1. Glomerular hyperfiltration is a common risk factor for accelerated GFR decline in young adults with autosomal polycystic kidney disease (ADPKD)
G. Gentile * #, D. Mastroluca¥, A. Perna*, G.Remuzzi * #, P. Ruggenenti* #
* Clinical Research Center for Rare Diseases “Aldo & Cele Daccò”, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Italy
¥ Division of Nephrology, University “La Sapienza”, Rome, Italy
# Division of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
Background
Materials & Methods
Over a median (IQR) of 6 (3.5-9) years of follow-up, creatinine clearance declined by 4.42 (9.35 to 0.97) and 0.50 (5.1 to -2.78) mL/min/1.73 m2 in patients with or without glomerular hyperfiltration, respectively (p= ). The difference between the two groups remained statistically significant ever after adjustment for age, sex and systolic blood pressure (p= 0.002; Figure 2).
Patient age:
27.2 yrs
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited monogenic disorder characterized by progressive cystic expansion and glomerular filtration rate (GFR) decline associated with different extrarenal manifestations. According to recent epidemiological data, ADPKD affects about one out of 3,000 people1 and is responsible for 10% of patients on long-term dialysis. Renal hyperfiltration - in addition to progressive disruption of kidney parenchyma and traditional risk factors such as arterial hypertension – may play an independent role in the progressive kidney function loss of children with ADPKD3. Data from the “Effects of A Long-Acting somatostatin on Disease progression in Nephropathy due to autosomal dominant polycystic kidney disease (ALADIN) trial2 suggest that glomerular hyperfiltration may play a role in disease progression even in adults. In fact, in the Octreotide LAR treatment arm, the rate of long-term GFR decline inversely correlated with short-term (six-month) GFR reduction, a finding that strongly suggested that the protective effect of this medication against progressive renal function loss was at least partly mediated by amelioration of glomerular hyperfiltration (Figure 1). To formally test the role of glomerular hyperfiltration in this context, we took advantage of a large cohort of ADPKD adult patients referred to our outpatient clinic and prospectically monitored by serial GFR measurements from 1998 to 2013.
Age < 35 years
Follow-up period ≥ 1 year
At least 3 measurements of creatinine clearance
Among 900 ADPKD outpatients of “Papa Giovanni XXIII” Hospital (Bergamo, Italy), we identified all consecutive young adults with or without glomerular hyperfiltration (defined as a baseline creatinine clearance > 140 mL/min/1.73 m2), who fulfilled the following selection criteria:
Patient age: yrs
GFR decline
-10 -6
P = 0.002
(mL/min/1.73m2/year) -4 -2 -8
Figure 3
Discussion
In the present study we found that ADPKD patients with glomerular hyperfiltration to start with have a faster GFR decline as compared to non-hyperfiltering patients. Moreover, higher initial GFR independently predicts faster renal function loss in this context. Altogether, these findings converge to indicate that glomerular hyperfiltration plays an independent pathogenenetic role in renal disease progression of adult patients with ADPKD. In this context, hyperfiltering patients could be those who benefit the most of specific interventions with somatostatin analogues. Drugs that ameliorate glomerular hyperfiltration, such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), might have an additional renoprotective effect in this context. Whether and to what these medications may synergize the renoprotective effects of somatostatin analogues in patients with ADPKD is worth investigating in prospective controlled trials.
Age (median, IQR)
Gender (M/F)
29.1 ( )
Systolic BP (mmHg)
Diastolic BP (mmHg)
76.0 ( )
s. Creatinine (mg/mL)
0.90 (0.76 – 1.08)
CrCl (mL/min/1.73m2)
110.0 (86.0 – 129.0)
Proteinuria (g/24h)
0.13 (0.07 – 0.20)
14.0 (13.4 – 15.1)
45/46
Haemoglobin(g/dL)
Glycaemia (mg/dL)
Uric acid (mg/dL)
Total cholesterol (mg/dL)
HDL cholesterol (mg/dL)
89.0 (84.0 – 97.0)
4.6 (3.9 – 5.3)
191 ( )
55 ( )
124.0 ( )
Parameter
Overall
(n=91)
Hyperfiltering
(n= 11)
Non-hyperfiltering
(n= 80)
27.2 ( )
29.2 ( )
9/2
36/44
120.0 ( )
125.0 ( )
48 (48-48)
51 (56-67)
172 ( )
191 ( )
78.0 (63.0 – 81.0)
75.5 ( )
0.73 (0.70 – 0.91)
0.94 (0.80 – 1.08)
169.0 (162.0 –209.0)
102.5 (84.5 – 122.0)
0.20 (0.08 – 0.25)
0.12 (0.07 – 0.20)
14.6 (14.1 – 15.8)
14.0 (13.2 – 15.1)
89.0 (87.0 – 96.0)
89.0 (84.0 –97.0)
5.0 (3.5 – 5.5)
4.6 (4.3 – 5.2)
Table 1. Baseline patient characteristics
Data are medians and interquartile ranges or percentages, as appropriate
Main results
Triglycerides (mg/dL)
81 (56-143)
19 (15-48)
3.6 ( )
Potassium (mmol/L)
19 (15-23)
16 (12-24)
AST (UI/L)
0.70 ( )
ALT (UI/L)
0.72 ( )
0.72 ( )
Total bilirubin (mg/dL)
141 ( )
140 (
4.2 (3.9-4,5)
4.3 ( )
9.4 ( )
4.2 ( )
Sodium (mmol/L)
3.6 ( )
3.6 ( )
9.3 ( )
Calcium (mg/dL)
Phosphorus (mg/dL)
16 ( )
20 (17-31)
107.5 ( )
18.5 (15-23)
We identified 91 patients. Of them, 11 (12.1%) were hyperfiltering and 81 had a creatinine clearance ranging from 41 and 138 mL/min/1.73 m2 (Table 1).
Hyperfiltering
Non-hyperfiltering
Figure 2
References
At final visit, median creatinine clearance had decreased by 1.5 mL/min/1.73 m2 in normofiltering patients and by 57 mL/min/1.73 m2 in the hyperfiltering ones (p< ). In addition, higher baseline creatinine clearance significantly correlated (p < , r= 0.44) with faster GFR decline over time. Projected trajectories of GFR decline in the two patient groups showed that the initial GFR gap (exceeding 60 mL/min/1.73 m2) between normofiltering and hyperfiltering patients was fully abrogated over less than 20 years of follow-up (Figure 3). Thus, on subsequent follow-up the GFR difference between the two patient groups was expected to increase in favor of the initially normofiltering patients (Figure 3, dashed lines).
Neumann HP et al. Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany. Nephrol Dial Transplant 2013; 28:
Caroli A et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 2013; 382:
Helal I et al. Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011; 6:
Figure 1
Objectives
The present study was primarily aimed at evaluating whether and to what extent glomerular hyperfiltration independently contributes to GFR decline in young adults with ADPKD