Volume 67, Issue 3, Pages 829-848 (March 2005) Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD)  Carsten Bergmann, Jan Senderek, Ellen Windelen, Fabian Küpper, Iris Middeldorf, Frank Schneider, Christian Dornia, Sabine Rudnik- Schöneborn, Martin Konrad, Claus P. Schmitt, Tomas Seeman, Thomas J. Neuhaus, Udo Vester, Jutta Kirfel, Reinhard Büttner, Klaus Zerres  Kidney International  Volume 67, Issue 3, Pages 829-848 (March 2005) DOI: 10.1111/j.1523-1755.2005.00148.x Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 1 Summary of the clinical outcome of affected siblings of 48 multiplex pedigrees. Genotypes of families are given in the second column. Males: squares; females: circles. Diagonal lines denote deceased patients. Different fillings of symbols are explained below the figure. Abbreviations are: SCr, serum creatinine; RTX, renal transplantation; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis; portal HTN, portal hypertension; LTX, liver transplantation. Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 1 Summary of the clinical outcome of affected siblings of 48 multiplex pedigrees. Genotypes of families are given in the second column. Males: squares; females: circles. Diagonal lines denote deceased patients. Different fillings of symbols are explained below the figure. Abbreviations are: SCr, serum creatinine; RTX, renal transplantation; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis; portal HTN, portal hypertension; LTX, liver transplantation. Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 2 Kaplan-Meier curves were constructed for renal function analysis of the 164 neonatal survivors included in the present study. The lower curve depicts the proportion of patients with serum creatinine levels below 100 μmol/L, the middle curve those of individuals with serum creatinine values below 200 μmol/L, and the upper one indicates the proportion of patients without end-stage renal disease (ESRD) at a given age. Accordingly, our study cohort revealed an actuarial renal survival rate (end point defined as start of dialysis/RTX or by death due to ESRD) of 86% at 5 years, 71% at 10 years, 66% at 15 years, and 42% at 20 years. At the end of the study, 38 patients received dialysis treatment for ESRD, were transplanted, or died due to ESRD. Mutation types identified in these 38 patients are shown above the ESRD curve indicating the age when the respective individual first received renal replacement therapy (X is truncating mutation, M is missense mutation, and - is an unidentified allele). The mean age ESRD occurred in patients with a truncating mutation on one parental allele was 7.2 years (N = 16), in patients carrying missense changes on both alleles 10.1 years (N = 11). Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 3 The development of serum creatinine (SCr) values of 22 patients (13 males and 9 females) with at least one serum creatinine level above 200 μmol/L during the observation period is depicted. The color of the curves indicates the mutation status of patients (red is the compound of truncating and missense mutation; green is the missense mutation on both alleles; blue is the single truncating or missense change, second mutation not identified). Patients whose first available serum creatinine value was already above 200 μmol/L (N = 16) are not included in this figure. Deterioration of renal function rapidly set in above a serum creatinine level of about 200 μmol/L. Almost every patient who reached that point developed end-stage renal disease (ESRD) within a period of less than 5 years. The mean age patients with a truncating mutation on one allele reached a serum creatinine value of about 200 μmol/L was 4.1 years (N = 7), patients carrying missense changes on both alleles had a mean age of 7.2 years (N = 10). Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 4 Kidney lengths measured by ultrasound related to age of 78 patients (40 male and 38 females) of the present study. In most individuals multiple values at different ages were encountered, however, for clarity only initial and final values are presented. All but six patients (92%) had a kidney length above or on the 97th centile for age (= normal kidney length for age +2 SD scores). In males (squares), kidney lengths ranged between +1 and +17 SD, in females (circles) between 0 and +12 SD. The color indicates the mutation status of patients (red is the compound of truncating and missense mutation; green is the missense mutation on both alleles; blue is the single truncating or missense change, second mutation not identified). Correlations were neither observed between kidney length and serum creatinine levels, between kidney length and duration of the disease nor between kidney length and mutation type. Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 5 Kaplan-Meier survival curve for all 186 individuals of the current series (overall survival rate at 1 year of age of 85% (81% males and 89% females) (NS) with most cases of death in the peri-/neonatal period related to respiratory insufficiency). Of those patients who survived the first month of life, 95% were alive at 1 year, 94% at 5 years, and 92% at 10 years. In total, a number of 13 neonatal survivors (8%) (6 males and 7 females) died during the observation period at a median age of 5.6 years. Mutation types identified in these 13 patients are shown below the curve when the respective individual passed away (X is truncating mutation; M is missense mutation; - is unidentified allele). In six patients death occurred during the first year of life with predominant extrarenal causes [cardiorespiratory insufficiency (N = 3), end-stage renal disease (ESRD) with sepsis (N = 2), pneumonia (N = 1)]. ESRD with sepsis was also causative for demise in six patients at later ages of life (1 to 23½ years). One male died at the age of 22 years due to ESRD complicated by pneumonia and esophageal variceal bleeding. Perpendicular bars indicate the age of surviving patients at last examination (censored patients). Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 6 Renal disease variability among patients of the present and two previous studies9,33who survived the neonatal period and carry the same set of PKHD1 mutations. Different symbols represent different mutation sets (depicted below). In case consecutive measurements of serum creatinine (SCr) levels were available, these are linked by lines. Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Kidney International 2005 67, 829-848DOI: (10. 1111/j. 1523-1755. 2005 Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Kidney International 2005 67, 829-848DOI: (10. 1111/j. 1523-1755. 2005 Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Kidney International 2005 67, 829-848DOI: (10. 1111/j. 1523-1755. 2005 Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Kidney International 2005 67, 829-848DOI: (10. 1111/j. 1523-1755. 2005 Kidney International 2005 67, 829-848DOI: (10.1111/j.1523-1755.2005.00148.x) Copyright © 2005 International Society of Nephrology Terms and Conditions