Plasma renin activity: An early marker of progressive renal disease in posterior urethral valves.

INTRODUCTION: A significant number of children with posterior urethral valves (PUV) develop chronic renal failure (CRF) due to activation of the renin angiotensin system (RAS). We investigated the role of plasma renin activity (PRA) in these cases and sought to establish a relationship between the accepted criteria of renal damage and PRA. AIMS AND
OBJECTIVES: The aim of this study is to establish the relationship between PRA and CRF.
MATERIALS AND METHODS: The records of 250 patients with PUV were reviewed. Multiple linear regression analysis was used to assess correlations between PRA, grade of reflux, presence of scars and raised creatinine and decrease in glomerular filtration rates (GFR). A P < 0.5 was considered as significant.
RESULTS: A total of 58 patients were included. Their mean age was 16 years, range 5.3-24.2 years, mean follow-up period was 12.6 ± 3.6 years. At diagnosis, 22/58 (38%) patients were in CRF and 36/58 (62%) patients had normal renal function (RF). The mean PRA after treatment was higher in those who developed CRF than in those with normal RF (12.6 ± 10.2 vs. 34.6 ± 14.2 ng/ml/24 h, P = 0.02). Mean GFR at 1 year of age were 48 ± 9.8 ml/min/1.73 m(2) and 86 ± 12.5 ml/min/1.73 m(2) respectively (P = 0.005). PRA correlated negatively with GFR, t = -2.816. CONFIDENCE INTERVAL: P = 0. 007. In the temporal plot over a period of 14 years, a rise in PRA preceded the fall in GFR in patients who developed CRF.
CONCLUSIONS: This study shows that RAS is activated earlier in kidneys susceptible to damage. PRA could be investigated as a marker for the early detection and prevention of ongoing renal damage.

INTRODUCTION

Posterior urethral valves (PUV) are the most common cause of obstructive uropathy, which leads to renal failure in childhood.[1] PUV represents a disease spectrum with varying severity and has profound effects on the bladder as well as the upper tracts. Though the short-term outcome for boys with PUV is presently very good, long-term prognosis is still far from satisfactory. The incidence of end stage renal disease (ESRD) in valve patients varies from 24% to 33% depending upon the duration of follow-up.[123] Various factors have been reviewed, which can help in counseling parents as well as guiding treatment.[4] Since long-term renal deterioration is common in PUV patients, early identification of detrimental factors can help in guiding therapy. Emerging evidence has highlighted the pivotal role of the renin angiotensin system (RAS) as a mediator of renal injury and interstitial fibrosis in other renal diseases.[56] Plasma renin activity (PRA) as an indicator of activation of the RAS has not been studied in patients with PUV. In this prospective study, we serially measured PRA and sought to establish the relationship between accepted criteria of renal damage and PRA through a post-hoc analysis. This was a continuation of the study already conducted by the senior author and published previously.[7]

MATERIALS AND METHODS

Out of the 250 patients of PUV registered and followed prospectively at our pediatric urology clinic between January 1998 and December 2012, those satisfying the following inclusion criteria were included in this study. A post-hoc analysis was performed to obtain the results after obtaining clearance from the institutional ethics committee. The inclusion criteria were:

Follow-up for at least 5 years after valve fulguration.

Availability of serial PRA levels (at least at 6 monthly intervals).

Exclusion criteria:

Parents or patients refusing consent.

Incomplete data

History of any antihypertensive use.

Abnormal bladder function on urodynamic studies.

A total of 58 patients fulfilled these criteria and were included in the analysis. Those with abnormal bladder dynamics were excluded because this may have affected the results. All these cases were managed according to the step ladder protocol developed and reported previously by the senior author and involved direct valve fulguration with cold knife in stable cases while in unstable cases initial catheterization was done and in those stabilizing on catheter valve fulguration was done, in those remaining unstable after 48 h of catheterization high diversion as bilateral ureterostomy was done. Vesicostomy was made in those cases where small cystoscopes were not available for valve fulguration.[48] Abnormal bladder dynamics was defined as the presence of very high detrusor pressure, high uninhibited detrusor pressure and very poor compliance. The records of patients were reviewed regarding the time of valve fulguration, adequacy of fulguration on micturating cystourethrogram (MCU) and serum creatinine. Renal scars were studied using Tc99m dimercaptosuccinic acid scans. A grade of reflux was recorded by MCU according to the International classification.[9] Split renal function (RF) and glomerular filtration rates (GFR) were measured by diethylenetriaminepentaacetic acid scans (multiple sampling method calculated each time using venous blood samples obtained at 60, 90, 150 and 180 min after). Percentage change in GFR was calculated by the formula adopted by Smellie et al.[10] PRA was measured by radio immunoassay using commercially available kit SB REN-2 (DiaSorin, Stillwater, Minnesota, USA), before and after valve fulguration (normal PRA values were: 1-12 months = 4-8 ng/ml/h; 1-3 years = 1-9 ng/ml/h; 3-6 years = 1-5 ng/ml/h; 6-15 = 1.4-2.6 ng/ml/h; 15-18 years ≤ 4.3 ng/ml/h).[7]

Patients were classified as those with chronic renal failure (CRF) and those without CRF at the last follow-up. The GFR, creatinine and PRA values of these cases were then compared data were reported as a mean standard deviation. Statistical comparisons between groups means were carried out by the unpaired Student t-test while proportions were compared by means of the Yates corrected Chi-square test. Multiple linear regression analysis was used to assess the correlations between PRA, such as grade of reflux, the presence of scars and raised creatinine and decrease in GFR. A P < 0.5 was considered as significant. All statistical analysis was performed using the StataCorp. 2009. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP.

RESULTS

During the analysis, 58 patients were included in the study. The age at valve fulguration in these cases ranged from 2 months to 6 years. Their mean age at last follow-up was 16 years (range: 5.3-24.2 years), with a mean follow-up period of 12.6 ± 3.6 years. At diagnosis, 32 patients presented with unilateral or bilateral (21) high-grade vesicoureteral reflux (VUR), 18 had low grades of VUR as grades 1 or 2 while eight had no documented reflux. The initial treatment consisted of valve fulguration in 49/58 (84.4%) patients, vesicostomy in 5/58 (9%) and ureterostomy in 4/58 (9%). Of the 49 patients, initially treated with valve fulguration, 14/49 (28.5%) had presented with azotemia and 35/49 (71.4%) had normal RF. All patients who underwent ureterostomy had severe azotemia.

Mean serum creatinine, PRA and GFR in all patients at follow-up were 1.2 ± 0.8 mg/dl, 16.3 ± 14.6 ng/ml/24 h and 69 ml/min/1.73 m2/body surface area, respectively. At the time of last follow-up on this study, 22/58 (38%) patients were in CRF (GFR <80 ml/min/1.73 m2) and 36/58 (62%) patients had normal RF. Out of these 22, two were those who had azotemia at presentation and subsequently continued to have renal failure, 17/49 with primary valve fulguration and 3/5 with vesicostomy were those who were initially stable and subsequently developed CRF at last follow-up. While out of the four cases that presented with azotemia and underwent bilateral ureterostomy, azotemia resolved in two and renal failure got established in remaining two in last follow-up.

In boys who subsequently developed CRF, the mean PRA values even after initial treatment were higher than in those who did not develop CRF (12.6 ± 10.2 vs. 34.6 ± 14.2 ng/ml/24 h, P = 0.02); however, serum creatinine values were not discriminatory between those who subsequently developed CRF and those who did not (2.1 ± 0.7 mg/dl vs. 1.8 ± 0.3 mg/dl, P = 0.05) [Table 1]. The mean GFR at 1 year of age was 48 ± 9.8 ml/min/1.73 m2 in the former and 86 ± 12.5 ml/min/1.73 m2 in the latter, (P = 0.005). In a multilogistic regression analysis of the relationship of PRA and creatinine with GFR, only PRA was found to negatively correlate with GFR, t = –2.816, confidence interval: P = 0.007 [Table 2 and Figure 1]. Serum creatinine however did not correlate with the fall in GFR. The rise of PRA occurred prior to fall in GFR [Figure 2]. This gap in the duration between the rise of PRA and fall in GFR was statistically significant.

Table 1

Mean plasma rennin activity and glomerular filtration rate in patients with and without renal failure

Table 2

Multilogistic regression analysis between plasma rennin activity and creatinine as predictors of fall in glomerular filtration rate

Figure 1

Temporal relationship between plasma rennin activity, glomerular filtration rate (GFR) and creatinine over a period of 12 years in patients who developed renal failure, N = 22/58 (38%). Yellow line, blue line and red line represent plasma rennin activity, GFR and creatinine respectively. Note-in the middle part of the figure there is a rise in the value of plasma rennin activity though the values of creatinine and GFR have remained stable suggestive high sensitivity of plasma rennin activity

Figure 2

Scatter plot of plasma rennin activity and glomerular filtration rate showing negative correlation

DISCUSSION

PUV are the most common cause of obstructive uropathy in the pediatric age group, which leads to renal failure.[1] The incidence of ESRD in valve patients varies from 24% to 33% depending on the duration of follow-up.[23] The age at renal failure has been variously reported to a range from 6 months to 14 years in various studies.[211] This implies that long-term renal deterioration is common in PUV patients and depends upon many factors. The challenge in the management of these patients would therefore lie in early identification of patients at risk and instituting therapy, which could retard the pace of progressive renal deterioration. From time to time several prognostic criteria such as, age at presentation, GFR, serum creatinine, presence or absence of reflux and renal scars have been recognized as predictors of renal damage.[4] These currently accepted criteria enable detection of renal damage only when the disease is advanced. In the present analysis of 58 patients with PUV, mean PRA was high in all but four patients. Most of patients with a GFR of 80-ml/min/1.73 m2 at 1 year of age had normal RF at the end of the study. In the multilogistic regression analysis of independent variables like PRA and serum creatinine with dependent variable GFR, only PRA was found to correlate with GFR [Table 1].

The prognostic potential of PRA is further strengthened by the interpretation of plot between PRA, GFR and creatinine. It is clear from the pilot that the rise in PRA occurred much before GFR began to fall. The rise in PRA proceeds the fall in GFR by a significant duration. This was statistically significant. The deterioration of RF is known to occur at prepubertal period due to many factors.[12] It has been demonstrated that there is tubulointerstitial damage in congenital uropathies.[13] In such patients activation of RAS has been documented, of which PRA is one such manifestation.[14] Clinical and experimental evidence accumulating over the last decade convincingly suggests that RAS is a key player in the complex mechanisms of CRF.[1516] Renin is released from juxtaglomerular cells, which cleaves angiotensinogen, produced in the liver to generate Angiotensin I (ANG I). ANG I is converted by the angiotensin-converting enzyme into the active substance Angiotensin II (ANG II). Although, hemodynamic effects of ANG II certainly contribute to renal damage.[17] This vasopeptide is a multifarious cytokine engaged in many non-hemodynamic processes as well. These include profibrogenic actions and inflammation, through the induction of transforming growth factor-β1 (TGF-β1), an important profibrogenic mediator leading to tubulointerstitial fibrosis.[18] Tubulointerstitial damage is known to occur in the kidneys of patients with PUV.[2] This notion is supported by the experimental evidence that local RAS is activated and contributes to tubulointerstitial scarring in obstructive uropathy in remnant kidney models.[19] Animal experiments suggest that some of these pathophysiological effects may be transduced by AT2 receptors.[20] Thus, there is convincing evidence that RAS plays a central role in the progression of chronic renal diseases. Our data provide evidence that there is ongoing renal damage in patients with PUV even after valve fulguration. The currently accepted criteria of renal damage such as grade of reflux, fall in GFR, scarring and raised creatinine are variable and may not be consistently present in all cases with RF deterioration. It is therefore important to identify a reliable marker, which is consistently elevated even at the onset of early renal damage. PRA is one such marker that reflects the beginning of RAS activation and thus early recognition of children with ongoing renal damage.[21] Fall in GFR is currently accepted to be the most sensitive marker of early renal parenchymal damage. In our study of 58 patients with PUV, the fall in GFR was preceded by a rise in PRA by a significant interval, implying that RAS is activated much earlier than the fall in GFR was evident. It is hoped that this report should form the basis for further studies on the role of RAS, both, in the early detection and prevention of ongoing renal damage.