Correspondence
A Novel Mutation of the PKD2 Gene in a Japanese Patient With Autosomal Dominant Polycystic Kidney Disease and Complete Situs Inversus To the Editor: A 61-year-old woman was admitted to our hospital with general fatigue. Laboratory tests showed kidney failure, and imaging showed visceral inversion with polycystic liver and kidneys (Fig 1). Autosomal dominant polycystic kidney disease (ADPKD) with complete situs inversus was diagnosed. Polycystins 1 and 2, proteins encoded by the PKD1 and PKD2 genes, respectively, are known to localize to renal tubular primary cilia. In addition, experiments in mice have shown that polycystin
2 has a role in left-right determination during embryogenesis.1 In humans, the association of PKD2 mutations with left-right laterality defects was reported first in 2011.2 In our patient, we identified a novel heterozygous mutation at nucleotide 973 in the coding sequence of PKD2. The mutation, a substitution of cytosine by thymine, changes the arginine codon at amino acid 325 to a TGA stop codon, suggesting that mutant form of polycystin 2 is prematurely truncated. It is likely that our patient’s PKD2 mutation caused both ADPKD and complete situs inversus with a possible involvement of cilia dysfunction. Machiko Oka, MD1 Toshio Mochizuki, MD, PhD2 Shuzo Kobayashi, MD, PhD1 1 Shonan Kamakura General Hospital Kamakura, Kanagawa, Japan 2 Tokyo Women‘s Medical University Tokyo, Japan
Acknowledgements Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
References 1. McGrath J, Somlo S, Makova S, et al. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell. 2003;114(1):61-73. 2. Bataille S, Demoulin N, Devuyst O, et al. Association of PKD2 (polycystin 2) mutations with left-right laterality defects. Am J Kidney Dis. 2011;58(3):456-460. Received May 20, 2014. Accepted in revised form May 23, 2014. Originally published online August 20, 2014. Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014.05.023
RESEARCH LETTERS Weight Loss, Adipokines, and Quality of Life After Sleeve Gastrectomy in Obese Patients With Stages 3-4 CKD: A Randomized Controlled Pilot Study
Figure 1. (A) Radiograph of the chest shows dextrocardia and elevated left diaphragm. (B) Abdominal computed tomographic scan shows polycystic liver at the left and polycystic kidneys. 660
To the Editor: Weight-loss interventions in obese CKD patients significantly reduce proteinuria and hyperfiltration,1,2 yet few studies included patients with moderate to severe CKD. Renal and systemic inflammation decline and eGFR may improve with bariatric surgery in moderate CKD,3-5 although this has not been examined in a randomized controlled trial. Leptin and adiponectin have proand anti-inflammatory properties, respectively, yet changes in these adipokines and the effects of weight loss on insulin resistance, metabolic syndrome, and atherosclerosis may alter with reduced kidney function. Roux-en-Y gastric bypass and adjustable gastric banding have been associated with adverse outcomes in CKD patients, not evident with sleeve gastrectomy.6 This randomized, controlled, parallel-design, pilot study investigated whether the greater weight loss achieved with sleeve gastrectomy (intervention) would improve eGFR, proteinuria (urinary PCR), quality-of-life (QoL) measures, insulin resistance, inflammation, and adipokine response compared to best medical care (control) in obese patients with stages 3-4 CKD. This prospective study was conducted across 3 university teaching hospitals in London, United Kingdom; was approved by the London Surrey Borders Research Ethics Committee (09/H0806/69); followed the principles of the Declaration of Helsinki; and was registered at Am J Kidney Dis. 2014;64(4):658-665
Correspondence Table 1. Baseline Characteristics of Obese Patients With Stages 3-4 CKD Randomized to Sleeve Gastrectomy or Best Medical Care Intervention (n 5 5)
Control (n 5 6)
51 [47.5, 55]
53 [46.5, 66]
0.8
5
4
0.5
Ethnicity (no.)
3 white, 2 black
3 white, 3 black
0.9
Diabetes (no.)
1
4
0.2
Metabolic syndrome (no.)
5
6
0.9
Antihypertensive use (no.)
5
6
0.9
Statin use (no.)
4
3
0.6
Parameter Age (y) Female sex (no.)
Pa
BMI (kg/m2)
40.3 [37.3, 43.5]
37.4 [35.8, 40.0]
0.1
Weight (kg)
111 [104.8, 116.0]
105.2 [101.3, 113.0]
0.7
51.9 [50.9, 53.0]
49.6 [43.5, 52.7]
0.4
Waist circumference (cm)
127.1 [126.9, 128.0]
120.8 [118.4, 125.5]
0.2
Serum creatinine (mg/dL)
1.39 [1.27, 2.47]
2.01 [1.58, 2.74]
0.3
Serum cystatin C (mg/L)
1.84 [1.31, 2.47]
2.33 [2.00, 2.55]
0.5
40 [24, 48]
32 [24, 35]
0.5
Fat mass (kg)
eGFRMDRD (mL/min/1.73 m2) Unadjusted eGFRMDRD (mL/min)
51 [31, 60]
40 [32, 45]
0.6
eGFRcr-cys(CKD-EPI) (mL/min/1.73 m2)
37 [22, 53]
28 [23, 32]
0.6
Unadjusted eGFRcr-cys(CKD-EPI) (mL/min)
48 [29, 67]
35 [31, 39]
0.5
eGFRcys(CKD-EPI) (mL/min/1.73 m2)
34 [22, 54]
26 [23, 30]
0.6
Unadjusted eGFRcys(CKD-EPI) (mL/min) Systolic / diastolic blood pressure (mm Hg) Urinary PCR (mg/mmol) Insulin resistance, as HOMA-IR
44 [29, 68]
33 [30, 38]
0.6
118 [116, 142] / 80 [72, 88]
135 [117, 144] / 81 [65, 92]
0.5 / 0.9
31.8 [24.3, 77.5]
22.2 [12.5, 31.8]
0.6
3.0 [1.8, 8.5]
7.8 [4.5, 25.6]
0.2
Adiponectin (mg/L)
11.6 [10.4, 19.2]
10.2 [9.2, 15.9]
0.5
Leptin (mg/L)
34.7 [33.3, 78.6]
86.8 [36.5, 96.2]
0.4
Interleukin 6 (ng/L)
1.9 [0.7, 4.4]
2.1 [1.1, 3.8]
0.9
Tumor necrosis factor a (ng/L)
0.7 [0.5, 1.8]
1.0 [0.9, 1.1]
0.7
High-sensitivity C-reactive protein (mg/L) HADS Anxiety / Depression scores SF-36 Physical Domain / Mental Domain scores
5.0 [1.6, 16.2]
4.1 [3.5, 11.2]
0.9
7 [5, 9] / 7 [6, 8]
5 [3, 12] / 6 [4, 8]
0.7 / 0.5
26 [25, 31] / 51 [47, 52]
45 [28, 50] / 47 [45, 54]
0.03 / 0.8
Note: Data expressed as median [25th, 75th percentile] unless otherwise stated. Abbreviations: BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; cr, creatinine; cys, cystatin C; eGFR, estimated glomerular filtration rate; HADS, Hospital Anxiety and Depression Scale; HOMA-IR, homeostasis model assessment of insulin resistance; MDRD, Modification of Diet in Renal Disease; PCR, protein-creatinine ratio; SF-36, 36-Item Short Form health-related quality of life questionnaire; a P values obtained with independent-samples Mann-Whitney U test, t test, or Fisher exact test, as appropriate.
ClinicalTrials.gov (NCT01053130). Recruitment from outpatient nephrology clinics ran from March 2010 to June 2011. Inclusion and exclusion criteria are listed in Item S1, which also provides detailed methods (including detail on treatments) and outcome measures. Patients were randomly assigned using a concealed computergenerated random allocation sequence and were followed up for 12 months. BMI, weight loss, body composition, serum adipokines and markers of inflammation, PCR, HOMA-IR, insulin dose, and QoL measures (SF-36, HADS) were measured. eGFR was calculated using the 4-variable MDRD Study equation7 and the CKD-EPI cystatin C and creatinine–cystatin C equations8 and also calculated in body surface area (BSA)-unadjusted form. Between-group differences at 12 months were determined by analysis of covariance with adjustment for baseline values, or Hodges-Lehman median difference. As shown in the Item S1 flow diagram, 182 patients meeting the inclusion criteria were invited to participate; 16 provided informed consent; 5 of 8 and 6 of 8 patients in the intervention and control groups, respectively, completed the study. There were no statistically significant between-group differences in baseline characteristics (Table 1) except in SF-36 Physical Domain score. Table 2 lists 12-month changes and Between-Group 12-month differences in outcomes. Compared to the control group, the intervention group had greater reductions in BMI, weight, waist circumference, and fat mass at 12 months (all P # 0.001; Item S1). Adherence Am J Kidney Dis. 2014;64(4):658-665
to treatment, percent weight loss, percent excess weight loss, and safety and adverse events are given in Item S1. For all eGFR equations, small postintervention eGFR increases were reversed after removal of the adjustment for standardized BSA; thus, BSA-unadjusted eGFR did not differ between groups at 12 months (Table 2). PCR decreased in the intervention group and increased in the control group, but the between-group difference was not statistically significant (P 5 0.1). At 12 months, in the intervention versus the control group, adiponectin increased, HOMA-IR decreased; HADS Anxiety and Depression scores decreased, and SF-36 Physical Domain scores increased (all P , 0.05). Daily mean insulin dose differed by 236 (95% CI, 269 to 23) units in the intervention versus control group. This is the first randomized controlled study of sleeve gastrectomy versus best medical care in obese patients with stages 3-4 CKD. Significant weight loss was achieved after 12 months in the intervention versus control groups, with no change in BSAunadjusted eGFR. BSA-adjusting eGFR in obese individuals when weight loss occurs may be unnecessary because the number of nephrons does not change.9 An improvement in eGFR with weight loss after bariatric surgery may reflect decreasing underestimation of eGFR as BSA decreases toward the standard 1.73 m2. The intervention favorably changed serum adiponectin and insulin resistance at 12 months, which may suggest reversal of podocyte 661
Correspondence Table 2. Changes in Measured Parameters at 12 Months in Obese Patients With Stages 3-4 CKD After Sleeve Gastrectomy or Best Medical Care Intervention (n 5 5)
Control (n 5 6)
Adjusted Between-Group Differencea
212.0 6 2.0
21.2 6 0.9
210.8 [213.2, 28.4]b
Weight (kg)
232.8 6 6.5
23.3 6 2.9
229.0 [236.4, 222.3]b
Fat mass (kg)
226.8 6 6.5
22.4 6 3.2
224.1 [232.5, 215.7]b
Waist circumference (cm)
232.4 6 10.2
22.0 6 5.4
229.1 [240.6, 217.6]b
Serum creatinine (mg/dL)
20.1 6 0.1
10.1 6 0.5
20.19 [20.73, 0.35]
20.07 6 0.29
10.1 [20.36, 0.56]
Parameter BMI (kg/m2)
0 6 0.32
Serum cystatin C (mg/L) eGFRMDRD (mL/min/1.73 m )
13 6 6
22 6 5
15 [23, 13]
Unadjusted eGFRMDRD (mL/min)
23 6 5
23 6 6
10.5 [28, 9]
eGFRcr-cys(CKD-EPI) (mL/min/1.73 m2)
14 6 8
065
12 [27, 11]
Unadjusted eGFRcr-cys(CKD-EPI) (mL/min)
23 6 6
21 6 6
22 [211, 8]
eGFRcys(CKD-EPI) (mL/min/1.73 m )
14 6 9
11 6 5
11 [29, 11]
Unadjusted eGFRcys(CKD-EPI) (mL/min)
22 6 6
066
23 [213, 7]
2
2
216.5 6 29.1
18.6 6 12.2
224.2 [255.9, 7.5]
22.4 [22.95, 21.42]
20.9 [24.2, 8.3]
27.7 [228.8, 20.5]b
14.3 [2.0, 10.1]
20.5 [22.6, 0.6]
6.1 [1.0, 19.8]b
265.8 6 207.2
27.3 6 59.6
211.5 [2108.3, 85.3]
Interleukin 6 (ng/L)
22.8 6 8.0
117.4 6 38.4
215.8 [258.5, 26.9]
Tumor necrosis factor a (ng/L)
10.3 6 4.2
12.1 6 1.8
20.5 [22.1, 1.2]
High-sensitivity C-reactive protein (mg/L)
26.9 6 7.7
25.0 6 10.3
22.4 [26.3, 1.6]
25 6 1 / 26 6 3
063 / 061
24 [28, 21]b / 25 [28, 23]b
119 6 8 / 11 6 11
25 6 6 / 23 6 13
122 [8, 36]b / 17 [29, 23]
Urinary PCR (mg/mmol) Insulin resistance, by HOMA-IR Adiponectin (mg/L) Leptin (mg/L)
HADS Anxiety / Depression scores SF-36 Physical Domain / Mental Domain scores
Note: Intervention and control data presented as mean 6 SD or median [25th, 75th percentile]. a Mean difference (95% confidence interval), intervention versus control group at 12 months, adjusted for baseline value, or Hodges-Lehman median difference (95% confidence interval) between groups at 12 months. b P , 0.05.
damage, reflected by a nominal reduction in proteinuria in this group.10 A similar metabolic response was achieved with a 12-week very-low-calorie diet in diabetic nephropathy patients,11 indicating that weight loss per se may improve metabolic status. The improvement in QoL in the intervention group versus the control group is an important positive patient-focused outcome because decreasing SF36 Physical Domain score is associated with CKD progression.12 This pilot study’s primary strength is the randomized design. However, recruitment was difficult, with a low rate of uptake. Measurement of adipokines and inflammation markers with weight loss provided some information for possible mechanistic effects of a reduction in adiposity in obese CKD patients. The major limitations are the sample size, limiting the applicability and external validity of the results, and the modest reduction in energy intake achieved in the control group. In conclusion, compared to best medical care, sleeve gastrectomy was associated with positive changes in QoL, adiponectin, insulin use, and insulin resistance, with no change in BSA-unadjusted eGFRs. Our results are hypothesis generating, and the effect of weight loss on glomerular and tubular damage by changes in adiponectin and insulin resistance in obese CKD patients warrants further study. Helen L. MacLaughlin, PhD,1,2 Wendy L. Hall, PhD2 Ameet G. Patel, FRCS,1 Rochelle M. Blacklock, BSc1 Pauline A. Swift, PhD, FRCP,3 Mysore K. Phanish, PhD, MRCP3 Tracy Dew, MSc,1 Paramit Chowdhury, PhD, MRCP4 Tom A.B. Sanders, PhD,2 and Iain C. Macdougall, MD, FRCP1 1 King’s College Hospital NHS Foundation Trust, London 2 Diabetes and Nutritional Sciences Division, King’s College London 3 Epsom and St Helier University Hospitals NHS Trust, Surrey 4 Guy’s and St Thomas’ Hospital NHS Foundation Trust, London United Kingdom Corresponding author:
[email protected] 662
Acknowledgements Support: This study was supported by a Doctoral Fellowship awarded to Dr MacLaughlin by King’s College Hospital NHS Foundation Trust. The funders had no role in the study design; collection, analysis, and interpretation of data; or writing the report. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: HLM, AGP, ICM; data acquisition: HLM, RMB, PAS, MKP, PC; data analysis/interpretation: HLM, WLH, TD, PAS, TABS, ICM; statistical analysis: HLM, TABS; supervision or mentorship: WLH, AGP, ICM, TABS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. HLM takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and registered) have been explained.
Supplementary Material Item S1. Supplementary methods and results. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.06.011) is available at www.ajkd.org
References 1. Afshinnia F, Wilt TJ, Duval S, Esmaeili A, Ibrahim HN. Weight loss and proteinuria: systematic review of clinical trials Am J Kidney Dis. 2014;64(4):658-665
Correspondence and comparative cohorts. Nephrol Dial Transplant. 2010;25(4): 1173-1183. 2. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(10):1565-1574. 3. Fenske WK, Dubb S, Bueter M, et al. Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis. 2013;9(4):559-568. 4. Bueter M, Dubb SS, Gill A, et al. Renal cytokines improve early after bariatric surgery. Br J Surg. 2010;97(12):1838-1844. 5. Navaneethan SD, Yehnert H. Bariatric surgery and progression of chronic kidney disease. Surg Obes Relat Dis. 2009;5: 662-665. 6. MacLaughlin HL, Hall WL, Patel AG, Macdougall IC. Laparoscopic sleeve gastrectomy is a novel and effective treatment for obesity in patients with chronic kidney disease. Obes Surg. 2012;22(1):119-123. 7. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol. 2000;11:0828A. 8. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29. 9. Friedman AN, Moe S, Fadel WF, et al. Predicting the glomerular filtration rate in bariatric surgery patients. Am J Nephrol. 2013;39(1):8-15. 10. Fornoni A. Proteinuria, the podocyte, and insulin resistance. N Engl J Med. 2010;363(21):2068-2069. 11. Friedman AN, Chambers M, Kamendulis LM, Temmerman J. Short-term changes after a weight reduction intervention in advanced diabetic nephropathy. Clin J Am Soc Nephrol. 2013;8(11):1892-1898. 12. Pagels AA, Soderkvist BK, Medin C, Hylander B, Heiwe S. Health-related quality of life in different stages of chronic kidney disease and at initiation of dialysis treatment. Health Qual Life Outcomes. 2012;10(1):71. Received March 2, 2014. Accepted in revised form June 9, 2014. Originally published online July 30, 2014. Ó 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014.06.011
We used mixed-effects models to test for an overall (fixed) time effect (baseline, 6 months, 12 months) with random repeated participant effects and performed paired t tests to assess differences from baseline. Associations between quantitative factors were examined using Pearson correlation coefficient. Multiple readings were corrected using generalized estimating equations. Statistical analyses were performed using SAS, version 9.1. Continuous data are presented as mean 6 SD. Eleven white women aged 50 6 12 (range, 28-68) years participated (Table 1), 9 undergoing standard Roux-en-Y gastric bypass, and 2 biliopancreatic diversion/duodenal switch. Preoperative BMI was 46 6 5 kg/m2; 2 patients had diabetes. BMI decreased to 33 6 5 and 28 6 2 kg/m2 at 6 and 12 months, respectively, after surgery (P , 0.001). At baseline, 7 patients required a median of 1 (IQR, 0-3) antihypertensive medication, while at 12 months only 4 required
Table 1. Patient Characteristics at Baseline and 6 and 12 Months After Bariatric Surgery Baseline Female sex
11 (100%)
Age (y)
49.5 6 11.5
Diabetes
To the Editor: Obesity (BMI . 30 kg/m2) is associated with glomerular hyperfiltration, glomerular hypertrophy, and proteinuria, which are all potentially harmful.1 Although bariatric surgery can achieve sustained long-term weight loss, is recommended by consensus guidelines,2 and is associated with overall decreased mortality,3 renal effects of this acute weight loss on glomerular hyperfiltration are not fully known, and the accuracy of GFR estimating equations before and after the procedure is unclear. Patients with BMI . 40 kg/m2 undergoing bariatric surgery4 were recruited, and comprehensive evaluation (including 24-hour urine collection, serum creatinine, and dietary intake assessment by FFQ5) was conducted at an outpatient visit before and 6 and 12 months after surgery. eGFR was calculated by the CKD-EPI creatinine equation6; mGFR was determined using renal iothalamate clearance.7 BSA was estimated from height and weight.8
Am J Kidney Dis. 2014;64(4):658-665
12 mo
— — —
— — —
Hemoglobin A1c, nondiabetics
5.4 6 0.3
5.0 6 0.5
5.2 6 0.5
Hemoglobin A1c, diabetics
9.1 6 3.7
6.2 6 0.8
6.6 6 1.3
Hypertension Weight (kg)
7 (64%)
—
—
121.2 6 18.4 87.1 6 18.2a 75.7 6 9.2a
BMI (kg/m2)
45.7 6 5.0
32.5 6 5.2a
28.4 6 2.0a
Systolic blood pressure
124 6 13
120 6 16
118 6 10
Diastolic blood pressure
70 6 8
69 6 10
69 6 11
Blood pressure medications
1.4 6 1.3
0.6 6 0.8
0.5 6 0.8b
0.8 6 0.2
0.8 6 0.1
0.7 6 0.1
1,342 6 434 1,019 6 213
1,035 6 255
Serum creatinine (mg/dL) Urine creatinine (mg/24 h) Creatinine clearance (mL/min)
120 6 64
95 6 30
98 6 27
Lothalamate clearance (mL/min)
121 6 32
93 6 34
90 6 24b
BSA-unadjusted eGFRCKD-EPI (mL/min)
108 6 28
102 6 29
94 6 20
Adjusted iothalamate clearance (mL/min/1.73 m2)
95 6 26
83 6 22
85 6 20
BSA-adjusted eGFRCKD-EPI (mL/min/1.73 m2)
84 6 20
92 6 19
90 6 16
Urine albumin (mg/24 h)
Gastric Bypass Surgery and Measured and Estimated GFR in Women
2 (18%)
6 mo
20.5 6 10.4 14.8 6 11.4
17.1 6 10.9
Intake assessment by FFQ Calories (kcal/24 h) Carbohydrates (g/24 h) Fat (g/24 h) Protein (g/24 h) Sugar (g/24 h)
2,248 6 816 1,209 6 795b 1,509 6 784b 285 6 116 157 6 114b 200 6 130b 79.5 6 35 39 6 25b 51 6 25b 108 6 51 65 6 42 71 6 38 105 6 87 129 6 75 90 6 79b
Diet-dependent urine variables Sodium (mEq/24 h) Sulfate (mmol/24 h) Uric acid (mg/24 h) Phosphorus (mg/24 d) Volume (mL/24 h)
170 6 104 94 6 40b 136 6 60 23 6 12 11 6 5b 14 6 6b b 670 6 360 360 6 129 404 6 135b 897 6 417 446 6 172b 553 6 168b 2,091 6 768 1,317 6 540b 1,596 6 569
Note: Unless otherwise indicated, values expressed as mean 6 SD. Abbreviations: BMI, body mass index; BSA, body surface area; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; FFQ, food frequency questionnaire; SD, standard deviation. a P , 0.001 versus baseline. b P , 0.05 versus baseline.
663
