Vesicoureteric Reflux and Reflux Nephropathy as Seen at a Tertiary Care Adult Nephrology Service in India—An Analysis of 86 Patients

Abstract

Clinical features and risk factors for renal failure in patients with reflux nephropathy (RN) as seen in an adult nephrology service are likely to be different than those seen in a pediatric service. There are only a few studies on adults with vesicoureteric reflux (VUR) and RN and data on RN as seen in developing countries is still evolving. Retrospective analysis of records of patients diagnosed to have VUR by conventional micturating cystourethrogram over a 13 year period, as seen in the adult nephrology services of this tertiary care hospital in north India was carried out. Results are presented as mean ± 2 SD. Unpaired t-test was used to compare means, chi-square test to define associations, and logistic regression analysis was done to define risk factors. Out of 86 patients diagnosed to have VUR, 69 (80.2%) were males and 22 (25.6%) were children. The mean age at presentation was 24.3 ± 14.5 years and at onset of symptoms was 19.6 ± 14.8 years. Sixty-nine (80.2%) patients had chronic renal failure (CRF) at presentation, including 33 (38.4%) patients who already had end stage renal failure (ESRF) at presentation in whom reflux was diagnosed during routine pretransplant evaluation and these constituted 5.5% of all ESRF patients. The clinical features at presentation were hypertension in 51 (59.3%), recurrent urinary tract infection (UTI) in 31 (36.1%), history of stones in 7 (8.1%), and gross hematuria in 4 (4.7%). Patients with history of recurrent UTI were more likely to be females (p<0.01) and to present without renal failure (p<0.05). Proteinuria >1 g/day was significantly associated (p<0.02) with hypertension at presentation. Patients who presented with renal failure were more likely to be males (p<0.05), not to have history of recurrent UTI (p<0.05), have proteinuria >1 g/day (p < 0.02) and higher grades (grades IV and V) of reflux (p<0.05). On logistic regression analysis, higher age of onset (odds ratio 4.6, p<0.03), proteinuria >1 g/day (odds ratio 3.8, p<0.05), and male gender (odds ratio 3.5, p<0.05) were significant risk factors for presentation for the first time with renal failure. The clinical features and course of VUR and RN as seen in India are different from those reported from elsewhere. The vast majority of patients in India are males and almost two thirds do not have a past history of UTI. Renal failure is present in more than three fourths of patients when a diagnosis of reflux is made and one third of all patients present with ESRD. Patients with a prior history of UTI are more commonly females and are less likely to have renal failure at presentation. Higher age of onset of symptoms, proteinuria >1 g/day and male gender were risk factors for the development of renal failure. It is likely that these asymptomatic patients remain undetected during childhood, presenting late only after having incurred severe renal damage.

• Chronic pyelonephritis
• Chronic renal failure
• Reflux nephropathy
• Risk factors
• Vesicoureteric reflux

Introduction

Vesicoureteric reflux (VUR) leading to reflux nephropathy (RN) is an important cause of end stage renal failure (ESRF) worldwide. However, this entity has not received adequate attention, primarily because of problems associated with evolution of its nomenclature. In the European Dialysis and Transplant Association Registry, end stage reflux nephropathy (ESRN) was included under seven different diagnostic categories and during the period ranging from 1979 to 1983 accounted for 1.8–15.3% of all ESRF patients.[[1]] Reflux nephropathy, which is included as a separate entity in the Australia and New Zealand Dialysis and Transplant Registry, was present in 4.5% of patients entering the dialysis program in 1998.[[2]]

Although well described in infants and young children, there are only few studies on adults with VUR and RN. Moreover data on reflux nephropathy as seen in developing countries such as ours, are still evolving.[[3]] Chronic pyelonephritis was the cause of chronic renal failure (CRF) in 7.3% of 2028 Indian patients.[[4]] Among 835 patients of CRF reported by Mittal et al., chronic interstitial nephritis constituted 16.5% of cases.[[5]] We had earlier reported our data on 435 consecutive patients of CRF in which chronic interstitial nephritis accounted for 14.4%.[[6]] All these three published Indian series did not include RN as a separate category of chronic renal failure. There is a common perception that patients with VUR and RN are diagnosed late in India. Diagnosis is usually made when patients are investigated for the cause of hypertension, CRF or when a micturating cystourethrogram is done pre-transplant in those presenting with ESRF. The aim of this article is to present the clinical features and course of VUR and RN as seen in an adult renal unit of a large tertiary care center in India and to describe the risk factors for presentation with renal failure in patients with VUR.

Patients and Methods

This retrospective study included patients diagnosed to have VUR by conventional micturating cystourethrogram (MCU) over a 13 year period from 1985 to 1997 as seen in the adult nephrology services of this tertiary care teaching hospital in north India. Both children and adults with VUR with or without RN were included since children were also referred to the adult nephrology service of this Institute, in the absence of a pediatric nephrology unit. Relevant past history, age at onset of symptoms and presentation, clinical features, and laboratory data were recorded. The presence or absence of renal scarring as documented by intravenous urogram (IVU) or ultrasound (USG) was noted. Primary VUR was defined as reflux demonstrated on a MCU in the absence of any other abnormality of the lower urinary tract. Reflux nephropathy was defined as the presence of characteristic focal or diffuse scars in an IVU or an USG examination in patients with demonstrable VUR on a conventional MCU. Vesicoureteric reflux was graded according to defined criteria.[[10]] Micturating cystourethrogram was done in patients with recurrent urinary tract infections and as part of pretransplant evaluation. Patients were said to be hypertensive if their mean blood pressure was >110 mm Hg or in children, more than the 95th percentile for their age and gender. Renal failure was defined as a serum creatinine >1.5 mg/dL. End stage renal failure was defined as a calculated creatinine clearance of <5 mL/min and/or requiring maintenance dialytic support.

Results are presented as mean ± 2 SD. Unpaired t-test was used to compare means. Chi-square test was applied to define associations. Logistic regression analysis was done to define risk factors.

Results

Out of 86 patients diagnosed to have VUR, 69 (80.2%) were males. There were 22 (25.6%) children. The mean age at presentation to our center was 24.3 ± 14.5 years (range 0–60 years, median 25.5 years) and at onset of symptoms was 19.6 ± 14.8 years (range 0–56 years, median 20 years). Sixty-nine (80.2%) patients had CRF at presentation. These included 33 (38.4%) patients who already had ESRF at presentation with a mean age of 30.8 ± 9.6 years (Table 1), in whom reflux was diagnosed during routine pre-transplant evaluation. ESRN constituted 5.5% of all ESRF patients.

Table 1. Clinical characteristics of patients with VUR

Clinical features	No renal failure (n = 17)	Renal failure (n = 36)	End stage renal failure (n = 33)
Males	10	28	31
Females	7	8	2d
Adults	9	22	33
Children	8	14	0
Age at onset of symptoms (yrs)	12.7 ± 14.7	15.2 ± 15.6e	27.2 ± 10.8a
Age at presentation (yrs)	20.7 ± 18.4	20.1 ± 14.5e	30.8 ± 9.6a
Recurrent UTI	10	16f	5b
Hematuria	0	1	3
Renal stones	2	3	2
Hypertension	8	17f	26c
Serum creatinine (mg/dL)	0.9 ± 0.2	3.9 ± 1.7	—
Proteinuria (>1 g/day)	2	11	16
Bilateral VUR	13	21	22

^ap<0.0005;

^bp<0.002;

^cp<0.005;

^dp<0.02 (end stage renal failure vs. renal failure and no renal failure);

^ep<0.001;

^fp<0.01 (renal failure vs. end stage renal failure). UTI: urinary tract infection, VUR: vesicoureteric reflux.

The clinical features at presentation (Table 1) were hypertension in 51 (59.3%), recurrent urinary tract infection (UTI) in 31 (36.1%), history of stones in 7 (8.1%), and gross hematuria in 4 (4.7%). Adults were more likely (p<0.05) to have renal failure and hypertension at first presentation. Fourteen out of 22 (63.6%) children had evidence of rickets and growth retardation. The mean serum creatinine was 3.9 ± 1.8 mg/dL. Quantitative estimation of urinary protein excretion was available in 64 (74.4%) patients. The mean 24 h urine protein was 1.1 ± 0.9 g. Thirty-five patients (54.7%) had <1.0 g/day proteinuria at presentation, 27 (42.2%) had proteinuria between 1 and 3 g/day. Only two patients (3.1%) had >3 g/day proteinuria. Eleven patients with CRF at presentation progressed to ESRF after a mean follow up of 6.2 ± 5.7 years. Four out of 17 patients (23.5%) with normal renal function at presentation developed renal failure during a mean follow up of 7.2 ± 5.4 years. Thirty-one patients (36.1%) of RN underwent living related renal transplantation during the study period.

There were a total of 142 refluxing ureters in 86 patients. Reflux was unilateral in 30 (34.9%) patients. The maximum grade of reflux was grade V in 21 (24.4%) and grade IV in 25 (29.1%) patients and ten patients (11.6%) had only a grade I reflux. The median grade of reflux was 3 on either side. Those with higher grades of VUR (grades IV and V) were more likely to have renal failure (p<0.05) at presentation.

All patients had USG examination and 19 patients had an IVU. The characteristic renal scarring of RN as demonstrated by USG or IVU was found in 70 (81.4%) patients. Fifty-four (77%) had evidence of bilateral renal scarring. Among these patients, MCU demonstrated bilateral VUR in only 42 (77.8%), with the remainder exhibiting only unilateral reflux. Patients with bilateral VUR were more likely to have a history of recurrent UTI (p<0.05). There were no other significant differences in the clinical features in patients with unilateral vs. bilateral VUR.

Patients with history of recurrent UTI were more likely to be females (p < 0.01) and to present without renal failure (p<0.05). Proteinuria >1 g/day was significantly associated (p<0.02) with hypertension at presentation. Patients who presented with renal failure were more likely to be males (p<0.05), not to have history of recurrent UTI (p < 0.05), have proteinuria >1 g/day (p<0.02), and higher grades (grades IV and V) of reflux (p<0.05) (Table 2). Patients with ESRF at presentation were more likely to be males (p<0.02), have higher incidence of hypertension (p<0.005) with no history of recurrent UTI (p<0.002). On logistic regression analysis, higher age of onset (odds ratio 4.6, p<0.03), proteinuria >1 g/day (odds ratio 3.8, p<0.05), and male gender (odds ratio 3.5, p<0.05) were significant risk factors for presentation for the first time with renal failure.

Table 2. Clinical features associated with development of renal failure in patients with VUR

Clinical features	Renal failurea (n = 69)	No renal failure (n = 17)	p Value
Age at onset (years)	20.9 ± 14.7	12.7 ± 14.7	NS
Age at presentation (years)	25.3 ± 13.4	20.7 ± 18.4	NS
Male	59	10
Female	10	7	<0.05
UTI	21	10
No UTI	48	7	<0.05
Hypertension	43	8
No hypertension	26	9	NS
Proteinuria <1 g/day	4	11
Proteinuria >1 g/day	27	2	<0.02
Reflux grade I–III	28	12
Reflux grade IV and V	41	5	<0.05

^aIncludes end stage failure, NS: not significant, UTI: urinary tract infection, VUR: vesicoureteric reflux.

Discussion

The clinical features and course of VUR and RN as seen in India are different from that reported from elsewhere. In almost all the reported series there is a marked female preponderance.[[7]], [[8]], [[9]], [[10]], [[11]] One of the possible explanations for the higher proportion of females in various adult series is that milder cases are largely clinically unapparent in the male, but apparent in the female because of their predisposition to UTI, while more severe cases occur with equal frequency in males and females. Thus while females more often present with UTI alone, males present more commonly with features suggesting renal damage.[[10]] However males constituted 80% of all our patients, with a significantly higher proportion of them presenting with renal failure. The higher proportion of males could also partly be related to various social factors prevalent in this country leading to under utilization of medical services by females.[[6]] In addition, a referral bias with referral of only patients with renal failure to nephrology services such as ours, providing dialysis and transplant facilities, could also account for the higher proportion of males in this study. Although females predominate in most studies on RN, there is evidence pointing to proportionally greater number of males having severe scarring associated with renal failure.[[10]], [[12]]

End stage reflux nephropathy constituted 5.5% of our total ESRF patients entering the transplant program. This is similar to the 4.5% reported by the ANZ data and 3.3% by Salvatierra and Tanagho[[13]] but lower than 11.3% reported by Bailey et al.,[[14]] 15% by Kincaid-Smith et al.,[[15]] and 30% by Bakshandeh et al.[[16]] The lower figures in this study could probably be related to late diagnosis of RN in our patient population. Because demonstrable reflux disappears with age, some patients of RN may have been missed as patients with no demonstrable VUR by conventional MCU at the time of evaluation were not included. That 54 of our patients had documented bilateral renal scars and only 42 (77.8%) had bilateral VUR demonstrated by MCU is another pointer towards disappearance of demonstrable reflux with age. As this study is from a tertiary care adult nephrology service, the true incidence of VUR and RN in the general population will not be represented. While 38.4% of our patients were already in ESRF at the first presentation, 11 out of 36 patients (30.5%) who had mild to moderate renal failure at presentation progressed to ESRF after a mean follow up of 6.2 ± 5.7 years. Zhang and Bailey[[9]] reported that 2% of 294 patients had renal failure at presentation and 24% had renal failure after a mean follow up of 34 years.

Approximately 80% of our patients had renal failure at the time reflux was first demonstrated as compared to 10.2–52.5% of patients in various large series of adult RN.[[17]] The mean age (30.8 ± 9.6 years) of RN patients with ESRF is much lower than that of patients with ESRF due to other causes as reported earlier by us and others[[5]], [[6]] from India. In our study, patients presenting with renal failure were more likely to be males, with no past history of recurrent UTI and have more severe grades of reflux. This group included 38% patients who were already in ESRF when diagnosis of RN was first made. In these patients, VUR was demonstrated during routine pre transplant work up. Patients with ESRF were older, more likely to be males, have hypertension and were less likely to have had prior history of recurrent UTI. In 37% of adult patients without urinary tract symptoms reported by Zucchelli and Gaggi,[[17]] renal failure occurred in 62.6%, as compared to 33.3% of those who were symptomatic (p<0.005). There were no significant differences in the degree of proteinuria, grades of reflux, or severity of renal scarring in patients presenting with ESRF or milder degrees of renal failure due to RN.

Urinary tract infection is the commonest manifestation of VUR and RN in children. Although VUR can be demonstrated in 32.5–36% of infants with UTI,[[18]], [[19]] 63–87% adults with VUR have been reported to have UTI in the past,[[8]], [[10]], [[17]] with UTI more frequently seen in women than men.[[9]], [[10]] However only one third of our patients had a history of recurrent UTI and these were more likely to be females and those with bilateral VUR. The reasons for the reduced incidence are unclear. Although controversial,[[20]] RN can occur with ongoing reflux even in the absence of infection. Episodes of UTI occur less frequently after adolescence and absence of a positive past history of UTI in our predominantly adult population may also be related to failure to recollect the history or a truly low incidence. It is possible that past episodes of UTI were not correctly diagnosed and responded to common antibiotics routinely prescribed for febrile episodes in children in this country. It is likely that the frequency of complications such as renal failure is significantly lower in those with UTI, as symptomatic patients are detected at an earlier stage.

Significant proteinuria (>1 g/day) was seen in 45.3% of patients in this study. As reported by others,[[9]], [[21]] we found a significant association between >1 g/day proteinuria and the occurrence of renal failure. Overall nearly 60% of our patients had hypertension at presentation. Association between severe hypertension and bilateral RN has been reported,[[8]], [[9]] but we did not observe the same. Although we found that hypertension was significantly associated with the presence of >1g/day of proteinuria, both of which are signs of renal damage, we did not find any association with gender, grades of reflux, or renal failure. Thirty-four to 56% of patients with VUR have hypertension[[10]], [[17]], [[22]] and a significant association of male sex with hypertension and proteinuria has been reported.[[10]]

Zucchelli and Gaggi found higher incidence of male gender, proteinuria >0.2 g/day, hypertension, and renal failure in asymptomatic adults with reflux nephropathy.[[17]] While in children, the most frequent clinical presentation is UTI, nearly 50% of all adults had renal failure, proteinuria, or hypertension as the main reason for the first nephrological investigation. The observation that frequency of complications such as proteinuria, hypertension, and renal failure is significantly higher in patients without a history of UTI suggests that patients with asymptomatic reflux during childhood, undetected for long period of time may incur more severe renal damage[[17]] and is particularly true for our patients.

Severity of reflux during infancy and childhood is the single most important factor determining whether renal damage will occur. At the time VUR is confirmed, renal scarring is present with an increasing incidence with age: 10% in preterm infants, 26% in children <8 years, 47% in children >8 years, and 94% in adults.[[12]] Malek et al. found a significant correlation between the grades of renal scarring and of VUR in adults.[[23]] However Zucchelli and Gaggi did not find any such correlation.[[17]] Although we did not grade the severity of RN by the number and extent of renal scars, we demonstrated a correlation between the severity of VUR and renal failure at presentation. Several authors[[8]], [[9]], [[10]], [[24]] have reported a higher incidence of complications in bilateral RN, but we did not find any significant difference between unilateral and bilateral RN.

Male gender, absence of history of recurrent UTI, proteinuria >1 g/day, and higher grades of reflux were significantly associated with presentation with renal failure in our study. On logistic regression, only higher age of onset of symptoms, proteinuria >1 g/day, and male gender were significant risk factors. Similar findings were reported by E1-Khatib et al. in adult RN patients where proteinuria, elevated serum creatinine, bilateral scarring, male, and hypertension were risk factors in descending order of significance.[[10]] Males in this study most commonly (69%) presented with features of renal damage–hypertension and proteinuria.

In conclusion, the clinical features and course of VUR and RN as seen in India are different from those reported from elsewhere. End stage reflux nephropathy constituted 5.5% of all ESRF patients. More than one third of patients presented very late and were first diagnosed when they already had ESRF. Almost two thirds did not have a past history of UTI. The majority of patients were males, and already had features of renal damage at presentation. Patients with a prior history of UTI were more commonly females and were less likely to have renal failure at the time of presentation. On logistic regression, higher age of onset of symptoms, proteinuria >1 g/day, and male gender were risk factors for the development of renal failure. It is likely that these asymptomatic patients remained undetected during childhood, presenting late only after having incurred severe renal damage.