CJASN ePress. Published on March 5, 2015 as doi: 10.2215/CJN.06680714
Article
CKD and Its Risk Factors among Patients with Cystinuria Caroline Prot-Bertoye, Sa€ ıd Lebbah, Michel Daudon, Isabelle Tostivint, Pierre Bataille, Franck Bridoux, Pierre Brignon, Christian Choquenet, Pierre Cochat, Christian Combe, Pierre Conort, St e phane Decramer, Bertrand Dor e, Bertrand Dussol, Marie Essig, Nicolas Gaunez, Dominique Joly, Sophie Le Toquin-Bernard, Arnaud M e jean, Paul Meria, Denis Morin, Hung Viet N’Guyen, Christian No€ e l, Michel Normand, Michel Pietak, Pierre Ronco, Christian Saussine, Michel Tsimaratos, G e rard Friedlander, Olivier Traxer, Bertrand Knebelmann, and Marie Courbebaisse on behalf of the French Cystinuria Group
Abstract Background and objectives Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. Design, setting, participants, & measurements This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. Results Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3–72.1) years and median diagnosis delay was 1.3 (0–45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8–70.7). Among the 314 patients aged $16 years, using the last available plasma creatinine, 22.5% had an eGFR$90 ml/min per 1.73 m2 (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60–89, 45–59, 30–44, 15–29, and ,15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P,0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size ,10 cm in patients aged $16 years (4.39 [2.00 to 9.62]; P,0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P,0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR,60 ml/min per 1.73 m2 (2.7 [1.5 to 5.1]; P=0.001).
Due to the number of contributing authors, the affiliations are provided in the Supplemental Material. Correspondence: Dr. Marie Courbebaisse, Department of Physiology, Functional Renal Explorations Service, Georges Pompidou European Hospital, 20 rue Leblanc, 75 015 Paris, France. Email: marie. courbebaisse@egp. aphp.fr
Conclusions CKD and high BP occur frequently in patients with cystinuria and should be routinely screened. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.06680714
Introduction Cystinuria (OMIM 220100), an autosomal recessive hereditary disease, is the most frequent monogenic cause of renal calculi, and is responsible for 1% and 8% of nephrolithiasis in adults and children, respectively (1,2). Cystinuria affects dibasic amino acid and cystine reabsorption in the renal proximal tubule. Because of its poor solubility at a typical urine pH of ,7, excess cystine results in urinary cystine stone recurrent formation. The final diagnosis mainly relies on stone analysis, urinary cystine crystal identification, or urinary cystine measurement. Alkaline hyperdiuresis is the cornerstone of the management. Sulfhydryl derivatives can sometimes be added to facilitate urinary cystine solubilization. In cases of stone formation, urological procedures must be performed. To date, few studies have evaluated comorbidities associated with cystinuria. This study aimed to determine epidemiologic and clinical characteristics, medical and surgical treatments, and comorbidities among cystinuric patients. To better characterize this pathology, we conducted a retrospective multicenter www.cjasn.org Vol 10 May, 2015
study in France. We focused on the prevalence of CKD and high blood pressure (HBP) among cystinuric patients and on their determinants.
Materials and Methods Study Population We conducted a national retrospective cohort study from April 2010 to January 2012. In April 2010, we contacted all 150 French departments of nephrology, urology, and pediatrics (likely to treat patients with kidney stones) by mail to ask physicians to complete a questionnaire. Thirty-one percent of the contacted departments participated in the study. All patients with a diagnosis of cystinuria confirmed by stone analysis, crystalluria, urinary cystine excretion, or Brand reaction (3) were eligible for inclusion. In France, the screening is proposed for at-risk siblings. Data were treated anonymously. The Advisory Committee on Information Processing Research in the Field of Health approved this study (approval no. 10.640bis). Copyright © 2015 by the American Society of Nephrology
1
2
Clinical Journal of the American Society of Nephrology
Data Collection The database included epidemiologic and clinical characteristics, laboratory data, medical and surgical treatments, and comorbidities. For the analysis, episodes of ARF were excluded. eGFR was calculated using the last available plasma creatinine (PCr) from the Modification of Diet in Renal Disease (MDRD; version 4) equation (4) in patients aged $16 years at that time or the Schwartz equation (5) in patients aged ,16 years if the size was available concomitantly to creatinine measurement. In the absence of recorded albuminuria, we defined CKD as an eGFR,60 ml/min per 1.73 m2 according to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 clinical practice guidelines (6). When available concomitantly to the last creatinine measurement, proteinuria was considered as significant if it was .0.5 g per 24 hours. Severe impairment of renal parenchyma was defined as a history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size ,10 cm in patients aged $16 years (7) during follow-up. Diagnosis of HBP was retained if the patient was declared by the physician to suffer from hypertension during follow-up, irrespective of antihypertensive treatment. No cut-off of BP was given to the physician. Diagnosis of obesity during follow-up relied on a body-mass index $30 kg/m2 or a positive answer to the question regarding obesity. Statistical Analyses Data are presented as medians (minimum to maximum), means (SD), and percentages. For continuous data, means were compared with a t test or ANOVA when more than two groups were studied. Correlations were assessed with the Pearson coefficient. Categorical data were compared with a chi-squared test or Fisher’s exact test when appropriate. We used univariate analysis to study the risk of CKD and HBP. Only variables found to be significant in univariate analysis were included in multivariate analysis using a logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for the probability of having CKD or HBP were calculated for each of these variables. A P value ,0.05 was considered significant.
Results Epidemiologic Characteristics of the Patients and Treatments We collected data from 442 patients (220 male participants) through 47 clinical departments: 23 specialized in nephrology (n=250), eight in urology (n=101), and 16 in pediatrics (n=91). Epidemiologic characteristics are described in Table 1. Male and female patients had a similar median age at presentation (P=0.60). The median delay from first symptoms to diagnosis was the same in later years compared with earlier years. This delay was longer among patients who were older at first symptoms (median 0.33 [0–45.7] years if age at first symptoms was ,16 years; median 3.04 [0–45.7] years if first symptoms occurred after 16 years; P,0.001). Diagnosis modalities depended on the age at diagnosis: $16 years, diagnosis was mostly based on renal colic (79.6% versus 33.1% for patients aged ,16 years; P,0.001); and ,16 years, diagnosis came from screening in one third of patients (31.0% versus 0% $16 years; P,0.001) and after urinary tract
infection in 10.3% of patients (versus 1.0% $16 years; P,0.001). Only 40 patients were symptom free at diagnosis and remained asymptomatic during follow-up. Most patients were treated with supportive measures (Table 1). The types of urological procedures per patient are described in Table 2. CKD In the entire population of 442 patients, five (1.1%, n=four men) progressed to ESRD requiring RRT at a median age of 35.0 (11.8–70.7) years and only one was aged ,16 years. The delay between onset of symptoms and RRT varied from 6.2 to 35.0 years. Four of these patients have received kidney transplants. Among the 128 patients aged ,16 years, eGFR could be recorded for 58 (45%). Among them, 48 (82.2%), seven (12.1%), one (1.7%), 2 (3.4%), zero (0%), and zero (0%) had an eGFR$90 ml/min per 1.73 m2, an eGFR of 60–89 ml/min per 1.73 m2, and CKD stage 3a, 3b, 4, and 5, respectively. Among these 58 patients, proteinuria could be recorded for 24. Only one child, whose eGFR was $90 ml/min per 1.73 m2, had significant proteinuria. In order to standardize eGFR calculated using the last available PCr, we restricted analysis to the group of patients aged $16 years at that time (n=314). The median age of this adult cohort was 38.7 years (16.2–86.6); of these, 51.6% were aged 16–39 years, 30.6% were aged 40–59 years, and 17.8% were aged $60 years. Within this population of 314 patients, 14 (4.5%) suffered from diabetes, 40 (13.3%) were obese, and 88 (28.6%) had HBP. Last PCr was measured with a median delay of 19.0 (0–65.5) years after first symptoms. Median eGFR was 71.8 ml/min per 1.73 m2 (5.4–171.7). Eighty-four (26.8%) patients had impaired renal function as indicated by an eGFR,60 ml/min per 1.73 m2. The distribution of eGFR values is normal and is represented in Figure 1A. The distribution of eGFR according to the KDIGO 2012 clinical practice guidelines is represented in Figure 1B. For the study of renal parenchyma damage, data were available for 234 patients within the cohort of 314 adult patients. Among these, 117 (50%) had severe renal parenchyma damage: 82 had at least one kidney with a reduced size ,10 cm, 34 had a history of partial/total nephrectomy (32 for lithiasis and two for tumor and tuberculosis), and one patient had a solitary congenital kidney. Among patients with at least one measurement of kidney size and/or a history of partial/total nephrectomy followed by PCr assessment (n=197), severe renal parenchyma damage was significantly associated with CKD (Table 3). The variables associated with CKD in univariate analysis are shown in Table 3. The distribution of CKD according to age and sex is represented in Figure 2. In multivariate analysis, CKD was associated with age (OR, 1.05; 95% CI, 1.03 to 1.07; P,0.001), hypertension (OR, 3.30; 95% CI, 1.54 to 7.10; P=0.002), and severe damage of renal parenchyma (OR, 4.39; 95% CI, 2.00 to 9.62; P,0.001). After excluding classic CKD risk factors (HBP, severe damage of renal parenchyma, diabetes mellitus, and obesity), the prevalence of CKD was 4.2%, 15.4%, and 20.0% among patients aged 16–39 years (n=48), 40–59 years (n=13), and $60 years, respectively (n=5). Among adult patients, proteinuria could be recorded concomitantly to the last creatinine measurement for 113 (36%). Among them, one of 25 (4%) with an eGFR$90 ml/min per 1.73 m2, two of 59 (3.4%) with an eGFR of 60–89 ml/min per
Clin J Am Soc Nephrol 10: ccc–ccc, May, 2015
CKD and Its Risk Factors among Patients with Cystinuria, Prot-Bertoye et al.
3
Table 1. Epidemiologic characteristics of the 442 patients and treatments
Characteristic
Value
Median age at last follow-up (yr) Male sex Age at diagnosis (yr) age ,16 16# age ,40 40# age ,60 age $60 Ethnicity White Black African Other Diabetes Obesity Hypertension Median time from initial symptoms to last follow-up (yr) Median age at presentation (yr) Male participants Female participants Median age at diagnosis (yr) Median time from first symptoms to diagnosis (yr) Diagnostic tools Stone analysis Cystinuria assessment Crystalluria Brand reaction Several Symptoms leading to diagnosis Renal colic Family screening Urinary tract infection Hematuria Bladder calculi Staghorn calculi Spontaneous expulsion of a stone Combined symptoms Other Fortuitous discovery Medical treatment (% of patients) Urinary alkalinization D-penicillamine or tiopronin Captopril Urological procedure among 402 symptomatic patients (% of patients) At least one urological procedure At least one lumbotomya or ureterolithotomy At least one minimally invasive procedure (endoscopy, shock wave lithotripsy or percutaneous surgery) Median time from first symptoms to first surgical procedure (yr)
32.5 (0.3–86.6) 49.9 20.5 41.7 24.1 13.7 74.3 0 25.7 3.8 10.4 21.4 15.8 (0.1–65.6) 16.7 (0.3–72.1) 16.5 (0.3–72.1) 17.1 (0.3–72.1) 18.5 (0.0–74.3) 1.3 (0.0–45.7) 57.7 28.5 3 1.9 8.9 60.6 11.9 5.0 2.4 2.1 2.1 0.8 7.9 5.6 1.6 90.6 88.8 52.2 12.9 89.9 42.6 80.1 0.5 (0.0–45.7)
Data are given as medians (minimum to maximum) or percentages unless otherwise stated. a Lumbotomy is defined as extraperitoneal open surgery by lumbotomy (incision on the lumbar fossa).
1.73 m2, two of 15 (13.3%) with CKD stage 3a, six of nine (66.7%) with CKD stage 3b, and three of five (60%) with CKD stage 4 had significant proteinuria (correlation coefficient between eGFR and proteinuria=20.46; P,0.001). Patients with stage 5 CKD had no available proteinuria. Hypertension Among pediatric patients, only one (girl, aged 10 years at diagnosis with an eGFR of 63 ml/min per 1.73 m2 and no overt proteinuria) had HBP. Eighty-eight (28.6%) of the
314 patients aged $16 years suffered from HBP during follow-up. In adult patients, Table 4 summarizes the univariate analysis of HBP risk and Figure 3 represents HBP distribution according to age and sex. In multivariate analysis, hypertension was associated with male sex (OR, 2.3; 95% CI, 1.3 to 4.1; P=0.003), age (OR, 1.06; 95% CI, 1.04 to 1.08; P,0.001), and an eGFR,60 ml/min per 1.73 m2 (OR, 2.7; 95% CI, 1.5 to 5.1; P=0.001). After excluding comorbidities usually associated with HBP (CKD, renal parenchymal damage, and obesity), the prevalence of HBP was 9.8%,
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Clinical Journal of the American Society of Nephrology
Table 2. Number and types of urological procedures per patient in the 442 cystinuric patients
No. of Procedures
Patients Who Had Each Procedure (%)
Urological Procedure
Lumbotomya Ureterolithotomy Partial nephrectomy Total nephrectomy Percutaneous nephrolithotomy Rigid ureteroscopy Flexible ureteroscopy Shock wave lithotripsy Vesical surgery Vesical endoscopy All procedures a
Mean 6 SD
Median (Minimum to Maximum)
1 procedure
$2 procedures
0.5861.01 0.1260.45 0.0260.13 0.0760.26 1.1761.87 0.5661.31 0.6761.48 2.0263.38 0.0560.23 0.0560.29 5.1565.53
0 (0–6) 0 (0–4) 0 (0–1) 0 (0–1) 0 (0–12) 0 (0–10) 0 (0–9) 1 (0–30) 0 (0–2) 0 (0–4) 4 (0–36)
20.5 6.1 1.8 7.1 18.4 17.2 9.5 14.8 4.4 2.8 9.6
14.2 2.3 0 0 28.0 11.6 16.4 38.8 0.2 0.7 71.4
Lumbotomy is defined as extraperitoneal open surgery by lumbotomy (incision on the lumbar fossa).
34.8%, and 33.3% among patients aged 16–39 years (n=61), 40–59 years (n=23), and $60 years (n=6), respectively.
Discussion We have herein analyzed data on a large series of cystinuric patients, the largest one to our knowledge. Our results highlight a high prevalence of CKD, based on MDRD eGFR, and a high prevalence of hypertension among cystinuric patients. The median age at diagnosis in our population was 18.5 years, but about 20% of patients were diagnosed after age 35 years. Although there is agreement that cystinuria should be diagnosed as soon as possible in order to better prevent nephrolithiasis recurrence, the median delay from first symptoms to diagnosis was 1.3 years (average 5.9568.99), but the diagnosis was delayed $5 years in more than one third of patients. The average diagnosis delay was 6.9 years (0–48) in a previous retrospective study (8). In our study, we show that 27% of the 314 cystinuric patients aged $16 years had impaired renal function as indicated by an eGFR,60 ml/min per 1.73 m2 and only 22.5% had an eGFR$90 ml/min per 1.73 m2, so considered as strictly normal. A study of British patients estimated the
prevalence of CKD stages 3–5 at 8.5% of the general population aged .18 years (mean age 58.1618.1 years), with a prevalence ,1% in individuals aged 18–44 years, around 5% for those aged 45–64 years, and around 32% for those aged .64 years (9). CKD stages 3–4 did not exceed 2%, 4%, and 15% in individuals aged 20–39 years, 40–59 years, and 60–69 years, respectively, in the US National Health and Nutrition Examination Survey (10). The prevalence of CKD in our population was far higher than in these studies, although our patients were younger and had fewer comorbidities. The association between CKD and stones has been debated in many studies. The incidence and prevalence of CKD is significantly higher in patients with nephrolithiasis (11). However, the risk of CKD depends on the type of stones. Patients with hereditary stone diseases, including cystinuria, have been shown to be at higher risk of CKD than patients with other stone disease (12–14), and it has been reported that patients with cystine stones had a lower GFR than those with other kinds of stones (15–17). In the field of cystinuria, depending on the definition of renal impairment and duration of follow-up, the prevalence of CKD ranges from 5.8% (n=40) (15) to 30% (n=40) (18) in limited series. There are only two other
Figure 1. | Distribution of GFR (eGFR using the MDRD equation, version 4) calculated from the last available plasma creatinine measurement in the 314 patients aged ‡16 years. (A) Overall distribution of GFR. (B) Distribution of GFR according to the Kidney Disease Improving Global Outcomes classification. MDRD, Modification of Diet in Renal Disease.
260 40 282
Obesity No Yes
Age at first symptoms (yr)
82 (30)
78 (5–172)
113
60 (21)
69 (20)
20.32
62 (14–110)
70 (31–117)
233
79
$30
Median time: first symptoms—treatment (yr) ,5
55
88 (27) 82 (29)
86 (24–172) 76 (5–165)
79 69
81 (30) 71 (24)
20.19
77 (27) 61 (19)
80 (26) 60 (22)
75 (26) 57 (18)
54 (20)
87 (26) 65 (17)
75 (27) 74 (26)
Average eGFR (SD) or Correlation Coefficient
20.45
76 (23–172) 71 (5–153)
74 (5–172) 63 (19–121)
75 (19–172) 61 (5–121)
73 (5–172) 62 (25–78)
54 (14–108)
82 (5–172) 66 (23–117)
72 (5–172) 72 (19–165)
Median eGFR (Minimum to Maximum)
282
20#–,30
Median time: first symptoms—creatinine (yr) ,10 10#–,20
110 172
220 88
High BP No Yes
,16 $16
294 14
Diabetes No Yes
56
162 96
Age (yr) 16# age ,40 40# age ,60
age $60
170 144
Sex Female Male
Considered Parameters
No. of Patientsa
,0.001
,0.001
,0.001
,0.001
0.01
0.001
,0.001
,0.001
0.001
,0.001
0.79
P Value
Table 3. Univariate analysis of risk of CKD stages 3–5 (eGFR
Article
CKD and Its Risk Factors among Patients with Cystinuria Caroline Prot-Bertoye, Sa€ ıd Lebbah, Michel Daudon, Isabelle Tostivint, Pierre Bataille, Franck Bridoux, Pierre Brignon, Christian Choquenet, Pierre Cochat, Christian Combe, Pierre Conort, St e phane Decramer, Bertrand Dor e, Bertrand Dussol, Marie Essig, Nicolas Gaunez, Dominique Joly, Sophie Le Toquin-Bernard, Arnaud M e jean, Paul Meria, Denis Morin, Hung Viet N’Guyen, Christian No€ e l, Michel Normand, Michel Pietak, Pierre Ronco, Christian Saussine, Michel Tsimaratos, G e rard Friedlander, Olivier Traxer, Bertrand Knebelmann, and Marie Courbebaisse on behalf of the French Cystinuria Group
Abstract Background and objectives Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. Design, setting, participants, & measurements This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. Results Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3–72.1) years and median diagnosis delay was 1.3 (0–45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8–70.7). Among the 314 patients aged $16 years, using the last available plasma creatinine, 22.5% had an eGFR$90 ml/min per 1.73 m2 (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60–89, 45–59, 30–44, 15–29, and ,15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P,0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size ,10 cm in patients aged $16 years (4.39 [2.00 to 9.62]; P,0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P,0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR,60 ml/min per 1.73 m2 (2.7 [1.5 to 5.1]; P=0.001).
Due to the number of contributing authors, the affiliations are provided in the Supplemental Material. Correspondence: Dr. Marie Courbebaisse, Department of Physiology, Functional Renal Explorations Service, Georges Pompidou European Hospital, 20 rue Leblanc, 75 015 Paris, France. Email: marie. courbebaisse@egp. aphp.fr
Conclusions CKD and high BP occur frequently in patients with cystinuria and should be routinely screened. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.06680714
Introduction Cystinuria (OMIM 220100), an autosomal recessive hereditary disease, is the most frequent monogenic cause of renal calculi, and is responsible for 1% and 8% of nephrolithiasis in adults and children, respectively (1,2). Cystinuria affects dibasic amino acid and cystine reabsorption in the renal proximal tubule. Because of its poor solubility at a typical urine pH of ,7, excess cystine results in urinary cystine stone recurrent formation. The final diagnosis mainly relies on stone analysis, urinary cystine crystal identification, or urinary cystine measurement. Alkaline hyperdiuresis is the cornerstone of the management. Sulfhydryl derivatives can sometimes be added to facilitate urinary cystine solubilization. In cases of stone formation, urological procedures must be performed. To date, few studies have evaluated comorbidities associated with cystinuria. This study aimed to determine epidemiologic and clinical characteristics, medical and surgical treatments, and comorbidities among cystinuric patients. To better characterize this pathology, we conducted a retrospective multicenter www.cjasn.org Vol 10 May, 2015
study in France. We focused on the prevalence of CKD and high blood pressure (HBP) among cystinuric patients and on their determinants.
Materials and Methods Study Population We conducted a national retrospective cohort study from April 2010 to January 2012. In April 2010, we contacted all 150 French departments of nephrology, urology, and pediatrics (likely to treat patients with kidney stones) by mail to ask physicians to complete a questionnaire. Thirty-one percent of the contacted departments participated in the study. All patients with a diagnosis of cystinuria confirmed by stone analysis, crystalluria, urinary cystine excretion, or Brand reaction (3) were eligible for inclusion. In France, the screening is proposed for at-risk siblings. Data were treated anonymously. The Advisory Committee on Information Processing Research in the Field of Health approved this study (approval no. 10.640bis). Copyright © 2015 by the American Society of Nephrology
1
2
Clinical Journal of the American Society of Nephrology
Data Collection The database included epidemiologic and clinical characteristics, laboratory data, medical and surgical treatments, and comorbidities. For the analysis, episodes of ARF were excluded. eGFR was calculated using the last available plasma creatinine (PCr) from the Modification of Diet in Renal Disease (MDRD; version 4) equation (4) in patients aged $16 years at that time or the Schwartz equation (5) in patients aged ,16 years if the size was available concomitantly to creatinine measurement. In the absence of recorded albuminuria, we defined CKD as an eGFR,60 ml/min per 1.73 m2 according to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 clinical practice guidelines (6). When available concomitantly to the last creatinine measurement, proteinuria was considered as significant if it was .0.5 g per 24 hours. Severe impairment of renal parenchyma was defined as a history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size ,10 cm in patients aged $16 years (7) during follow-up. Diagnosis of HBP was retained if the patient was declared by the physician to suffer from hypertension during follow-up, irrespective of antihypertensive treatment. No cut-off of BP was given to the physician. Diagnosis of obesity during follow-up relied on a body-mass index $30 kg/m2 or a positive answer to the question regarding obesity. Statistical Analyses Data are presented as medians (minimum to maximum), means (SD), and percentages. For continuous data, means were compared with a t test or ANOVA when more than two groups were studied. Correlations were assessed with the Pearson coefficient. Categorical data were compared with a chi-squared test or Fisher’s exact test when appropriate. We used univariate analysis to study the risk of CKD and HBP. Only variables found to be significant in univariate analysis were included in multivariate analysis using a logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for the probability of having CKD or HBP were calculated for each of these variables. A P value ,0.05 was considered significant.
Results Epidemiologic Characteristics of the Patients and Treatments We collected data from 442 patients (220 male participants) through 47 clinical departments: 23 specialized in nephrology (n=250), eight in urology (n=101), and 16 in pediatrics (n=91). Epidemiologic characteristics are described in Table 1. Male and female patients had a similar median age at presentation (P=0.60). The median delay from first symptoms to diagnosis was the same in later years compared with earlier years. This delay was longer among patients who were older at first symptoms (median 0.33 [0–45.7] years if age at first symptoms was ,16 years; median 3.04 [0–45.7] years if first symptoms occurred after 16 years; P,0.001). Diagnosis modalities depended on the age at diagnosis: $16 years, diagnosis was mostly based on renal colic (79.6% versus 33.1% for patients aged ,16 years; P,0.001); and ,16 years, diagnosis came from screening in one third of patients (31.0% versus 0% $16 years; P,0.001) and after urinary tract
infection in 10.3% of patients (versus 1.0% $16 years; P,0.001). Only 40 patients were symptom free at diagnosis and remained asymptomatic during follow-up. Most patients were treated with supportive measures (Table 1). The types of urological procedures per patient are described in Table 2. CKD In the entire population of 442 patients, five (1.1%, n=four men) progressed to ESRD requiring RRT at a median age of 35.0 (11.8–70.7) years and only one was aged ,16 years. The delay between onset of symptoms and RRT varied from 6.2 to 35.0 years. Four of these patients have received kidney transplants. Among the 128 patients aged ,16 years, eGFR could be recorded for 58 (45%). Among them, 48 (82.2%), seven (12.1%), one (1.7%), 2 (3.4%), zero (0%), and zero (0%) had an eGFR$90 ml/min per 1.73 m2, an eGFR of 60–89 ml/min per 1.73 m2, and CKD stage 3a, 3b, 4, and 5, respectively. Among these 58 patients, proteinuria could be recorded for 24. Only one child, whose eGFR was $90 ml/min per 1.73 m2, had significant proteinuria. In order to standardize eGFR calculated using the last available PCr, we restricted analysis to the group of patients aged $16 years at that time (n=314). The median age of this adult cohort was 38.7 years (16.2–86.6); of these, 51.6% were aged 16–39 years, 30.6% were aged 40–59 years, and 17.8% were aged $60 years. Within this population of 314 patients, 14 (4.5%) suffered from diabetes, 40 (13.3%) were obese, and 88 (28.6%) had HBP. Last PCr was measured with a median delay of 19.0 (0–65.5) years after first symptoms. Median eGFR was 71.8 ml/min per 1.73 m2 (5.4–171.7). Eighty-four (26.8%) patients had impaired renal function as indicated by an eGFR,60 ml/min per 1.73 m2. The distribution of eGFR values is normal and is represented in Figure 1A. The distribution of eGFR according to the KDIGO 2012 clinical practice guidelines is represented in Figure 1B. For the study of renal parenchyma damage, data were available for 234 patients within the cohort of 314 adult patients. Among these, 117 (50%) had severe renal parenchyma damage: 82 had at least one kidney with a reduced size ,10 cm, 34 had a history of partial/total nephrectomy (32 for lithiasis and two for tumor and tuberculosis), and one patient had a solitary congenital kidney. Among patients with at least one measurement of kidney size and/or a history of partial/total nephrectomy followed by PCr assessment (n=197), severe renal parenchyma damage was significantly associated with CKD (Table 3). The variables associated with CKD in univariate analysis are shown in Table 3. The distribution of CKD according to age and sex is represented in Figure 2. In multivariate analysis, CKD was associated with age (OR, 1.05; 95% CI, 1.03 to 1.07; P,0.001), hypertension (OR, 3.30; 95% CI, 1.54 to 7.10; P=0.002), and severe damage of renal parenchyma (OR, 4.39; 95% CI, 2.00 to 9.62; P,0.001). After excluding classic CKD risk factors (HBP, severe damage of renal parenchyma, diabetes mellitus, and obesity), the prevalence of CKD was 4.2%, 15.4%, and 20.0% among patients aged 16–39 years (n=48), 40–59 years (n=13), and $60 years, respectively (n=5). Among adult patients, proteinuria could be recorded concomitantly to the last creatinine measurement for 113 (36%). Among them, one of 25 (4%) with an eGFR$90 ml/min per 1.73 m2, two of 59 (3.4%) with an eGFR of 60–89 ml/min per
Clin J Am Soc Nephrol 10: ccc–ccc, May, 2015
CKD and Its Risk Factors among Patients with Cystinuria, Prot-Bertoye et al.
3
Table 1. Epidemiologic characteristics of the 442 patients and treatments
Characteristic
Value
Median age at last follow-up (yr) Male sex Age at diagnosis (yr) age ,16 16# age ,40 40# age ,60 age $60 Ethnicity White Black African Other Diabetes Obesity Hypertension Median time from initial symptoms to last follow-up (yr) Median age at presentation (yr) Male participants Female participants Median age at diagnosis (yr) Median time from first symptoms to diagnosis (yr) Diagnostic tools Stone analysis Cystinuria assessment Crystalluria Brand reaction Several Symptoms leading to diagnosis Renal colic Family screening Urinary tract infection Hematuria Bladder calculi Staghorn calculi Spontaneous expulsion of a stone Combined symptoms Other Fortuitous discovery Medical treatment (% of patients) Urinary alkalinization D-penicillamine or tiopronin Captopril Urological procedure among 402 symptomatic patients (% of patients) At least one urological procedure At least one lumbotomya or ureterolithotomy At least one minimally invasive procedure (endoscopy, shock wave lithotripsy or percutaneous surgery) Median time from first symptoms to first surgical procedure (yr)
32.5 (0.3–86.6) 49.9 20.5 41.7 24.1 13.7 74.3 0 25.7 3.8 10.4 21.4 15.8 (0.1–65.6) 16.7 (0.3–72.1) 16.5 (0.3–72.1) 17.1 (0.3–72.1) 18.5 (0.0–74.3) 1.3 (0.0–45.7) 57.7 28.5 3 1.9 8.9 60.6 11.9 5.0 2.4 2.1 2.1 0.8 7.9 5.6 1.6 90.6 88.8 52.2 12.9 89.9 42.6 80.1 0.5 (0.0–45.7)
Data are given as medians (minimum to maximum) or percentages unless otherwise stated. a Lumbotomy is defined as extraperitoneal open surgery by lumbotomy (incision on the lumbar fossa).
1.73 m2, two of 15 (13.3%) with CKD stage 3a, six of nine (66.7%) with CKD stage 3b, and three of five (60%) with CKD stage 4 had significant proteinuria (correlation coefficient between eGFR and proteinuria=20.46; P,0.001). Patients with stage 5 CKD had no available proteinuria. Hypertension Among pediatric patients, only one (girl, aged 10 years at diagnosis with an eGFR of 63 ml/min per 1.73 m2 and no overt proteinuria) had HBP. Eighty-eight (28.6%) of the
314 patients aged $16 years suffered from HBP during follow-up. In adult patients, Table 4 summarizes the univariate analysis of HBP risk and Figure 3 represents HBP distribution according to age and sex. In multivariate analysis, hypertension was associated with male sex (OR, 2.3; 95% CI, 1.3 to 4.1; P=0.003), age (OR, 1.06; 95% CI, 1.04 to 1.08; P,0.001), and an eGFR,60 ml/min per 1.73 m2 (OR, 2.7; 95% CI, 1.5 to 5.1; P=0.001). After excluding comorbidities usually associated with HBP (CKD, renal parenchymal damage, and obesity), the prevalence of HBP was 9.8%,
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Clinical Journal of the American Society of Nephrology
Table 2. Number and types of urological procedures per patient in the 442 cystinuric patients
No. of Procedures
Patients Who Had Each Procedure (%)
Urological Procedure
Lumbotomya Ureterolithotomy Partial nephrectomy Total nephrectomy Percutaneous nephrolithotomy Rigid ureteroscopy Flexible ureteroscopy Shock wave lithotripsy Vesical surgery Vesical endoscopy All procedures a
Mean 6 SD
Median (Minimum to Maximum)
1 procedure
$2 procedures
0.5861.01 0.1260.45 0.0260.13 0.0760.26 1.1761.87 0.5661.31 0.6761.48 2.0263.38 0.0560.23 0.0560.29 5.1565.53
0 (0–6) 0 (0–4) 0 (0–1) 0 (0–1) 0 (0–12) 0 (0–10) 0 (0–9) 1 (0–30) 0 (0–2) 0 (0–4) 4 (0–36)
20.5 6.1 1.8 7.1 18.4 17.2 9.5 14.8 4.4 2.8 9.6
14.2 2.3 0 0 28.0 11.6 16.4 38.8 0.2 0.7 71.4
Lumbotomy is defined as extraperitoneal open surgery by lumbotomy (incision on the lumbar fossa).
34.8%, and 33.3% among patients aged 16–39 years (n=61), 40–59 years (n=23), and $60 years (n=6), respectively.
Discussion We have herein analyzed data on a large series of cystinuric patients, the largest one to our knowledge. Our results highlight a high prevalence of CKD, based on MDRD eGFR, and a high prevalence of hypertension among cystinuric patients. The median age at diagnosis in our population was 18.5 years, but about 20% of patients were diagnosed after age 35 years. Although there is agreement that cystinuria should be diagnosed as soon as possible in order to better prevent nephrolithiasis recurrence, the median delay from first symptoms to diagnosis was 1.3 years (average 5.9568.99), but the diagnosis was delayed $5 years in more than one third of patients. The average diagnosis delay was 6.9 years (0–48) in a previous retrospective study (8). In our study, we show that 27% of the 314 cystinuric patients aged $16 years had impaired renal function as indicated by an eGFR,60 ml/min per 1.73 m2 and only 22.5% had an eGFR$90 ml/min per 1.73 m2, so considered as strictly normal. A study of British patients estimated the
prevalence of CKD stages 3–5 at 8.5% of the general population aged .18 years (mean age 58.1618.1 years), with a prevalence ,1% in individuals aged 18–44 years, around 5% for those aged 45–64 years, and around 32% for those aged .64 years (9). CKD stages 3–4 did not exceed 2%, 4%, and 15% in individuals aged 20–39 years, 40–59 years, and 60–69 years, respectively, in the US National Health and Nutrition Examination Survey (10). The prevalence of CKD in our population was far higher than in these studies, although our patients were younger and had fewer comorbidities. The association between CKD and stones has been debated in many studies. The incidence and prevalence of CKD is significantly higher in patients with nephrolithiasis (11). However, the risk of CKD depends on the type of stones. Patients with hereditary stone diseases, including cystinuria, have been shown to be at higher risk of CKD than patients with other stone disease (12–14), and it has been reported that patients with cystine stones had a lower GFR than those with other kinds of stones (15–17). In the field of cystinuria, depending on the definition of renal impairment and duration of follow-up, the prevalence of CKD ranges from 5.8% (n=40) (15) to 30% (n=40) (18) in limited series. There are only two other
Figure 1. | Distribution of GFR (eGFR using the MDRD equation, version 4) calculated from the last available plasma creatinine measurement in the 314 patients aged ‡16 years. (A) Overall distribution of GFR. (B) Distribution of GFR according to the Kidney Disease Improving Global Outcomes classification. MDRD, Modification of Diet in Renal Disease.
260 40 282
Obesity No Yes
Age at first symptoms (yr)
82 (30)
78 (5–172)
113
60 (21)
69 (20)
20.32
62 (14–110)
70 (31–117)
233
79
$30
Median time: first symptoms—treatment (yr) ,5
55
88 (27) 82 (29)
86 (24–172) 76 (5–165)
79 69
81 (30) 71 (24)
20.19
77 (27) 61 (19)
80 (26) 60 (22)
75 (26) 57 (18)
54 (20)
87 (26) 65 (17)
75 (27) 74 (26)
Average eGFR (SD) or Correlation Coefficient
20.45
76 (23–172) 71 (5–153)
74 (5–172) 63 (19–121)
75 (19–172) 61 (5–121)
73 (5–172) 62 (25–78)
54 (14–108)
82 (5–172) 66 (23–117)
72 (5–172) 72 (19–165)
Median eGFR (Minimum to Maximum)
282
20#–,30
Median time: first symptoms—creatinine (yr) ,10 10#–,20
110 172
220 88
High BP No Yes
,16 $16
294 14
Diabetes No Yes
56
162 96
Age (yr) 16# age ,40 40# age ,60
age $60
170 144
Sex Female Male
Considered Parameters
No. of Patientsa
,0.001
,0.001
,0.001
,0.001
0.01
0.001
,0.001
,0.001
0.001
,0.001
0.79
P Value
Table 3. Univariate analysis of risk of CKD stages 3–5 (eGFR
