One of the most notable morbidities of VUR relates to the development of CKD. CKD has been known to develop in 3–11.4 % of patients with VUR and on long-term follow-up may be as high as 18 % by 15 years [96, 106, 107]. VUR is the third most common cause of CKD in children [106]. Some have found a serum creatinine >0.6 mg/dL to be the most important predictive factor for progression to CKD [108]. Older age at diagnosis is also a strong risk factor development of CKD, which has important implications for those diagnosed later in life. Bilateral high-grade VUR is also a risk factor: in those with bilateral high-grade VUR, prevalence of CKD can be higher at 15–54 %, compared with 11 % for those with unilateral VUR [107, 108]. Additional risk factors for the development of CKD in VUR include hypertension, grade V VUR, proteinuria, bilateral renal damage, and prolonged delay from time of UTI to diagnosis. Of note, those with prenatally detected VUR are no more likely than those detected after febrile UTI to have chronic renal insufficiency [108].

The presence of scar is crucial in the progression to CKD. In the setting of bilateral renal scars, one study with three decades of follow-up found CKD prevalence at 83 %, with 19 % of those as moderate to severe. In contrast, 68 % with unilateral and 58 % with no scars had CKD, all cases mild [96]. While CKD in this study was found among patients without renal scarring, many series have found that those without scars do not develop CKD [107, 109]. It is thought that with parenchymal loss from scarring, hyperfiltration in remnant glomeruli causes glomerulosclerosis, activation of the renin–angiotensin system, and progressive renal deterioration [110, 111]. Puberty and the demands of increased growth may be a turning point for this development. Elevated urinary α1-microglobulin may serve as an early harbinger for this deterioration [112], with the development of proteinuria representing more advanced renal deterioration and poor prognosis [16, 113–116]. Previous studies identified a significant risk of developing CKD in long-term follow-up of patients with VUR [40, 117]; in recent years, though, the likelihood of developing CKD due to VUR has improved from 11 to 2 % [107].

Historically, in older series, VUR was the etiology of ESRD in up to 25–50 % of pediatric cases [118–121], representing the most common cause of ESRD in children. Similarly, VUR was a cause of ESRD in 5–16 % of adults with renal failure [17, 40, 117, 120, 122–126]. Today, however, due to successful strategies at detection and management, patients with a history of VUR represent only 5 % of the pediatric ESRD population [127]. VUR is a much less common etiology in pediatric patients undergoing dialysis (3.5 %) [128] and those receiving renal transplants (5.2 %) [129]. Of note, these numbers only relate to primary VUR; VUR in conjunction with other underlying urologic etiologies are listed separately in this registry. Likewise, the proportion of adults with ESRD with VUR as a cause is much lower at 0.22 % [130].

Based on this discrepancy between the high prevalence of VUR and the low prevalence of VUR as an underlying diagnosis in pediatric ESRD, relatively few cases of VUR progress to ESRD: it can be extrapolated that VUR leads to ESRD in roughly 0.7–13.4 per million patients, depending on one’s estimate of VUR in the general population [127, 131–133]. Risk factors for progression include older patients, as well as patients with bilateral disease, bilateral grade V disease, a more advanced CKD stage, renal scarring, proteinuria, hypertension, and a history of UTI [54, 121, 134]. One study with one of the longest follow-up periods (37 years) assessed the development of ESRD in a Finnish population with VUR and found a strong risk for development in patients with renal scarring and renal impairment [96]. In this study, 7 % progressed to ESRD: 4.5 % had died due to renal disease, 2.6 % had undergone transplant, and 0.3 % were on dialysis. On ultrasound, 34 % had unilateral scarring, 24 % had bilateral scarring, and 67 % had evidence of renal impairment. Finally, VUR also predisposes to early progression of ESRD in children with other genitourinary anomalies, i.e., solitary kidney, bilateral hypoplasia, and posterior urethral valves [135].

Reflux nephropathy is postulated to exert systemic morbidity as well, secondary to the renal injury it causes.

Studies on the long-term follow-up of patients with VUR are imperfect in several ways. Firstly, for some of the earliest studied patients, follow-up may be as long as 40 years, and more modern treatment paradigms, including concomitant management of voiding dysfunction, may yield different outcomes than those achieved by the medicine practiced decades ago. Additionally, those detected decades ago, before the era of prenatal ultrasound and sibling screening, may represent a selection bias towards those with higher degrees of symptomatic UTI, renal scarring and reflux nephropathy. Further, many studies from decades prior utilized IVP for scar detection, rather than the more sensitive nuclear medicine tests that are available today. With nuclear medicine tests replacing IVP for this indication, subtler scarring is detectable presently, and older studies generally represent a cohort with more advanced disease [54]. Thus, long-term outcomes of patients with VUR should be understood within the context of these historical differences. Outcomes may presumably be improved for today’s cohort of VUR patients, but only time will tell.

Secondly, many older studies are fraught with methodological limitations. These include inconsistent or incomplete VUR grade reporting, vague inclusion criteria for UTI, lack of distinction between febrile and afebrile UTI, and varied methods of detecting renal lesions (i.e., IVP, US, or DMSA). Further, most of the older (and even current) studies on outcomes in reflux nephropathy are retrospective and have a wide range of patient selection criteria, and few have long-term follow-up into adulthood.

Thirdly, reflux nephropathy may develop due to a multitude of etiologies as discussed, including congenital renal dysplasia, acquired pyelonephritic scar, and high-pressure sterile reflux. In some, a single cause may be at play, whereas in others, a pathologic continuum may exist. Clinically, these etiologies are often difficult to tease out, and academically, most studies are not designed to make this distinction. As a result, there is limited ability to quantify the acquired, ongoing effects of VUR on reflux nephropathy vs. those that are congenital and immutable.

Despite these limitations, certain patterns commonly emerge that may be helpful in providing management recommendations. The regular assessment of overall renal function, split renal function, blood pressure, and somatic growth in patients with VUR is imperative. Assessment of creatinine level may also be important, both at baseline and as needed on follow-up. Any abnormality in these settings may be an indicator of underlying renal damage, and if this occurs, subsequent efforts should be made to prevent continued renal damage. In addition, treating hypertension and proteinuria (both of which contribute to further renal deterioration) represents an additional front in the prevention of ESRD. ACE-I or angiotensin receptor blockade should be considered a first-line therapy in patients with hypertension or proteinuria related to VUR. Prompt initiation of antibiotics in the setting of acute pyelonephritis also helps limit renal scar formation. Finally, multiple options exist in addressing and treating VUR (which will be discussed in later sections), with the hopes of minimizing the development and worsening of reflux nephropathy.

Certain populations are at risk for VUR-related morbidity as adults. Three such notable groups are pregnant women, those who have undergone renal transplant, and those with spina bifida.

VUR was first identified as a pathologic entity in adulthood [252, 253] roughly a decade after its importance in childhood was recognized [14]. Currently, as most cases of VUR resolve or are corrected in childhood, present data on VUR in adulthood is limited. Theoretically, VUR in adulthood may occur for a variety of reasons: undetected VUR from childhood, de novo primary VUR, and de novo secondary VUR.

It is unclear whether primary VUR in adulthood is due to the same pathophysiology as in childhood and whether its development is de novo in adulthood or simply “silent” VUR detected later in life. Roughly 35 % of adults with VUR report a history of childhood UTI [91], while many report only recent symptom onset around the time of detection [254]. As the onset and duration are generally unknown, complications such as scarring and renal insufficiency only become apparent later in the disease process [21].

Primary VUR in adulthood is much more common in women by a factor of roughly 5–18 to 1 [31, 33–36, 38, 124, 252, 253, 255, 256]. This is in contrast to the relatively more equal sex distribution seen in VUR in childhood [33, 38, 159]. This may be due to women’s greater likelihood of presenting with UTI symptoms (as they are at greater anatomic risk for UTI in general), with men’s presentation generally more delayed until more advanced effects of reflux nephropathy ensue [257]. Alternatively, the exacerbation of hypertension and proteinuria in pregnancy among women with VUR may explain increased detection rates in women. In the 60- to 70-year-old age group, a greater proportion of patients with VUR are men, largely attributed to a higher incidence of secondary VUR due to bladder outlet obstruction [255, 258].

The most common signs and symptoms that lead to VUR diagnosis in adults are UTI (64 %), proteinuria (14 %), and asymptomatic bacteriuria (13 %) [257]. Most (87 %) have a history of UTI, although UTI onset and frequency are variable [257]. While one historical series cited a 50 % rate of VUR among adults with recurrent pyelonephritis [162], that number is much likely lower at 2.3–9 % [259–261]. Rare presenting signs and symptoms include hypertension, flank or back pain, and renal failure (10 % each) [257].

Most women with VUR (70 %) present initially with UTI [256, 257], and some (14 %) present with aymptomatic bacteriuria [21, 257]. Women are 12 and 7 times more likely to have symptoms of lower and upper UTI, respectively [257]. When a history of UTI is absent, hypertension upon initiating contraceptive pills or in pregnancy may be another common scenario of presentation in women. Between 5 and 33 % of women present in the setting of pregnancy-related complications [35, 39, 124, 182, 183, 256, 257, 262]. Proteinuria and renal insufficiency are much less frequent initial findings in women, seen in 10 % and 7 %, respectively, but may be present in as many as 17 % and 13 %, respectively, upon further evaluation [257].

Conversely, men more commonly present with symptoms of nephropathy, such as hypertension, proteinuria (37 %), and impaired renal function (31 %), and less frequently with complaints of UTI (25 %) or asymptomatic bacteriuria (6 %) [256, 257, 263]. On evaluation, as many as 56 % and 44 % of men have impaired renal function and proteinuria, respectively. Men also are commonly diagnosed incidentally when being evaluated for other urinary complaints [262].

In adult patients presenting with VUR, up to 89 % demonstrate renal scarring (depending on modality of presentation). This is in contrast to the 42 % seen by Lahdes-Vasama et al. [96] of patients with VUR diagnosed in childhood and 30-year follow-up. Thus, VUR not detected until adulthood seems to allow for the interim, silent development of renal morbidity during this time. Roughly 18–37 % have evidence of renal function impairment. Risk factors for renal function impairment on multivariable analysis include elevated creatinine, proteinuria, hypertension, bilateral VUR, male sex, and recurrent UTI [36, 117, 256, 264].

Hypertension in adults diagnosed with VUR is relatively common at 13–56 %, usually falling between 30 and 40 %, with incidences varying widely depending on the definition of hypertension [31, 32, 34–40, 117, 124, 140, 256, 257, 265, 266]. This is higher than the incidence seen in children with VUR, likely representing other confounding factors that contribute to hypertension in adulthood, but also in part relating to the natural history of uncorrected VUR [152]. In the adult population, hypertension may be anywhere from 2.6 to 8 times more common in those with bilateral VUR [31, 35, 37, 117, 257], although others have found no differences in rates of hypertension between those with unilateral and bilateral VUR [32, 34, 38]. Hypertension is up to 4 times as common in those diagnosed over age 45 [257]. Hypertension and severity of hypertension is also increased among those with renal insufficiency [190, 257] and renal scarring [266]. In those presenting in early adulthood with bilateral scarring or a solitary kidney, by the time renal function deterioration is noted on serum creatinine level, there is a 92 % incidence of hypertension [190, 257]. Men and women with VUR in adulthood have relatively similar rates of hypertension at 44 % and 32 %, respectively [257]. The incidence of malignant hypertension is relatively low at less than 2 % [39, 257] and is generally described only in those with extensive renal damage [190].

Previously, VUR was a cause of ESRD in 5–16 % of adults with ESRD [17, 40, 117, 122–126], although that number is much lower presently at 0.22 % [130] due to successful strategies at detection and management. VUR-related ESRD may occur at any age but typically peaks in the third to fourth decade of life [267]. VUR as a cause of ESRD is more common in middle-aged women with ESRD than men (ages 34–65 years), but at other ages, ESRD due to VUR occurs at equal rates among the sexes [125]. El-Khatib et al. [256] found that in adults with VUR and reflux nephropathy, the presence of proteinuria represented the best predictor for progression to ESRD; the presence of VUR itself was not an independent predictor of ESRD development.

No clinical guidelines exist for the evaluation of adult VUR as they do for children. Typically, imaging for the evaluation of UTI in an adult is limited to those with complicated UTIs or immunocompromised patients [268]. Adult patients who experience pyelonephritis and who have a personal history of corrected VUR or family history of VUR may also be considered for evaluation [269]. Adult women of child-bearing age with acute pyelonephritis may be evaluated as well [270], as identification could allow for correction or other management that would minimize the risk of pregnancy-related complications. Additional indications for evaluation for VUR may include those with flank pain upon bladder filling and those preparing to undergo renal transplant and with a history of UTI. VUR may also be considered as a potentially reversible cause of hypertension in select cases, even in the presence of normal renal function [271].

As in children, VCUG may be utilized in adults to evaluate for the presence of VUR [255, 272]. In patients with negative VCUGs but a strong suspicion of VUR, several techniques have been utilized to detect occult VUR. These include cyclic VCUG (which relies on multiple cycles of emptying and filling) [273]; performance of VCUG during the acute infection, once proper antibiotic therapy is initiated [274]; and PIC cystography, which relies on Positioning the Instillation of Contrast at the ureteral orifice during cystoscopy [275]. Nuclear medicine studies may also be used to assess renal scarring. Strong consideration should be made to whether VUR presenting in adulthood is secondary to voiding dysfunction or neuropathic bladder, so urodynamics should always be considered for these patients.

Preventing episodes of pyelonpehritis and minimizing renal morbidity are the two major goals of VUR management. Management strategies may include the utilization of prophylactic antibiotics, prompt initiation of antibiotics for pyelonephritis once it develops (already discussed), surgical techniques to eliminate VUR, and correcting any underlying bowel bladder dysfunction (BBD).

Debate exists as to whether the progressive reflux nephropathy related to VUR is preventable with intervention. Traditional thinking espouses that VUR predisposes to pyelonephritis, which leads to progressive renal deterioration, and that more severe VUR leads to greater degrees of renal damage [62, 78, 168, 276]. This is the belief that is predominantly held regarding treatment of VUR and is the rationale for most attempts at risk stratification and management. Certain groups of patients fit this model, such as some female patients with mild to moderate reflux detected at a relatively later point, who go on to develop recurrent pyelonephritis and renal scarring [55, 58].

However, there is an alternative theory that maintains that the renal damage associated with VUR relates to underlying renal dysplasia. In this theory, renal damage exists prior to the development of UTI, and is thus progressive despite seemingly successful medical and surgical interventions that prevent pyelonephritis. This seems particularly true for certain subgroups, such as infant males with dilating VUR, i.e., grades III–V [55, 56, 59, 61, 62, 277–280]. These patients are known to progress to CKD [16, 86, 112, 281], and in this cohort, reflux nephropathy follows its own natural progression despite aggressive treatment or number of episodes of pyelonephritis [9, 55, 56, 103, 280, 282]. Studies from the 1980s in children demonstrated that surgery is ineffective in preventing renal damage [281, 283, 284]. Further, even after VUR resolves, whether by spontaneous resolution or surgical correction, renal function may deteriorate and new scars may form [284–286]. Discouragingly, despite more aggressive medical and surgical treatment paradigms of VUR in place since the 1960s, the rate of ESRD due to reflux nephropathy has remained unchanged [287, 288].

The need for treatment of VUR in adulthood is even more debatable. Certainly, symptomatic reflux that results in recurrent pyelonephritis, new renal scarring, or deteriorating renal function merits consideration for treatment [289]. Additionally, certain patients may be at increased risk for the sequelae of febrile UTI in adulthood, such as pregnant women [290].

However, the potential for benefit from surgical correction of VUR is unclear. There is inconclusive evidence that surgical correction reduces the risk of pyelonephritis in pregnant women [187, 191], and even after correction, much morbidity stems from the presence of renal scars and renal impairment that has already been acquired. However, many still prefer surgical correction for women of child-bearing age. Additionally, adult kidneys are less susceptible to infection [291] and much less susceptible to scar formation after age 5 [292]. Kidneys have also achieved their growth potential by adulthood [290], and so the risk of impaired renal growth is moot. Finally, even the presence of severe renal scarring is not itself an absolute indication for surgical treatment, as correction for this indication has not been shown to provide any benefit in adult patients [37, 293].

Thus, despite decades of research on VUR and its management, much about the natural history of reflux nephropathy remains debated and incompletely known. While medical and surgical treatment of VUR is certainly legitimate, it is important to keep these controversies and limitations in mind in order to understand that reflux nephropathy may be progressive despite “successful” therapies for VUR and that not all VUR requires treatment in order to achieve VUR resolution or sequelae-free outcomes. It is this disease heterogeneity that makes treatment decisions so challenging.

Most cases of childhood reflux either resolve or improve with age [107, 151, 294]. The 5-year likelihood of spontaneous resolution is excellent for low-grade VUR (82–90 % for grade I and 80 % for grade II), whereas dilating VUR less frequently resolves spontaneously (46 % for grade III, 30 % for grade IV, and 13 % for grade V) [295–299]. Resolution is much more likely and quicker in unilateral vs. bilateral cases [120, 297–299], although others have found conflicting results [5, 300, 301]. Reflux is also more likely to resolve spontaneously in boys than in girls, usually due to high rates of resolution of low-grade VUR in boys [5, 70, 299]. Further, 94 % of patients with normal bladder function will achieve spontaneous resolution, vs. 0 % without in one study [302]. Overall, roughly 10–40 % of cases of reflux will persist [290, 299].

Once children reach approximately age 5 or 6, when the likelihood of spontaneous resolution decreases substantially, there is considerable debate on optimal management of persistent reflux, ranging from continued prophylaxis, cessation of prophylaxis, and surgical intervention (open or endoscopic). Many will opt to correct higher grades of reflux or bilateral reflux at this point; yet, more controversial are the lower grades, for which surgical correction is not as clearly indicated. Further, while long-term antibiotic prophylaxis is generally well tolerated by patients, parents may grow weary of continued antibiotic prophylaxis, with inconvenience and cost becoming a nuisance, and compliance may become a concern. This may be particularly true for patients with relatively early diagnoses and prolonged duration on continuous antibiotic prophylaxis (CAP). Additionally, new renal scars may still form at this age. One study evaluating the cessation of antibiotics in children at this age with minimal UTI and scarring history found VUR resolution in 19.6 %, UTI in 11.8 % and no new scar formation when followed for a mean of 3.7 years [303]. However, long-term studies on the outcomes of antibiotic cessation in the setting of persistent reflux are not available. Further concerns in prolonged observation include the need for ongoing radiologic imaging, which may result in emotional and financial costs to patients and families [304]. Additional concerns exist over the potential for DNA damage and malignancy due to ionizing radiation [305]. Modern equipment and techniques have lowered but not eliminated this risk [306–310].

Just prior to the onset of puberty, spontaneous resolution becomes even less likely. Debate exists regarding the need for surgical intervention in low-grade reflux that persists on approach to puberty [311]. Lenaghan et al. [15] found a 27 % rate of resolution after age 14 years. In fact, the risk of pyelonephritis and new renal scar formation is low in this population, and this may reason in favor of antibiotic cessation, even if reflux persists. Conversely, while VUR may have a lower incidence of sequelae in adolescence, many note the morbidity of VUR and reflux nephropathy in women who become pregnant. While it has not been conclusively established whether this morbidity relates to the ongoing presence of reflux or the already sustained renal insult, many opt to correct VUR in this cohort of girls, prior to their child-bearing years.

The management of persistent reflux into later childhood and adolescence remains controversial and varies with grade of reflux, laterality, presence of reflux nephropathy, occurrence of UTI while on or off CAP, patient gender as it relates to the potential for morbidity with the onset of sexual activity and with pregnancy later in life, and family preference. Several of these topics will be discussed in later sections.

Unlike childhood VUR, primary VUR and VUR detected in adulthood does not generally resolve with time [293], as the intramural distal ureter no longer elongates with growth [312].

With reflux of infected urine representing an important cause of acquired renal scar, the most immediate concern in patients with VUR is UTI prevention. Many treatment options exist, all aimed at reducing the incidence of UTI—specifically febrile UTI. These are broadly centered on medical management, which includes prophylactic antibiotics, prompt initiation of therapeutic antibiotics, and optimization of BBD, as well as surgical correction with endoscopic, open, and robotic techniques. Medical and surgical options for managing hypertension may also be considered. Most literature on VUR treatment and outcomes are described for pediatric populations; however, the same techniques are utilized in adults.

The association between BBD and VUR in childhood is well-known. Roughly 1/2–1/3 of children with BBD have VUR [410–413], and slightly greater than 1/2 of children with VUR have BBD [7]. The presence of BBD portends a greater risk of febrile UTI and a lower likelihood of spontaneous resolution of VUR [414]. BBD also undermines success following ureteral reimplant [415] and endoscopic injection [291].

The association between VUR and voiding dysfunction continues into adulthood, and it is unclear whether this voiding dysfunction represents a cause or effect of the VUR. In middle-aged adults with a history of childhood VUR, 40 % have abnormal urine flow curves [416]. Higher rates of abnormal flow curves are present in those who had previously undergone an operation for their VUR (55 % vs. 30 %), with interrupted or weak flow representing the most common abnormal findings (seen in 45 % of all patients). Stress and urge incontinence among women are also more common in this group (35 % vs. 16 % and 20 % vs. 11 %, respectively), as are UTIs. Urodynamic findings in adult women with a history of VUR further demonstrate urethral sphincter overactivity (in 70 %), decreased bladder sensitivity, and large capacity bladders [417].

AUA Guidelines on the management of childhood VUR recommend treatment if there is evidence of BBD [291]. This may include behavioral therapy and biofeedback, alpha-blockers, anticholinergic medications, and constipation management. In children, behavioral modification along with antibiotic prophylaxis can resolve VUR in 36.8 % and downgrade it in an additional 21.1 % [418]. The addition of anticholinergics can resolve VUR in up to 45 % [419]. VUR resolution with these methods yields a decrease in breakthrough UTI [410, 418]. Further, antibiotic prophylaxis, anticholinergic medication, biofeedback, and psychological counseling in various combinations may eliminate infection in 64 % and resolve VUR in 53 % [420].

In contrast, there is debate as to whether treating BBD affects rates of spontaneous resolution in adulthood [299, 421–423]. Despite its prevalence, no guidelines exist for assessing and managing BBD in adults with VUR. Practitioners should have a high index of suspicion for BBD when evaluating adult patients and should develop treatment strategies specifically aimed at BBD if it is detected.

In cases of VUR-related hypertension requiring extensive antihypertensive therapy, nephrectomy or partial nephrectomy of the scarred atrophic renal unit may be considered, as this may alleviate the renin–angiotensin–aldosterone mediated process. Tash et al. [105] demonstrated success of partial nephrectomy in treating select cases of renin-mediated hypertension in patients with reflux nephropathy and focal renal hypoplasia (i.e., Ask-Upmark kidney), which may represent a similar pathology. However, one must weigh the risks of further renal compromise in these patients already at risk for renal impairment. In this scenario, nephrectomy should be reserved only for patients with uncontrolled or malignant hypertension [138].