The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions

Technetium 99m-dimercaptosuccinic acid (DMSA) scintigraphy has emerged as the imaging agent of choice for the detection and evaluation of acute pyelonephritis and renal cortical scarring in children. Consequently, DMSA scintigraphy provides a unique opportunity to study the progression of renal damage and functional loss from the initial insult of acute pyelonephritis to the subsequent development of irreversible renal scarring. Over the last few years, clinical and experimental investigations using DMSA renal scintigraphy have provided new insights into the etiology, pathophysiology, and clinical outcome of acute pyelonephritis in children. These studies have confirmed the primary role of the acute inflammatory response, associated with both reflux and nonreflux pyelonephritis, in the etiology of irreversible renal scarring. Furthermore, several studies have shown that renal scarring can be prevented or diminished by the early diagnosis and treatment of pyelonephritis. This review highlights these recent observations and makes recommendations regarding current clinical and future research applications. Received April 10, 1996; received in revised form August 5, 1996; accepted August 9, 1996     

The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above. Received: 17 February 1999 / Revised: 30 June 1999 / Accepted: 7 July 1999     

Management of vesicoureteral reflux in children

Background. Vesicoureteral reflux (VUR) in children has been reported in many studies. However, the management of VUR is still controversial. Methods. One hundred and fourteen children with primary VUR were divided into two treatment groups: medical (group A) and surgical (group B). The clinical courses and X-ray films of cystography and intravenous pyelography of these children were reviewed retrospectively, using the International Reflux Study Committee Classification. Results. In children less than 1 year of age, VUR was observed more frequently in boys. However, this ratio was reversed in children aged 2 years or more. Sixty-three percent of all refluxing ureters had reflux of grade III or higher at the initial examination. Spontaneous cessation of VUR was observed in 17% of group A ureters, and all had grade III or less reflux. Renal parenchymal scars were already present at the initial examination in 23% of kidneys with refluxing ureters. Recurrent urinary tract infections became less frequent after anti-reflux surgery. The progression of renal scars and renal growth retardation was observed more frequently in group B children. Conclusions. From these observations, it appeared that surgical management of VUR did not prevent the progression of renal scarring or renal growth retardation. Early detection of and intervention in VUR may prevent the progression of renal scarring and renal growth retardation. However, a multicenter, prospective, randomized controlled study would be necessary to confirm these findings. Received: October 4, 1999 / Accepted: January 15, 2000     

Imaging strategies for vesicoureteral reflux diagnosis

The prevalence of vesicoureteral reflux (VUR), although reported to be low in the general population, is high in children with urinary tract infection (UTI), first degree relatives of patients with known VUR and children with antenatal hydronephrosis. In addition, it has been shown that VUR and UTIs are associated with renal scarring, predisposing to serious long-term complications, i.e., hypertension, chronic renal insufficiency and complications of pregnancy. Therefore, diagnostic imaging for the detection of VUR in the high-risk groups of children has been a standard practice. However, none of these associations has been validated with controlled studies, and recently the value of identifying VUR after a symptomatic UTI has been questioned. In addition, several studies have shown that renal damage may occur in the absence of VUR. On the other hand, some patients, mainly males, may have primary renal damage, associated with high-grade VUR, without UTI. Recently, increasing skepticism has been noted concerning how and for whom it is important to investigate for VUR. It has been suggested that the absence of renal lesions after the first UTI in children may rule out VUR of clinical significance and reinforces the redundancy of invasive diagnostic techniques. Therefore, the priority of imaging strategies should focus on early identification of renal lesions to prevent further deterioration.     

Evaluation of acute pyelonephritis with DMSA scans in children presenting after the age of 5 years

It is generally believed that infants are more susceptible to development of renal scarring after pyelonephritis than children over 5 years old. This view has led to differences in investigations and treatment according to age. The aim of this prospective study was to assess the occurrence of renal parenchymal lesion in children over 5 years admitted with a first-time symptomatic urinary tract infection (UTI). Between October 2000 and April 2002, 52 children aged over 5 years who were admitted to our department with probable acute pyelonephritis (APN) and a positive urine culture were included in this study. All children received antibiotics for 14 days. During the acute phase of infection, scintigraphy with technetium-99 ^m -labeled dimercaptosuccinic acid (DMSA) and ultrasonography (US) were done. Voiding cystourethrography (VCUG) was performed in all children early in the course of the illness, generally within 5–7 days of hospitalization. When scintigraphy showed renal parenchymal changes, repeat scintigraphy was done after at least 3 months to assess the progression of renal abnormalities. Of the 52 children with a first-time documented pyelonephritis, cortical scintigraphy showed renal lesion in 41 children (78.8%). US was normal in all children with normal renal scintigraphy, while it detected renal abnormalities in 16 of the 41 (39 %) with abnormal scintigraphy ( p <0.0001). Topographic analysis of the 165 focal lesions showed that 42.4% were localized to the upper poles, 17.5% to the middle third, and 40% to the lower poles of the kidneys. Repeat scintigraphy showed persistent lesions corresponding to those on the initial scan in nine (28.2%) of the 32 children. Renal lesions had partly regressed in 23 (71.8%) of the patients who underwent repeat scintigraphy. Vesicoureteral reflux was observed in 13.4% of kidneys and renal parenchymal abnormalities were identified in 71.4% and 72.2% of renal units, respectively, with and without reflux ( p >0.05). In conclusion, our data did not confirm the conventional opinion that the risk of renal scarring after pyelonephritis is low in children over the age of 5 years. Our findings suggest that renal scintigraphy may be a more appropriate method of investigation than VCUG for evaluation of the children over 5 years with acute pyelonephritis. Additionally, the frequency of scintigraphic changes is high, and a strategy based exclusively on ultrasound findings would miss about 61% of the abnormal renal units. We recommend that all children, irrespective of age, will benefit from further investigations that might prevent or limit the development of scarring process and renal complications.     

Prognostic value of the acute DMSA scan in children with first urinary tract infection

We attempted to verify in a group of 101 children with first urinary tract infection whether it was possible to identify groups of patients with different risks of developing renal scarring by taking into account both the extent of kidney involvement documented in the acute phase of infection using a dimercaptosuccinic acid (DMSA) scan, and the presence or absence of vesicoureteral reflux (VUR). The frequency of persistent lesions in kidneys with mild-moderate lesions (less than 50% of kidney involvement) in the presence of VUR or in non-refluxing kidneys was similar (P=0.1447), while the frequency of persistent lesions in kidneys with severe lesions in the presence of VUR was significantly higher than the frequency of persistent lesions in non-refluxing kidneys (P=0.0089). The extent of kidney involvement and the presence of VUR make possible the identification of different categories of risk of scarring: in the ”low risk group” (normal kidney with/without VUR) the risk of scarring is 0%; in the ”intermediate risk group” (mild lesions with/without VUR; extensive lesions without VUR) the risk of scarring is between 14% and 38%, while in the ”high risk group” (extensive lesions with VUR) the risk of scarring is 88%. Quantifying the risk of scarring could help in planning the treatment or in modifying the later strategy. Received: 5 June 2000 / Revised: 23 January 2001 / Accepted: 24 April 2001     

Clinicopathological study of vesicoureteral reflux (VUR)-associated pyelonephritis in renal transplantation

Abstract:  We retrospectively studied the occurrence of vesicoureteral reflux (VUR)-associated pyelonephritis using renal biopsies obtained from the transplanted kidneys, and correlated the histological changes with clinical parameters. Out of a total of 131 renal biopsies performed between 1990 and 2001 on renal transplant patients at the department of Urology of Nagasaki University Graduate School of Biomedical Sciences, 12 patients showed pyuria more than twice in a single year. Seven of these 12 patients were available for determining VUR by voiding cystourethrography (VCUG). Cystoureterography demonstrated VUR in three of seven studied patients with pyuria. A histopathological examination revealed dilatation of both proximal and distal tubules in renal biopsies of transplant patients with VUR, compared to renal biopsies of transplant patients without VUR, or non-transplanted patients with thin membrane disease. One of the patients with VUR showed advanced features of chronic pyelonephritis in four consecutive biopsies at different time points, suggesting a late stage of reflux nephropathy in the transplanted kidney. We conclude from our study that the occurrence of VUR-related pyelonephritis may be one of the important long-term complications in the survival of renal allografts.     

Predictors of renal scar in children with urinary infection and vesicoureteral reflux

We evaluated the predictors of renal scar in children with urinary tract infections (UTIs) having primary vesicoureteral reflux (VUR). Data of patients who were examined by dimercaptosuccinic acid (DMSA) scintigraphy between 1995 and 2005 were evaluated retrospectively. Gender, age, reflux grade, presence/development of scarring, breakthrough UTIs, and resolution of reflux, were recorded. The relation of gender, age and VUR grade to preformed scarring and the relation of gender, age, VUR grade, presence of preformed scarring, number of breakthrough UTIs and reflux resolution to new scarring were assessed. There were 138 patients [male/female (M/F) 53/85]. Multivariate analysis showed that male gender [odds ratio (OR) 2.5], age ≥ 27 months in girls (OR 4.2) and grades IV–V reflux (OR 12.4) were independent indicators of renal scarring. On the other hand, only the presence of previous renal scarring was found to be an independent indicator for the development of new renal scar (OR 13.4). In conclusion, while the most predictive variables for the presence of renal scarring among children presenting with a UTI were male gender, age ≥ 27 months in girls, and grades IV–V reflux, the best predictor of new scar formation was presence of previous renal scarring.     

Plasma and urinary adrenomedullin levels in children with renal parenchymal scar and vesicoureteral reflux

Adrenomedullin (AM) is a strong vasodilator peptide with proven antimitogenic and antiproliferative effects in renal mesangial cells, as well as diuretic and natriuretic actions. Its gene expression is stimulated by endotoxins (lipopolysacharides) and cytokines. Consequently, its plasma and urinary levels are known to deviate from normal levels in many renal diseases. The purpose of this study is to determine plasma and urinary AM levels in children with renal parenchymal scar (RPS) and vesicoureteral reflux (VUR). The study was carried out on 74 children with recurrent urinary tract infections, arranged in groups: 25 patients with RPS with VUR (group I), 16 patients with RPS without VUR (group II), 12 patients with VUR without RPS (group III) and 21 healthy children as the control group. Plasma and urinary AM concentrations were both determined by high performance liquid chromotography (HPLC). Plasma AM was measured as picomoles per milliliter (pM/ml) and urinary AM as pM/mg urinary creatinine. In addition, serum creatinine, creatinine clearance and fractional sodium excretion (FE_Na) were measured. All cases with RPS and VUR had normal blood pressure levels. The plasma AM levels were higher, although not significantly, in the control group (56.2±14.0 pM/ml) than in group I (50.6±4.2 pM/ml), group II (49.6±3.7 pM/ml) and group III (50.6±3.6 pM/ml) ( P =0.162). The urinary AM levels were higher in the control group (80.1±33.9 pM/mg) than in the three study groups (52±7.6 pM/mg, 58.6±7.5 pM/mg and 44.2±6.4 pM/mg; P =0.003, P =0.002 and P =0.002, respectively). There were no differences among the 4 groups (group I, group II, group III and the control group) in terms of FE_Na and creatinine clearance ( P >0.05 and P >0.05, respectively). The finding that diminished urinary AM levels in patients with RPS and VUR implies that AM can be a prognostic factor in the long-term follow-up of cases with these diseases.