Pregnancies in women with and without renal scarring after urinary infections in childhood.

OBJECTIVE--To compare the outcome of pregnancy in women with and without renal scarring after childhood urinary infections with that in unmatched controls. DESIGN--Retrospective study of pregnancies in women prospectively followed up from their first recognised urinary infection. SETTING--Tertiary referral centre in Gothenburg. SUBJECTS--111 Women attending an outpatient clinic for women with urinary infection during 1975-83, of whom 41 (65 pregnancies) were studied (19 women with renal scarring (32), 22 without scarring (33)), and 65 controls (65) randomly selected and matched for parity, age, smoking habits, and date of delivery. MAIN OUTCOME MEASURES--Urinary infections and complications in pregnancy. RESULTS--The incidence of bacteriuria during first pregnancies was significantly greater in women with (9, 47%) and without (6, 27%) renal scarring after childhood urinary infection than in controls (1, 2%) (p less than 0.001, 0.01 respectively). Symptomatic infections were seen only among women with a history of urinary infection: four women with renal scarring (three of whom had vesicoureteric reflux) developed pyelonephritis and three cystitis, and one woman without scarring developed pyelonephritis. Mean blood pressure was higher among women with severe renal scarring than controls (4/11 v 3/44; p less than 0.05) before and during pregnancy. There was no significant difference in the incidence of pre-eclampsia, operative delivery, prematurity, or birth weight. CONCLUSIONS--Women with a history of previous urinary infections had a high incidence of bacteriuria during pregnancy, and those with renal scarring and persistent reflux were prone to develop acute pyelonephritis. The risk of serious complications in pregnancy, however, was not increased in women with severe renal scarring, possibly owing to their continuous clinical supervision.     

Genetics of Vesicoureteral Reflux

Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder to the upper urinary tract. It is the most common congenital urological anomaly affecting 1-2% of children and 30-40% of patients with urinary tract infections. VUR is a major risk factor for pyelonephritic scarring and chronic renal failure in children. It is the result of a shortened intravesical ureter with an enlarged or malpositioned ureteric orifice. An ectopic embryonal ureteric budding development is implicated in the pathogenesis of VUR, which is a complex genetic developmental disorder. Many genes are involved in the ureteric budding formation and subsequently in the urinary tract and kidney development. Previous studies demonstrate an heterogeneous genetic pattern of VUR. In fact no single major locus or gene for primary VUR has been identified. It is likely that different forms of VUR with different genetic determinantes are present. Moreover genetic studies of syndromes with associated VUR have revealed several possible candidate genes involved in the pathogenesis of VUR and related urinary tract malformations. Mutations in genes essential for urinary tract morphogenesis are linked to numerous congenital syndromes, and in most of those VUR is a feature. The Authors provide an overview of the developmental processes leading to the VUR. The different genes and signaling pathways controlling the embryonal urinary tract development are analyzed. A better understanding of VUR genetic bases could improve the management of this condition in children.     

Epidemiology of urinary tract diseases in general practice

During a one-year morbidity survey of urinary tract diseases in general practice 741 cases were diagnosed. Only about half of all the patients with symptoms of urinary tract infection had significant bacteriuria. In young women urinary tract infections and symptoms from the urinary tract without bacteriuria—in particular urethritis—were found to predominate. In middle-aged women, the urinary tract symptoms were ascribed increasingly to genital prolapse, while incidence of urolithiasis was the highest in any group, and urinary tract infections became less frequent. The prevalence of urinary tract infection showed another increase in elderly women, and recurrent/chronic pyelonephritis, which occurs with a steadily increasing prevalence throughout all age groups, became common.In younger male urological patients diseases with symptoms of urinary tract infection without bacteriuria were predominant, whereas prostatitis and urinary tract infections were less frequent. In middle-aged men, urolithiasis was especially frequent, while an increasing proportion of elderly men had prostatic hypertrophy, urinary tract infections, and recurrent/chronic pyelonephritis.     

Part III – Treatment of Ureterovesical Reflux

Of 134 girls with demonstrable ureterovesical reflux, 61 (105 ureters) had the reflux surgically corrected with an overall surgical cure rate of 97 percent. In the remaining 73 children (112 ureters), the reflux was treated conservatively with medical management alone. During the follow-up period no significant differences were demonstrated in the overall incidence of urinary tract infection; two years following corrective operation or medical treatment more than 50 percent of both medically and surgically treated children were still experiencing infections. A pronounced decrease, however, occurred in the incidence of clinical pyelonephritis among the surgically treated group. Following correction of reflux, the incidence of pyelonephritis was similar in both medically and surgically treated cases and was approximately the same as that found in a comparable group of children without reflux.In approximately two-thirds of refluxing renal units in which there was evidence of clubbing and scarring before medical or surgical therapy, deterioration progressed during the follow-up period. In most of these cases infection control was felt to be inadequate with episodes of clinical pyelonephritis occurring during the period of medical management, or, in the surgically treated group, occurring just before corrective operation and the scar appearing within two years after operation.The majority of renal units in which calyceal clubbing and parenchymal scarring was present had the most severe grades of reflux.     

Secretor state and renal scarring in girls with recurrent pyelonephritis

Abstract The non-secretor phenotype was significantly associated with the occurrence of renal scarring among patients with recurrent pyelonephritis. Girls ( n = 77) with recurrent pyelonephritis were followed from the first known episode of infection for up to twelve years with repeated radiological investigations. They were divided into two categories: those with renal scars ( n = 35) and those who did not develop scars ( n = 42). There was a significant over-representation of non-secretors among the patients with scarring, (14/35, 40%) compared to the healthy controls (21.8%, P < 0.05). The frequency of non-secretors among the girls who did not develop scars in spite of repeated episodes of acute pyelonephritis was not significantly different from the healthy controls (9/42, 21%, n.s.). This study provides a basis for analysis of the influence of secretor state on host-parasite interaction in the urinary tract.     

Retrospective studies of urinary infections in the elderly

Retrospective analysis of the urinary infection course involved 55 elderly patients. The patients were divided into groups basing on the clinical diagnosis. These groups included patients with obstructive chronic pyelonephritis and the patients with lower urinary infections. It was found that reinfections occur in the elderly patients with both upper and lower urinary infections while recurrence is seen in case of the upper urinary infections. Bacteriuria is significantly more frequent in the obstructive chronic pyelonephritis than in other urinary infections. This form of bacteriuria is frequently accompanied by exacerbations than in bacteriuria of periodic origin. Arterial blood hypertension is frequent in the elderly with urinary infections but its incidence does not correlate with the localization of the infection. Decompensated renal failure in the course of the urinary infections in the elderly is nearly always combined with arterial blood hypertension.     

Altered clinical and histological features of male MM mouse pyelonephritis associated with a change in its microbiology

Radical changes in the clinical, microbiological and histological features of spontaneous pyelonephritis in MM male mice occurred when they were transferred to a new environment after Caesarean derivation. Although the incidence of pyelonephritis remained the same, the survival age was increased. The renal histology indicated a shift to a more chronic form of pyelonephritis with renal amyloidosis as a common feature. At autopsy much more renal scarring was seen, resulting in the 'shrunken' kidney typical of chronic pyelonephritis. Renal lymphocytic accumulations were commonly found in MM mice, but they were also seen frequently in C57BL mice and in germfree stocks of both strains: no association was found between these lesions and pyelonephritis.     

Urinary tract infections in children. An update.

Urinary tract infection is a common and frequently recurring condition in children. The susceptibility of the host, the presence of urinary tract abnormalities, and the virulence of the urinary pathogens are of primary importance in the development of the infection. Renal parenchymal scarring, hypertension, and renal insufficiency are well-established complications of the infection in children. To reduce the risk of renal damage, diagnosis and treatment must be prompt. The diagnosis demands radiologic evaluation of the urinary tract in all boys, all children younger than 5 years, all patients with voiding dysfunction, and school-aged girls with recurrent infection to identify those patients with vesicoureteral reflux, obstruction, or other urinary tract abnormalities. Both voiding cystourethrography and renal ultrasonography are the initial examinations to use to determine the next appropriate study. Children with vesicoureteral reflux or with recurrent urinary tract infections should receive prophylactic antibiotic therapy and should be observed closely to prevent renal scarring.     

Part II – Roentgenologic Aspects

Roentgen findings in 107 girls under the age of ten years who had proven recurrent urinary tract infections were analyzed. From the excretory urograms done on these children, renal and pelvocalyceal outlines were accurately traced. Subsequently, renal length and parenchymal thickness at multiple points were measured. The presence or absence and grade of reflux were determined by voiding cystourethrography. Finally, the clinical history was correlated with the roentgen findings.With three exceptions, scarring and clubbing in the presence of infection occurred only in refluxing renal units. Kidneys exposed to a higher grade of reflux more frequently showed scarring and clubbing (p<0.001). Seventeen out of 40 renal units either developed or had increase in clubbing and scarring while the patients were being followed. After surgical correction of reflux, 16 of 24 previously clubbed and scarred kidneys showed progression of the lesions, usually within 24 months after operation. All children whose kidneys showed progression after surgical operation had experienced an episode of acute urinary infection with chills and fever before operation.No significant difference existed in the age at clinical onset of infection in patients with ureteral reflux with or without roentgen evidence of clubbing and scarring. This study documents the close relationship between clubbing and scarring and reflux in the presence of urinary infection in infants and children.     

Glomerular filtration rate in schoolgirls with covert bacteriuria.

Clearance of technetium-99m-labelled diethylenetriaminepenta-acetic acid was used to measure total and individual kidney glomerular filtration rates in 48 girls with covert bacteriuria. The mean (+/- SD) of the total rates of 18 girls with scarred kidneys (99 +/- 24 ml/min/1.73 m2) was significantly (0.005 greater than p greater than 0.002) lower than that in 30 girls with unscarred kidneys (119 +/- 18 ml/min/1.73 m2). This reduction in glomerular filtration was related to the loss of kidney substance associated with scarring rather than to vesicoureteric reflux. The glomerular filtration rate was unrelated to the duration of bacteriuria. These findings suggest that in girls aged 4 and over neither vesicoureteric reflux nor covert bacteriuria contributes to the progression of kidney damage.     

Cobalt Tumor of the Thyroid Gland

Diminutive kidney, hypoplasia or atrophic pyelonephritis, may be the cause of hypertension, lumbar or abdominal pain, obscure gastrointestinal symptoms or chronic urinary infection accompanied by chills and fever. A hypoplastic kidney is prone to infection and stone formation.Diagnosis includes meticulous x-ray examination and renal function studies employing the more accurate quantitative phenolsulfonphthalein test of each kidney.Nephrectomy is the treatment for unilateral disease causing symptoms; localized atrophic pyelonephritis is amenable to partial resection.Since urinary stasis invites infection, obstructing ureteral strictures should be dilated. Pyelectasis, secondary to ptosis, and ureteropelvic obstruction should be corrected by nephropexy or plastic repair. These conservative measures may prevent renal destruction.Sixteen patients were subjected to nephrectomy: Six because of persistent pain and chronic infection and ten because of hypertension. The six with pain and chronic urinary infection were relieved. In six of the ten with hypertension, the disease recurred within six months to seven years.     

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.     

Urinary tract infections; problems in medical management

The lesion principally responsible for chronic, or recurrent, urinary tract infection is a focus in the interstitial tissue of the kidney. Most cursory antimicrobial therapy suppresses the manifestations of lower urinary tract involvement but does not eradicate the renal focus. In order to cure rather than merely suppress the infection, it is imperative that, as early as possible, steps be taken to isolate and identify the etiologic microorganism and to determine its sensitivity to antimicrobial agents. Based on this information sufficient amounts of drug should be given for an adequate period (probably at least two weeks) to eradicate the infection within the renal tissue. Such a program would tend to reduce the number of cases in which irreversible renal failure develops from chronic pyelonephritis.     

Cobalt tumor of the thyroid gland

Diminutive kidney, hypoplasia or atrophic pyelonephritis, may be the cause of hypertension, lumbar or abdominal pain, obscure gastrointestinal symptoms or chronic urinary infection accompanied by chills and fever. A hypoplastic kidney is prone to infection and stone formation.Diagnosis includes meticulous x-ray examination and renal function studies employing the more accurate quantitative phenolsulfonphthalein test of each kidney. Nephrectomy is the treatment for unilateral disease causing symptoms; localized atrophic pyelonephritis is amenable to partial resection. Since urinary stasis invites infection, obstructing ureteral strictures should be dilated. Pyelectasis, secondary to ptosis, and ureteropelvic obstruction should be corrected by nephropexy or plastic repair. These conservative measures may prevent renal destruction.SIXTEEN PATIENTS WERE SUBJECTED TO NEPHRECTOMY: Six because of persistent pain and chronic infection and ten because of hypertension. The six with pain and chronic urinary infection were relieved. In six of the ten with hypertension, the disease recurred within six months to seven years.     

Secretor state and renal scarring in girls with recurrent pyelonephritis

The non-secretor phenotype was significantly associated with the occurrence of renal scarring among patients with recurrent pyelonephritis. Girls (n = 77) with recurrent pyelonephritis were followed from the first known episode of infection for up to twelve years with repeated radiological investigations. They were divided into two categories: those with renal scars (n = 35) and those who did not develop scars (n = 42). There was a significant over-representation of non-secretors among the patients with scarring, (14/35, 40%) compared to the healthy controls (21.8%, P less than 0.05). The frequency of non-secretors among the girls who did not develop scars in spite of repeated episodes of acute pyelonephritis was not significantly different from the healthy controls (9/42, 21% n.s.). This study provides a basis for analysis of the influence of secretor state on host-parasite interaction in the urinary tract.     

Assessing vesicoureteral reflux in live inbred mice via ultrasound with a microbubble contrast agent

Vesicoureteral reflux (VUR) is a common pediatric anomaly linked to renal scarring and hypertension. Although there are many mouse VUR models, cystograms have previously only been performed in euthanized animals, thus preventing serial assessments for VUR in the same animal and not delineating "live" physiology. Our purpose was to develop a live murine cystogram assay that could be used serially to track reflux. We injected microbubbles via transurethral catheters into bladders of C57BL6/J and C3H/HeJ inbred mouse strains that are known to have low and high VUR rates, respectively. We performed ultrasound to visualize microbubbles in the renal pelvis to determine feasibility of the procedure. We then repeated the microbubble ultrasound using a transducer allowing for visualization of both kidneys and ureters simultaneously and for 3 dimensional (3D) reconstruction. We then performed "euthanized" cystograms on all mice for comparison. C3H/HeJ mice had a strong and persistent microbubble signal in the renal pelvis and ureters bilaterally with low-contrast infusion volumes (<100 μl) and similarly showed bilateral reflux by euthanized cystograms. With larger infused volumes (≥150 μl), C57BL6/J mice had small volumes of microbubbles in the renal pelvis that cleared quickly and did not show reflux on euthanized cystograms. Thus, using animal models of known VUR, we demonstrate the utility of contrast-enhanced ultrasound to visualize reflux in live mice.     

URINARY TRACT INFECTIONS—Problems in Medical Management

The lesion principally responsible for chronic, or recurrent, urinary tract infection is a focus in the interstitial tissue of the kidney. Most cursory antimicrobial therapy suppresses the manifestations of lower urinary tract involvement but does not eradicate the renal focus. In order to cure rather than merely suppress the infection, it is imperative that, as early as possible, steps be taken to isolate and identify the etiologic microorganism and to determine its sensitivity to antimicrobial agents. Based on this information sufficient amounts of drug should be given for an adequate period (probably at least two weeks) to eradicate the infection within the renal tissue. Such a program would tend to reduce the number of cases in which irreversible renal failure develops from chronic pyelonephritis.     

Mouse models of short- and long-term foreign body in the urinary bladder: analogies to the bladder segment of urinary catheters.

Catheter-associated bacteriuria is the most common infection occurring in hospitals, where urethral catheters are generally in place for a few days, and in nursing homes, where catheters may be in place for months or years. We developed murine models with intrabladder urinary catheters for studying complications of bacteriuria in short- and long-term catheterization. In the short-term model, a catheter segment was inserted transurethrally and lay free within the bladder lumen. Half of the animals expelled segments during a 2-to-7-day period, durations similar to catheterizations in hospitalized patients. For studies of long-term catheter use, the catheter segment was secured within the bladder by a single suture for up to 12 months. Antibiotics administered for 7 days after catheter placement and housing mice in cages with wire screen floors reduced spontaneous bacteriuria to an acceptably low incidence rate of only 7%. Proteus mirabilis bacteriuria of high concentration provoked the same complications that are common in patients with long-term catheters: acute pyelonephritis, chronic renal inflammation, and struvite stone formation. These models allow inoculation of the bacteria of interest and are suitable for studies of short- and long-term foreign body-associated bacteriuria and its complications.     

The role of taurine in renal disorders

This article examines the actions of taurine on models of renal dysfunction, the potential mechanisms of taurine action and the possible clinical significance of these findings. Our laboratory has written previously on the role of taurine in renal function and we have focused upon the normal physiology of the kidney and on the mechanisms and regulation of the renal transport of taurine. This review is a distinct change of emphasis in that we describe a number of studies which have evaluated various aspects of renal dysfunction, including hypertension and proteinuria, specific glomerular and tubular disorders, acute and chronic renal conditions, urinary tract conditions including infection and nephrolithiasis, and diabetic nephropathy. The subject of chronic kidney disease and renal transplantation will also be examined relative to β amino acid. The studies evaluated will be mainly recent ones, recognizing that older reviews of the role of this taurine in the kidney are available.     

Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up.

OBJECTIVE--Determination of the long term incidence of uraemia, hypertension, and toxaemia in pregnancy associated with non-obstructive focal renal scarring after pyelonephritis in childhood 25-35 years earlier. DESIGN--27 Year follow up of patients with non-obstructive focal scarring identified from a retrospective review of intravenous urograms performed in childhood between 1951 and 1967. SETTING--Paediatric primary referral centre and urological clinic in tertiary referral centre. PATIENTS--30 Patients (mean age 33 (range 22-41] with non-obstructive focal renal scarring first detected between 1951 and 1967 and a history of febrile urinary tract infection. MAIN OUTCOME MEASURE--Hypertension and complications of renal damage. RESULTS--Three patients had developed end stage renal disease, seven had developed hypertension, two of 16 women had a history of toxaemia during pregnancy, and seven patients had undergone renal surgery during follow up. Of the 20 patients who had neither had renal surgery nor had end stage renal disease, all had a significantly lower glomerular filtration rate and renal plasma flow and higher diastolic blood pressure, mean arterial blood pressure, plasma renin activity, and serum beta 2 microglobulin concentration than 13 healthy age matched controls. Diastolic blood pressure and plasma renin activity were positively correlated (r = 0.50, p less than 0.05) and so were fractional sodium excretion and both systolic and diastolic blood pressures (r = 0.54, p less than 0.01, r = 0.51, p less than 0.01 respectively). The progress of renal damage was unrelated to the incidence of recurrent infections. CONCLUSIONS--Children with focal renal scarring due to pyelonephritis are at high risk of serious long term consequences. It is essential that they are given adequate attention and care during adolescence and pregnancy.