Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Abstract

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function.

Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218).

Results: A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3-12.0); NPHP1, 13.5 years (interquartile range 10.5-16.5); NPHP4, 16.0 years (interquartile range 11.0-25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7-28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline.

Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling.

Keywords: end-stage kidney disease; genetic variant severity; genotype-phenotype correlations; kidney survival; nephronophthisis; prognostic factors.

Graphical abstract

Figure 1

Patient recruitment. Phenotypic data of 383 genetically characterized individuals was obtained from 3 independent sources: the Network of Early Onset Cystic Kidney Diseases clinical registry (n = 105), an online survey sent out to the members of the ERKNet (n = 60) and a complementary literature search (n = 218). Homogeneous data from 116 NPHP1 patients obtained from the Network of Early Onset Cystic Kidney Diseases registry (n = 80) and the online survey (n = 36) was fused for analyzes of impact of clinical factors. Gene-specific and variant-related kidney survival was analyzed including all 383 genetically characterized individuals (NPHP1: n = 116; NPHP3: n = 101; NPHP4: n = 81; NPHP11/TMEM67: n = 85) originating from the Network of Early Onset Cystic Kidney Diseases registry (n = 105), the online survey (n = 60) and a comprehensive literature search (n = 218). ERKNet, European Reference Network for Rare Kidney Diseases.

Figure 2

Gene-related kidney survival. Differences in gene-related kidney survival displayed as Kaplan–Meier survival curve (a) and median age (black line)/interquartile range for the onset of ESKD in 50%, 25% and 75% of participants (b). Significant statements: NPHP1 vs. NPHP3: P < 0.0001; NPHP1 versus NPHP4: P < 0.003; NPHP1 versus NPHP11: P = 0.057; NPHP3 versus NPHP4: P < 0.0001; NPHP3 versus NPHP11: P < 0.0001; NPHP4 versus NPHP11: P = 0.539; NPHP1 versus NPHP3 vs. NPHP4 versus NPHP11: P < 0.0001. ESKD, end-stage kidney disease.

Figure 3

Variant-related kidney survival. Genetic variants for NPHP3, NPHP4, and NPHP11/TMEM67 were subclassified into truncating/truncating, truncating/missense or missense/missense, defined by the presence of either 2 loss of function, 1 loss of function and 1 missense mutation or 2 missense mutations. The NPHP1 group was divided into biallelic truncating including a homozygous deletion and others. NPHP3 (n = 98) (a); NPHP4 (n = 81) (b); NPHP1 (n = 116) (c); NPHP11 (n = 85) (d).

Figure 4

Cross-sectional analysis of NPHP1 patients identifying clinical factors. Multivariate cross-sectional analysis identifying clinical factors for an early onset of ESKD in patients with NPHP1 gene variations (a). Univariate cross-sectional analysis of NPHP1 patients displaying the differences in annual deltaGFR (e.g., eGFR slope = deltaGFR male - deltaGFR female) for multiple clinical characteristics: ACEI treatment and most strikingly arterial hypertension were associated with an accelerated GFR decline; however, in a multivariate approach adjusted for each characteristic, only the influence of arterial hypertension remained significant (b). ACEI, angiotensin-converting enzyme inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio.

Figure 5

Representative eGFR trajectories from 4 patients with biallelic NPHP1 variants and temporary ACEI treatment. In all 4 cases, eGFR decline was more pronounced under the influence of ACEIs compared with no treatment-irrespective of CKD stage and age. However, no statistical significance was reached. ACEI, angiotensin-converting enzyme inhibitor; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.