Kidney volume and function in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease characterized by the progressive enlargement of innumerable renal cysts that lead to the deterioration of kidney function [1‐3]. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study showed that baseline total kidney volume (TKV) predicted the subsequent rate of an increase in volume, independently of age [4]. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function.

In a more recent study on CRISP participants, height-adjusted TKV (ht-TKV) predicted the risk of developing renal insufficiency in ADPKD patients within 8 years of follow-up [5]. The reason for adopting ht-TKV as an adjusted TKV marker in this study was to minimize the differences in adjusted TKV values between men and women. Other adjusted TKV markers, such as body surface-adjusted TKV (bs-TKV) or log-converted TKV (log-TKV), were compared from the standpoint of minimizing the differences between men and women. It remains unclear which adjusted TKV marker correlates best with renal function.

On the other hand, the results from three recent prospective clinical trials examining the effect of mammalian target of rapamycin inhibitors on disease progression of ADPKD have not demonstrated an association between changes in TKV and glomerular filtration rate (GFR) [6‐8]. These studies might have used too short a period for examining the relationship between TKV and functional changes.

If TKV correlates with kidney function, it will be a useful clinical marker of renal function since (1) it can be measured reliably, and (2) it changes by a measurable amount during a relatively short period of time (mean % increase of TKV is 5–6 % per year) [9]. In contrast, kidney function, measured by estimated GFR (eGFR), decreases at a slow rate of 0–3 ml/min/1.73 m² per year depending on the chronic kidney disease (CKD) stage [10]. Taking the measurement variation of eGFR into consideration, it is difficult to detect a small change as significant, especially during early CKD stages when a relatively small amount of eGFR decreases from a relatively large baseline eGFR.

For the above reasons, we reappraised the relationship between kidney volume and kidney function (using eGFR). If a significant relationship between two parameters was confirmed, the characteristics of these parameters and their changes (slopes) in relation to age and CKD stage were examined.

All patients fulfilled Ravine’s diagnostic criteria of ADPKD. One hundred and eighty-eight patients with ADPKD gave informed consent to take part in an observational clinical study protocol measuring TKV once a year with simultaneous collection of 24-h urine for determination of creatinine clearance (Ccr) and urinary protein excretion between April 2007 and July 2012. Patients with end-stage renal disease (ESRD) underwent TKV measurement only. Of 188 patients, 70 underwent TKV measurement three times or more. Two patients who received laparoscopic cyst fenestration, one patient with a ureteral stone with hydronephrosis during the study period, and three patients with baseline ESRD were excluded from analysis.

Serum creatinine was measured enzymatically. Kidney function was estimated with Ccr using 24-h urine, reciprocal creatinine and eGFR. eGFR was calculated using the following formula—eGFR (male) = 194 × Cr^−1.094 × Age^−0.287, and eGFR (female) = eGFR (male) × 0.739. This equation is a Japanese coefficient of the modified Isotope Dilution Mass Spectrometry−Modification of Diet in Renal Disease (IDMS–MDRD) Study [11]. The staging of kidney function is based on the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for CKD [12] using the final eGFR measurement.

TKV was measured by high-resolution magnetic resonance imaging (MRI) using a volumetric measurement of cross-sectional imaging, as described in the report from the CRISP study [13]. Gadolinium enhancement was not used for safety reasons. TKV was adjusted by height (ht-TKV, ml/m), body surface area (bs-TKV, ml/m²) and log-converted form (log-TKV, log[ml]). Kidney volume was measured by one radiologist (KK). Intrareader reliability was extremely high—the correlation coefficient was 0.999 for ten different single kidney volume measurements at different times when blind to first measurement. The mean of the % difference between two measurements was 0.29 ± 3.28 (SD) %.

Twenty-four-hour urinary protein excretion was expressed as the mean value of several measurements for each patient. The slopes of TKV, adjusted TKV parameters and kidney function parameters were calculated using linear regression analysis for each patient. %TKV was calculated with baseline TKV as 100 %.

The study protocol was approved by an institutional review board (09-56), and the study was conducted in accordance with the guidelines of the Declaration of Helsinki. All participants gave written informed consent to use their clinical data for medical research.

Between April 2007 and July 2012, 188 patients with ADPKD attending our clinic were followed annually by measuring TKV with MRI and 24-h urine collection. Among them, 70 patients repeated MRI and 24-h urine measurements three times or more. Six patients with a medical history affecting kidney volume, such as laparoscopic fenestration and baseline ESRD, were excluded from the study, leaving 64 patients for analysis (67 % were female).

Four of the 64 patients had ESRD and one died of cerebral hemorrhage during this observation period. Baseline characteristics and the annual change rate (slope) of kidney function and volume are shown in Table 1. Mean slope of %TKV and eGFR were 5.9 % per year and −1.0 ml/min/1.73 m² per year, respectively.

The present study confirmed the significant relationship between TKV and kidney function, which was reported by CRISP studies [4, 5, 14‐16]. Among adjusted TKV parameters, log-TKV correlated with eGFR most significantly. As the CRISP study showed that TKV increased exponentially and GFR decreased linearly [4], it is reasonable that log-TKV correlates with kidney function better than the other adjusted TKV parameters [14].

Final eGFR but not baseline eGFR correlated with the eGFR slope. This observation is in agreement with our previous report [10], in which the eGFR slope had no correlation with baseline eGFR. The kidney function remains well preserved for many years but decreases rapidly at a later stage [1, 17]. This characteristic profile of renal function progression is explained by a compensatory adjustment for the loss of GFR. Compensatory adjustments make the decline in GFR slow or close to zero until certain stages [1]. GFR is maintained within the normal range despite decreased renal plasma flow in children and young adult patients with ADPKD [18‐20]. In early stages, the decrease in renal plasma flow due to structural distortion in ADPKD is partially compensated for by an increased glomerular filtration fraction to renal plasma flow, but these adaptations eventually prove inadequate and kidney function starts to decline at a faster rate [21]. Those observations and hyperfiltration hypothesis are collectively in accordance with the present finding that the eGFR slope becomes more negative as eGFR decreases (Table 2).

The eGFR slope is relatively constant in relation to age (Fig. 4b). In our previous study, changes of reciprocal creatinine in 106 patients plotted against age showed that the progression patterns of renal function deterioration were different among patients [10]. Individual variation in renal functional progression might be a parallel characteristic to the wide distribution of kidney size growth, as shown in Fig. 3. Due to individual differences, the mean yearly change in eGFR (eGFR slope) as a whole patient group seemed to be constant, at least after ~30 years of age.

TKV increases each year in most patients with ADPKD (Fig. 3), but no significant correlation between age and TKV was seen in the present study (Table 3). Similar findings were reported in the CRISP study [4]. The reason for this insignificant correlation between TKV and age is probably the wide individual variation in TKV. It is interesting to note that the TKV slope was constant at all ages, but the %TKV slope and log-TKV slope decreased as age advanced (Table 3; Fig. 5d). This finding has already been reported with the slopes expressed as a percent per year being significantly lower in the older age group (p = 0.02) [4]. The mechanism of this saturation-like phenomenon is speculated as follows—the rate of kidney volume enlargement (ml/year) is constant throughout life (Table 3), but the growth rate (%/year) becomes lower because the denominator (kidney volume) increases every year. The same explanation is applicable to log-converted kidney volume.

The highly significant correlation between baseline as well as final TKV and TKV slope is an obvious result of a large kidney being the consequence of a rapid increase in kidney volume. Although genotype was not determined in the present study, it is known that faster growth is generally associated with PKD1 genotype [4]. A large kidney volume was associated with a more rapid declining slope of iothalamate-measured GFR as well as of eGFR in the present study (Fig. 2a), indicating that a large kidney volume is associated with decreased kidney function [4]. Recently, Chapman et al. reported that baseline ht-TKV ≥600 cc/m predicted the risk of developing renal insufficiency within 8 years [5]. The present study is not long enough to quantitatively predict the risk of renal insufficiency but supports the view that TKV is a prognostic biomarker in ADPKD.

In summary, this study confirmed that TKV is a clinically meaningful surrogate marker in ADPKD because it correlates with kidney function and predicts functional disease progression. Patients with larger TKV are at higher risk of developing ESRD.