Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than three months, with implications for health.[1,2] It has emerged as one of the leading non-communicable causes of morbidity and mortality worldwide. A systematic review and meta-analysis estimated the global prevalence of CKD stages 1 to 5 at roughly 13%,[3] and population surveys in the United States have reported similar figures.[4] The burden is disproportionately high in low- and middle-income countries, where diabetes, hypertension and limited access to renal replacement therapy converge.[5,6]. India carries a particularly heavy load. Estimates of CKD prevalence in the general population range from about 4% to 17% depending on the population screened and the definition applied,[7,8] and the incidence of end-stage renal disease is substantial but poorly captured by registries.[9] The Indian CKD Registry identified diabetic nephropathy as the leading cause of CKD, followed by chronic glomerulonephritis and hypertensive nephrosclerosis.[10] Late presentation, high out-of-pocket costs of dialysis and a shortage of nephrologists mean that many patients reach advanced disease before specialist care begins.[11] The skin is an organ that is affected early and prominently by kidney failure. Progressive loss of renal function results in retention of uraemic toxins, disturbances of calcium, phosphorus and parathyroid metabolism, anaemia, immune dysregulation, autonomic and peripheral neuropathy, and altered sweat and sebaceous gland function. Dialysis, immunosuppressive and other drug therapy, and the underlying systemic diseases add further cutaneous change.[12,13,14] The resulting spectrum is wide: xerosis, uraemic pruritus, pigmentary change, pallor, nail and hair abnormalities, infections, purpura, acquired perforating dermatosis, calciphylaxis, nephrogenic systemic fibrosis and a number of bullous or photosensitive eruptions have all been described.[15,16]. Early studies from Europe and North America documented cutaneous abnormalities in the great majority of uraemic patients,[17,18] and several Indian studies have since confirmed high prevalence, with xerosis and pruritus as dominant complaints.[19,20,21] However, reported frequencies differ widely between series because of differences in the stage of CKD, the proportion of dialysis patients, climatic and socio-economic factors, skin type and the examination method. Indian data that compare patients before and after the start of dialysis, and that relate skin findings to biochemical markers, remain limited. Cutaneous disease in CKD is not merely a cosmetic issue. Pruritus, in particular, disturbs sleep, causes depression and has been associated with poorer survival in haemodialysis patients.[22,23] Some manifestations, such as calciphylaxis and nephrogenic systemic fibrosis, are disabling or life-threatening and demand prompt recognition.[24,25] Dermatological problems are often not volunteered and therefore not examined for in busy nephrology clinics. A better understanding of local patterns can help clinicians anticipate, detect and treat these conditions early. The present study was therefore undertaken with the following objectives: (1) to determine the prevalence and spectrum of dermatological disorders in patients with CKD; (2) to compare the pattern between patients on conservative management and those on maintenance haemodialysis; and (3) to correlate cutaneous manifestations, especially pruritus, with the stage of CKD, underlying aetiology and biochemical parameters.

Study design, setting and duration This was a hospital-based, cross-sectional, observational study conducted in the Departments of Dermatology of a tertiary care teaching hospital in India over a period of 12 months. The study was approved by the Institutional Ethics Committee and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants in a language they understood. Sample size The sample size was calculated using the formula n = Z²pq/d², with an expected prevalence of cutaneous manifestations (p) of 75% based on previously published Indian series,[19,20] a 95% confidence level (Z = 1.96) and an absolute precision (d) of 6%. This gave a minimum of 200 patients, who were enrolled by consecutive sampling. Inclusion and exclusion criteria Patients aged 18 years or above with CKD stage 3 to 5, including those on maintenance haemodialysis (stage 5D) for at least three months, were included. CKD was defined and staged according to the KDIGO criteria using the estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI equation.[2] Patients with acute kidney injury, kidney transplant recipients, those on systemic immunosuppressive therapy, pregnant women, patients with a documented chronic dermatosis (for example psoriasis, atopic dermatitis or vitiligo) that pre-dated the diagnosis of CKD, and patients unwilling to participate were excluded. Data collection and clinical examination A pre-designed, pre-tested proforma was used to record demographic details, residence, occupation, duration and aetiology of CKD, comorbidities (diabetes mellitus and hypertension), duration and frequency of dialysis, and drug history. A detailed dermatological history was elicited, followed by a complete examination of the skin, scalp hair, nails and visible mucosae under natural light, by a dermatologist. Dermoscopy, potassium hydroxide mounts, Gram stain, culture and skin biopsy were performed whenever clinically indicated to confirm the diagnosis. Xerosis was diagnosed by the presence of dry, rough, scaly skin, and pallor was assessed on the conjunctivae, palms and nail beds. Pruritus was defined as itching of the skin present for at least one week and was graded using a 10-point visual analogue scale (VAS): mild (1 to 3), moderate (4 to 7) and severe (8 to 10). Its distribution (generalised or localised), diurnal pattern, effect on sleep, and the presence of secondary changes such as excoriations or prurigo nodules were noted.[26]. Laboratory investigations Venous blood samples were collected (pre-dialysis in haemodialysis patients) for haemoglobin, blood urea, serum creatinine, serum calcium (albumin-corrected), serum phosphorus and intact parathyroid hormone (iPTH). The calcium-phosphorus (Ca × P) product was calculated for each patient. Statistical analysis Data were entered in Microsoft Excel and analysed using SPSS version 25.0 (IBM Corp., Armonk, NY). Categorical variables are presented as numbers and percentages and were compared with the chi-square test (Fisher's exact test when expected cell counts were below 5). Continuous variables are expressed as mean ± standard deviation and compared with the independent-samples t-test or one-way ANOVA. A two-tailed p value below 0.05 was taken as statistically significant.

Demographic and clinical profile A total of 200 patients with CKD were studied. The mean age was 49.6 ± 13.2 years (range 19 to 82 years), with the largest group (29.0%) in the 51 to 60 year bracket. There were 124 males (62.0%) and 76 females (38.0%), a male-to-female ratio of 1.6:1. Diabetes mellitus and hypertension were present in 78 (39.0%) and 164 (82.0%) patients respectively (Table 1). Table 1: Demographic profile of the study population (n = 200) Variable Number (n) Percentage (%) Age group (years) 18–30 14 7.0 31–40 32 16.0 41–50 48 24.0 51–60 58 29.0 61–70 36 18.0 >70 12 6.0 Sex Male 124 62.0 Female 76 38.0 Residence Rural 112 56.0 Urban 88 44.0 Comorbidities Diabetes mellitus 78 39.0 Hypertension 164 82.0 Mean age 49.6 ± 13.2 years. Diabetic nephropathy was the commonest cause of CKD (78 patients, 39.0%), followed by hypertensive nephrosclerosis (26.0%) and chronic glomerulonephritis (17.0%). Most patients were at an advanced stage: 124 (62.0%) had stage 4, stage 5 or stage 5D disease. Seventy-two patients (36.0%) were on maintenance haemodialysis, with a mean duration of dialysis of 28.4 ± 19.6 months (Table 2). Table 2: Aetiology and stage of CKD (n = 200) Variable Number (n) Percentage (%) Aetiology of CKD Diabetic nephropathy 78 39.0 Hypertensive nephrosclerosis 52 26.0 Chronic glomerulonephritis 34 17.0 Chronic interstitial nephritis 14 7.0 Polycystic kidney disease 8 4.0 Obstructive uropathy 8 4.0 Unknown / others 6 3.0 Stage of CKD (KDIGO) Stage 3 (eGFR 30–59) 34 17.0 Stage 4 (eGFR 15–29) 42 21.0 Stage 5, not on dialysis (eGFR < 15) 52 26.0 Stage 5D, on haemodialysis 72 36.0 Overall spectrum of cutaneous manifestations At least one cutaneous manifestation was present in 186 of 200 patients (93.0%); only 14 patients (7.0%) had no abnormality. The commonest finding was xerosis (134 patients, 67.0%), followed by pruritus (59.0%), pallor (48.0%), nail changes (44.0%), infections (35.0%), pigmentary changes (37.0%) and oral mucosal changes (31.0%). Less frequent findings included hair changes, purpura and ecchymoses, asteatotic or stasis eczema, and acquired perforating dermatosis. Two patients (1.0%) had calciphylaxis and two (1.0%) had uraemic frost (Table 3). The mean number of manifestations per patient was 3.7 ± 1.8. Table 3: Spectrum of cutaneous manifestations in CKD (n = 200; multiple manifestations per patient) Manifestation Number (n) Percentage (%) Xerosis 134 67.0 Pruritus 118 59.0 Pallor 96 48.0 Nail changes 88 44.0 Pigmentary changes (hyperpigmentation) 74 37.0 Cutaneous infections (any) 70 35.0 Oral mucosal changes 62 31.0 Hair changes 36 18.0 Eczema (asteatotic / stasis) 22 11.0 Purpura / ecchymoses 20 10.0 Acquired perforating dermatosis 14 7.0 Drug eruptions 8 4.0 Bullous eruption (pseudoporphyria) 4 2.0 Calciphylaxis 2 1.0 Uraemic frost 2 1.0 Infections: patients with at least one infection; some had more than one type. Comparison between non-dialysis and haemodialysis patients The 128 patients not on dialysis (stages 3, 4 and 5) were compared with the 72 patients on haemodialysis. The overall frequency of any cutaneous manifestation did not differ significantly (92.2% vs 94.4%, p = 0.55). However, xerosis (77.8% vs 60.9%, p = 0.015), pruritus (75.0% vs 50.0%, p < 0.001), hyperpigmentation (50.0% vs 29.7%, p = 0.004), nail changes (58.3% vs 35.9%, p = 0.002) and purpura or ecchymoses (16.7% vs 6.3%, p = 0.018) were significantly more common among haemodialysis patients. Pallor, hair changes, fungal and bacterial infections and acquired perforating dermatosis were more frequent on dialysis but did not reach statistical significance (Table 4). Table 4: Cutaneous manifestations in non-dialysis versus haemodialysis patients Manifestation Non-dialysis (n = 128) n (%) Haemodialysis (n = 72) n (%) p value Any manifestation 118 (92.2) 68 (94.4) 0.55 Xerosis 78 (60.9) 56 (77.8) 0.015* Pruritus 64 (50.0) 54 (75.0) < 0.001* Pallor 56 (43.8) 40 (55.6) 0.109 Hyperpigmentation 38 (29.7) 36 (50.0) 0.004* Nail changes 46 (35.9) 42 (58.3) 0.002* Hair changes 20 (15.6) 16 (22.2) 0.243 Fungal infections 24 (18.8) 20 (27.8) 0.139 Bacterial infections 8 (6.3) 10 (13.9) 0.070 Purpura / ecchymoses 8 (6.3) 12 (16.7) 0.018* Acquired perforating dermatosis 6 (4.7) 8 (11.1) 0.087† * Statistically significant (p < 0.05), chi-square test. † Fisher's exact test. Pruritus Pruritus was the second commonest complaint, affecting 118 patients (59.0%). It was mild in 32.2%, moderate in 44.1% and severe in 23.7%. It was generalised in 61.0% and localised, mostly to the back and the limbs, in 39.0%. More than half (54.2%) reported worsening at night, and 40.7% had disturbed sleep. Excoriations were seen in 47.5% and lichenified plaques or prurigo nodules in 11.9% of those with pruritus (Table 5). Table 5: Characteristics of pruritus (n = 118) Characteristic Number (n) Percentage (%) Severity (VAS) Mild (1–3) 38 32.2 Moderate (4–7) 52 44.1 Severe (8–10) 28 23.7 Distribution Generalised 72 61.0 Localised 46 39.0 Associated features Nocturnal exacerbation 64 54.2 Sleep disturbance 48 40.7 Excoriations 56 47.5 Lichenification / prurigo nodularis 14 11.9 Biochemical comparison showed that patients with pruritus had significantly lower haemoglobin, and higher blood urea, serum creatinine, calcium, phosphorus, Ca × P product and iPTH, than patients without pruritus (Table 6). Table 6: Biochemical parameters in patients with and without pruritus Parameter (mean ± SD) Pruritus (n = 118) No pruritus (n = 82) p value Haemoglobin (g/dL) 8.9 ± 1.6 9.8 ± 1.8 < 0.001 Blood urea (mg/dL) 142.6 ± 41.8 118.4 ± 38.2 < 0.001 Serum creatinine (mg/dL) 7.8 ± 2.9 5.9 ± 2.6 < 0.001 Serum calcium (mg/dL) 9.0 ± 0.8 8.6 ± 0.9 0.001 Serum phosphorus (mg/dL) 6.4 ± 1.4 5.3 ± 1.2 < 0.001 Ca × P product (mg²/dL²) 57.6 ± 13.8 45.6 ± 11.2 < 0.001 Intact PTH (pg/mL) 412.6 ± 208.4 286.2 ± 174.6 < 0.001 Independent-samples t-test. Nail, infective and oral changes Eighty-eight patients (44.0%) had one or more nail abnormalities. Half-and-half nails (Lindsay's nails) were the commonest (21.0%), followed by subungual hyperkeratosis (12.0%), ridging or brittleness (10.0%), Beau's lines and Muehrcke's lines (9.0%), koilonychia (7.0%), onycholysis (6.0%), splinter haemorrhages (5.0%) and pitting (4.0%) (Table 7). Table 7: Nail changes (n = 200; multiple changes per patient) Nail change Number (n) Percentage (%) Half-and-half nails 42 21.0 Subungual hyperkeratosis 24 12.0 Ridging / brittle nails 20 10.0 Beau's / Muehrcke's lines 18 9.0 Koilonychia 14 7.0 Onycholysis 12 6.0 Splinter haemorrhages 10 5.0 Nail pitting 8 4.0 Infections were present in 70 patients (35.0%). Fungal infections were the most frequent (22.0%), with tinea corporis or cruris, onychomycosis, pityriasis versicolor and candidiasis. Bacterial infections occurred in 9.0%, viral infections (herpes zoster and warts) in 7.0% and scabies in 6.0% (Table 8). Oral mucosal changes were noted in 62 patients (31.0%), most commonly xerostomia (19.0%), pale mucosa (15.0%) and uraemic fetor (12.0%) (Table 9). Table 8: Cutaneous infections (n = 200) Infection Number (n) Percentage (%) Fungal (total) 44 22.0 Tinea corporis / cruris 16 8.0 Onychomycosis 14 7.0 Pityriasis versicolor 8 4.0 Candidiasis 6 3.0 Bacterial (total) 18 9.0 Furuncle / abscess 7 3.5 Cellulitis 5 2.5 Impetigo / folliculitis 6 3.0 Viral (total) 14 7.0 Herpes zoster 6 3.0 Viral warts 8 4.0 Scabies 12 6.0 Table 9: Oral mucosal changes (n = 200) Oral finding Number (n) Percentage (%) Xerostomia 38 19.0 Pale mucosa 30 15.0 Uraemic fetor (ammoniacal odour) 24 12.0 Coated tongue / glossitis 20 10.0 Stomatitis / oral ulcers 12 6.0 Gingival hyperplasia 10 5.0 Any oral change: 62 patients (31.0%). Diabetic versus non-diabetic patients Among the 78 diabetic patients, xerosis (74.4% vs 62.3%) and pruritus (64.1% vs 55.7%) were more frequent than in non-diabetic patients, though not significantly. Fungal infections were significantly commoner in the diabetic group (33.3% vs 14.8%, p = 0.002). Diabetic dermopathy (23.1%) and acanthosis nigricans (17.9%) were seen only in diabetic patients (Table 10). Table 10: Selected manifestations in diabetic and non-diabetic CKD patients Manifestation Diabetic (n = 78) n (%) Non-diabetic (n = 122) n (%) p value Xerosis 58 (74.4) 76 (62.3) 0.077 Pruritus 50 (64.1) 68 (55.7) 0.240 Fungal infections 26 (33.3) 18 (14.8) 0.002* Bacterial infections 10 (12.8) 8 (6.6) 0.130 Diabetic dermopathy 18 (23.1) – – Acanthosis nigricans 14 (17.9) – – * Statistically significant (p < 0.05), chi-square test. Relation to stage of CKD The burden of cutaneous disease increased progressively with stage. The proportion with at least one manifestation was 82.4% in stage 3, 90.5% in stage 4, 100% in stage 5 not on dialysis and 94.4% in stage 5D. The mean number of manifestations per patient rose from 2.2 ± 1.1 in stage 3 to 4.7 ± 1.7 in stage 5D (ANOVA, p < 0.001), and the prevalence of xerosis and pruritus climbed in parallel (Table 11). Table 11: Cutaneous manifestations according to stage of CKD Stage n ≥ 1 manifestation n (%) Mean number ± SD Xerosis n (%) Pruritus n (%) Stage 3 34 28 (82.4) 2.2 ± 1.1 17 (50.0) 11 (32.4) Stage 4 42 38 (90.5) 3.0 ± 1.3 26 (61.9) 21 (50.0) Stage 5 (ND) 52 52 (100.0) 4.0 ± 1.5 35 (67.3) 32 (61.5) Stage 5D (HD) 72 68 (94.4) 4.7 ± 1.7 56 (77.8) 54 (75.0) p value 0.021 < 0.001 0.015 < 0.001 ND: not on dialysis; HD: haemodialysis. Mean number compared by ANOVA; proportions by chi-square test for trend.

Cutaneous abnormalities were almost universal in this series: 93.0% of 200 patients with CKD had at least one. This is in keeping with the very high frequencies reported in the classic European and American studies and with Indian reports in which cutaneous findings were present in the large majority of patients with chronic renal failure. The marginally lower figure than the highest published series may reflect the inclusion of patients in stage 3, who have fewer manifestations, whereas many earlier reports were confined to dialysis populations.[27] The rise in the mean number of manifestations from 2.2 in stage 3 to 4.7 in stage 5D indicates that skin involvement tracks the severity of uraemia, a relationship also observed in an Indian comparison of dialysis and non-dialysis patients. Xerosis was the commonest finding (67.0%) and was significantly more frequent in haemodialysis patients (77.8%) than in non-dialysis patients (60.9%). Xerosis in CKD is attributed to atrophy of eccrine and sebaceous glands, reduced stratum corneum hydration, and ultrafiltration-related dehydration; abnormal skin barrier function and low skin surface lipids have been demonstrated.[28,29] Indian studies have likewise identified xerosis and pruritus among the most frequent dermatoses in CKD, particularly in patients on haemodialysis. Our finding that a higher proportion of dialysis patients are affected is concordant with these data. Emollient therapy, reduction of hot baths and gentle cleansers should be offered to all patients early in the course of disease. Pruritus affected 59.0% of our patients and 75.0% of those on haemodialysis, a frequency near the upper end of the range reported internationally. In the DOPPS cohort, roughly two-fifths of haemodialysis patients had moderate to extreme itch, and the symptom was linked with poor sleep, depression and a higher risk of death. Other series have reported similarly variable frequencies, partly because of differing definitions.[30,31] The pathogenesis remains multifactorial and not fully understood; proposed mechanisms include accumulation of uraemic toxins, hyperparathyroidism, divalent-ion abnormalities with mast cell activation, systemic inflammation, neuropathic change and an imbalance between the mu- and kappa-opioid systems.[32] In keeping with this, we found significantly higher phosphorus, Ca × P product and iPTH, and lower haemoglobin, among patients with pruritus. An association of itch with elevated calcium and phosphorus has been reported by other investigators,[33] while adequacy of dialysis has been shown to improve pruritus in some studies.[34] The sleep disturbance (40.7%) and nocturnal worsening (54.2%) we recorded stress the substantial effect on quality of life. Treatment options for uraemic pruritus have expanded over the last decades. Ultraviolet B phototherapy was one of the first effective interventions,[35] and gabapentin has been shown to reduce itch in haemodialysis patients in a randomised trial.[36] Kappa-opioid receptor agonists such as nalfurafine have given encouraging results in multicentre studies,[37,38] although availability in India is limited. Given the association between itch and mineral-bone disorder seen in our patients, optimisation of dialysis dose, phosphate binders, vitamin D analogues and anaemia correction should be addressed before or alongside symptomatic therapy. Hyperpigmentation was present in 37.0% overall and in half of the haemodialysis group. A sallow, yellowish-brown or diffuse grey-brown hue, especially over sun-exposed areas, is attributed to retention of urochromes and carotenoids and to increased melanocyte-stimulating hormone activity caused by reduced renal clearance. Pallor, seen in 48.0% of patients, reflects anaemia of CKD, and the significantly lower haemoglobin in patients with pruritus suggests that anaemia is a marker of overall disease burden. The frequent occurrence of purpura and ecchymoses in haemodialysis patients (16.7%) is explained by uraemic platelet dysfunction and repeated heparin exposure during dialysis. Nail changes were seen in 44.0% of our patients, with half-and-half nails in 21.0%. This distinctive pattern, in which the proximal nail is white and the distal portion red-brown, was first characterised by Lindsay and is relatively specific to renal failure.[39] Other changes such as subungual hyperkeratosis, Beau's lines, Muehrcke's lines and splinter haemorrhages were also seen, consistent with earlier Indian and international series. Nail abnormalities were significantly commoner in haemodialysis than in non-dialysis patients (58.3% vs 35.9%), possibly related to a longer duration of uraemia, hypoalbuminaemia and repeated vascular access procedures. Infections occurred in 35.0% of patients. Fungal infections predominated (22.0%), in line with studies that demonstrate a high frequency of superficial mycoses in dialysis populations and were significantly more frequent in diabetic than in non-diabetic patients (33.3% vs 14.8%). Impaired cell-mediated immunity, neutrophil dysfunction, malnutrition, hyperglycaemia, a warm and humid climate and crowded living conditions probably contribute in the Indian setting. The occurrence of scabies in 6.0% of patients is clinically important, since pruritus due to scabies may be misattributed to uraemia and is easily missed. A higher but non-significant frequency of bacterial infection among haemodialysis patients (13.9%) likely reflects vascular access, skin breakdown from scratching and the immunocompromised state. Acquired perforating dermatosis (APD) was present in 7.0% of patients and was commoner in haemodialysis patients (11.1%) than in non-dialysis patients (4.7%), although the difference was not significant. APD is characterised by transepidermal elimination of collagen and elastic fibres, and appears to be provoked by scratching or microtrauma in a setting of diabetes and renal failure.[40,41] Its association with intense pruritus emphasises the importance of effective itch control. Although uncommon, serious cutaneous complications deserve emphasis. Two patients (1.0%) had calciphylaxis, a painful and often fatal condition associated with a raised Ca × P product, secondary hyperparathyroidism, diabetes and warfarin use, in which early recognition and multi-disciplinary management may improve outcomes. Four patients had pseudoporphyria-like bullous lesions, a recognised phenomenon in dialysis patients that is distinct from true porphyria cutanea tarda.[42] Nephrogenic systemic fibrosis was not observed, but it remains an important consideration in any patient with advanced CKD who receives gadolinium-based contrast, and the risk is greatest with agents of linear structure.[43] Our observations in diabetic patients, namely the greater frequency of fungal infection and the exclusive occurrence of diabetic dermopathy and acanthosis nigricans, illustrate how the primary disease modifies the cutaneous picture of CKD. Since diabetic nephropathy is the leading cause of CKD in India this group deserves particular vigilance, including foot and interdigital examination. The clinical implications are clear. First, nearly every patient with CKD has a skin problem, so brief skin, nail and mucosal examination should be part of every nephrology review. Second, because skin disease increases with dialysis vintage and with abnormalities of mineral metabolism, control of anaemia, phosphate and PTH has a dermatological as well as a systemic rationale. Third, a joint nephrology-dermatology clinic would provide timely diagnosis and treatment, particularly in resource-limited settings where the burden of CKD is rising. Limitations The study was cross-sectional and single-centre, which limits causal inference and generalisability. Cutaneous manifestations were recorded at one point in time, and seasonal variation was not assessed. Dialysis adequacy (Kt/V) and inflammatory markers were not measured, and no quality-of-life instrument was applied. Larger multicentre longitudinal studies are needed to confirm these findings.

Dermatological disorders are present in more than nine out of ten patients with CKD, with xerosis, pruritus, pallor, nail changes and pigmentary alterations the most frequent. The burden and variety of lesions increase with advancing stage and haemodialysis, and pruritus is closely related to anaemia, hyperphosphataemia and secondary hyperparathyroidism. Fungal infections are significantly commoner among diabetic patients. Early dermatological evaluation, regular skin care, vigilance for infections, scabies and serious conditions such as calciphylaxis, and optimal control of mineral-bone and haematological parameters can reduce morbidity and improve quality of life in CKD patients.

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