Altered vasopressin release and osmotic regulation during exercise in patients with pyelonephritic renal scarring

Children and adults with pyelonephritic renal scarring are at high risk of developing hypertension. The objectives of the present investigation were to study if it is possible to detect early disturbances in blood pressure (BP) control and secretion of hormones involved in the regulation of BP and renal function, in patients with renal scarring. We studied renal function at rest, BP regulating hormones and BP at rest and during graded bicycle exercise until exhaustion. The 22 patients with renal scarring had significantly lower glomerular filtration rate and renal blood flow than the 13 healthy age-matched controls. At rest, the patients had higher diastolic (p less than 0.01) and mean arterial BP (p less than 0.02), higher plasma renin (p = 0.06) and higher serum osmolality (p less than 0.001) but there were no significant differences in systolic BP, angiotensin II, aldosterone or vasopressin (AVP). The patients with renal scarring had higher AVP than the controls during light and moderate exercise and 15 min after maximal exercise. BP and renal hormones increased significantly but similarly during exercise in both patients and controls. There were no significant differences in BP control or release of pressure-regulating hormones at maximal exercise. Maximal exercise did not evoke pathological BP response in normotensive young adults with pyelonephritic renal scarring. The increase in serum osmolality and hypersecretion of AVP during light and moderate exercise may be important in the pathogenesis of hypertension in this group of patients.     

Acquired renal scars in children

To determine the important factors involved in the etiology of renal scarring we studied 37 children with renal scars seen at our hospital since 1965. This is the second largest series reported to date. Children who had neurogenic bladders or any structural abnormalities of the urinary tract other than vesicoureteral reflex were excluded. The study group included 36 girls and 1 boy. The average age at first detection of renal scars was 5.7 years. Acute pyelonephritic episodes, which were treated early and aggressively, infrequently led to renal scarring. However, the initial prolonged or poorly treated episode of acute pyelonephritis was followed invariably by the development of renal scarring. The severity of renal scarring was related to the grade of vesicoureteral reflux (p less than 0.05), although some scars did develop in the absence of reflux. Neither the shape and position of the ureteral orifice nor the ureteral tunnel length correlated with the severity of renal scarring. Treatment with prophylactic antibiotics may have lessened the severity of renal scarring (0.1 less than p less than 0.2) but treatment with reimplantation surgery did not appear to alter the course of renal scarring. This study suggests that the key to the prevention of renal scarring is the early and aggressive treatment of acute pyelonephritis.     

Urinary infection,reflux and renal scarring in females continuously followed for 13–38 years

This study describes the pattern of urinary tract infections (UTI) in 87 females prospectively followed for a median of 23 years from their first recognized symptomatic infection in childhood. At 16 years of age they were selected for follow-up into adulthood because of renal scarring (reflux nephropathy) in 45 and recurrent UTI in 42. The attack rate (number of urinary tract infections per individual per observation year) was highest during the 1st year of life (1.9), with a gradual decrease to the lowest rate (0.2) at age 11–15 years. A moderately increased attack rate (0.4), was seen in the late teens, extending through to the mid twenties. The proportion of infections having a pyelonephritic character decreased with age and number of infection episodes, but not in females with severe renal scarring. Pyelonephritic infections were correlated with vesicoureteric reflux, and renal scarring to low age at the index infection, total number of pyelonephritic episodes and reflux. Females with renal scarring continued to have a high proportion of pyelonephritic recurrences after 10 years of age, implying that they risk progressive renal disease and should be closely followed into adulthood.     

Overrepresentation of blood group non-secretors in adults with renal scarring

Host factors are important in the pathogenesis of pyelonephritic renal scarring. The present study used blood group secretor state as a population marker to determine if patients developing renal scarring are a selected subgroup of individuals with urinary tract infections (UTI). Non-secretors represented 15/43 (35%) of the patients with renal scarring but only 7/41 (17%) of the patients without renal scarring (p = 0.059 and NS respectively vs. healthy controls 22%). The frequency of non-secretors among P1 phenotype patients with renal scarring was 38% (p = 0.05 vs. healthy controls). Among the patients born after the introduction of regular use of antibiotic treatment for UTI the frequency of non-secretors was 55% in the scarred group compared to 13% in the unscarred group (p = 0.011). Thus, in this younger group of patients with renal scarring 6/10 (60%) of the non-secretors developed renal scars compared to 5/32 (16%) of the secretors (p less than 0.05). Our data confirm that blood group non-secretors are overrepresented in patients with non obstructive renal scarring suggesting that blood group non-secretor state might be a host marker to consider for the subgroup of individuals with recurrent UTI at risk to develop renal scars. Renal function was not influenced by blood group secretor state. The mean glomerular filtration rate within the scarred group was similar for secretors and non-secretors (80 ml/min X 1.73 m2 and 79 ml/min X 1.73 m2, respectively). Whether blood group secretor state also is involved in the scarring process remains to be investigated.     

Clinical and radiological follow-up of chronic non-obstructive pyelonephritis. A retrospective study covering thirty years

The outcome of uni- or bilateral chronic pyelonephritis was retrospectively studied in 26 patients. The material consists of all positive intravenous urographies performed at the hospital during three years in the 1950s and the follow-up time was approximately 30 years. Development of uraemia or death owing to renal disease occurred in 15% of the patients. The majority of patients with unilateral pyelonephritic changes showed unchanged scarring during the years, while progressive scarring mainly occurred in younger patients. The development of renal failure was found in patients with extensive bilateral scarring, proteinuria and hypertension.     

Urine interleukin-1beta in children with acute pyelonephritis and renal scarring

AIM: Acute pyelonephritis is a common infectious disease in children and can result in permanent renal damage. Interleukin (IL)-1beta is an important inflammatory mediator that appears early during bacterial infection. This prospective study examined urine IL-1beta levels in children with acute pyelonephritis documented by (99m)Tc-dimercaptosuccinic acid (DMSA) scan, and also evaluated whether this cytokine correlated with renal scarring. METHODS: A total of 75 children aged 1-121 months with a diagnosis of first-time febrile urinary tract infection (UTI) were studied. The following inflammatory markers were assessed: fever, white blood cell (WBC), neutrophil, C-reactive protein (CRP) and urine IL-1beta. Urine samples were collected for IL-1beta measurement by enzyme-linked immunosorbent assay before and after antibiotic treatment of the infection. Follow-up DMSA scan was performed at 6-12 months after the acute pyelonephritis to detect renal scarring. Twenty children with other febrile illnesses served as non-renal febrile controls. RESULTS: The 75 children were divided into acute pyelonephritis (n = 41) and lower UTI (n = 34) groups according to the findings of DMSA scans. Fever, WBC count, neutrophil count and CRP were significantly higher in the children with acute pyelonephritis than in those with lower UTI (all P < 0.001). The initial urine IL-1beta levels of children with acute pyelonephritis were significantly higher when compared with lower UTI and non-renal febrile controls (P < 0.001). Urine IL-1beta in children with acute pyelonephritis was positively correlated with fever, CRP, WBC, neutrophil and leucocyturia. Renal scarring was found in 12 (29.3%) of the 41 children with acute pyelonephritis. The mean age was significantly lower in the children with renal scarring compared with those without (P < 0.05). CONCLUSION: These results have shown that urine IL-1beta level may serve as a useful marker for the early detection of acute pyelonephritis in febrile children. Young children are at a risk of the development of renal scarring following acute pyelonephritis.     

Urinary tract infections in infants and children -- a consensus on diagnostic, therapy and prophylaxis

Urinary tract infections (UTI) are among the most common bacterial infections in infants and children.The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition. Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.     

Harnwegsinfektionen im Säuglings- und Kindesalter

Urinary tract infections (UTI) are among the most common bacterial infections in infants and children. The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition. Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.     

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     

Outcome of kidneys in patients treated for vesicoureteral reflux (VUR) during childhood.

BACKGROUND: Outcome of renal function and blood pressure (BP) at early middle age was clarified in patients treated for vesicoureteral reflux (VUR) during childhood. METHODS: Information of renal function was available from 147 (55%) of 267 patients treated for non-obstructive VUR of any grade. Twelve patients had died of kidney-related conditions and eight had gone into terminal uraemia. A total of 127 patients participated in the study. RESULTS: The mean age of the participants was 41 years. No signs of renal scars were detected by ultrasound examination in 53 (42%) subjects. Unilateral scarring was seen in 44 (35%) and bilateral in 30 (24%) subjects. Glomerular filtration rate (GFR) showed moderate or severe renal insufficiency in four (3%) participants, all with bilateral scars. Normal GFR was found in one-third of the patients. Twenty-five (83%) subjects with bilateral scars and 60 (62%) of the other participants had abnormal GFR values (P < 0.05). Proteinuria was found in 12 (9%) and albuminuria in 30 (24%) participants. Hypertension was diagnosed earlier in 14 (11%) patients, eight having bilateral scarring (P < 0.01). Diastolic BP was significantly lower in subjects without scars compared with those having scars in one or both kidneys (P < 0.05). CONCLUSIONS: Renal function was slightly lowered in more than half of the participants. Findings of the participants with unilateral scarring or unscarred kidneys were similar, except for the increased tendency for hypertension in subjects with scars. A total of 83% of the patients with bilateral kidney scars had lowered kidney function, a quarter presented with proteinuria and a half with hypertension. Long-term follow-up for all the patients with earlier VUR is emphasized.     

Procalcitonin as a predictor of renal scarring in infants and young children

The aim of this study was to evaluate the usefulness of procalcitonin (PCT) as a marker of renal scars in infants and young children with a first episode of acute pyelonephritis. Children aged 7 days to 36 months admitted for first febrile urinary tract infection (UTI) to a pediatric emergency department were prospectively enrolled. The PCT concentration was determined at admission. Acute ^99mTc-dimercaptosuccinic acid (DMSA) scintigraphy was performed within 7 days of admission and repeated 12 months later when abnormal findings were obtained on the first scan. Of the 72 children enrolled in the study, 52 showed signs of acute pyelonephritis (APN) on the first DMSA scan. A follow-up scintigraphy at the 12-month follow-up performed on 41 patients revealed that 14 (34%) patients had developed renal scars; these patients also presented significantly higher PCT values than those without permanent renal lesions [2.3 (interquartile range 1–11.6) vs. 0.5 (0.2–1.4) ng/mL; p = 0.007]. A comparison of the PCT concentration in patients with febrile UTI without renal involvement, with APN without scar development and with APN with subsequent renal scarring revealed a significant increasing trend (p = 0.006, Kruskal–Wallis test). The area under the ROC curve for scar prediction was 0.74 (95% confidence interval 0.61–0.85), with an optimum statistical cut-off value of 1 ng/mL (sensitivity 78.6%; specificity 63.8%). Based on these results, we suggest that serum PCT concentration at admission is a useful predictive tool of renal scarring in infants and young children with acute pyelonephritis.     

Incidence of microalbuminuria in children with pyelonephritic scarring

There is experimental evidence that loss of renal parenchyma results in hyperfiltration in the remnant glomeruli followed by development of glomerulosclerosis. Microalbuminuria, i.e., a urinary albumin excretion rate of 20 – 200 μg/min, is considered to be an early predictor of diabetic glomerulosclerosis. Hypothetically, increased urinary albumin excretion in patients with pyelonephritic scarring may also indicate glomerulosclerosis, with risk for future deterioration of renal function. This study was performed to determine the incidence of increased albumin excretion in children with mild to moderate pyelonephritic scarring, and to relate the information to glomerular filtration rate (GFR; clearance of inulin) and effective renal plasma flow (clearance of para-aminohippuric acid), as well as to the degree of scarring. The functional investigations were performed under water diuresis. Fifty-seven children, aged 1.7 – 17.9 years, with pyelonephritic renal scarring were included in the study. Nine young healthy adults were used as controls. The GFR was significantly lower in the children with pyelonephritic scarring than in the controls (median 93 ml/min per 1.73 m², range 48 – 133 vs. 111 ml/min per 1.73 m², range 89 – 121, P<0.05), and the urine albumin excretion was significantly higher (median 20 μg/min per 100 ml GFR, range 0.8 – 170 vs. 9.2 μg/min per 100 ml GFR, range 3.3 – 21, P<0.05). An inverse correlation was found between urine albumin excretion and GFR. Increased urine albumin excretion was found in 70% of the children with a GFR below 90 ml/min per 1.73 m² compared with 41% of the children with a GFR above this level. Increased urine albumin excretion (>20 μg/min per 100 ml GFR) was found in 51% of the children with pyelonephritic scarring, while only 14% had increased age-adjusted serum creatinine concentrations. The high incidence of microalbuminuria in children with pyelonephritic scarring indicates long-term follow-up until the ultimate outcome has been better defined. Received January 17, 1995; received in revised form and accepted April 2, 1996     

Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood — a 27-year follow-up

In a previous report the long-term prognosis of 30 patients with renal scarring after pyelonephritis in childhood was described. In this study, we have related the extent of renal scarring present in childhood to the conditions in early adulthood. A radiological progression of searring from childhood to adulthood was seen in one-third of the kidneys. The 7 patients with bilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate and higher plasma vasopressin at follow-up than 13 healthy controls. The 20 patients who had unilateral searring in childhood had a smaller renal area, lower glomerular filtration rate, higher diastolic blood pressure and higher plasma renin at follow-up than controls; 4 had hypertension. The most important finding was that children with unilateral disease are at risk of serious long-term complications. Filtration fraction at follow-up was higher in patients with extensive renal scarring in childhood compared with those with a normal renal area or small scars in childhood (r=–0.43,P<0.05). This may indicate glomerular hyperfiltration by remnant glomeruli. This paper emphasizes the potential seriousness of childhood urinary tract infections especially when early infantile infections are overlooked. A follow-up of more than 4 decades may be necessary before the ultimate prognosis can be established, especially in patients with unilateral renal disease. It is advised that most patients with post-infectious renal scars are followed as high-risk patients, and that treatment continuity is established between paediatricians, nephrologists and, when required, obstetricians.to Author for further revision and received in revised form May 28, 1991     

The IL-6 −174G/C polymorphism and renal scarring in children with first acute pyelonephritis

Urinary tract infections (UTI) are common in infants and children and may result in serious complications, such as renal scarring, hypertension, and renal failure. Identification of the new markers in relation to acute pyelonephritis (APN) and its treatment is essential for designing interventions that would minimize tissue damage. This prospective study investigated the first UTI infection in 71 children (age range: 1–24 months) in respect to interleukin-6 (IL-6) ?174G/C polymorphism and renal scarring. The patients were divided into an APN group and a lower UTI group according to dimercaptosuccinic acid (DMSA). The IL-6 ?174G/C genotypes were determined by tetra-primer ARMSPCR. Serum IL-6 was significantly higher in the APN group than in the group with lower UTI (p?<?0.05). In both groups, the ?174G/C genotype and allele frequencies did not differ significantly from the control group. The highest white blood cell (WBC) count was observed in the CC genotype (p?<?0.05). A non-significant trend toward higher serum IL-6 was observed in children with CC genotype. On follow-up DMSA imaging performed 6 months later, renal scarring was detected in 36.9% of APN children. We did not find the significant association of IL-6 ?174G/C polymorphism with APN and/or postinfectious renal scarring. These results indicate that serum IL-6 concentrations were significantly higher in children with APN than in patients with lower UTI.     

Are antireflux procedures indicated in patients with small pyelonephritic kidneys?

Antireflux surgery was successfully performed in 16 adults and children with bilateral or unilateral vesicoureteral reflux associated with a small pyelonephritic kidney. Although in 14 cases of the preoperative 131I-Hippuran clearance of the affected unit was less than 100 ml/min/1.25 m2, in 10 cases renal function was stabilized or slightly improved postoperatively. Only 1 child showed a severe deterioration of renal function. All 16 patients were cured of their acute pyelonephritis. Surgical correction of the reflux had no beneficial effect on renal size or renal scars. Urinary tract infection was eliminated in 12 of the 16 cases. It can be concluded that a small pyelonephritic kidney associated with a vesicoureteral reflux should not be removed even if its isotopic clearance is less than 100 ml/min.     

The role of gadolinium enhanced magnetic resonance imaging for children with suspected acute pyelonephritis

PURPOSE: The diagnosis of pyelonephritis is primarily clinical. However, the history and physical findings can be confusing in children, leading to adjunctive nuclear renal cortical scintigraphic studies (99mtechnetium dimercapto-succinic acid [DMSA]) to confirm the diagnosis. Nonetheless, ambiguity occurs when differentiating between acute pyelonephritis and chronic scarring. We report our initial experience with gadolinium enhanced inversion recovery magnetic resonance imaging (MRI) to diagnose acute pyelonephritis. MATERIALS AND METHODS: Nine patients 7 months to 18 years old (mean age 81 months) underwent MRI to confirm radiographically a clinical suspicion of acute pyelonephritis. All patients had at least 1 prior episode of clinical pyelonephritis. Data were collected to determine whether acute pyelonephritic changes could be differentiated from chronic pyelonephritis on the basis of MRI characteristics. RESULTS: Of the 9 patients 4 were identified as having acute pyelonephritis on MRI (persistently high signal intensity after gadolinium), 2 demonstrated evidence of postpyelonephritic scar (parenchymal loss without change in signal intensity), 1 had evidence of acute pyelonephritis and chronic changes, and 2 had a completely normal examination (decreased signal intensity after gadolinium). At our institution the billable cost of MRI to the patient is $1,329, while the billable cost of 99mtechnetium DMSA is $1,459. All patients younger than 6 years required intravenous sedation for MRI, whereas 70% of those younger than 6 years require intravenous sedation for DMSA scanning at our institution. MRI provided greater anatomical detail regarding the renal architecture without radiation exposure, and allowed the unambiguous diagnosis of acute versus chronic pyelonephritis scar in a 1-time (versus often multipart for DMSA) imaging study. CONCLUSIONS: In cases where adjunctive imaging studies are useful to make a diagnosis gadolinium enhanced inversion recovery magnetic resonance imaging allows the detection of acute pyelonephritis rapidly, cost-effectively and safely in the pediatric population.     

Girls prone to urinary infections followed into adulthood. Indices of renal disease

This study describes blood pressure and renal function, as well as indices of renal disease, in females with and without renal scarring followed from their first urinary tract infection (UTI) in childhood. Of the 111 patients with a median follow-up time of 15 years, 54 had renal scarring (reflux nephropathy) on urography, which was severe in 19 and moderate in 35. The glomerular filtration rate was lower in patients with severe renal scarring and correlated with renal area on urography. However, the filtration rate was decreased below the lower reference limit in only 7 patients, with a lowest value of 70 ml/min per 1.73 m². The diastolic blood pressure was higher in women with severe scarring. Hypertension of at least 140/90 mmHg was diagnosed in 3 of 54 (5.5%) females with renal scarring, 2 before and 1 at the follow-up examination. The excretion of albumin in urine was low and not correlated to filtration rate. Tubular enzymes in urine were similar in all groups. Thus the renal function was well preserved and the incidence of hypertension low. Within this range of renal function, the level of albumin in urine did not predict the degree of renal scarring.     

Childhood reflux and urinary infection: a follow-up of 10–41 years in 226 adults

To ascertain the outcome of childhood vesico-ureteric reflux (VUR), 226 adults (37 males), mean age 27 years, were studied after 10–35 years, extended to 41 years by postal questionnaire in 161. At presentation (mean age 5 years) all had VUR (grade III–V in 68) and urinary tract infection (UTI); there was renal scarring in 85 (acquired before referral in 11 and during follow-up in 1), hypertension in 6 and impaired renal function in 5. They were managed and followed prospectively by one paediatrician; 63% of these children remained free from UTI; VUR persisted in 63 and had resolved in 69% of 193 children managed medically. At follow-up, 61% of adults had remained free from infection; 17 adults had hypertension and/or raised plasma creatinine, 16 with scarred kidneys. Their deterioration was predictable because of scar type, blood pressure or plasma creatinine levels in childhood. No new scars developed after puberty. Renal growth rates were unaffected by initial severity or persistence of VUR. On the later questionnaire, 9 further adults, mean age 38 years, had moderate hypertension. The adults with complications were those with extensive renal scarring and/or at least borderline hypertension in childhood. Those with VUR, but no scarring, and managed carefully in childhood, did not suffer serious consequences as adults. There is a need for early recognition and treatment of children with VUR and UTI to limit scar development. Received November 27, 1997; received in revised form and accepted April 17, 1998     

Biochemical fingerprinting of urinary Escherichia coli causing recurrent infections in women with pyelonephritic renal scarring.

A biochemical fingerprinting system, especially designed for subtyping of Escherichia coli and suitable for screening large number of bacterial strains was used in a long-term follow-up study of 19 women with non-obstructive pyelonephritic renal scarring and recurrent urinary infections in order to examine whether recurrent infections mostly are relapses or reinfections in this group of patients. Seventy-six recurrent infections occurred during a 47-month follow-up (0.09 infections per observation month). The majority of the recurrences were reinfections (58/76, 76%) and 18 (24%) were relapses caused by E. coli. Approximately 50% of relapses and reinfections caused by E. coli were symptomatic while the majority of reinfections caused by other bacteria were asymptomatic (23/30, 77%). In one patient a relapse of E. coli infection occurred more than two years (745 days) after the initial infection. Reinfections may occur early (7 days) after cessation of antimicrobial therapy in this group of patients. Two patients had an episode of symptomatic bacteriuria 51 and 56 days after asymptomatic bacteriuria with the same E. coli strain was detected. Biochemical fingerprinting of the E. coli isolates revealed that they belong to a wide variety of biochemical phenotypes which indicates that they are not members of widespread uropathogenic clones.     

Managing urinary tract infections

Urinary tract infections (UTI) are common in childhood. Presence of pyuria and bacteriuria in an appropriately collected urine sample are diagnostic of UTI. The risk of UTI is increased with an underlying urological abnormality such as vesicoureteral reflux, constipation, and voiding dysfunction. Patients with acute pyelonephritis are at risk of renal scarring and subsequent complications such as hypertension, proteinuria with and without FSGS, pregnancy-related complications and even end-stage renal failure. The relevance and the sequence of the renal imaging following initial UTI, and the role of antimicrobial prophylaxis and surgical intervention are currently undergoing an intense debate. Prompt treatment of UTI and appropriate follow-up of those at increased risk of recurrence and/or renal scarring are important.