- Email: [email protected]
Familial Vesicoureteral Reflux and Reflux Related Morbidity in Relatives of Index Patients with High Grade Vesicoureteral Reflux
Vesicoureteral Reflux
Familial Vesicoureteral Reflux and Reflux Related Morbidity in Relatives of Index Patients with High Grade Vesicoureteral Reflux Manuela Hunziker and Prem Puri* From the National Children’s Research Centre, Our Lady’s Children’s Hospital and National Children’s Hospital, Dublin, Ireland
Purpose: The familial nature of vesicoureteral reflux is well recognized. However, there is little information about the prevalence of vesicoureteral reflux and reflux related morbidity in the relatives of index patients with vesicoureteral reflux. Therefore, we determined the prevalence of vesicoureteral reflux and reflux related morbidity in first, second and third-degree relatives of index patients with high grade vesicoureteral reflux. Materials and Methods: Between 1998 and 2010 the parents of 259 index patients with grade III-V vesicoureteral reflux were asked permission to screen siblings younger than age 6 years for vesicoureteral reflux. Parents of index patients with affected siblings were contacted to obtain detailed information regarding vesicoureteral reflux, recurrent urinary tract infections, end stage renal disease, hypertension and nephrectomy among first, second and thirddegree relatives. Results: A total of 300 siblings of the 259 index patients were found to have vesicoureteral reflux on voiding cystourethrography. In terms of the other relatives of the 259 index patients 127 also had radiologically proven vesicoureteral reflux. Reflux related morbidity among the first, second and third-degree relatives included end stage renal disease in 21, nephrectomy in 12 and hypertension in 4. Of the 212 siblings who had dimercapto-succinic acid scans 49 (23.1%) showed evidence of renal scarring. In 73% of the relatives vesicoureteral reflux was seen on the mother’s side. Conclusions: This study, the first to our knowledge, provides important information regarding reflux related morbidity in a large cohort of familial vesicoureteral reflux in first, second and third-degree relatives of index patients. Our data clearly show that there is an increased risk of reflux related morbidity among the relatives of index patients with vesicoureteral reflux and this finding has implications for counseling.
Abbreviations and Acronyms DMSA ⫽ dimercapto-succinic acid ESRD ⫽ end stage renal disease UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrogram VUR ⫽ vesicoureteral reflux * Correspondence: National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin – 12, Ireland (telephone: ⫹353 1 4096420; e-mail: [email protected]).
Key Words: vesico-ureteral reflux, family, morbidity, siblings PRIMARY vesicoureteral reflux is the most common congenital urological abnormality in children, occurring in 30% to 40% of those presenting with a urinary tract infection.1,2 The association of VUR, UTI and renal parenchymal damage is well-known. Renal parenchymal damage can be congenital or acquired segmental scarring. Congenital reflux nephropathy
occurs as a result of abnormal embryological development with subsequent renal dysplasia and is largely seen in male infants with high grade VUR. Acquired renal scarring is more common in female children and occurs as a result of an acute inflammatory reaction caused by bacterial infection of the renal parenchyma during UTI.
0022-5347/12/1884-1463/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.02.024 Vol. 188, 1463-1466, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
www.jurology.com
1463
1464
VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
The familial nature of VUR is well recognized. Familial clustering of VUR has been described by several groups, with a prevalence between 27% and 51% in the siblings of index patients with VUR and a 66% rate in children whose parents previously had reflux.3–5 Reflux associated nephropathy is a major cause of hypertension and ESRD. Marra et al reviewed data on children with chronic renal failure and found that those with VUR accounted for 26% of all children with chronic renal failure.6 In the North American pediatric population reflux nephropathy is reported to be the 4th leading cause of dialysis and transplantation with 5.3% of transplant cases and 3.5% of dialysis cases having a diagnosis of reflux nephropathy.7 Although familial clustering of VUR is well recognized, there is a relative lack of information on reflux related morbidity in the relatives of index patients with VUR. Therefore, we determined the prevalence of VUR and reflux related morbidity in the first, second and third-degree relatives of index patients with high grade VUR.
METHODS Between 1998 and 2010 the parents of 259 index patients with grade III–V VUR were asked permission to screen siblings younger than age 6 years for VUR. Families with 2 or more siblings with any grade VUR were included in the analysis. Reflux was confirmed in all index patients and siblings by VCUG. Patients with VUR secondary to neurogenic bladder or posterior ureteral valves were excluded from study. Parents of index patients with affected siblings were contacted by telephone, and asked about a history of VUR among first, second and third-degree relatives of the index patients, eg mother, father, siblings or any other family members on the mother’s or father’s side. If there was a positive history of VUR in other family members, a detailed history was taken regarding recurrent UTIs, ESRD, hypertension and nephrectomy among the first-degree (ie parents, siblings), second-degree (ie aunts, uncles, nieces, nephews, grandparents) and third-degree (ie first cousins) relatives. Whenever possible the family member or his or her parents were contacted to verify the history. Hospital records and x-ray images were further evaluated to confirm details of the history and prove the diagnosis of VUR. In cases of generations earlier than those of the mother and father it was not possible to verify VUR by VCUG. In index patients and in siblings renal scarring was evaluated by DMSA scintigraphy and classified into 3 groups of mild (focal defects in uptake between 40% and 45%), moderate (uptake of renal radionuclide between 20% and 40%) and severe (shrunken kidney with relative uptake less than 20%). In children presenting with a urinary tract infection DMSA scans were performed at least 4 months after the first urinary tract infection.
RESULTS A total of 300 siblings of the 259 index patients were found to have VUR on VCUG. The number of families with 2, 3, 4 and 5 siblings affected was 223, 32, 3 and 1, respectively. There were 108 families who had 127 other relatives in addition to those siblings with radiologically proven VUR, including 37 with reflux related morbidity (table 1). Of the relatives 21 had ESRD, 14 needed renal transplantation and 7 were on dialysis. In 93 (73%) of the 127 relatives VUR was seen on the mother’s side (table 2). There were 92 families with 1 family member with VUR other than siblings. There were 14 families with 2 other family members, 1 family with 3 other family members and 1 family with 4 other family members with VUR. First-Degree Relatives Of the 259 families 11 mothers (4.2%) had radiologically proven VUR, including 1 mother who underwent nephrectomy at the age of 6 years due to severe reflux nephropathy. Ureteral reimplanation was performed in 3 mothers and another 3 had undergone endoscopic treatment to cure VUR as a child. The remaining 4 mothers were treated with antibiotics for breakthrough urinary tract infections. Of 11 mothers 3 (27.3%) had reflux nephropathy with no complications. In addition, 19 other mothers had a history of recurrent urinary tract infections. There were 7 (2.7%) fathers of index patients with radiologically proven VUR, including 5 who underwent nephrectomy for poorly functioning kidney and 2 who were treated conservatively for breakthrough urinary tract infections. Of the 300 siblings with VUR 125 (42%) were diagnosed after a UTI and 175 (58%) were diagnosed after screening. The prevalence of VUR in siblings after screening was 42% (175 of 414 siblings screened). A total of 247 (82%) siblings were younger than age 3 years Table 1. VUR and reflux related morbidity in relatives of 259 families
Family Members First-degree: Mother Father Siblings Second-degree: Aunts, uncles or grandparents Third-degree: First cousins Great-aunts, great-uncles or greatgrandparents
No. VUR
No. Nephrectomy
11 7 300
1 5 1
36
5
65 8
No. End Stage Renal Disease
No. Hypertension
11
3
3 7
1
VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
Table 2. Relatives with VUR on maternal or paternal side
First-degree relatives: Parents Second-degree relatives: Aunts Uncles Grandmothers Grandfathers Third-degree relatives: Cousins Great-aunts Great-uncles Great-grandmothers Totals
No. Maternal
No. Paternal
11
7
15 2 5 2
7 5 1 1
54 1 2 1
11 1 1 —
93 (73.2%)
34 (26.8%)
and 53 (18%) were 3 to 6 years old. DMSA scans were performed in 212 siblings and 49 (23.1%) showed evidence of renal scarring compared to 38% of the index patients. Mild, moderate and severe scarring was seen in 23 (47%), 19 (39%) and 7 (14%) siblings, respectively. Second-Degree Relatives There were 15 aunts and 4 uncles of index patients in this series who were diagnosed with VUR as a child. In addition to these relatives, nephrectomy due to reflux related poorly functioning kidney was performed in 2 aunts, 2 grandmothers and 1 grandfather. Furthermore, 11 second-degree relatives had a history of ESRD due to VUR as a child, including 4 aunts, 2 uncles and 5 grandparents. There were 9 family members who needed kidney transplantation and 2 relatives who were on dialysis. In addition, 3 second-degree relatives were diagnosed with hypertension. Of the 36 aunts, uncles and grandparents with VUR, 28 aunts or uncles had radiologically proven VUR, whereas in 8 grandparents the source of data was historical, confirmed by family members. Interestingly 1 uncle who underwent kidney transplantation was the twin brother of the mother and in another family 1 aunt who underwent kidney transplantation was the mother’s twin sister. In both families the mother herself had no history of any kidney disease. Our survey also showed that 24 second-degree relatives experienced recurrent urinary tract infections for several years. Third-Degree Relatives A total 65 first cousins from 48 different families were found to have VUR on VCUG. Of those relatives 1 had ESRD at age 23 years and 2 cousins from the same family died of reflux related kidney failure. There were 16 first cousins who had recurrent urinary tract infections for several years. Three great-aunts, 3 great-uncles and 1 greatgrandmother had a history of ESRD. Another great-
1465
aunt had a history of hypertension due to previously treated reflux. In great-aunts, great-uncles and greatgrandmothers the source of data was historical, and was confirmed by family members.
DISCUSSION The chance of a multifactorial trait or condition occurring again depends on how closely the family member with the trait is related to other family members. It is well-known that family members share a certain percentage of genes in common, depending on their relationship. For example, firstdegree relatives (parents, children and siblings) have 50% of genes in common, second-degree relatives (aunts, uncles, nieces, nephews and grandparents) have 25% of genes in common and third-degree relatives (first cousins, great-aunts, great-uncles and great-grandparents) have 12.5% of genes in common. In this study we identified 259 families with familial VUR in which 559 children (259 index patients and 300 siblings) were affected. In addition, there were 127 other first, second and third-degree relatives with proven VUR. In 73% of the relatives (other than siblings) VUR was seen on the mother’s side. This is the largest collection of families with first, second and third-degree relatives affected with VUR from 1 center. VUR is known to occur in families with a prevalence of 27% to 51% in siblings of index patients with VUR and a 66% rate of VUR in offspring of parents with previously diagnosed reflux. We were able to determine the true prevalence of VUR only in the first-degree relatives. In the second and third-degree relatives a true prevalence could not be ascertained because the source of data was historical and confirmed by family members. The prevalence of radiologically proven VUR in first-degree relatives was 4.2% in mothers, 2.7% in fathers and 42% in siblings. The most striking finding in this study was the reflux related morbidity observed in the first, second and third-degree relatives of index patients affected with VUR. Of siblings with VUR 23% had renal scarring on DMSA scans with more than half of them having moderate to severe scarring. Among the second and third-degree relatives 21 patients had ESRD with 14 needing renal transplantation and 7 on dialysis. Furthermore, 12 second and thirddegree relatives had undergone nephrectomy for reflux nephropathy, and 4 had hypertension. In the present study the rate of reflux related morbidity observed in first-degree relatives was low compared to second or third-degree relatives. We believe that the higher incidence of reflux related morbidity in previous generations, eg grandparents, greataunts, great-uncles or great-grandparents, may be due to a delayed diagnosis of VUR in the past.
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VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
The most serious morbidity associated with VUR is renal scarring. It is well recognized that renal parenchymal injury in VUR occurs early, in most patients before the age of 3 years. It has been reported that the risk of renal scarring after an episode of acute pyelonephritis is substantially increased in children with high grade VUR, affecting up to 89% of children with grade IV and V VUR.8 Renal scarring in VUR is considered to occur as a result of 1 of the 3 mechanisms of 1) reflux of infected urine with interstitial inflammation and damage, 2) reflux of sterile urine, which may damage the kidney due to mechanical pressure and 3) abnormal embryological development with resulting renal dysplasia. Renal parenchymal damage in the first 2 groups may be preventable with the early detection and treatment of VUR. In the third group in which damage is congenital, it is mandatory to discover reflux at an early stage to prevent exposure to UTI and avoid progression of renal damage. A major goal of screening siblings of index patients with VUR is the identification of children who may be at risk for renal parenchymal damage. Most renal scars are present when reflux is discovered at initial evaluation for UTI in infants and young children. A recent large study of sibling screening for VUR reported a significant decrease in renal scarring in asymptomatic siblings compared to those siblings who had least 1 known UTI.9 The greatest benefit was observed in siblings younger than age 3 years, thus confirming the benefit of screening such a population. However, on the basis of our study it is not possible to advocate that screening extended family members for VUR and then applying our current management protocols for VUR would change
the incidence and severity of reflux related morbidity. Only prospective randomized controlled trials can address this issue definitively. There are some limitations of this study. We only screened siblings of index patients with dilating reflux (grade III to V VUR). It is likely that we missed several siblings for whom the index patients had low grade reflux. Furthermore, reflux related morbidity in second and third-degree relatives may be underestimated because some relatives who were classified as not affected may have had VUR in the past which resolved spontaneously. Another limitation of our study is that the source of data in the majority of patients with ESRD was historical and confirmed by family members. It is possible that the history may have been inaccurate in relation to the etiology of ESRD, particularly for older relatives. This study clearly shows that there is an increased risk of reflux related morbidity among the relatives of index patients with VUR. Parents should be warned of the increased rate of reflux in siblings and counseled regarding screening. Furthermore, long-term concerns regarding recurrent UTIs, renal scarring, hypertension and familial VUR in the child’s siblings and offspring should be discussed with the family.
CONCLUSIONS This study provides important information regarding reflux related morbidity in a large cohort of familial VUR in first, second and third-degree relatives of index patients. Our data clearly show that there is an increased risk of reflux related morbidity among the relatives of index patients with VUR, and this has implications for counseling.
REFERENCES 1. Cooper CS: Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009; 6: 481.
4. Noe HN, Wyatt RJ, Peeden JN Jr et al: The transmission of vesicoureteral reflux from parent to child. J Urol 1992; 148: 1869.
7. Brakeman P: Vesicoureteral reflux, reflux nephropathy, and end-stage renal disease. Adv Urol 2008; 508949.
2. Smellie JM, Barratt TM, Chantler C et al: Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. Lancet 2001; 357: 1329.
5. Parekh DJ, Pope JC 4th, Adams MC et al: Outcome of sibling vesicoureteral reflux. J Urol 2002; 167: 283.
8. Swerkersson S, Jodal U, Sixt R et al: Relationship among vesicoureteral reflux, urinary tract infection and renal damage in children. J Urol 2007; 178: 647.
3. Chertin B and Puri P: Familial vesicoureteral reflux. J Urol 2003; 169: 1804.
6. Marra G, Oppezzo C, Ardissino G et al: Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? Data from the ItalKid Project. J Pediatr 2004; 144: 677.
9. Menezes M and Puri P: Familial vesicoureteral reflux–is screening beneficial? J Urol 2009; 182: 1673.
Familial Vesicoureteral Reflux and Reflux Related Morbidity in Relatives of Index Patients with High Grade Vesicoureteral Reflux Manuela Hunziker and Prem Puri* From the National Children’s Research Centre, Our Lady’s Children’s Hospital and National Children’s Hospital, Dublin, Ireland
Purpose: The familial nature of vesicoureteral reflux is well recognized. However, there is little information about the prevalence of vesicoureteral reflux and reflux related morbidity in the relatives of index patients with vesicoureteral reflux. Therefore, we determined the prevalence of vesicoureteral reflux and reflux related morbidity in first, second and third-degree relatives of index patients with high grade vesicoureteral reflux. Materials and Methods: Between 1998 and 2010 the parents of 259 index patients with grade III-V vesicoureteral reflux were asked permission to screen siblings younger than age 6 years for vesicoureteral reflux. Parents of index patients with affected siblings were contacted to obtain detailed information regarding vesicoureteral reflux, recurrent urinary tract infections, end stage renal disease, hypertension and nephrectomy among first, second and thirddegree relatives. Results: A total of 300 siblings of the 259 index patients were found to have vesicoureteral reflux on voiding cystourethrography. In terms of the other relatives of the 259 index patients 127 also had radiologically proven vesicoureteral reflux. Reflux related morbidity among the first, second and third-degree relatives included end stage renal disease in 21, nephrectomy in 12 and hypertension in 4. Of the 212 siblings who had dimercapto-succinic acid scans 49 (23.1%) showed evidence of renal scarring. In 73% of the relatives vesicoureteral reflux was seen on the mother’s side. Conclusions: This study, the first to our knowledge, provides important information regarding reflux related morbidity in a large cohort of familial vesicoureteral reflux in first, second and third-degree relatives of index patients. Our data clearly show that there is an increased risk of reflux related morbidity among the relatives of index patients with vesicoureteral reflux and this finding has implications for counseling.
Abbreviations and Acronyms DMSA ⫽ dimercapto-succinic acid ESRD ⫽ end stage renal disease UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrogram VUR ⫽ vesicoureteral reflux * Correspondence: National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin – 12, Ireland (telephone: ⫹353 1 4096420; e-mail: [email protected]).
Key Words: vesico-ureteral reflux, family, morbidity, siblings PRIMARY vesicoureteral reflux is the most common congenital urological abnormality in children, occurring in 30% to 40% of those presenting with a urinary tract infection.1,2 The association of VUR, UTI and renal parenchymal damage is well-known. Renal parenchymal damage can be congenital or acquired segmental scarring. Congenital reflux nephropathy
occurs as a result of abnormal embryological development with subsequent renal dysplasia and is largely seen in male infants with high grade VUR. Acquired renal scarring is more common in female children and occurs as a result of an acute inflammatory reaction caused by bacterial infection of the renal parenchyma during UTI.
0022-5347/12/1884-1463/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.02.024 Vol. 188, 1463-1466, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
www.jurology.com
1463
1464
VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
The familial nature of VUR is well recognized. Familial clustering of VUR has been described by several groups, with a prevalence between 27% and 51% in the siblings of index patients with VUR and a 66% rate in children whose parents previously had reflux.3–5 Reflux associated nephropathy is a major cause of hypertension and ESRD. Marra et al reviewed data on children with chronic renal failure and found that those with VUR accounted for 26% of all children with chronic renal failure.6 In the North American pediatric population reflux nephropathy is reported to be the 4th leading cause of dialysis and transplantation with 5.3% of transplant cases and 3.5% of dialysis cases having a diagnosis of reflux nephropathy.7 Although familial clustering of VUR is well recognized, there is a relative lack of information on reflux related morbidity in the relatives of index patients with VUR. Therefore, we determined the prevalence of VUR and reflux related morbidity in the first, second and third-degree relatives of index patients with high grade VUR.
METHODS Between 1998 and 2010 the parents of 259 index patients with grade III–V VUR were asked permission to screen siblings younger than age 6 years for VUR. Families with 2 or more siblings with any grade VUR were included in the analysis. Reflux was confirmed in all index patients and siblings by VCUG. Patients with VUR secondary to neurogenic bladder or posterior ureteral valves were excluded from study. Parents of index patients with affected siblings were contacted by telephone, and asked about a history of VUR among first, second and third-degree relatives of the index patients, eg mother, father, siblings or any other family members on the mother’s or father’s side. If there was a positive history of VUR in other family members, a detailed history was taken regarding recurrent UTIs, ESRD, hypertension and nephrectomy among the first-degree (ie parents, siblings), second-degree (ie aunts, uncles, nieces, nephews, grandparents) and third-degree (ie first cousins) relatives. Whenever possible the family member or his or her parents were contacted to verify the history. Hospital records and x-ray images were further evaluated to confirm details of the history and prove the diagnosis of VUR. In cases of generations earlier than those of the mother and father it was not possible to verify VUR by VCUG. In index patients and in siblings renal scarring was evaluated by DMSA scintigraphy and classified into 3 groups of mild (focal defects in uptake between 40% and 45%), moderate (uptake of renal radionuclide between 20% and 40%) and severe (shrunken kidney with relative uptake less than 20%). In children presenting with a urinary tract infection DMSA scans were performed at least 4 months after the first urinary tract infection.
RESULTS A total of 300 siblings of the 259 index patients were found to have VUR on VCUG. The number of families with 2, 3, 4 and 5 siblings affected was 223, 32, 3 and 1, respectively. There were 108 families who had 127 other relatives in addition to those siblings with radiologically proven VUR, including 37 with reflux related morbidity (table 1). Of the relatives 21 had ESRD, 14 needed renal transplantation and 7 were on dialysis. In 93 (73%) of the 127 relatives VUR was seen on the mother’s side (table 2). There were 92 families with 1 family member with VUR other than siblings. There were 14 families with 2 other family members, 1 family with 3 other family members and 1 family with 4 other family members with VUR. First-Degree Relatives Of the 259 families 11 mothers (4.2%) had radiologically proven VUR, including 1 mother who underwent nephrectomy at the age of 6 years due to severe reflux nephropathy. Ureteral reimplanation was performed in 3 mothers and another 3 had undergone endoscopic treatment to cure VUR as a child. The remaining 4 mothers were treated with antibiotics for breakthrough urinary tract infections. Of 11 mothers 3 (27.3%) had reflux nephropathy with no complications. In addition, 19 other mothers had a history of recurrent urinary tract infections. There were 7 (2.7%) fathers of index patients with radiologically proven VUR, including 5 who underwent nephrectomy for poorly functioning kidney and 2 who were treated conservatively for breakthrough urinary tract infections. Of the 300 siblings with VUR 125 (42%) were diagnosed after a UTI and 175 (58%) were diagnosed after screening. The prevalence of VUR in siblings after screening was 42% (175 of 414 siblings screened). A total of 247 (82%) siblings were younger than age 3 years Table 1. VUR and reflux related morbidity in relatives of 259 families
Family Members First-degree: Mother Father Siblings Second-degree: Aunts, uncles or grandparents Third-degree: First cousins Great-aunts, great-uncles or greatgrandparents
No. VUR
No. Nephrectomy
11 7 300
1 5 1
36
5
65 8
No. End Stage Renal Disease
No. Hypertension
11
3
3 7
1
VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
Table 2. Relatives with VUR on maternal or paternal side
First-degree relatives: Parents Second-degree relatives: Aunts Uncles Grandmothers Grandfathers Third-degree relatives: Cousins Great-aunts Great-uncles Great-grandmothers Totals
No. Maternal
No. Paternal
11
7
15 2 5 2
7 5 1 1
54 1 2 1
11 1 1 —
93 (73.2%)
34 (26.8%)
and 53 (18%) were 3 to 6 years old. DMSA scans were performed in 212 siblings and 49 (23.1%) showed evidence of renal scarring compared to 38% of the index patients. Mild, moderate and severe scarring was seen in 23 (47%), 19 (39%) and 7 (14%) siblings, respectively. Second-Degree Relatives There were 15 aunts and 4 uncles of index patients in this series who were diagnosed with VUR as a child. In addition to these relatives, nephrectomy due to reflux related poorly functioning kidney was performed in 2 aunts, 2 grandmothers and 1 grandfather. Furthermore, 11 second-degree relatives had a history of ESRD due to VUR as a child, including 4 aunts, 2 uncles and 5 grandparents. There were 9 family members who needed kidney transplantation and 2 relatives who were on dialysis. In addition, 3 second-degree relatives were diagnosed with hypertension. Of the 36 aunts, uncles and grandparents with VUR, 28 aunts or uncles had radiologically proven VUR, whereas in 8 grandparents the source of data was historical, confirmed by family members. Interestingly 1 uncle who underwent kidney transplantation was the twin brother of the mother and in another family 1 aunt who underwent kidney transplantation was the mother’s twin sister. In both families the mother herself had no history of any kidney disease. Our survey also showed that 24 second-degree relatives experienced recurrent urinary tract infections for several years. Third-Degree Relatives A total 65 first cousins from 48 different families were found to have VUR on VCUG. Of those relatives 1 had ESRD at age 23 years and 2 cousins from the same family died of reflux related kidney failure. There were 16 first cousins who had recurrent urinary tract infections for several years. Three great-aunts, 3 great-uncles and 1 greatgrandmother had a history of ESRD. Another great-
1465
aunt had a history of hypertension due to previously treated reflux. In great-aunts, great-uncles and greatgrandmothers the source of data was historical, and was confirmed by family members.
DISCUSSION The chance of a multifactorial trait or condition occurring again depends on how closely the family member with the trait is related to other family members. It is well-known that family members share a certain percentage of genes in common, depending on their relationship. For example, firstdegree relatives (parents, children and siblings) have 50% of genes in common, second-degree relatives (aunts, uncles, nieces, nephews and grandparents) have 25% of genes in common and third-degree relatives (first cousins, great-aunts, great-uncles and great-grandparents) have 12.5% of genes in common. In this study we identified 259 families with familial VUR in which 559 children (259 index patients and 300 siblings) were affected. In addition, there were 127 other first, second and third-degree relatives with proven VUR. In 73% of the relatives (other than siblings) VUR was seen on the mother’s side. This is the largest collection of families with first, second and third-degree relatives affected with VUR from 1 center. VUR is known to occur in families with a prevalence of 27% to 51% in siblings of index patients with VUR and a 66% rate of VUR in offspring of parents with previously diagnosed reflux. We were able to determine the true prevalence of VUR only in the first-degree relatives. In the second and third-degree relatives a true prevalence could not be ascertained because the source of data was historical and confirmed by family members. The prevalence of radiologically proven VUR in first-degree relatives was 4.2% in mothers, 2.7% in fathers and 42% in siblings. The most striking finding in this study was the reflux related morbidity observed in the first, second and third-degree relatives of index patients affected with VUR. Of siblings with VUR 23% had renal scarring on DMSA scans with more than half of them having moderate to severe scarring. Among the second and third-degree relatives 21 patients had ESRD with 14 needing renal transplantation and 7 on dialysis. Furthermore, 12 second and thirddegree relatives had undergone nephrectomy for reflux nephropathy, and 4 had hypertension. In the present study the rate of reflux related morbidity observed in first-degree relatives was low compared to second or third-degree relatives. We believe that the higher incidence of reflux related morbidity in previous generations, eg grandparents, greataunts, great-uncles or great-grandparents, may be due to a delayed diagnosis of VUR in the past.
1466
VESICOURETERAL REFLUX AND RELATED MORBIDITY IN RELATIVES OF INDEX PATIENTS
The most serious morbidity associated with VUR is renal scarring. It is well recognized that renal parenchymal injury in VUR occurs early, in most patients before the age of 3 years. It has been reported that the risk of renal scarring after an episode of acute pyelonephritis is substantially increased in children with high grade VUR, affecting up to 89% of children with grade IV and V VUR.8 Renal scarring in VUR is considered to occur as a result of 1 of the 3 mechanisms of 1) reflux of infected urine with interstitial inflammation and damage, 2) reflux of sterile urine, which may damage the kidney due to mechanical pressure and 3) abnormal embryological development with resulting renal dysplasia. Renal parenchymal damage in the first 2 groups may be preventable with the early detection and treatment of VUR. In the third group in which damage is congenital, it is mandatory to discover reflux at an early stage to prevent exposure to UTI and avoid progression of renal damage. A major goal of screening siblings of index patients with VUR is the identification of children who may be at risk for renal parenchymal damage. Most renal scars are present when reflux is discovered at initial evaluation for UTI in infants and young children. A recent large study of sibling screening for VUR reported a significant decrease in renal scarring in asymptomatic siblings compared to those siblings who had least 1 known UTI.9 The greatest benefit was observed in siblings younger than age 3 years, thus confirming the benefit of screening such a population. However, on the basis of our study it is not possible to advocate that screening extended family members for VUR and then applying our current management protocols for VUR would change
the incidence and severity of reflux related morbidity. Only prospective randomized controlled trials can address this issue definitively. There are some limitations of this study. We only screened siblings of index patients with dilating reflux (grade III to V VUR). It is likely that we missed several siblings for whom the index patients had low grade reflux. Furthermore, reflux related morbidity in second and third-degree relatives may be underestimated because some relatives who were classified as not affected may have had VUR in the past which resolved spontaneously. Another limitation of our study is that the source of data in the majority of patients with ESRD was historical and confirmed by family members. It is possible that the history may have been inaccurate in relation to the etiology of ESRD, particularly for older relatives. This study clearly shows that there is an increased risk of reflux related morbidity among the relatives of index patients with VUR. Parents should be warned of the increased rate of reflux in siblings and counseled regarding screening. Furthermore, long-term concerns regarding recurrent UTIs, renal scarring, hypertension and familial VUR in the child’s siblings and offspring should be discussed with the family.
CONCLUSIONS This study provides important information regarding reflux related morbidity in a large cohort of familial VUR in first, second and third-degree relatives of index patients. Our data clearly show that there is an increased risk of reflux related morbidity among the relatives of index patients with VUR, and this has implications for counseling.
REFERENCES 1. Cooper CS: Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009; 6: 481.
4. Noe HN, Wyatt RJ, Peeden JN Jr et al: The transmission of vesicoureteral reflux from parent to child. J Urol 1992; 148: 1869.
7. Brakeman P: Vesicoureteral reflux, reflux nephropathy, and end-stage renal disease. Adv Urol 2008; 508949.
2. Smellie JM, Barratt TM, Chantler C et al: Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. Lancet 2001; 357: 1329.
5. Parekh DJ, Pope JC 4th, Adams MC et al: Outcome of sibling vesicoureteral reflux. J Urol 2002; 167: 283.
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