M Thomas
  • C Carlson
  • T F Kolon
  • G E Tasian
  • J H Greenberg
  • S L Furth
  • DI Chu
Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery
  • J Mishra
  • C Dent
  • R Tarabishi
  • MM Mitsnefes
  • Q Ma
  • C Kelly
  • SM Ruff
  • K Zahedi
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  • J Bean
  • K Mori
  • J Barasch
  • P Devarajan
2021) SEER Cancer Statistics Review
  • N Howlader
  • Na
  • M Krapcho
  • D Miller
  • A Brest
  • M Yu
  • J Ruhl
  • Z Tatalovich
  • A Mariotto
  • D R Lewis
  • H S Chen
  • E J Feuer
  • K A Cronin
Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) (2021) SEER Cancer Statistics Review, 1975-2018, National Cancer Institute., Bethesda, MD, https:// seer. cancer. gov/ csr/ 1975_ 2018/, based on November 2020 SEER data submission, posted to the SEER web site.
  • C Akyuz
  • B Yalcin
  • I Yildiz
  • V Hazar
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  • G Tokuc
  • F Akici
  • N Buyukpamukcu
  • G Kale
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