Unilateral ureteropelvic junction obstruction (UPJO) is the most common prenatally detected disease leading to hydronephrosis. The obstructive anatomic lesion leads to varying degrees of hydronephrosis, ranging from no apparent effect on renal function to atrophy. Furthermore, the natural course of hydronephrosis varies from spontaneous resolution to progressive deterioration and may take upwards of 3 years for a kidney to declare itself. The objectives of this article are to update our knowledge regarding the evaluation and management of UPJO in depth and to discuss the emerging value of urinary proteome analysis to the clinical arena.
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Obstructive diseases of the urinary tract in the newborn can lead to infant death, kidney failure, and in those who survive, chronic kidney disease and early heart disease in adolescence and adulthood.
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In the Western Hemisphere, despite the availability of prenatal maternal sonography and advanced imaging, obstructive diseases of the urinary tract account for most cases of end-stage kidney disease and consume a large chunk of health care expenditure in this segment of the population.
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Early diagnosis by virtue of maternal sonography (secondary to hydronephrosis) affords opportunities to arrest or slow down the progression of renal functional deterioration. However, renal function can deteriorate by as much as 50% before it can be detected.
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Despite the magnitude of the problem, the renal response to human obstructive uropathy and subsequent disease progression remain poorly understood. This obscurity is compounded by the fact that current methods of diagnosis of renal impairment are insensitive (serum creatinine level) or invasive (tissue biopsy).
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Early detection and prevention of progressive renal damage are feasible and important strategies with long-term benefits to the individual and society. Urinary tract obstruction leading to hydronephrosis consists of a spectrum of conditions resulting in a range of renal functional impairment.
Introduction
Obstructive diseases of the urinary tract in the newborn can lead to infant death, kidney failure, and in those who survive, chronic kidney disease and early heart disease in adolescence and adulthood. In the Western Hemisphere, despite the availability of prenatal maternal sonography and advanced imaging, obstructive diseases of the urinary tract account for most cases of end-stage kidney disease and consume a large chunk of health care expenditure in this segment of the population. Early diagnosis by virtue of maternal sonography (secondary to hydronephrosis) affords opportunities to arrest or slow down the progression of renal functional deterioration. However, renal function can deteriorate by as much as 50% before it can be detected. Despite the magnitude of the problem, the renal response to human obstructive uropathy and subsequent disease progression remain poorly understood. This obscurity is compounded by the fact that current methods of diagnosis of renal impairment are insensitive (serum creatinine level) or invasive (tissue biopsy). The early detection and prevention of progressive renal damage are feasible and important strategies with long-term benefits to the individual and society. Urinary tract obstruction leading to hydronephrosis consists of a spectrum of conditions resulting in a range of renal functional impairment. Unilateral ureteropelvic junction obstruction (UPJO) is the most common prenatally detected disease leading to hydronephrosis. The obstructive anatomic lesion leads to varying degrees of hydronephrosis, ranging from no apparent effect on renal function to atrophy ( Fig. 1 ). Furthermore, the natural course of hydronephrosis varies from spontaneous resolution to progressive deterioration and may take upwards of 3 years for a kidney to declare itself. The objectives of this article are to update our knowledge regarding the evaluation and management of UPJO in depth and to discuss the emerging value of urinary proteome analysis to the clinical arena.
Clinical scenarios
Patient Number 1
A 2-month-old boy presented with a history of prenatally detected left hydronephrosis, which was confirmed postnatally to be consistent with grade IV (see Fig. 1 C). The anteroposterior diameter (AP) of the left renal pelvis was 2.15 cm. The AP diameter is by convention a standardized measurement of the degree of hydronephrosis obtained on the midtransverse view (see Fig. 1 D). Other methods have been described but have not gained widespread use. The workup consisted of a voiding cystourethrogram, which was normal, and a furosemide technetium 99m ( 99m Tc) mercapto-acetyl-triglycine (MAG 3) renal scan to assess kidney function. MAG-3 is a molecule that is almost exclusively a renal plasma flow agent, excreted by secretion in the proximal tubules and coupled to a radiotracer ( 99m Tc). Following injection, the radiotracer is followed over the kidneys, and time versus activity curves are generated. The deconvolution of these curves yields a value referred to as percent extraction of the radionuclide for each kidney and another referred to as the t ½ . The latter is the time it takes for half of the radiotracer activity to leave the kidney following the administration of a standard dose of Lasix (1 mg/kg). The extraction factor is a surrogate for individual kidney function and the t½ is the drainage function of the renal pelvis. Surgery is recommended when the percent extraction is reduced to less than 40% for the hydronephrotic kidney and the t½ exceeds 30 minutes. A 10% or less extraction fraction is usually taken to indicate the presence of a burned-out and nonsalvageable hydronephrotic kidney. Different combinations of the grade of hydronephrosis, the percent extraction, the t½ can exist and more importantly may change over time. In patient number 1, these values were 49.6% and 10 minutes respectively and, therefore, the authors elected to follow this asymptomatic infant with watchful waiting. Over the following 3 years, the natural course of the disease unfolded and by 27 months of age, the percent extraction had decreased to 39.2% and the t½ increased to 18.2 minutes ( Fig. 2 ). This toddler remained asymptomatic throughout this period. Progression has occurred in 28% of the authors’ cohort of 25 patients followed over a period of time averaging 30 months and ranging from 6 to 48.
The course of this real case scenario demonstrates the difficulty in recommending surgery in an asymptomatic infant. It also demonstrates the limits of current imaging methods and the least cost-effective method of evaluation and management of this disease. There is a real need for biomarkers that are diagnostic for early functional deterioration and others that are prognostic for disease progression. This patient was found to have intrinsic UPJO at surgery, and a follow-up ultrasound at 9 months demonstrated almost complete resolution of the hydronephrosis. The histology of the ureteropelvic junction revealed a smooth muscle wall comprised of irregular bundles around a narrow lumen. The adjacent renal pelvis demonstrated smooth muscle hypertrophy and mild mononuclear inflammatory cell infiltrates. The kidney biopsy in similar patients reveals glomerular sclerosis, interstitial inflammation, and tubular atrophy with protein casts ( Fig. 3 ). In this and an additional 24 patients, urinary specimens were obtained at presentation, during the first year of life, and at surgery. These specimens were subjected to analysis by mass spectrometry (see later discussion). The findings were compared with urine specimens obtained from 21 age-matched control individuals.
Patient Number 2
This 5-week-old boy presented with left grade IV UPJO. The AP diameter of the hydronephrotic kidney was 2.0 cm and a MAG-3 diuretic renal scan revealed a 53.7% extraction and a t½ of 5 minutes. The hydronephrosis did resolve over a 20-month period to a final AP of 0.31 cm. He remained asymptomatic throughout the course of his follow-up. In the authors’ experience, resolution of hydronephrosis by ultrasound has been observed as early as 14 months after neonatal presentation and as late as 49 months. Patients in whom the hydronephrosis resolves still require to be followed albeit less intensively. Typically, the authors ask the parents to return patients for follow-up ultrasound studies at 5, 10, and 15 years of age. Delayed emergence of hydronephrosis has been described, and a few will present in adolescence with flank pain.
Patient Number 3
This baby girl presented at 1 month of age with left grade IV hydronephrosis secondary to UPJO. Her renal scan revealed a 48.8% extraction by the hydronephrotic kidney and a t½ of 6.3 minutes. She has now been followed for 3 years with a near stable AP diameter and remains asymptomatic ( Fig. 4 ).
Because of the lack of a sensitive marker of early kidney function, the authors are planning on following her indefinitely unless the patient develops symptoms or the hydronephrosis resolves or increases. Patients like this little girl represent most of their cohort (58%). Ten percent of this cohort of patients has been shown to loose kidney function over time, which is primarily caused by a loss to follow-up. This group also raises the question whether an opportunity to repair the hydronephrosis is being missed during the first 6 months of life when the kidney is still developing. During this period of time, the tubule lengthens by 3 times and the glomerular filtration rate (GFR) matures by 60%. The concept of renal reserve has been recently introduced as an additional parameter of overall renal function. Renal reserve is defined as the kidney’s capacity to increase its basal GFR by at least 20% in response to a protein load. It is different from early functional deterioration (not yet reflected in the serum creatinine) in the presence of a normal contralateral unit. There is considerable evidence in the literature demonstrating that renal pelvic dilation alone activates several responses mediated by stretch and mechanoreceptors with effects on the renal tubule, mesangial cells, and the renal microvasculature.
Clinical scenarios
Patient Number 1
A 2-month-old boy presented with a history of prenatally detected left hydronephrosis, which was confirmed postnatally to be consistent with grade IV (see Fig. 1 C). The anteroposterior diameter (AP) of the left renal pelvis was 2.15 cm. The AP diameter is by convention a standardized measurement of the degree of hydronephrosis obtained on the midtransverse view (see Fig. 1 D). Other methods have been described but have not gained widespread use. The workup consisted of a voiding cystourethrogram, which was normal, and a furosemide technetium 99m ( 99m Tc) mercapto-acetyl-triglycine (MAG 3) renal scan to assess kidney function. MAG-3 is a molecule that is almost exclusively a renal plasma flow agent, excreted by secretion in the proximal tubules and coupled to a radiotracer ( 99m Tc). Following injection, the radiotracer is followed over the kidneys, and time versus activity curves are generated. The deconvolution of these curves yields a value referred to as percent extraction of the radionuclide for each kidney and another referred to as the t ½ . The latter is the time it takes for half of the radiotracer activity to leave the kidney following the administration of a standard dose of Lasix (1 mg/kg). The extraction factor is a surrogate for individual kidney function and the t½ is the drainage function of the renal pelvis. Surgery is recommended when the percent extraction is reduced to less than 40% for the hydronephrotic kidney and the t½ exceeds 30 minutes. A 10% or less extraction fraction is usually taken to indicate the presence of a burned-out and nonsalvageable hydronephrotic kidney. Different combinations of the grade of hydronephrosis, the percent extraction, the t½ can exist and more importantly may change over time. In patient number 1, these values were 49.6% and 10 minutes respectively and, therefore, the authors elected to follow this asymptomatic infant with watchful waiting. Over the following 3 years, the natural course of the disease unfolded and by 27 months of age, the percent extraction had decreased to 39.2% and the t½ increased to 18.2 minutes ( Fig. 2 ). This toddler remained asymptomatic throughout this period. Progression has occurred in 28% of the authors’ cohort of 25 patients followed over a period of time averaging 30 months and ranging from 6 to 48.
The course of this real case scenario demonstrates the difficulty in recommending surgery in an asymptomatic infant. It also demonstrates the limits of current imaging methods and the least cost-effective method of evaluation and management of this disease. There is a real need for biomarkers that are diagnostic for early functional deterioration and others that are prognostic for disease progression. This patient was found to have intrinsic UPJO at surgery, and a follow-up ultrasound at 9 months demonstrated almost complete resolution of the hydronephrosis. The histology of the ureteropelvic junction revealed a smooth muscle wall comprised of irregular bundles around a narrow lumen. The adjacent renal pelvis demonstrated smooth muscle hypertrophy and mild mononuclear inflammatory cell infiltrates. The kidney biopsy in similar patients reveals glomerular sclerosis, interstitial inflammation, and tubular atrophy with protein casts ( Fig. 3 ). In this and an additional 24 patients, urinary specimens were obtained at presentation, during the first year of life, and at surgery. These specimens were subjected to analysis by mass spectrometry (see later discussion). The findings were compared with urine specimens obtained from 21 age-matched control individuals.
Patient Number 2
This 5-week-old boy presented with left grade IV UPJO. The AP diameter of the hydronephrotic kidney was 2.0 cm and a MAG-3 diuretic renal scan revealed a 53.7% extraction and a t½ of 5 minutes. The hydronephrosis did resolve over a 20-month period to a final AP of 0.31 cm. He remained asymptomatic throughout the course of his follow-up. In the authors’ experience, resolution of hydronephrosis by ultrasound has been observed as early as 14 months after neonatal presentation and as late as 49 months. Patients in whom the hydronephrosis resolves still require to be followed albeit less intensively. Typically, the authors ask the parents to return patients for follow-up ultrasound studies at 5, 10, and 15 years of age. Delayed emergence of hydronephrosis has been described, and a few will present in adolescence with flank pain.
Patient Number 3
This baby girl presented at 1 month of age with left grade IV hydronephrosis secondary to UPJO. Her renal scan revealed a 48.8% extraction by the hydronephrotic kidney and a t½ of 6.3 minutes. She has now been followed for 3 years with a near stable AP diameter and remains asymptomatic ( Fig. 4 ).
