1. Background
Renal transplant has been an effective treatment for end-stage renal disease, resulting in the improved quality of life and survival of patients (1). This treatment is more cost-effective than dialysis (2), and its prevalence is increasing among people. In patients undergoing renal transplantation, urine volume increases during the night (3). In healthy adults, nights are associated with a significant decrease in urine production and excretion of water and soluble substances (4). Nocturnal polyuria refers to the excessive excretion of urine at night. The normal range of nocturnal urine volume appears to be wide in large populations with a narrower age range. Overall, it has been established that nocturnal polyuria is a component of nocturia (5).
Normally, blood pressure shows a circadian rhythm, with higher levels during the day and lower levels at night. In healthy people, systolic and diastolic blood pressure usually reduces by approximately 10% at night (dipping). On the other hand, nondipping refers to the absence of blood pressure reduction at night. Overall, nondippers face more tissue damage, strokes, dementia, left ventricular hypertrophy, and microalbuminuria, compared to others (6-8).
Several studies have suggested that nondipping can prompt a decline in glomerular filtration rate (GFR) among patients with or without chronic renal diseases (9, 10). Renal transplant recipients often complain of an abnormal increase in urinary output at night, leading to sleep disorders and reduced efficiency during the day (11). Some studies have shown an inverse circadian rhythm in urine production after renal transplant (12-15). Moreover, some studies have introduced bladder dysfunction, renal denervation, psychological stress (16, 17), and nocturnal nondipping blood pressure as the etiological factors. However, findings are limited and the underlying pathophysiological mechanisms are not well-defined (11). In addition, more excretion of sodium and absorption in edema have been suggested at night.
According to some studies, although uncontrolled systemic hypertension is associated with poor survival and allograft outcomes of patients after renal transplant, nondipping systolic blood pressure at night is not recognized as an independent factor for deterioration of renal function after renal transplant (18-20). Therefore, we aimed to evaluate the prevalence of nocturia and nocturnal polyuria and to determine some of the associated factors in patients undergoing renal transplantation.
2. Methods
This cross sectional study included 128 renal transplant patients above 18 years, who were referred to nephrology clinics in 2016. Recipients who had undergone renal transplant at least 1 month ago and had a creatinine level below 2 mg/dL were included in the study. On the other hand, the exclusion criteria were as follows: 1, diabetes mellitus (DM) or diabetes insipidus (DI); 2, use of diuretics; 3, urinary tract infection or obstruction; 4, urinary catheterization or nephrostomy; and 5, clean intermittent catheterization (CIC).
The patients’ information, including demographics (eg, age and sex), dialysis duration before renal transplant, transplant duration, underlying cause of renal failure, immunosuppressive drugs, and peripheral edema, was collected. The patients were asked to collect 24-hour urine samples at home in 2 separate bottles at 2 intervals, ie, from wakeup time in the morning (after 1 micturition) until sleep time at night (working time; day bottle) and from sleep time at night until wakeup time in the morning (resting time; night bottle).
Since we aimed to assess the hemodynamic effects on urine volume, it was necessary to keep the circadian rhythm intact. We asked the patients to collect the urine samples in the day bottle since their wakeup time in the morning until night. They were asked to go to bed 1 hour before the usual time and collect their urine in the day bottle at the time of sleep. They were also asked to collect their urine in the night bottle; the first urine sample in the morning after waking up was considered as part of the nocturnal interval.
Urine volume, creatinine, sodium, osmolarity, and creatinine clearance were measured at resting and working time. Nocturia was defined as voiding more than twice at night, while nocturnal polyuria was defined as working-to-resting urine volume ratio below 2. Monitoring of ambulatory 24-hour blood pressure was performed simultaneously with measurements of blood pressure every 0.5 hour. The findings, including the mean arterial pressure (MAP) during the day and night, were also evaluated. Normal blood pressure dipping at night was defined as ΔMAP above 10%. ΔMAP was calculated as follows (11):
Equation 1.
Patients were classified into 3 categories, based on the nocturnal decline in MAP: dippers (ΔMAP > 10%), nondippers (0 ≤ ΔMAP ≤ 10%), and reverse dippers (increased nocturnal MAP). The serum level of cyclosporine was also measured. Dimensions of the transplanted kidney, postvoid residual (PVR) urine, and prostate size were evaluated by a radiologist, using ultrasonography (model Aplio300; Toshiba). PVR below 50 cc (normal PVR) is suggestive of sufficient emptying of the bladder (21). Overall, the normal kidney size is 10 - 12 cm in length and 4 - 5 cm in width (22). Also, the normal size of prostate is less than 25 - 30 mL (23).
Data were entered into SPSS version 19 and analyzed using descriptive statistics (mean and ratio), Chi square test, student’s t test, and logistic regression analysis.
3. Results
Overall, 14 out of 128 patients were excluded due to lack of cooperation. Among 114 patients, 66 (57.9%) were male and 48 (42.1%) were female. The mean age of the participants was 43.16 ± 12.43 years (18 - 78 years). Based on the findings, 81 (71.1%) patients had nocturia, and 77 (67.5%) patients had nocturnal polyuria. The analyses showed that patients with nocturia were significantly older than those without nocturia (46.59 ± 11.06 vs. 37.48 ± 13.20; P = 0.003, OR, 1.05). However, the difference in age between patients with and without nocturnal polyuria was not significant (45.38 ± 11.16 vs. 41.32 ± 14.42; P = 0.16).
Comparison of gender among patients with and without nocturia and nocturnal polyuria was not significant. The transplant duration and dialysis duration before renal transplant were not significantly different among patients with and without nocturia; similar findings were reported for nocturnal polyuria, underlying diseases, and edema. As the findings revealed, 92 patients were using cyclosporine, 14 patients were using tacrolimus, and 8 patients were on noncalcineurin inhibitors. Table 1 demonstrates the background information of the patients.
Table 1.The Demographic Information of the Patients
| Nocturia | Nocturnal Polyuria | ||||||
|---|---|---|---|---|---|---|---|
| Yes | No | P Value | Yes | No | P Value | ||
| Age | 11.06 ± 46.59 | 13.20 ± 37.48 | 0.003 | 11.16 ± 45.38 | 14.42 ± 41.62 | 0.160 | |
| Gender | Male | 46 | 20 | 0.700 | 43 | 23 | 0.520 |
| Female | 35 | 13 | 34 | 14 | |||
| Transplant duration (months) | 51.29 ± 62.72 | 35.34 ± 52.88 | 0.170 | 58.03 ± 50.03 | 65.00 ± 41.73 | 0.970 | |
| Dialysis duration (months) | 19.37 ± 20.94 | 14.20 ± 20.42 | 0.190 | 19.63 ± 21.32 | 14.14 ± 19.42 | 0.17 | |
| Underlying disease | Hypertension | 30 | 10 | 0.600 | 28 | 12 | 0.530 |
| Glomerulonephritis | 6 | 5 | 7 | 4 | |||
| Unknown | 28 | 12 | 28 | 12 | |||
| Unknown | 2 | 2 | 1 | 3 | |||
| Autosomal dominant polycystic kidney disease | 6 | 3 | 5 | 4 | |||
| Urologic disease | 8 | 1 | 7 | 2 | |||
| Hereditary disease | 1 | 0 | 1 | 0 | |||
| Edema | 2 | 1 | 0.860 | 2 | 1 | 0.970 | |
| Immunosuppressive drug | Tacrolimus | 7 | 7 | 0.17 | 6 | 8 | 0.06 |
| Noncalcineurin inhibitor | 6 | 2 | 7 | 1 | |||
| Cyclosporine | 68 | 24 | 64 | 28 | |||
As shown in Table 2, there was no significant difference in the size of the transplanted kidney, prostate size, PVR, serum cyclosporine level, and MAP (day and night) between patients with and without nocturia or nocturnal polyuria. According to the findings, 63 (55.3%) patients were nondippers, 38 (33.3%) patients were reverse dippers, and 13 (11.4%) patients were dippers. In patients with nocturia, a nondipping pattern of blood pressure, followed by reverse dipping, was more common than dipping, as in patients with nocturnal polyuria (P < 0.001).
Table 2.The Results of Analyses Among Patients
| Nocturia | Nocturnal polyuria | ||||||
|---|---|---|---|---|---|---|---|
| Yes | No | P Value | Yes | No | P Value | ||
| Size of transplanted kidney (mm) | Normal | 69 | 24 | 0.11 | 66 | 27 | 0.25 |
| Small | 2 | 0 | 1 | 1 | |||
| Large | 10 | 9 | 10 | 9 | |||
| Size of prostate (mm) | Normal | 43 | 16 | 0.18 | 40 | 19 | 0.32 |
| Large | 4 | 3 | 4 | 4 | |||
| Residual urine (mL) | < 50 cc | 77 | 30 | 0.40 | 73 | 34 | 0.54 |
| 50 - 200 cc | 4 | 3 | 4 | 3 | |||
| > 200 cc | 0 | 0 | 0 | 0 | |||
| Serum cyclosporine level (C0) | < 100 | 11 | 10 | 0.07 | 11 | 10 | 0.11 |
| 100 - 400 | 55 | 15 | 52 | 18 | |||
| > 400 | 1 | 0 | 1 | 0 | |||
| Mean arterial pressure (mmHg) | Day | 90.97 ± 8.74 | 90.16 ± 9.80 | 0.73 | 90.69 ± 8.93 | 90.89 ± 9.29 | 0.96 |
| Night | 89.40 ± 10.43 | 84.76 ± 7.79 | 0.21 | 89.68 ± 10.46 | 84.60 ± 7.77 | 0.11 | |
| Nocturnal blood pressure dipping | Dipper | 4 | 9 | < 0.001 | 1 | 12 | < 0.001 |
| Nondipper | 44 | 19 | 44 | 19 | |||
| Reverse dipper | 33 | 5 | 32 | 6 | |||
| Urine Na (meq/L) | Activity | 60.67 | 72.60 | 0.06 | 58.16 | 76.54 | < 0.001 |
| Rest | 48.30 | 29.63 | < 0.001 | 47.32 | 33.70 | < 0.001 | |
| Urine osmolality (mosm/kg H2O) | Activity | 409.25 | 393.93 | 0.59 | 416.88 | 397.72 | 0.18 |
| Rest | 376.91 | 403.03 | 0.31 | 386.75 | 397.72 | 0.77 | |
| Creatinine clearance (mL/min) | Activity | 84.93 | 98.2 | < 0.001 | 84.90 | 96.36 | < 0.001 |
| Rest | 61.18 | 51.12 | 0.04 | 62.14 | 50.21 | < 0.001 | |
Urine sodium excretion and creatinine clearance at rest were significantly higher in patients with nocturia and nocturnal polyuria, compared to patients without these conditions (P < 0.001). The odds ratios (OR) of urine sodium at rest for nocturia and nocturnal polyuria were 1.06 and 1.03, respectively. Moreover, ORs of creatinine clearance at rest for nocturia and nocturnal polyuria were 1.01 and 1.02, respectively, while the OR of creatinine clearance for nocturia and nocturnal polyuria were 0.97 and 0.98, respectively; however, urine osmolarity showed no significant differences. As indicated in Table 3, different immunosuppressive drugs could not affect nocturnal blood pressure dipping.
Table 3.The Immunosuppressive Drugs and Nocturnal Blood Pressure Dipping
| Dipper | Nondipper | Reverse dipper | P Value | ||
|---|---|---|---|---|---|
| Immunosuppressive drugs | Tacrolimus | 10 | 53 | 29 | 0.48 |
| Noncalcineurin | 3 | 6 | 5 | ||
| Cyclosporine | 0 | 4 | 4 |
4. Discussion
Nocturia and nocturnal polyuria are symptoms of a variety of pathological conditions, including DM (24), cardiovascular diseases (25), renal diseases (26, 27), and enuresis (28). It seems that different pathological mechanisms are responsible for abnormal circadian rhythm in diuresis (11). In children with enuresis, lack of a nocturnal increase in arginine vasopressin (AVP) level, disorders in hormones regulating renal sodium (aldosterone and angiotensin II), and overproduction of prostaglandin E2 (PGE2) have been reported (28-31). The overnight decrease in blood pressure leads to an increase in AVP (32). Therefore, increased blood pressure, even an overnight increase in MAP, may inhibit AVP release from the hypothalamus and result in higher levels of urination during the night (11).
Natriuresis and atrial natriuretic peptide disorders are found in renal disorders (27). The present study showed that the prevalence of nocturia, not nocturnal polyuria, increases with aging (P = 0.003 and P = 0.16, respectively). This finding is incompatible with a previous study, which showed that the increased prevalence of nocturia by aging is not due to increased urine volume, but other factors such as bladder compliance. In the mentioned study, increased urine volume and nocturnal polyuria increased the prevalence of nocturia by aging.
The observed discrepancy between the mentioned study and the present research may be attributed to differences in the study population and sampling methods. In our study, diabetic patients were not recruited, whereas in the mentioned study, diabetic patients were also evaluated. However, in consistence with the previous study, nocturia and nocturnal polyuria were not significantly correlated with gender and renal transplant duration (33).
The correlation of nocturia and nocturnal polyuria with average dialysis duration before renal transplant was not significant in our patients (P = 0.19 and P = 97, respectively). This finding was incompatible with a previous study, indicating a significantly longer dialysis duration before transplant in patients with nocturia and nocturnal polyuria (33). This incompatibility is probably due to differences in the average dialysis duration before renal transplant (5 years in the mentioned study vs. 17 months in the present study). Patients waiting for renal transplant, who undergo dialysis, often have decreased urine output and lower urinary tract dysfunctions (34), such as urinary frequency, nocturia, and low bladder compliance. Since patients in the mentioned study had a longer dialysis period before transplant than those in the present study, lower bladder compliance and dysfunction were reported; our findings are consistent with this study.
Regarding the underlying diseases, our patients were mostly in the categories of hypertension (n, 40; 35.1%) and unknown origin (n, 40; 35.1%). The prevalence of underlying diseases was not significantly different in patients with nocturia and polyuria, which can be due to the exclusion of patients with underlying diseases influencing polyuria and nocturia, such as DM and DI. Nevertheless, a previous study stated that DM is a risk factor for polyuria and nocturnal polyuria (32). The findings can be also related to the control of underlying diseases before renal transplant.
Since most of our patients had no edema (111 out of 114 patients), peripheral edema was not correlated with nocturnal polyuria and nocturia (P = 0.86 and P = 0.97, respectively). Moreover, nocturia and nocturnal polyuria were not significantly correlated with the transplanted kidney size and prostate size. A previous study, performed on 30 500 men for prostate, lung, and colorectal cancer screening, concluded that the posterior surface of the prostate on digital rectal examination (DRE) was significantly correlated with nocturia on multiple analyses (35). The difference between the present and latter studies may be due to the use of ultrasonography for evaluating the prostate size in our study, which is more accurate than DRE.
Since patients with nocturia and nocturnal polyuria had a normal PVR (< 50 mL), the correlation of nocturia and nocturnal polyuria with PVR was not significant. In the current study, no level of cyclosporine led to an increase in nocturia or nocturnal polyuria. Some studies have evaluated the impact of immunosuppressive drugs on overnight dipping, showing no significant difference between cyclosporine and tacrolimus in dipping (11) or between sirolimus and cyclosporine in overnight dipping (36).
The day and night MAPs were not significantly different among patients with and without nocturia or nocturnal polyuria. In a previous study, daytime MAP was similar among the patients, ie, patients with transplant duration less than 12 weeks, patients with transplant duration more than 52 weeks, and controls. However, night MAP was significantly higher in patients with transplant duration less than 12 weeks in comparison with the control group (11). The discrepancy with the present study is probably related to the inclusion of a control group in the mentioned study, while no control group was recruited in our study.
In our patients with nocturia and nocturnal polyuria, the number of nondippers and reverse dippers was significantly higher than dippers (P < 0.001; OR, 1.05 in nocturia; OR, 1.06 in nocturnal polyuria). Overnight blood pressure nondipping was associated with decreased day-to-night urine volume ratio in renal transplant recipients. This finding is suggestive of rhythmic disorders in blood pressure among transplant recipients. Previous studies have also shown the effect of overnight hypertension on overnight micturition. Moreover, the following observations were reported: a significant decrease in day-to-night urine volume ratio, a significant increase in night MAP, an insignificant increase in day MAP, abnormal circadian rhythms, and disorders in the 24-hour blood pressure profile with a nondipping pattern (11, 32, 36-39).
In the present study, patients with nocturia had a higher level of overnight urine sodium, compared to patients without nocturia; the same finding was reported in patients with nocturnal polyuria (P = 0.001). Day and night urine osmolarity was not significantly different among patients with and without nocturia, similar to nocturnal polyuria. In a previous study, urine osmolality in patients with transplant duration < 12 weeks decreased at night, while in patients with transplant duration > 52 weeks, a slight increase in overnight urine osmolality was observed; however, there was no significant correlation with the average urine osmolality.
There was no significant difference between the 2 groups in terms of total sodium excretion. Since sodium is the most important determinant of osmolarity, the insignificant difference in osmolarity and the significant difference in urine sodium may be justified by the total and overnight fluid intake and increased urine volume due to water diuresis, lower osmolarity, or solute diuresis. The mentioned study showed an insignificant correlation between 24-hour fluid intake and overnight urine osmolality; however, the present study did not evaluate fluid intake volume and its correlation with urine volume and osmolarity (11).
In another study, patients with nocturnal polyuria had more overnight water intake and sodium clearance, while they showed lower overnight osmolarity in comparison with patients without polyuria (40). It should be noted that this study was not conducted on renal transplant recipients. In the present study, we found that patients with nocturia and nocturnal polyuria had more creatinine clearance at resting time (P = 0.04 and P < 0.001, respectively) and less creatinine clearance at working time, compared to patients without nocturia or nocturnal polyuria (P < 0.001). This finding may be due to differences in the position of the transplanted kidney and its blood supply, which can increase during rest time and lead to higher creatinine clearance.
4.1. Conclusion
Overall, nocturia and nocturnal polyuria are common complaints of renal transplant recipients. In the present study, nocturia increased with aging, while nocturnal polyuria did not, which can be suggestive of factors other than increased urine volume (regardless of underlying diseases such as poor DM control), leading to polyuria. Nocturia and nocturnal polyuria increased with the abnormal circadian rhythm of blood pressure. Therefore, most renal transplant recipients with nocturia or nocturnal polyuria had nondipping patterns, followed by reverse dipping patterns of blood pressure. Moreover, solute diuresis in renal transplant recipients led to the increased prevalence of nocturia and nocturnal polyuria. Whether water diuresis leads to an increase in urine volume or not, total and nighttime fluid intake should be measured in these patients. Since nondipping blood pressure is associated with more tissue damage and poor renal outcomes (6-8, 38), control of hypertension and changes in the time of antihypertensive drug administration (for improving nocturnal blood pressure dipping) may prevent the adverse effects of nondipping patterns, improve the renal outcomes, and decrease tissue damage.
