Individual Renal Function in Polycystic Kidney Disease

CLINICAL NUCLEAR MEDICINE Volume 26, Number 6, pp 518 524 2001, Lippincott Williams & Wilkins Individual Renal Function in Polycystic Kidney Disease A Follow-Up Study ANDREAS D. FOTOPOULOS, M.D.,* KOSTAS KATOPODIS, M.D., OLGA BALAFA, M.D., AFRODITI KATSARAKI, M.D., RIGAS KALAITZIDIS, M.D., AND KOSTAS C. SIAMOPOULOS, M.D. Purpose: This study was undertaken to determine individual renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Materials and Methods: The authors initially examined (study t1) 25 patients with ADPKD (12 female, 13 male; ages 18 to 68 years). The serum creatinine concentration and glomerular filtration rate, measured by Tc-99m DTPA, were 1.5 0.56 mg/dl and 65.7 31 ml minute -1 1.73 m 2, respectively. Thirteen patients had a follow-up study (t2) 2 years after their initial evaluations. Individual renal function was assessed on Tc-99m DMSA renal scans. Results: The mean ( SD) difference between left kidney DMSA (DMSA-L) and right kidney DMSA (DMSA-R) was 7.04 % 16.48%. In 20 patients (80%), the left kidney had a lower percentage contribution to the total renal function compared with the right kidney. When the results of the two studies were compared, deterioration in renal function was noted. In the t1 study, the mean serum creatinine concentration and glomerular filtration rate were 1.7 mg/dl and 67.02 ml minute -1 1.73 m 2 respectively, and in the t2 study these values were 2.01 mg/dl and 57.15 ml minute -1 1.73 m 2, respectively. No difference, however, was found in individual renal function in the two studies. Conclusions: In patients with ADPKD, the percentage contribution of each kidney to total renal function is not equal and remains stable during the progression of renal failure. Key Words: Autosomal Dominant Polycystic Kidney Disease, Glomerular Filtration Rate, Individual Renal Function, Tc-99m DMSA, Tc-99m DTPA. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (AD- PKD) is the most common hereditary renal disorder and one of the leading causes of progressive renal insufficiency, accounting for 8% to 10% of patients with Received for publication July 19, 2000. Revision accepted January 20, 2001. Reprint requests: Kostas C. Siamopoulos, M.Sc., M.D., F.R.S.H., Professor of Medicine/Nephrology, Department of Internal Medicine, Medical School, University of Ioannina, GR 451 10, Ioannina, Greece. E-mail: ksiamop@uoi.gr From the Departments of Nuclear Medicine,* Nephrology, and Statistics, University Hospital, University of Ioannina Medical School, Ioannina, Greece end-stage renal failure (1). It is a multisystem disorder that may occur at any time in life, including in utero (2,3), and is characterized by cyst formation in ductal organs, particularly the kidneys and the liver (4). It can be caused by mutation on three specific chromosomes. In approximately 85% of persons with ADPKD, the gene responsible is located on the short arm of chromosome 16 (PKD type 1) (5 9). The remaining cases are secondary to a mutation of DNA on chromosome 4 (PKD type 2) (10) and an unidentified chromosome locus (PKD type 3) (11). In adults older than 30 years and most persons with the PKD type 1 gene, the kidneys have many cysts (12). By the time the patient is 50 years old, the kidneys, particularly in men, can be enormous, expanding to 40 cm long and weighing 8 kg (13). Despite their enormous size, fewer than 5% of all nephrons appear to be involved in cyst growth and development within the polycystic kidney (14). Alterations in renal function and complications arise as a consequence of the growth of cysts (15). There is substantial variability in the onset of renal failure, although in most patients normal renal function is maintained until the fifth decade of life (12,16,17). Once renal failure is established, progression generally occurs in less than 10 years (18), with end-stage renal failure developing in 60% of affected persons by the time they are 60 years old (19,20). Although the incidence of renal failure is well documented, there is no information regarding the renal function of each kidney and the percentage contribution to the total glomerular filtration rate (GFR) during the progression of renal failure. This study was prompted by the observation that the function of the left kidney in some patients with AD- 518

No. 6 INDIVIDUAL RENAL FUNCTION IN ADPKD Y Fotopoulos et al 519 PKD is more compromised compared with that of the right. Our aim in this study was to determine the renal function of each kidney in patients with ADPKD and to evaluate the rate of renal function loss from each kidney with the progression of renal failure. Patients Materials and Methods We examined 25 patients with ADPKD (13 male, 12 female; mean age, 42.8 years; age range, 18 to 68 years). A positive hereditary history was evident in all patients. In each case, the diagnosis of polycystic disease was established by the attending nephrologist using standard investigations including renal ultrasound or computed tomography. In all patients the serum creatinine concentration was determined by the Jaffe kinetic method, adapted for an autoanalyzer (Olympus AU 600). The GFR was measured using a Tc-99m DTPA urinary clearance method. Finally, individual renal function was assessed on Tc-99m DMSA scans and using the geometric mean method. Thirteen patients had a follow-up study within 2 years (range, 23 to 25 months). These patients included 7 men, with a mean age 46.7 years (age range, 23 to 68 years). The serum creatinine concentration in the first study was (mean SD) 1.7 0.64 mg/dl (range, 1 to 3.5 mg/dl), and in the second study it was 2.01 1.66 mg/dl (range, 1 to 7.2 mg/dl). This study was approved by the local research ethics committee of the University Hospital of Ioannina, and all patients gave full informed consent. Assessment of Renal Function Each patient was brought to the nuclear medicine department at the University Hospital of Ioannina after an overnight fast on 2 consecutive days. On day 1, the GFR was measured. On day 2, Tc-99m DMSA imaging was performed. On day 1, the patient was asked to drink 600 ml fluid 30 minutes before the test to initiate diuresis. An intravenous line was placed in one arm with a dextroseand-water (5%) infusion at 125 ml/hour. Immediately before Tc-99m DTPA administration, the patient was asked to void. Two syringes containing 1 mci (37 MBq) Tc-99m DTPA were prepared. One was used as a standard and the other was injected intravenously. The syringes were weighed on an analytical balance before and after injection or dilution. Blood samples from the opposite arm were drawn into heparin-prepared tubes for the renal Tc-99m DTPA clearance study 2, 3, and 4 hours after Tc-99m DTPA injection. Urine output was also measured at 2, 3, and 4 hours. Duplicate plasma and urine samples and a diluted Tc-99m DTPA standard were counted in a gamma well counter (Packard Crystal II 5400 series). Determination of the Glomerular Filtration Rate The Tc-99m DTPA urinary clearance was calculated from a modification of the standard U V P photometry method. The final clearance (2 to 4 hours) was calculated as the average of the clearance at 2 to 3 hours and (3 to 4 hours using the following formula: U V2-3h/P2.5h U V3-4h/P3.5h GFR (1) 2 Where U urine (counts per minute/ml) V voided urine (ml) P midpoint plasma (counts per minute/ml) Renal Function On day 2, patients underwent Tc-99m DMSA imaging for investigation of renal disease and estimation of individual renal function. All patients were well hydrated before DMSA was administered. An intravenous injection of Tc-99m DMSA (3 mci; 111 MBq) was administered. Four hours later, the patients were scanned in the supine position using a large-fieldof-view gamma camera (Siemens SP 175, Erlangen, Germany; low-energy, parallel-hole collimator; 500 kcounts in a 256 256 matrix). Paired anterior and posterior images were used to calculate the geometric mean count for each kidney. The geometric mean value was calculated as the square root of the product of background-corrected anterior and posterior kidney counts. Statistical Analysis Statistical analyses were performed using the Student s paired t test for each group, and probability values less than 0.05 were considered significant. Regressions were calculated using one-way analysis of variance. The significance of correlations were determined from Pearson s rank-order coefficients. Results Overall Renal Function At the start of the study (t1), in the 25 patients with ADPKD (13 male, 12 female), the serum creatinine concentration (mean SD) was 1.5 0.56 mg/dl (range, 0.9 to 3.5 mg/dl), whereas their GFR, measured with Tc-99m DTPA urinary clearance, was 65.7 31 ml minute -1 1.73 m 2 (range, 10 to 129). Individual Renal Function Of the population of 25 patients, the mean value of left kidney percentage contribution was 46.66% 17.9% (SD), the right kidney percentage contribution was 53.7% 8.7% (SD) (P 0.043), and the mean difference between the left and right kidneys was 7.04% 16.48% (SD). In most patients (n 20; 80% of cases), the renal function of the right kidney was greater than that of left kidney, which was 43.2% 3.7% (SD), with a mean value ranging from 36% to 50%. In the remaining five patients (20%), left kidney function was greater than

520 CLINICAL NUCLEAR MEDICINE June 2001 Vol. 26 Fig. 1. The first study in patient 1, a 59-year-old woman with ADPKD. The GFR was 82 ml minute -1 1.73 m 2. A Tc-99m DMSA scan shows multiple focal defects in both kidneys. Differential renal function: left, 39%; right, 61%. right kidney function, with a mean value of 59.4% 7.02% (SD) and range of 53% to 68%. Long-Term Follow-Up Thirteen of the patients with ADPKD had a follow-up study (t2) within 2 years of the first study (range, 23 to 25 months). All patients (7 male, 6 female) were clinically Fig. 2. The second study in patient 1. Two years later, the GFR was 73 ml minute -1 1.73 m 2. The Tc-99m DMSA scan shows generalized decreased uptake and increased size of the multiple focal defects in both kidneys. Differential renal function: left, 41%; right, 59%. stable in the previous 6 months. Their serum creatinine concentrations in the t1 study (mean SD) was 1.7 0.64 mg/dl (range, 1 to 3.5), whereas their GFR was

No. 6 INDIVIDUAL RENAL FUNCTION IN ADPKD Y Fotopoulos et al 521 TABLE 1. Change of Renal Function Parameters DMSA n 13 Scr mg/dl GFR* ml min 1 1.73 m 2 L (%) R (%) t1 1.7 0.64 67.02 35.26 46.83 7.16 53.15 7.18 t2 2.01 1.86 57.15 32.12 45.69 6.68 54.3 6.68 Alteration % 1 18.3 2 14.8 2 2.45 1 2.16 P 0.05 0.05 NS NS * Rate of GFR loss (D t1 t2/year) 4.93ml min 1 1.73 m 2. GFR, glomerular filtration rate; Scr, serum creatinine. Fig. 3. The first study in patient 2, a 48-year-old man with AD- PKD. The GFR was 129 ml minute -1 1.73 m 2. The Tc-99m DMSA scan shows multiple focal defects in both kidneys. Differential renal function: left, 45%; right, 55%. Fig. 4. The second study in patient 2. Two years later, the GFR was 108.5 ml minute -1 1.73 m 2. The Tc-99m DMSA scan shows multiple focal defects and large hypoactive areas, especially at the external part of the right kidney and at the upper pole of the left, with deformation of the contour. Differential renal function: left, 46%; right, 54%.

522 CLINICAL NUCLEAR MEDICINE Fig. 5. The first study in patient 3, a 56-year-old man with ADPKD. The GFR was 56 ml minute-1 1.73 m2. The Tc-99m DMSA scan shows multiple focal defects, with contour deformity in both kidneys. Differential renal function: left, 47%; right, 53%. 67.02 35.26 ml minute-1 1.73 m2 (range, 10 to 129 ml minute-1 1.73 m2). Compared with the first study, the serum creatinine concentration increased in the t2 study (mean SD) to 2.01 1.66 mg/dl (range, 1.0 to 7.2) and GFR decreased June 2001 Vol. 26 Fig. 6. The second study in patient 3. Two years later, the GFR was 63 ml minute-1 1.73 m2. The Tc-99m DMSA scan shows a slight deterioration. Differential renal function: left, 45%; right, 55%. (mean SD) to 57.15 32 ml minute-1 1.73 m2 (range, 7.7 to 132 ml minute-1 1.73 m2). In most of the 13 patients (80%) in whom follow-up studies were performed at 2 years left kidney function was less than that of the right, with a mean percentage contribution of 42.2% 4.3% (SD) (range, 35% to 50%). In the three remaining patients (20%), left kidney function was greater than that of the right, with a mean

No. 6 INDIVIDUAL RENAL FUNCTION IN ADPKD Y Fotopoulos et al 523 percentage contribution of 57.0% 1.7% (SD) (range, 55% to 58%). By comparing the results of the two studies (t1 and t2) in the 13 patients with ADPKD, we can see that renal function deteriorates (Figs. 1 to 6). The mean plasma creatinine value was 1.7 mg/dl in the first study and 2.0 mg/dl in the second, whereas GFR was 67 ml minute -1 1.73 m 2 in the first study and 57.1 ml minute -1 1.73 m 2 in the second study. However, there was no difference in the percentage contribution of each kidney in the two studies. The mean percentage contribution value of the left kidney was similar in the two studies (46.8% in the first compared with 45.7% in the second study), and the mean differences between the left and right kidneys in the first and second studies were not statistically significant (6.3% versus 8.6%; Table 1). Discussion Because cysts are present at birth in patients with ADPKD (21,22), it might be thought that impairment of renal function should follow a progressive course to terminal renal failure, suggesting linearity of the decrease in GFR from birth to end-stage renal failure. However, most patients with PKD type 1 maintain normal renal function for a prolonged period. Although the age of onset of renal failure varies, it usually occurs at age 40 years and leads rapidly to end-stage renal failure within approximately 10 years (18). The rate of decline in GFR in patients with ADPKD who have progressive renal failure was reported in one study (23) as a mean GFR loss of 5.8 ml minute -1 year -1, which is similar to our findings of 4.93 ml minute -1 year -1. Accurate GFR measurement is essential in patients with ADPKD, in whom small changes in renal function are clinically important. In previous studies, we and other investigators compared the reproducibility of several methods of GFR measurement (24). The reproducibility of creatinine clearance measurement is generally not good compared with radioisotopic methods, presumably because the method depends closely on patient compliance to provide complete urine collections. Another drawback of the use of the creatinine clearance method is that GFR is overestimated, particularly in patients with compromised renal function. This is due in part to the variability in endogenous production and increased tubular secretion of creatinine. For these reasons, the creatinine clearance method is not suitable for accurate serial measurements of GFR. In this study, we choose to use the Tc-99m DTPA urinary clearance method because of previously demonstrated good correlation with inulin clearance (the accepted gold standard), especially in the lower range of GFR values (25 27). Individual renal function helps the physician to make a clinical assessment of therapy and will help determine whether the right or the left kidney should be removed if nephrectomy is considered. In the current study, the percentage contribution of each kidney to renal function was assessed in all patients using a gamma camera and geometric mean method, which is effectively independent of kidney depth and size. In this study, we found that despite a deterioration of renal function between the two measurements (in studies t1 and t2), there was no difference in individual renal function, suggesting that the rate of loss of renal function is similar for both kidneys. We also found that in patients with ADPKD, the contribution of each kidney to total renal function is not equal, and the right kidney proved to be better in most patients (in both studies, in 80% of cases). The reason for this is unclear. It may relate to differences in hemodynamics resulting from anatomic alterations within the kidneys as a consequence of cyst growth. Another theory is that this difference is genetically determined. Further research is needed to clarify this observation. We have shown that, in patients with ADPKD, the percentage contribution of each kidney to the total renal function is unequal, with the right kidney proving to be more functional. The rate of loss of renal function is similar for both kidneys. This knowledge of the individual function of each kidney in patients with ADPKD may prove clinically useful when nephrectomy is considered. References 1. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 29:332, 1993. 2. Pretorius DH, Lee ME, Manco-Johnson ML, et al: Diagnosis of autosomal dominant polycystic kidney disease in utero and in the young infant. J Ultrasound Med 6:249, 1987. 3. 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