Hippokratia 2019, 23(2): 75-80
Güvercin B1, Kaynar K1, Arıca DA2, Kural BV3, Ulusoy Ş1, Cansız M1, Selçuk LB2, Akyüz A3, Kolaylı CC4
1Department of Nephrology, 2Department of Dermatology, 3Department of Biochemistry, 4Department of Public Health, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
Background: Cutaneous diseases are observed with increasing duration and severity of renal disease in patients with chronic kidney disease (CKD). This study aimed to elucidate dermatological manifestations at different stages of CKD and determine their relationship with interleukin 31 (IL-31), a T-cell cytokine that induces severe pruritus, and uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG), an enzyme that metabolizes ceramide, which plays an important role in moisturizing epidermis.
Methods: In this retrospective cohort study 145 patients with a mean age of 46 ± 17 years were categorized into hemodialysis (group 1), peritoneal dialysis (group 2), kidney transplant (group 3), CKD (group 4), and healthy control (group 5) groups. Serum IL-31 and UGCG levels were measured using enzyme-linked immunosorbent assay, and clinical dermatologists evaluated dermatological manifestations.
Results: In the overall cohort, pruritus was significantly and inversely correlated with glomerular filtration rate and serum hemoglobin and albumin levels (p <0.005). Additionally, pruritus was significantly more frequent in group 2 than in group 5; and significantly less frequent in group 3 than in groups 1, 2, and 4 (p =0.01). In group 4, the patients with longitudinal nail ridges had significantly higher serum IL-31 levels than those without longitudinal nail ridges in their nails (p =0.02). Furthermore, in group 2, the patients with pruritus had significantly lower UGCG levels than those without pruritus (p =0.045).
Conclusion: IL-31 might play a role in the development of longitudinal nail ridges, whereas UGCG might provide protection from pruritus and xerosis in patients with CKD. HIPPOKRATIA 2019, 23(2): 75-80.
Keywords: Chronic kidney disease, interleukin 31, nail and skin disorders, pruritus, uridine diphosphate glucose ceramide glucosyltransferase
Corresponding author: Prof. Dr. Kubra Kaynar, Karadeniz Teknik Üniversitesi, Tıp Fakültesi, Nefroloji Bilim Dalı, 61080 Trabzon, Turkey, tel: +905422415879, fax: +904623252270, e-mail: firstname.lastname@example.org
Chronic kidney disease (CKD), which is defined as the presence of structural and functional kidney damage or decreased kidney function based on an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m2 for three or more months, is a progressive systemic disorder that also affects other organs including skin1,2. Cutaneous involvement increases with the severity and duration of CKD, with a prevalence of 50-100 %. The most common dermatological manifestations of CKD are pruritus, xerosis, and pigmentation3.
Some studies have shown that interleukin 31 (IL-31), a T-cell cytokine predominantly produced by T helper 2 cells, is associated with and a key factor in pruritus4,5. Dorsal root ganglia neurons, the primary afferent neurons in skin, express IL-31 receptor α, which is involved in the neuro-immune cross-talk during acute and chronic pruritus6. For example, IL-31 was reported to inhibit keratinocyte differentiation and compromise the integrity of the skin barrier, particularly in patients with atopic dermatitis7. In addition, peripheral blood eosinophils from patients with bullous pemphigoid were shown to release higher levels of IL-31 than healthy controls8. Conversely, ceramides are vital components of the water barrier that arrange lipids in the stratum corneum of the mammalian skin9. The skin barrier function is primarily assigned to the outer epidermal layer, stratum corneum, which is composed of corneocytes and lipid-enriched extracellular matrix. Epidermal ceramides are synthesized from glucosylated intermediates, namely glucosylceramides, by uridine diphosphate (UDP) glucose ceramide glucosyltransferase (UGCG); these ceramides constitute the essential barrier lipids, comprising ultra-long-chain fatty acids9,10. UGCG is a metabolizing enzyme in the ceramide pathway. UGCG and IL-31 might be involved in the dermatological manifestations of patients with CKD through different mechanisms.
No study to date has reported the correlation between IL-31 or UGCG and skin and nail disorders in patients with CKD. Therefore the present study aimed to determine changes in UGCG and IL-31 levels and determine their relationship with skin and nail disorders in patients with CKD.
Materials and methods
Study design and patient characteristics
This retrospective cohort study included 145 patients (mean age: 46 ± 17 years) who were treated between 2014-2015 in Karadeniz Technical University, Farabi Hospital. The study subjects were categorized into the following groups based on their diagnoses: hemodialysis group (group 1) comprising 30 patients on chronic hemodialysis for 49 ± 44 months (mean age: 58 ± 16 years, mean Kt/V: 1.43 ± 0.24); peritoneal dialysis (PD) group (group 2) comprising 26 patients on chronic PD for 43 ± 37 months (mean age: 37 ± 14 years, mean Kt/V: 2.40 ± 0.78); kidney transplant group (group 3) comprising 30 patients with functioning kidney allografts (mean age: 40 ± 11 years, mean serum creatinine level: 1.48 ± 0.99 mg/dL, average allograft lifespan: 34 ± 50 months); CKD group (group 4) comprising 29 patients with stage 1-5 CKD (mean age: 57 ± 15 years, mean creatinine level: 4.56 ± 2.56 mg/dL); and control group (group 5) comprising 30 healthy individuals (mean age: 34 ± 12 years, mean serum creatinine level: 0.67 ± 0.25 mg/dL). The exclusion criteria were as follows: active infection, psychosis, primary skin disorders, cholestasis, active malignancy, age <18 years, and no consent. There was no patient fulfilling these criteria in our unit. The study groups were not homogenous with respect to age, sex, and duration of CKD due to the relatively low number of patients followed in the study clinic. Clinical dermatologists evaluated the dermatological manifestations of patients, including pruritus, xerosis, alopecia, excoriations, hyperpigmentation, and skin and nail lesions.
Blood samples collected to determine IL-31 and UCGC levels were centrifuged at 3,000 x g for 15 min, and serum samples were stored at -80 °C until analyses. IL-31 and UGCG levels were measured using commercial sandwich enzyme-linked immunosorbent assay (IL-31: lot number: 108993010, catalog number: BMS2041, eBioscience Technology Laboratory, Vienna, Austria; UCGC: lot number: 20150618, catalog number: E0738Hu, Bioassay Technology Laboratory, Korain Biotech Co. Ltd., Shanghai, China). The absorbance of the samples was measured at 450 nm using a VERSAmax (Molecular Devices CA, USA) adjustable microplate reader. Common biochemical parameters, including blood urea nitrogen (BUN), creatinine, and albumin, were measured in all patients and controls according to standard laboratory methods in the clinical laboratory. The study included previous single-pool Kt/V estimates for the hemodialysis group; these values were calculated using the pre- and post-dialysis BUN levels and the pre- and post-dialysis body weight measurements according to the two-BUN method by Daugirdas11. Previous records of dialysis adequacy of PD patients were assessed via calculations of urea clearance Kt/V from 24-h urine and dialysate12. The creatinine and urea clearance rates of the predialysis and kidney transplant patients were included in the study. In the predialysis and transplant groups, eGFR was estimated by the Modification of Diet in Renal Disease equation (MDRD) and by determining the averages of creatinine and urea clearance rates13,14.
All patients provided written informed consent after reading the study protocol. The study protocol was approved by the Ethics Committee of the School of Medicine at Karadeniz Technical University (decision No: 2013/144, date: 05/05/2014).
SPSS 13.0 (SPSS, Chicago, IL, USA) was used for statistical comparisons. Data are presented as numbers and percentages for categorical variables and as mean ± standard deviation or median (minimum-maximum) for continuous variables. The normality of the data distribution was analyzed with the one-sample Kolmogorov-Smirnov test. Normally and nonnormally distributed data between two independent groups were compared using Student’s t-test and the Mann-Whitney U test, respectively. Whereas normally and nonnormally distributed data among three or more independent groups were compared using one-way analysis of variance and the Kruskal-Wallis test, respectively. Post hoc comparisons were performed using Bonferroni’s test. Correlations were performed using Spearman’s test and chi-square test. Results with a p-value of <0.05 were considered to indicate statistical significance.
There were 145 patients, including 76 males, and 69 females, with a mean age of 46 ± 17 years, in the present study. The etiologies of kidney diseases, according to the study groups, are summarized in Table 1. The most common causes of kidney disease were hypertension in groups 1 and 3, glomerulonephritis in group 2, and diabetic kidney disease in group 4. The most common underlying cause of CKD in the entire study cohort was hypertension (31.95 %). The demographic characteristics of the study groups are presented in Table 2. The groups were not homogenous with respect to age, sex, eGFR, and duration of CKD (p <0.001). Additionally, there were differences in the frequencies of pruritus, xerosis, hyperpigmentation, and alopecia among the study groups (Table 3). Specifically, the frequency of pruritus was significantly higher in group 2 than in group 5 and significantly lower in group 3 than in groups 1, 2, and 4 (p =0.01) (Table 3). Conversely, there were no differences in the frequencies of prurigo nodularis (one patient in group 2), keratotic papules, bullous lesions (two patients in group 3), herpes labialis (one patient each in groups 3 and 4) and folliculitis among the five study groups. Lichen simplex chronicus and nephrogenic systemic fibrosis were not observed in any of the patients included.
The correlation analysis of the entire cohort revealed that pruritus was significantly and inversely correlated with eGFR, serum hemoglobin, and serum albumin levels (p =0.024, p =0.002, and p =0.001, respectively; Table 4). Additionally, the patients with xerosis had significantly higher serum ferritin, BUN, creatinine, potassium, and phosphorus levels than those without xerosis (Table 5). The laboratory results of all the study groups are presented in Table 6. There were no significant differences in serum IL-31 and UGCG levels among the study groups (Table 6).
Subungual hyperkeratosis was the most common nail pathology in group 4 (66.1 %), followed by longitudinal ridges (41.7 %). The nail changes were more frequent in patients with lower eGFR than in those with normal eGFR (p =0.043 and p =0.039, respectively). The frequencies of nail findings that were significantly different between groups 4 and 5 are presented in Table 7. The frequency of longitudinal nail ridges was not statistically different between groups 4 and 5. However, in group 4, the serum IL-31levels were significantly higher in patients with longitudinal nail ridges than in those without longitudinal nail ridges. Also, in group 3, the serum IL-31 levels were lower in patients with tinea pedis than in those without tinea pedis (Table 8). Furthermore, the patients with pruritus in group 2, those with xerosis in group 4, and those with splinter hemorrhages in group 3 had significantly lower UGCG levels than those without pruritus, xerosis, and splinter hemorrhages, respectively (p =0.045, p =0.01, and p =0.02, respectively; Table 9).
The relationship between kidneys and skin is closer than generally considered. Cutaneous manifestations of CKD present unpleasant sensation to patients and impair their quality of life with respect to many aspects15. Specifically, pruritus was reported to be associated with poor sleep, anxiety, and depression, even leading to suicide attempts16.
In the present study, xerosis (51.3 %), hyperpigmentation (43.4 %), alopecia (33 %), and pruritus (26 %) were the most frequently observed cutaneous findings of patients with CKD, in agreement with the previous studies17. The reported rate of xerosis is 59-93 % in patients with CKD, and its prevalence is higher in hemodialysis patients, similar to that observed in the present study18. Additionally, we found that the serum ferritin, potassium, phosphorus, and creatinine levels were significantly higher in patients with xerosis than those without xerosis. Dogramaci et al also found a significant relationship between xerosis and high ferritin levels19. We suggest that the unwanted presentation of xerosis and the associated unpleasant symptoms such as pruritus might be mitigated with the optimal control of these parameters. Conversely, the presence of xerosis should raise the suspicion of elevated serum ferritin, potassium, phosphorus, and creatinine levels in these patients.
Diffuse brown hyperpigmentation was the second most common cutaneous finding in the present study. In one study, the prevalence of pigmentary changes was 17.5 %20. There was no significant difference in the frequency of pigmentary changes among groups 1, 2, 3, and 4. Hyperpigmentation is considered to associate with the duration of dialysis, and β2-microglobulin levels21,22. We also found that the dialysis time was significantly longer in patients with hyperpigmentation than in those without hyperpigmentation in group 2. In the present study, the pruritus frequency was highest in group 2 and lowest in group 3. The frequency of anemia was higher among patients with pruritus than those without pruritus. Similarly, pruritus was reported to be related to anemia among predialysis patients in other studies23.
Regarding nail changes, some studies reported that half and half nail was the most common nail disorder in patients with CKD24. In the present study, subungual hyperkeratosis as the most common nail disorder (66.1 % of the patients with CKD), followed by longitudinal ridges, onycholysis, and leukonychia in 41.7 %, 27.8 %, and 20.9 % of the patients with CKD, respectively. These nail disorders were more frequent among patients with higher serum creatinine levels.
There were no differences in serum IL-31 and UGCG levels among the study groups. We also found that IL-31 was significantly associated with only longitudinal ridges and tinea pedis. Previous studies reported that pruritus was associated with IL-31 levels in patients undergoing hemodialysis patients4, whereas no study to date reported an association between nail disorders and IL-31 levels. However, a novel cytokine that controls signaling and regulates a wide range of biological functions such as the induction proinflammatory cytokines and, regulation of cell proliferation and tissue remodeling, IL-31 might play a role in genesis of longitudinal nail ridges based on the higher IL- 31 levels observed in patients with longitudinal nail ridges than in those without longitudinal nail ridges among the patients with CKD in group 425. These differences in results among the study groups might be due to the relatively small sample size of the study groups.
We found that the patients with pruritus in group 2, those with xerosis in group 4, and those with splinter hemorrhages in group 3 had significantly lower UGCG levels than those without these dermatological manifestations. Therefore, it is possible that high serum UCGC levels might provide protection from xerosis and pruritus in patients with CKD by supporting the integrity of the epidermis and the epidermal water barrier, which should be investigated in future studies based on the lack of studies to date on this.
The present study has several limitations that should be acknowledged, including the lack of homogeneity with respect to age, sex, eGFR, and duration of CKD.
In conclusion, dermatological manifestations associated with CKD are common, with the highest rates observed in patients with end-stage CKD. Awareness of these manifestations can aid in the accurate diagnosis and prognosis. Examination of skin and nails can provide clues about albumin, urea, ferritin, and phosphorus levels. Conversely, IL-31 might play a role in the development of longitudinal nail ridges, whereas UGCG might provide protection from pruritus and xerosis in patients with CKD. The findings of the present study should be validated in future studies with larger cohorts.
Conflict of interest
All authors declare that there are no conflicts of interest related to the study.
This study was supported by the Scientific Research Fund of Karadeniz Technical University. We thank Prof. Dr. Gamze Çan for her help in the statistical analyses.
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013; 3: 1-150. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf, date accessed: 5/1/2019.
2. Kurban MS, Boueiz A, Kibbi AG. Cutaneous manifestations of chronic kidney disease. Clin Dermatol. 2008; 26: 255-264.
3. Markova A, Lester J, Wang J, Robinson-Bostom L. Diagnosis of common dermapathies in dialysis patients: a review and update. Semin Dial. 2012; 25: 408-418.
4. Ko MJ, Peng YS, Chen HY, Hsu SP, Pai MF, Yang JY, et al. Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis. J Am Acad Dermatol. 2014; 71: 1151-1159.e1.
5. Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004; 5: 752-760.
6. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014; 133: 448-460.
7. Hänel KH, Pfaff CM, Cornelissen C, Amann PM, Marquardt Y, Czaja K, et al. Control of the Physical and Antimicrobial Skin Barrier by an IL-31-IL-1 Signaling Network. J Immunol. 2016; 196: 3233-3244.
8. Rüdrich U, Gehring M, Papakonstantinou E, Illerhaus A, Engmann J, Kapp A, et al. Eosinophils are a Major Source of Interleukin-31 in Bullous Pemphigoid. Acta Derm Venereol. 2018; 98: 766-771.
9. Jennemann R, Sandhoff R, Langbein L, Kaden S, Rothermel U, Gallala H, et al. Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J Biol Chem. 2007; 282: 3083-3094.
10. Amen N, Mathow D, Rabionet M, Sandhoff R, Langbein L, Gretz N, et al. Differentiation of epidermal keratinocytes is dependent on glucosylceramide: ceramide processing. Hum Mol Genet. 2013; 22: 4164-4179.
11. Daugirdas JT. Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol. 1993; 4: 1205-1213.
12. Tzamaloukas AH, Murata GH, Malhotra D, Sena P, Patron A. Urea kinetic modeling in continuous peritoneal dialysis patients. Effect of body composition on the methods for estimating urea volume of distribution. ASAIO J. 1993; 39: M359-M362.
13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130: 461-470.
14. Dombros N, Dratwa M, Feriani M, Gokal R, Heimbürger O, Krediet R, et al. European best practice guidelines for peritoneal dialysis. 2 The initiation of dialysis. Nephrol Dial Transplant. 2005; 20 Suppl 9: ix3-ix7.
15. Lopes GB, Nogueira FC, de Souza MR, Penalva MA, de Amorim JL, Pisoni RL, et al. Assessment of the psychological burden associated with pruritus in hemodialysis patients using the kidney disease quality of life short form. Qual Life Res. 2012; 21: 603-612.
16. Combs SA, Teixeira JP, Germain MJ. Pruritus in Kidney Disease. Semin Nephrol. 2015; 35: 383-391.
17. Raspha RS, Mahajan VK, Kumar P, Mehta KS, Chauhan PS, Rawat R, et al. Mucocutaneous Manifestations in Patients with Chronic Kidney Disease: A Cross-sectional Study. Indian Dermatol Online J. 2018; 9: 20-26.
18. Khanna D, Singal A, Kalra OP. Comparison of cutaneous manifestations in chronic kidney disease with or without dialysis. Postgrad Med J. 2010; 86: 641-647.
19. Dogramaci AC, Savas N, Ozer B, Duran N. Skin diseases in patients with beta-thalassemia major. Int J Dermatol. 2009; 48: 1057-1061.
20. Solak B, Acikgoz SB, Sipahi S, Erdem T. Cutaneuos findings in patients with predialysis chronic kidney disease. J Eur Acad Dermatol Venereol. 2016; 30: 1609-1613.
21. Murakami K, Wakamutsu K, Nakanishi Y, Takahashi H, Sugiyama S, Ito S. Serum levels of pigmentation markers are elevated in patients undergoing hemodialysis. Blood Purif. 2007; 25: 483-489.
22. Shibata M, Nagai K, Usami K, Tawada H, Taniguchi S. The quantitative evaluation of online haemodiafiltration effect on skin hyperpigmentation. Nephrol Dial Transplant. 2011; 26: 988-992.
23. Solak B, Acikgoz SB, Sipahi S, Erdem T. Epidemiology and determinants of pruritus in pre-dialysis chronic kidney disease patients. Int Urol Nephrol. 2016; 48: 585-591.
24. Koduru S, Delhi N, Parvathina SN, Siva Kumar V. Cutaneous and nail changes in patients of chronic kidney disease: observations in a tertiary care unit from South India. Hemodial Int. 2013; 17: 468-470.
25. Bağci IS, Ruzicka T. IL-31: a new key player in dermatology and beyond. J Allergy Clin Immunol. 2018; 141: 858-866.