Cutaneous Manifestations in Patients with Chronic Kidney Disease at Obafemi Awolowo University Teaching Hospitals Complex (Oauthc), Ile-Ife, Nigeria

CUTANEOUS MANIFESTATIONS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AT OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX (OAUTHC), ILE-IFE, NIGERIA

A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF THE FELLOWSHIP OF THE FACULTY OF INTERNAL MEDICINE

SUBSPECIALTY: DERMATOLOGY

CANDIDATE’S NAME: DR. ORIPELAYE MUFUTAU MUPHY MB,ChB (2004), Ife

CANDIDATE’S NUMBER: AF/009/09/005/996

DECLARATION

I hereby declare that the writing and execution of the study contained in this dissertation was carried out by me and it is original and has never been presented to any college for fellowship, nor has been submitted elsewhere for publication.

Signature:………………………. Date:…………………………..

Dr Oripelaye Mufutau Muphy

SUPERVISION

This study was carried out under our supervision at OAUTHC, Ile-Ife, Osun State, Nigeria

NAME OF SUPERVISORS: 1. PROFESSOR O. ONAYEMI CONSULTANT, DERMATOLOGY AND VENEREOLOGY, OAUTHC, ILE-IFE. Signature……………………. Date…………………………..

2. PROF (MRS) O A. OLASODE CONSULTANT, DERMATOLOGY AND VENEREOLOGY, OAUTHC, ILE-IFE. Signature……………………. Date…………………………..

3. PROFESSOR F.A. AROGUNDADE CONSULTANT, DEPARTMENT OF MEDICINE OAUTHC, ILE-IFE. Signature……………………. Date…………………………..

iii

HEAD OF DEPARTMENT’S CERTIFICATION

I hereby certify that the writing and execution of the study contained in this dissertation was carried out by Dr Oripelaye Mufutau Muphy under the supervision of Prof. O. Onayemi, Prof (Mrs) O. A. Olasode, and

Prof. F. Arogundade.

Signature:…………………………………

Prof. B. A. Kolawole

Department of Medicine,

Obafemi Awolowo University Teaching Hospitals Complex.

Ile-Ife, Osun state.

DEDICATION

To God for his faithfulness.

My wife Elizabeth Fiyinfoluwa and our two kids Ododo-Oluwa and

Otito-Oluwa.

ACKNOWLEDGEMENTS

I like to acknowledge my teachers and supervisors Prof. O. Onayemi,

Prof. O. Olasode and Prof. F.A. Arogundade. Their instructions, teaching and guardianship have largely helped in shaping my training. I am grateful to Dr. U. Ezejiofor and Dr L. Oke for painstakingly reading this manuscript and making useful suggestions. Dr F. Olanrewaju has been very supportive.

I will also like to appreciate the management of Obafemi Awolowo

University Teaching Hospitals Complex, for giving me the opportunity to be trained in the institution.

TABLE OF CONTENTS

TITLE PAGE i

DECLARATION ii

SUPERVISION iii

HOD’S CERTIFICATION iv

DEDICATION v

ACKNOWLEDGEMENTS vi

TABLE OF CONTENTS vii

LIST OF TABLES viii

LIST OF FIGURES ix

KEYS TO ABBREVIATIONS x

SUMMARY 1

CHAPTER ONE: INTRODUCTION 3

CHAPTER TWO: LITERATURE REVIEW 5

CHAPTER THREE: AIMS AND OBJECTIVES 24

CHAPTER FOUR: JUSTIFICATION OF STUDY 25

CHAPTER FIVE: METHODOLOGY 26

CHAPTER SIX: RESULTS 33

CHAPTER SEVEN: DISCUSSION 58

REFERENCES 72

APPENDIX:

1. PROFORMA 86 2. ETHICAL APPROVAL 89

vii

3. INFORMED CONSENT SHEET 90

LIST OF TABLES

TABLE 1 General characteristics of the patients

TABLE 2 The causes of chronic kidney disease

TABLE 3 The stages of chronic kidney Disease

TABLE 4 The prevalence of cutaneous manifestations among patients with

chronic kidney Disease

TABLE 5 The prevalence of infections among patients with chronic kidney

disease

TABLE 6 Cutaneous changes in patients with stage III, IV and V of chronic

kidney disease

TABLE 7 Association between the stages of chronic kidney disease and the

presence of cutaneous manifestations

TABLE 8 Association between the stages of chronic kidney disease and the

presence of specific cutaneous manifestations

viii

LIST OF FIGURES

FIGURE 1: The general prevalence of cutaneous manifestations in patients with

chronic kidney Disease

FIGURE 2: The type of treatment received by patients with chronic kidney disease

FIGURE 3: Xerosis on the legs of a patient with CKD

FIGURE 4: Hyperpigmentation shown on palms of a CKD patient with diffuse

hyperpigmentation

FIGURE 5: Half and half nail

FIGURE 6: Half and half nail

FIGURE 7: Tinea unguium in patient with CKD

FIGURE 8: Chronic paronychia

FIGURE 9: Pityriasis versicolor

FIGURE 10: Icthyosis in patient with CKD

FIGURE 11: Follicular hyperkeratosis in patient with CKD

FIGURE 12: Planter hyperkeratosis in patient with CKD

FIGURE 13: Alopecia in patient with CKD

FIGURE 14: Chronic leg ulcer in CKD patient

KEYS TO ABBREVIATIONS

ARF - Acute renal failure

ADPKD - Adult polycystic kidney disease

BOO - Bladder outlet obstruction

CGN - Chronic glomerulonephritis

CKD - Chronic kidney disease

CRF - Chronic renal failure

GFR - Glomerular filtration rate

HPT - Hypertension

NSF - Nephrogenic systemic fibrosis

NFD - Nephrogenic fibrosing dermopathy

MOPD - Medical out-patient department

PCT - Porphyria cutanea tarda

PTH - Parathyroid hormone

SUMMARY

INTRODUCTION

Cutaneous manifestations are common in patients with chronic kidney disease

(CKD) with prevalence ranging from 50-100% documented in previous studies.

Various cutaneous manifestations are reported in patients with CKD, and these vary from the more common xerosis, pruritus, hyperpigmentations, to the less common manifestations such as nephrogenic systemic fibrosis, bullous dermatosis of haemodialysis . These manifestations impact greatly on the quality of life of patients with CKD and in some instances have been reported to increase the morbidity and mortality in these patients.

AIMS AND OBJECTIVES

The general objective of this study was to determine the pattern of skin diseases in patients with CKD. The specific objectives were to determine the frequency of specific skin disease, documenting variation in cutaneous manifestations seen in stages 3, 4 and 5 of CKD, and to determine the peculiar skin manifestations in haemodialysis dependent (stages 5) CKD patients.

METHODOLOGY

The study was a cross sectional study conducted among patients with CKD attending the medical outpatients department of the Obafemi Awolowo University

Teaching Hospitals Complex, (OAUTHC) Ile-Ife. One hundred and twenty patients who met the inclusion criteria were recruited for the study after informed consent were obtained.

With the aid of a proforma, relevant clinical information were obtained from the patients and the patients also had appropriate investigations done to confirm the diagnosis of cutaneous disease and to determine the presence as well as the stage of

CKD. Patients with systemic diseases such as diabetes mellitus and systemic lupus erythematosus whose cutaneous manifestations could confound those of CKD were excluded from the study.

RESULTS

The occurrence of cutaneous changes was observed in the study to be 57.5%.

Xerosis was the commonest cutaneous manifestation observed. Other skin changes observed in these patients included, pruritus, chronic leg ulcer, hyper-pigmentary skin changes, icthyosis, plantar hyperkeratosis, follicular hyperkeratosis, arteriolar shunt dermatitis, alopecia, fungal and bacterial infections. Nail changes such as half and half nail, Mee’s lines were also documented. The pattern of cutaneous manifestations was not observed to vary significantly with the stages of chronic kidney disease.

CONCLUSION

Cutaneous manifestations were common in patients with CKD with xerosis being the commonest. Shunt dermatitis was found only in haemodialysis dependent patients.

CHAPTER ONE

INTRODUCTION

There is scarcely any systemic disease that has no cutaneous manifestation.

Diseases of the kidneys are no exception, as they present with cutaneous manifestations such as pruritus, calciphylaxis, nephrogenic fibrosing dermopathy, abnormal pigmentation and abnormal keratinization.1-3 Cutaneous infections, precancerous disorders, nail and hair changes have all been described.1-3 These cutaneous changes can form part of the basis for evaluation and management of chronic kidney disease (CKD).

The pattern of cutaneous manifestations of chronic kidney disease has been documented in various studies. Thomas et al studied 99 patients with CKD and observed 96 out of the 99 patients had at least one cutaneous manifestation attributable to CKD.1 Similar prevalence of 97% was documented in patients with end stage renal disease.2 Another study found that 89.1% of patients with CKD had at least one cutaneous manifestation.3 Nunley et al, reported that 50-100% of their patients with CKD had at least one cutaneous manifestation.4

Chronic kidney disease is very common globally with the prevalence approaching epidemic proportion. In a family practice population in Ile-Ife, a prevalence of 12.4% was reported by Afolabi et al.5 In the United States and Europe,

CKD is estimated to affect 10% to 13% of adults.6,7

The cutaneous manifestations of CKD could result from failure of excretory function, failure of endocrine function or following the management of CKD. Chronic kidney disease leads to accumulation of toxic waste materials in the body. Some of these waste materials have been implicated in the pathogenesis of cutaneous

3 manifestation of CKD.8 An example is bullous disease which is thought to be due to reduced excretion of porphyrin.8

The failure of endocrine function in CKD is thought to underlie the pathophysiology of pallor. This results from reduced production of erythropoietin causing anaemia. Some skin diseases such as uraemic pruritus in CKD patients were found to improve with administration of erythropoietin.9,10 Another endocrine function of the kidney includes the hydroxylation of 1-α hydroxycholecalciferol at position 25. The dysregulation of vitamin D and vitamin A has been proposed as a probable mechanism in the aetiology of acquired perforating dermatoses.11-13

Cutaneous manifestations, like shunt dermatitis, bullous diseases of haemodialysis are more specific to patients on dialysis while transplant patients have cutaneous manifestations attributable to immunosuppressant medications.14-16

Morbidity related to cutaneous manifestations of chronic kidney disease could be considerable.17 Uraemic pruritus is recognized as an indicator of increased risk of mortality in CKD.18 Calciphylaxis is associated with high mortality, with 1 year survival rate of 45% and 5 year survival rate of 35%.19-22 In view of the related morbidity of cutaneous conditions in patients with CKD, a study of its cutaneous manifestations will help to facilitate its diagnosis and management thereby reducing mortality.

CHAPTER TWO

LITERATURE REVIEW

Chronic kidney disease (CKD) is defined as kidney damage with or without decreased glomerular filtration rate (GFR), manifested as pathological abnormalities or markers of kidney damage.23 It has also been defined as GFR of less than

60ml/min/1.73m2 for greater than three months.23 It is a progressive disease that is characterized by an increasing inability of the kidney to excrete the products of protein metabolism, such as urea, maintain normal blood pressure and haematocrit. It also leads to derangements in the homeostasis of sodium, water, potassium and acid- base balance. The skin is also affected in the course of chronic kidney disease with about 89.1% to 97% of the patients presenting with cutaneous manifestations.1-3

Nunley et al reported that 50-100% of patients have at least one cutaneous manifestation.4

Afolabi et al documented the prevalence of CKD to be 10.4% when CKD was defined by persistent GFR below 60ml/min/173m2 and 12.4% when CKD was defined by persistent proteinuria.5 Chronic kidney disease is estimated to affect 10% to 13% of adults in the United States and Europe.6,7

The pathophysiology of chronic kidney disease

The primary function of the kidney is to maintain a constant extracellular fluid volume composition.24 This function is well preserved until late in the course of CKD.

Nephrons are lost due to the disease process, and the remaining nephrons undergo remarkable adaptive changes.24 These together compensate for the acquired loss of

5 renal function.24 However, despite the initial compensation, the progression of the disease continues. Two concepts proposed to enhance the progression of CKD are

‘Intact nephron hypothesis’24 and the ‘Trade-off hypothesis’.24

The ‘intact nephron hypothesis’ states that adapted nephrons behave like normal nephrons. Solute excretion increases markedly in each nephron, and this leads to osmotic diuresis thus causing failure in the regulation of sodium and water, with impaired sodium and water conservation.24 The kidney loses its ability to conserve fluid in the extracellular volume. The renal concentrating ability is lost, as well as the ability of the remaining nephrons to adjust to low and high intake of sodium, water, potassium and other dietary solutes.24

The “Trade – off” hypothesis on the other hand involves increased excretion of phosphate but at the expense of elevated parathyroid hormone level.24 As the GFR falls, the serum phosphate level rises, plasma calcium decreases, and the parathyroid hormone level increases thereby decreasing tubular reabsorption of phosphate and hence the serum phosphate returns to normal.24 Similarly, normal serum potassium level can be maintained at the expense of elevated aldosterone secretion.24

Some endocrine functions of the kidney are also lost as the kidney disease progresses. The kidney is responsible for hydroxylation of 1α hydroxy-cholecalciferol to 1,25dihydroxycholecalciferol. Dysregulation of vitamin D and vitamin A has been proposed to contribute to the pathogenesis of acquired perforating dermatoses.11-13,25

The erythropoietin produced by the kidneys decreases as CKD progresses and the

GFR decreases. This leads to progressively severe normochromic normocytic

6 anaemia and explains the pallor seen in patients with CKD. Administration of erythropoietin has been shown to improve pruritus in patients with CKD.9

Chronic kidney disease is a progressive and irreversible disease. Based on the

GFR, the National Kidney Foundation has suggested five stages for CKD.

 Stage 1 kidney damage with GFR ≥90 mls / min 1.73m2

 Stage 2 kidney damage with GFR 60-89 mls / min 1.73m2

 Stage 3 kidney damage with GFR 30-59 mls / min 1.73m2

Stage 3A kidney damage with GFR 45-59 mls / min 1.73m2

Stage 3B kidney damage with GFR 30-44 mls / min 1.73m2

 Stage 4 kidney damage with GFR 15-29 mls / min 1.73m2

 Stage 5 kidney damage with GFR <15 mls / min 1.73m2 or patients on

maintenance dialysis.23

There is no cure for CKD and the goals of therapy include slowing down the progression of kidney disease, treating the underlying cause, replacing lost kidney function and treating complications of the disease. The cutaneous complications affect the morbidity and subsequently reduce the quality of life of affected patients.17

The replacement of kidney function in form of dialysis, and renal transplantation has attendant cutaneous complications such as bullous disease of haemodialysis8 and complications relating to use of immunosuppressants in renal transplant patients.16

CUTANEOUS MANIFESTATIONS IN CHRONIC KIDNEY DISEASE

A wide variety of skin diseases occur in patients with chronic kidney disease.26

The cutaneous manifestations include pigmentary changes like hyperpigmentation,26,27 pallor,4,26 abnormal keratinization like xerosis and icthyosis.26

Uraemic pruritus is also a common manifestation which can present as prurigo nodularis in its severe form.28-30 Acquired perforating dermatoses, porphyria cutanea tarda, and pseudoporphyria have also been described.15,31 Calciphylaxis and benign nodular calcification are rare but portend worsening morbidity and mortality associated with CKD when present.19-22,32

Other cutaneous manifestations such as ‘half–and–half’ nails,33 transverse leuconychia, onycholysis, onychomycosis, subungual hyperkeratosis, and splinter haemorrhage have all been described as part of nail changes in patients with chronic kidney disease.26,27 Other skin appendages like the hair are not spared in patients with chronic kidney disease. Brittle hair, alopecia and sparse body hair are among the described cutaneous manifestations of CKD.26,27

Nephrogenic systemic fibrosis is a rare manifestation that has also been reported.34 Bacteria, fungal and viral skin infections are not uncommon in patients with CKD.35

The prevalence of cutaneous manifestations in CKD has been reported in various studies to range from 50 to 100%.1-4 The prevalence of specific skin disease also varies. Uraemic pruritus was reported to be 42-52%.28-30A range of 15-49% has also been reported for patients with chronic kidney disease36 while calciphylaxis has been reported as 4% in dialysis patients and 1% in other patients with CKD.19,32

Uraemic pruritus

Uraemic pruritus is noted to be present in 42-52% of patients with CKD.28-30

Ponticelli et al reported a range of 15-49% in patients with chronic kidney disease36Some other studies have reported a prevalence of about 50 - 90% in patients undergoing dialysis.4,9,15,37,38

The pruritus occurs intermittently and lasts only a few minutes in some patients, while in others it may be severe and prolonged, occurring both during the day and at night.29 It can be localized, affecting the back, limbs, chest and head.28

About 20-50% of patients present with generalized pruritus.28 Sweat and stress have been shown to worsen pruritus while cold and hot baths relieve it.17 Opinion however varies on the effect of dialysis on pruritus. Some studies showed that pruritus is aggravated by dialysis while others showed that dialysis relieves pruritus.28,39 The skin may appear normal or mildly xerotic. In some patients itching and scratching may lead to cutaneous lesions such as prurigo nodularis, keratotic papules in generalized pruritus and lichen simplex in localized pruritus.30,40 Secondary bacterial infection may also occur.30

Pruritus adversely affects the patient’s quality of life, causes sleep impairment, chronic fatigue and may have a negative influence on mental and physical capacity.17

The aetiology of pruritus in chronic kidney disease is poorly understood. However, two hypotheses on the pathophysiological mechanism have been postulated. The immune hypothesis and the opioid hypothesis.17,39,41

The immune hypothesis considers uraemic pruritus as an inflammatory systemic disease. This concept is supported by the fact that symptoms of pruritus improve following administration of immunosuppressive therapy such as ultraviolet

B(UVB), thalidomide and tacrolimus.17,39 Serum levels of inflammatory biomarkers like C- reactive protein and interleukin–6 have been documented to be higher in uraemic pruritus.42

The opioid hypothesis proposes that uraemic pruritus is a result of change in the endogenous opioidergic system, with over-expression of opioid µ-receptor in dermal cells and lymphocytes.41,43 Increased activity of the opioid µ-receptor, and down regulation of opioid k-receptor caused by the increased serum β-endorphin to dynorphinA ratio, explains the pruritus in patients with CKD.44 This is supported by the fact that k-receptor agonists like nalfurafine and µ-receptor antagonists like naltrexone reduce the severity of pruritus.45

Other factors implicated in the pathogenesis of uraemic pruritus include parathyroid hormone and divalent ions like calcium, phosphate and magnesium.

However, the levels of parathyroid hormone, calcium and phosphorus, have poor correlation with severity of pruritus. This implies that other factors are also important in the pathogenesis of pruritus.46

Histamine release by mast cells in response to substance-P, have also been implicated in the pathogenesis of uraemic pruritus. There is an increase in the number of dermal mast cells in patients with CKD and increased plasma levels of tryptase and histamine in patients with severe uraemic pruritus.47

Xerosis facilitates uraemic pruritus.47 It results from atrophy of sweat glands and sebaceous glands, with decreased dermal hydration.48

The treatment of uraemic pruritus includes the use of topical applications such as emollients (to hydrate stratum corneum),49 capsaicin cream and tacrolimus.

Preparations that contain natural lipids and endocannabinoids like fish oil, olive oil, primrose oil etc have also been used.50-52 Capsaicin reduces uraemic pruritus by reducing the level of substance P in cutaneous type c sensory nerve endings.53 The use of tacrolimus was demonstrated to improve pruritus without significant side effects.54

Several systemic therapies have also been found to be helpful. Ultraviolet B

(UVB) is effective in treatment of pruritus.55 The carcinogenic effect of radiation may be deplorable in fair complexioned individuals. The anticonvulsant gabapentin, reduces uraemic pruritus when given after dialysis.56 Naltrexone, an µ-opioid – receptor antagonist reduces pruritus45although large placebo – controlled trial could not confirm a significant difference in naltrexone and placebo.57 Nalfurafine, a K- opioid – receptor agonist, has been shown to reduce pruritus.45 Oral use of activated charcoal has also been shown to be beneficial.58 Thalidomide has also been shown to be efficacious in management of pruritus in CKD patients,59 though it is teratogenic.

Administration of erythropoietin induces a reversible reduction in plasma histamine concentration and decreases pruritus.9

Other treatment modalities include optimization of dialysis, subtotal parathyroidectomy and renal transplantation.37,38

Calciphylaxis

Calciphylaxis is not as common as uraemic pruritus. The incidence of calciphylaxis is estimated to be 4% in patients on dialysis, and less than 1% in patients with CKD.19,32 Calciphylaxis is associated with a 1-year survival rate of

45%.19-22,32

Calciphylaxis has a gradual onset, with livedo reticularis–like lesions which gradually transform over days or weeks into painful, subcutaneous, purpuric plaques and nodules. These later become necrotic ulcers covered with sloughs or dry scab.22

Calciphylaxis affects the abdomen, buttocks, thighs, and less commonly the distal extremities.19,20,60 Mortality however is reduced when the extremities are affected.61

The pathophysiology of calciphylaxis has been linked to imbalance between inducers and inhibitors of calcification of vascular walls.62 Osteopontin and morphogenic protein-4 induces vascular calcification and both are increased in vascular smooth muscle and dermal cells respectively.63 Vascular smooth muscle cells transform into osteoblast – like cells and express bone related proteins such as osteocacin, bone sialoprotein, type I collagen and osteopontin.64 Decreased production of inhibitors of vascular calcification such as fetuin A and osteoprogerin by inflammatory changes also occurs in uraemia.65 Aside from the imbalance between the inhibitors and inducers of calcification, changes in calcium and phosphate metabolism also contribute to the pathogenesis of calciphylaxis. The use of vitamin D analogues, hyperparathyrodism and deficiency of protein C or protein S favors calcification.32

Factors associated with increased risk of developing calciphylaxis are obesity, diabetes mellitus, female sex, caucasian, increased duration on renal replacement therapy and use of coumarin anticoagulants.19-22 The use of vitamin D analog, calcium containing phosphate binders, iron-substitution therapy and corticosteriods are also associated with increased risk.19-22

Laboratory evaluation usually demonstrates marked elevation of parathyroid hormone (PTH). The serum calcium and phosphate levels and calcium – phosphate product (Ca mg / dl x P04 mg/dl) are frequently only minimally elevated or it may be normal.61

The treatment of calciphylaxis focuses on wound care, provision of systemic antibiotics and use of analgesia. Split-skin grafting have also been used in wound care.20,21 Other treatment measures include restoring calcium and phosphate balance by use of dialysis, use of non-calcium phosphate binders such as sevelamer, and the discontinuation of vitamin D analog. Parathyroidectomy will be necessary when there is hyperparathyroidism.61,66 Sodium thiosulfate, reduces metastatic tissue calcification by chelating calcium from soft tissues.67 Oral and intravenous biphosphonate such as etidronate and pamidronate have also been used.68 Hyperbaric oxygen increases oxygen delivery to tissues and promotes wound healing in calciphylaxis.69

Nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) also known as nephrogenic fibrosing dermopathy(NFD), was first described in 1997.34 Like calciphylaxis, it is an

13 uncommon cutaneous manifestation of chronic kidney disease with about 215 confirmed cases reported as at 2006.70,71,72 This disorder resembles scleromyxedema in some of its aspects.70,71 It occurs in patients with chronic kidney disease, renal transplant patients and in patients with acute kidney injury.34

Patients with NFD, present with painful progressive fibrosis and thickening of the skin, with occasional involvement of the lungs heart, liver and esophagus.72

Patients also have progressively developing erythematous, sclerotic dermal plaques on the arm, and leg with sparing of the head and neck.72 Pruritus is also a common presentation.72 When a scleroderma – like plaque occurs adjacent to a joint, it results in contracture.72,73 The secondary complications reported to be associated with NSF include, increased hospital stay as well as 30% mortality.72-74 Exposure to gadolinium

(a contrast) before the onset of nephrogenic systemic fibrosis was confirmed in over

95% of reported cases.75 This finding reinforces the role of gadolinium in the pathogenesis of NSF. The half-life of gadolinium is increased from 1.3hrs to 60hrs when the GFR falls below 15ml/min/1.73m2.76 This increases the amount of dissociated gadolinium, with subsequent increased uptake by macrophages. The gadolinium uptake by macrophages attracts fibrocytes positive for CD 34 and procolagen-I.77,78 These fibrocytes can transform to fibroblast–like cells and produce hyaluronan and sulfated glycosaminoglycan.77,78 The tissue level of gadolinium has been found to be 35–fold to 150-fold higher in patients with NSF than in healthy volunteers exposed to gadolinium contrast agent.79 This further supports the gadolinium hypothesis.

A number of factors increase the risk of NSF. These include hypercoagulable state, recent vascular surgery, and deep venous thrombosis, failure of transplanted kidney, hepatic disease, hyperphosphatemia and use of high dose recombinant erythropoietin.72-74 Exposure to gadolinium based magnetic resonance imaging (MRI) contrast agent is associated with development of NSF in patients with chronic kidney disease.

The histopathology of nephrogenic systemic fibrosis resembles that of scleromyxedema, with proliferation of fibroblast and increased dermal and septal collagens and mucin.71 Dendritic cells and histiocytes are also present.80,81

There is no effective treatment at the moment. Various agents that have been tried with variable responses include corticosteroids, thalidomide, cyclophosphamide, sirolimus, cyclosporine, topical calcipotriene, psoralen and ultraviolet A (PUVA), imatinib mesylate, sodium thiousulphate and extracoporal photoresis.72-72

Physiotherapy may help to improve contracture.

Preventive measures in the management of NSF include avoidance or modification of risk factors mentioned above. Gadolinium base contrast is also avoided in patients with CKD.81 Where it is unavoidably indicated associated dialysis has been suggested.76

Pigmentary changes

Two types of hyperpigmentary skin changes are described in patients with

CKD.26,27 These include brown diffuse hyperpigmentation, and the yellow- grey discoloration.26,27 Diffuse hyperpigmentation occurs in about 43% of patients on

15 dialysis.26 Prevalence of 32.3% and 7.5% were reported in separate studies.1,3 Brown diffuse hyperpigmentation occurs in sun exposed areas. It arises as a result of accumulation of melanin and chromogens in the basal layer and superficial dermis following the inability of the kidney to excrete beta-melanocyte stimulating hormone

(β-MSH).4,26,82 Hyperpigmented macules localized to the palms and soles have also been reported by Pico et al83 and this is also attributable to failure of excretion of beta melanocyte stimulating hormone.26,83

The yellow – grey discoloration of the skin has been reported in 40% of patients with CKD.26,83 This is due to the retention of lipochromes and carotenoids in the epidermis and subcutaneous adipose tissue.4,83

Sunscreen, wearing protective clothing and avoidance of sunlight are beneficial in the management of these pigmentary changes.

Pallor

Pallor resulting from anaemia is commonly seen in patients with CKD.4,26

Anaemia in chronic kidney disease is secondary to reduced production of erythropoietin and increased haemolysis.26 Erythropoietin is employed in the treatment.4

Purpura and ecchymoses

Other cutaneous manifestations, described in patients with chronic kidney disease, are purpura and echymoses.26,27 About 20% of patients with CKD who are on dialysis were reported to present with easy bruising.26 This is as a result of vascular

16 fragility, abnormal platelet function, and use of heparin in dialysis.26 Purpura may also result from thrombocytopenia. Treatment with dialysis partially corrects this disorder.27

Abnormal keratinization

Changes attributable to abnormalities in keratinization of the skin in patients with CKD are common. These changes include xerosis, icthyosis, follicular keratosis, onychodystrophy and plantar hyperkeratosis.84,85

Cutaneous dryness (xerosis) is the most frequent cutaneous abnormality in uraemic patients.26 The prevalence of 66.7% was reported by Thomas et al.1 It varies from mild to severe in intensity26 and the extensor surface of legs and arms are most severely affected, with associated large dark scales.26 The pathogenesis of xerosis in patients with CKD is due to reduction in the size of eccrine sweat glands, as well as high dose diuretic treatment.26 Plasma and skin content of vitamin A and its carrier retinol-binding protein, which are increased in uraemic patients, have also been implicated in the pathogenesis.4,86,87

Acquired icthyosis has been noted in some patients with chronic kidney disease.4 A few patients have presented with keratosis pilaris–like lesions.26

Emollients are effective in the treatment of xerosis.4,26

Uraemic frost

Uraemic frost was a frequent cutaneous manifestation of chronic kidney disease in the pre-dialysis era.4

Uraemic frost occurs when the blood urea nitrogen level is more than 250 –

300mg/dl.4 The urea concentration in sweat is increased and after evaporation, there is a deposition of urea crystals on the skin surface.4,26,27 Uraemic frost presents as white or yellowish coating on the bearded area and other parts of the face, neck and trunk.26

Cutaneous infections

Cutaneous infections are noted in patients with chronic kidney disease. The impaired cellular and hormonal immunity predisposes these patients to cutaneous infection35.The common fungal skin infections in patients with chronic kidney disease are onychomycosis, tinea pedis, and pityriasis versicolor.26 The viral skin infection reported in patients with chronic kidney disease include, warts, herpes simplex and herpes zoster4,26. Bacterial skin infections such as acute paronychia, furuncles, carbuncles and impetigo have also been reported.26

Nail changes

The ‘half–and–half’ nail, also known as Lindsay’s nail is a typical presentation in patients with chronic kidney disease.33 It occurs in 15 to 50% of patients on dialysis.88 The distal portion of each nail is red, pink, or brown.33 It occupies 20 to

60% of the total nail length and is well demarcated with a proximal white portion.33

There is an increase in the number as well as increased wall thickening of the capillaries.33 The colour does not fade with pressure.4

Other changes observed in the nails of patients with chronic kidney disease are leukonychia, koilonychia, subungual hyperkeratosis, onycholysis, Mee’s lines,

Muehrcke’s lines, Beau’s lines and splinter hemorrhages.26,27 The “half-and–half" appearance disappears several months after successful renal transplantation.4

Hair changes

Hair is another skin appendage other than nail that is commonly affected in patients with chronic kidney disease.26,27 Hair changes have been reported in 10-30% of CKD patients who are on dialysis.26 The most common hair disorder in dialysis patients is diffuse hair loss of the scalp.26,27,88 The alopecia may be related to telogen effluvium (associated with severity of illness), xerosis, pruritus, or due to drugs

(heparin, antihypertensives, lipid lowering agents) used in these patients.4,27 Hair discoloration and fine brittle hair are also seen in patients with chronic kidney disease.26,27,89 Sparse body hair and dryness of the hair have also been described.26,27

Dry and lusterless hairs are due to decreased sebum production.26

Electron microscopy studies of the hair shaft, shows that all dialysis patients investigated had some hair shaft abnormalities.90The shaft abnormalities noted on electron microscopy included irregular diameter, flattening, as well as twisting of the shaft.90 Disordered depositions of the cuticular tiles were also noted.90

Treatment of hair changes include nutritional supplementation, and treatment of xerosis as well as the pruritus.4,26,27

Abnormal changes in oral mucosa

Changes affecting the oral mucosa have been reported in patients with chronic kidney disease.26,27 Xerostomia, macroglossia, scrotal tongue, furred tongue, gingivitis, ulcerative stomatitis, angular chelitis and uraemic breath have all been

19 described in patients with chronic kidney disease.26,27 The prevalence of macroglossia which was described to be 92% in patients with CKD is second only to that of xerostomia which is the commonest mucosal change in CKD.26

Ulcerative stomatitis which occurs when blood urea is greater than

150mg/100ml is enhanced by poor oral hygiene.26 High concentration of urea in the saliva, which is broken down to ammonia, produces the ammoniacal odour (uraemic fetor) found in some patients.26 Uraemic fetor is common when blood urea level is more than 200mg/100ml.

Angular cheilitis which may be found in association with coated tongue has also been noted in patients with CKD.26 Treatment is to ensure good oral hygiene and good nutritional supplementation.26

Precancerous and cancerous lesions

Immune suppression, which underlies the susceptibility to cutaneous infections, is also responsible for precancerous and cancerous changes observed in patients with chronic kidney disease.26 Basal cell carcinoma which occur in about 4% of patients on maintenance haemodialysis is the commonest tumour.26,91 Multiple actinic keratoses in sun exposed areas which may progress to squamous cell carcinoma have been described.26

CUTANEOUS MANIFESTATIONS ASSOCIATED WITH HAEMODIALYSIS

The cutaneous manifestations of CKD discussed so far in this review affect patients with CKD with or without maintenance haemodialysis. However, bullous

20 disease of haemodialysis (pseudoporphyria cutanea tarda), acquired perforating dermatoses and shunt dermatoses are more specific to patients on haemodialysis.

Bullous Disease of Haemodialysis

Pseudoporphyria cutanea tarda, which is a bullous disorder clinically and histopathologically indistinguishable from porphyria cutanea tarda, was described by

Gilchrest etal in 1975.15 Porphyria cutanea tarda (PCT) has been described in 5% of patient undergoing haemodialysis.8 It presents with bullae, on the dorsal surface of hands and feet, and sometimes on the face,31 and is frequently associated with facial hyperpigmentation and hypertrichosis.31 Bullous dermatosis of dialysis or pseudoporphyria occurs in 8 to 18% of patients on haemodialysis.8,15 Pseudoporphyria cutanea tarda is clinically similar to PCT. However, hypertrichosis is less common and plasma porphyrin levels are typically normal.92 Pseudoporphyria cutanea tarda can also be differentiated from porphyria cutanea tarda by the absence of hyperpigmentation and sclerodermoid changes.31

The aetiology of this phenomenon is not clear, but inadequate clearance of plasma – bound porphyrin precursors by urine excretion or haemodialysis may lead to porphyrin deposition in the skin.8,10 This manifests clinically as photosensitivity and subepidermal bullae.8,10 Pseudoporphyria may also occur in patients taking tetracycline, nabumetone, nalidixic acid, furosemide and phenytoin.92

The treatment is by sun protection and by the use of high flux membrane in dialysis.

Acquired Perforating Dermatosis

Acquired perforating dematosis is another cutaneous manifestation specific to patient on haemodialysis. This condition occurs in 10% of patients undergoing dialysis and is more common in black patients and in patients with diabetes mellitus.11,13,25,93 It presents with a linear confluence of papules with a central, oystershell–like keratotic plug on the trunk, extensor surfaces, proximal extremities, scalp and face.25,93

The aetiology is unknown, but inflammatory skin reactions secondary to uraemic toxins, uric acid, scratching–induced microtrauma have been proposed.93 In addition to the local inflammation, dysregulation of vitamin A or vitamin D, abnormality of collagen or elastic fibers as well as degradation of connective tissue cause dermal microdeposition of uric acid. These together with calcium pyrophosphate are among the proposed aetiology.13

Lubricant, steroids, keratolytics, vitamin A, cryotherapy, UVB therapy and isotretinoin have been employed in the treatment of acquired perforating dermatoses with variable degrees of success.93

Pseudo Kaposi’s Sarcoma

Pseudo kaposi’s sarcoma is a benign lesion, clinically and histologically similar to kaposi’s sarcoma.94 It occurs around anteriovenous fistula94 and the lesions consist of purplish nodules or papules.94 It is also commonly seen on the medial and lateral malleoli of both lower limbs. These papules and nodules slowly evolve into scaly crusted violaceous patches.94

Histology shows vascular and fibroblast proliferation in the superficial dermis.94 Mitotic figures and extravasated red blood cells are also present.94 It improves with removal of the arteriovenous fistula.94

Arteriovenous Shunt Dermopathies

Arteriovenous shunt dermatitis occurs in 8% of patients on chronic haemodialysis.95 It is characterized by irritant contact dermatitis from soaps, disinfectants, and alcohol used for skin cleansing during haemodialysis.

Conclusion

The skin in patients with chronic kidney disease presents with numerous changes some of which are considered in this review. These may be associated with morbidity which impacts negatively on the quality of life of these patients.17

CHAPTER THREE

AIMS AND OBJECTIVES

GENERAL OBJECTIVE

To determine the pattern of skin diseases in patients with chronic kidney disease

(CKD) presenting at Obafemi Awolowo University Teaching Hospitals Complex, Ile-

Ife.

SPECIFIC OBJECTIVES

1. To determine the frequency of specific skin diseases in CKD patients

2. To document the variations in cutaneous manifestations seen in stages 3, 4 and

5 of CKD

3. To determine the peculiar skin manifestations in haemodialysis dependent

(stage 5) CKD patients.

CHAPTER FOUR

JUSTIFICATION OF STUDY

Chronic kidney disease is a chronic illness that adversely affects quality of life and contributes to morbidity and mortality. The skin is a mirror through which manifestations of diseased organs could be seen. Since patients with CKD could present with the disease and even the progression of disease without significant systemic upset or symptoms, the cutaneous manifestations which may present in asymptomatic patients with CKD may be the basis for initial clinical suspicion of the presence of CKD

Should a consistent and significant relationship between cutaneous manifestations and stages 3, 4 and 5 of CKD be established as aimed in this study, it would corroborate the assessment of CKD based on the cutaneous manifestations.

This would also facilitate and improve the implementation of an initial treatment plan.

The management of CKD is focused on retarding the progression of the disease and improving the quality of life of affected patients. Chronic kidney disease causes increased morbidity with cutaneous changes which negatively impact on the patient’s quality of life.

This study will facilitate the diagnosis and management of skin diseases in patients with CKD. This would hopefully lead to an improvement in the standard of care and the quality of life of such patients.

CHAPTER FIVE

METHODOLOGY

STUDY LOCATION

The study is a cross sectional study conducted at the Obafemi Awolowo

University Teaching Hospitals Complex (OAUTHC) Ile-Ife . It is a 650 beds hospital located in the South-West geopolitical zone of Nigeria and serves patients population referred from various parts of the zone.

STUDY POPULATION

Subjects

CKD patients attending medical out-patient department (MOPD), at OAUTHC

Ile-Ife who met the inclusion criteria for CKD. The patients were recruited from

November 2013 to November 2014.

Inclusion Criteria

1. Patients with chronic kidney disease defined as GFR less than 60

ml/min/1.73m2 for more than three months.

2. Patients must be 18 years and above

3. Those who gave informed consent

Exclusion Criteria

1. CKD patients who had kidney transplant

2. Patient in whom the disease causing the CKD presented with both skin

and renal manifestations, such as systemic lupus erythematosus. This was

excluded by screening the patients using America College of Rheumatology

criteria and anti-double stranded DNA assay.96,97

3. Patients who did not give informed consent

4. Diabetic patients

5. HIV positive patients

6. Patients with liver disease

7. Patients on chemotherapy or corticosteroids

8. Patients younger than 18years

9. Patients with GFR greater than 60 ml/min/1.73 m2

Lower age limit of 18 years was chosen because individuals below this age are

not adults and by implication could not give informed consent.

STUDY DESIGN

This study was cross–sectional in design, to determine the prevalence and pattern of cutaneous manifestations in patients with CKD attending OAUTHC Ile-Ife.

Patients who met the inclusion criteria were recruited consecutively. With the aid of a proforma (appendix 1), relevant history of symptoms, aetiology and treatment received, were obtained. Detailed examination of the skin and its appendages was carried out. The skin examination was aided by magnifying lens. Examination of other systems was also done.

Laboratory investigations done included serum electrolytes, urea and creatinine. GFR was calculated using the Cockcroft-Gault equation stated as:

Creatinine clearance = {(140-age) x weight(kg) x (0.85 if female) x (1.212 if black)}

{0.813 x serum creatinine (umol/L)}.98

Fasting blood glucose (>7.0mmol/L) or 2 hour postprandial (>11.0mmol/L) was done to exclude diabetes mellitus. Serum anti-double stranded DNA assay done where necessary to exclude systemic lupus erythematosus. HIV I and II screenings were done. Skin biopsy, skin scrapings and nail clippings for fungal studies were done as appropriate. Renal and liver ultrasounds were done. Liver disease was excluded clinically using chronic stigmata of liver disease, and liver function tests as well as liver ultrasound as appropriate.

A subpopulation of patients with CKD on haemodialysis (stage 5) were also recruited in the study and evaluated as stated above.

ETHICAL CONSIDERATION

Approval of Ethics and Research Committee of the hospital was sought and obtained before the study was carried out (appendix 2). Informed consent was also obtained from all recruited patients (appendix 3).

The patients observed to have skin diseases were given prescription for treatment of the skin disease as a benefit to the patients.

DATA COLLECTION METHOD/SAMPLE SIZE

Patients were consecutively recruited at presentation and data collection aided by proforma.

SAMPLE SIZE

The sample size was calculated based on documented 89.1% prevalence of skin changes in patients with chronic kidney disease3.

Sample size for descriptive cross sectional study when studying proportion with population <10, 000 will be; nf = n/(1+n/N). nf = The designed sample size when population is less than 10,000.

N = the estimate of the population size. n = the desired sample size when population is more than 10,000.

= z2pq d2 .

P = the proportion in the target population estimated to have a

particular characteristics ( in this case 0.9).

Z = the standard normal deviation (using 95% confidence level = 1.96). d = degree of accuracy desired, set at 0.05. q = 1.0 - P.

So, n = (1.96)(1.96) x (0.9) x (0.1) 0.05-2..

n = 3.8416x 0.09 0.00025

= 138.4

Estimated annual chronic kidney disease patient presenting at medical outpatient OAUTHC, Ile-Ife is approximately 400 patients. nf = n (1+n/N)

= 138.4 (1+138.4/400)

= 102.84

= 103

Attrition of 10% = 0.1 x 103 = 10.3

Total sample size = 114

This was rounded up to 120

Protocol I: Clinical history

Data was obtained using proforma that included demographic data such as age, sex, occupation, educational level, date of diagnosis and duration of disease. Other relevant history to suggest aetiology of CKD, and types of skin manifestation or problem at present and in the past was also sought for and documented as appropriate .

Protocol II:

Thorough physical examination was conducted in the consulting room during which the whole body was examined in bright light for any abnormality . The nails and hair were also examined. The female patients were examined in the presence of a chaperone.

Magnifying lens was used where appropriate to aid evaluation of skin lesions.

Protocol III:-

Laboratory investigations: Patients had investigations such as serum electrolyte, urea and creatinine. The GFR was estimated using Cockcroft-Gault formula. Skin scrapings and nail clippings were collected in suspected cases of fungal infections and the keratin was dissolved using 10% potassium hydroxide (KOH) or 20% potassium hydroxide (KOH) respectively. The diagnosis of fungal infection was subsequently made by demonstration of fungal hyphae or yeast using light microscope and magnification of x40.

Skin biopsies for histology were done for confirmation of diagnosis where indicated. Other investigations that were done included fasting blood sugar, liver function test and HIV screening were done to exclude patients with diabetes mellitus, chronic liver disease and HIV infection. Anti-double stranded DNA assay were done where necessary.

DATA ANALYSIS

Data was analyzed using version 16.0 SPSS statistical software. The demographic characteristics and the cutaneous manifestations were presented using descriptive statistics such as frequency, percentage, mean, median and mode. The association between the stages of CKD and the cutaneous manifestations was presented using inferential statistics like chi-square. Tables and charts were used for presentation of data as appropriate.

LIMITATIONS

1. In validating the diagnosis of CKD which requires decrease GFR of more than

three months, initial GFR done prior to commencement of this study was

retrieved from patient’s records to complement the GFR done at point of

patient’s recruitment for the study.

2. Larger sample size would have been more appropriate but for the short

duration of the study

3. It is a hospital based study, a community based study would have been more

representative.

CHAPTER SIX

RESULTS

A total of one hundred and twenty patients with CKD were recruited for the study, and their socio-demographic characteristics such as age, gender, occupation, level of education and the presence of family history of CKD are depicted in table 1.

The age of the patients ranged from 18 years to 84 years. Patients in the age range of 21-40 years and 41-60 years constituted the highest proportions of 31.7% and 39.2% respectively. This put more than 70% of the patients in the age range of

21-60years. The mean age was 50.76 (±18.6) years old.

Seventy six (63.3%) patients were males while the remaining forty four

(36.7%) patients were females. The occupational status of the patients as reflected in table 1 showed that 13.3% were students, 34.1% were traders, 11.7% were civil servants, 5.0% were professionals, and 2.5% were unemployed while the remaining

33.3% were farmers, artisans, retirees etc. and were grouped together as unspecified categories.

The highest level of education attained by the patients was also shown in table 1. Thirteen patients (10.8%) had no education, twenty five patients (20.8%) each had primary education and another twenty five (20.8%) had secondary education, while fifty seven patients (47.5%) had tertiary education. The presence of family history of chronic kidney disease was found in 10.8% of the patients.

The duration of illness was also evaluated as shown in table 1. The minimum duration was 3 months and maximum was 216 months. The mean duration of illness of the patients studied was 32.37(±36.48) months.

The causes of chronic kidney disease in the patients recruited for the study as shown in table 2 were adult polycystic kidney disease (ADPKD), bladder outlet obstruction (BOO), chronic glomerulonephritis (CGN), hypertension (HPT) and sickle cell nephropathy. Chronic glomerulonephritis was the commonest cause of

CKD in the studied population where it causes 48.3% of CKD. Other causes of CKD in descending order of prevalence are hypertension (25.0%), bladder outlet obstruction (17.5%), adult polycystic kidney disease (7.5%), and sickle cell disease

(1.7%).

Figure 1 shows the treatment modalities used in the management of the patients. Ninety-one patients (75.8%) were on conservative treatment while 29 patients (24.2%) were on haemodialysis. Patients who have had renal transplant were not included in this study.

In table 3, patients participating in this study were sub classified based on the severity of CKD into stage 3 (GFR 30-59 mls / min 1.73m2), stage 4 (GFR 15-29 mls

/ min 1.73m2 ) and stage 5 (GFR <15 mls / min 1.73 m2). Forty three patients (35.8%) had stage 3 CKD, thirty six patients (30.0%) had stage 4 CKD while forty one patients (34.2%) had stage 5 CKD. Stage 1 and 2 of CKD were not included in the study because the GFR are greater than 60 mls / min 1.73m2

Table 1: General characteristics of the patients Characters Frequency Percentage Age 0-20 3 2.5 21-40 38 31.7

41-60 47 39.2 61-80 28 23.3 81-100 4 3.3 Total 120 100 Gender Male 76 63.3 Female 44 36.7 Total 120 100 Occupation Student 16 13.3 Trader 41 34.1 Civil servant 14 11.7 Professional 6 5.0 Unemployed 3 2.5 others 40 33.3 Total 120 100 Educational qualification None 13 10.8 Primary 25 20.8 Secondary 25 20.8 Tertiary 57 47.5 Total 120 100 Family history of chronic kidney disease 13 10.8 Yes 107 89.2 No 120 100 Total Duration of illness 3 months-2years 76 63 2years-5years 30 25 >5years 14 12 Total 120 100 Table 2: The causes of chronic kidney disease CAUSE OF CKD Frequency Percentage

Chronic glomerulonephritis 58 48.3

Hypertension 30 25.0

Bladder outlet obstruction 21 17.5

Adult polycystic kidney disease 9 7.5

Sickle cell nephropathy 2 1.7

TOTAL 120 100.0

42.5%

57.5% Present Absent

Figure 1a: Proportion of patients with cutaneous manifestations

32.5% 42.5% No cutaneous maniffestation

One cutaneous maniffestation

25% More than one cutaneous maniffestation

Figure 1b: Proportion of patients with cutaneous manifestations

Table 3: The stages of chronic kidney disease

STAGE OF CKD Frequency Percentage

3 43 35.8

4 36 30.0

5 41 34.2

Total 120 100.0

PREVALENCE AND PATTERN OF CUTANEOUS MANIFESTATIONS.

Cutaneous manifestations as shown in figure 2 were found in sixty nine patients (57.5%). Although some patients had more than one cutaneous disease, sixty nine (57.5%) patients had at least one manifestation while fifty one (42.5%) patients had no cutaneous manifestation.

The spectrum of cutaneous manifestations seen in this study and their proportions are shown in table 4. Xerosis was the commonest and was seen in thirty two patients (26.7%), pruritus was seen in sixteen patients (13.3%), hyperpigmentation in fifteen patients (12.5%), half and half nail in thirteen (10.8%) patients and pallor in thirteen (10.8%) patients. Others are icthyosis seen in eight

(6.7%) patients, fungal infections in eight (6.7%) patients, and follicular hyperkeratosis in three (2.5%) patients. Two cases each of Mee’s lines and alopecia were seen while a case of chronic leg ulcer, planter hyperkeratosis, arteriovenous shunt dermatitis, bacterial infection and uraemic frost were also seen.

Table 5 shows the prevalence of specific infections seen in this study. Fungal infections constituted the largest proportions of the infections seen, with eight

(88.9%) out of the nine cases of infections being fungal. A patient (11.1%) had bacterial infection (acute paronychia). Viral and parasitic infections were not seen in this study. The fungal infection seen included a case of tinea corporis, tinea faciei, tinea pedis and tinea unguium each constituting 11.1% of cutaneous infections respectively. Two patients (22.2%) had pityriasis versicolor and another two (22.2%) had chronic paronychia.

Table 6 shows the distribution of cutaneous manifestations within the various stages of CKD. Xerosis, and pruritus ranked highest among patients in stage 3 constituting 18.6% each. Xerosis pruritus and hyperpigmentation were the highest among patients in stage 4 CKD. In this stage, xerosis constituted 30.6% while pruritus and hyperpigmentation constituted 13.9% each. In patients with stage 5, xerosis and hyperpigmentation ranked highest constituting 31.7% and 17.1% respectively.

Xerosis was observed to be the commonest cutaneous manifestation in all the stages of CKD, except in stage 3 where it ranked equal with pruritus.

The frequency of xerosis, hyperpigmentation, half and half nail, and pallor increased progressively with the worsening of kidney function from stage 3 to stage 5.

On the contrary, pruritus was observed to decrease progressively with worsening of kidney function. Alopecia, mee’s lines, chronic leg ulcer although were few, they were found only in patients with stage 3 CKD. While follicular hyperkeratosis, planter hyperkeratosis, arteriovenous shunt dermatitis and uraemic frost were seen only in patients with stage 5 CKD. The only bacterial infection seen in this study was found in a patient with stage 4 CKD. However, four patients in this stage also had fungal infections making stage 4 the stage of CKD with the highest proportion of patients with infections. In addition to infections, the largest proportions of patients with icthyosis also presented with stage 4 CKD.

24.2%

Conservative Haemodialysis 75.8%

Figure 2: Pie chart showing treatment modalities of patients

Table 4: The prevalence of cutaneous manifestations among patients with chronic kidney disease (n=120)

Cutaneous manifestations Frequency Percentage Xerosis 32 26.7 Pruritus 16 13.3 Hyperpigmentation 15 12.5 Half and half 13 10.8 Pallor 13 10.8 Fungal infection 8 6.7 Icthyosis 8 6.7 Folicullar hyperkeratosis 3 2.5 Alopecia 2 1.7 Mee’s line 2 1.7 Chronic leg ulcer 1 0.8 Plantar hyperkeratosis 1 0.8 Arteriolar shunt dermatitis 1 0.8 Bacterial infection 1 0.8 Uraemic frost 1 0.8

Table 5: The prevalence of infections among patients with chronic kidney disease

(n=9)

Infections Frequency Percentage

Fungal infections

Tinea corporis 1 11.1

Tinea faciei 1 11.1

Tinea pedis 1 11.1

Tinea unguium 1 11.1

Chronic paronychia 2 22.2

Pityriasis versicolor 2 22.2

Bacterial infections

Acute paronychia 1 11.1

Total 9 100

Table 6: Cutaneous changes in patients with stage 3, 4 and 5 of chronic kidney

disease

CKD Stage 3 (n=43) Stage 4(n=36) Stage 5(n=41)

Skin changes frequency % within stage Frequency % within stage Frequency % within stage Xerosis 8 18.6 11 30.6 13 31.7 Pruritus 8 18.6 5 13.9 3 7.3 Hyperpigmentation 3 7.0 5 13.9 7 17.1 Half and half 3 7.0 4 11.1 6 14.6 Pallor 3 7.0 4 11.1 6 14.6 Fungal infection 3 7.0 4 11.1 1 2.4 Icthyosis 2 4.7 4 11.1 2 4.9 Follicular 0 0 0 0 3 7.3 Hyperkeratosis Alopecia 2 4.7 0 0 0 0 Mee’s line 2 4.7 0 0 0 0 Chronic leg ulcer 1 2.3 0 0 0 0 Plantar Hyperkeratosis 0 0 0 0 1 2.4 Arteriolar Shunt 0 0 0 0 1 2.4 Dermatitis Bacterial infection 0 0 1 2.8 0 0 Uraemic frost 0 0 0 0 1 2.4

Figure 3: Xerosis on the legs of a patient with CKD

Figure 4: Hyperpigmentation shown on palms of a CKD patient with difuse hyperpigmentation

Figure 5: Half and half nail

Figure 6: Half and half nail

Figure 7: Tinea unguium in patient with CKD

Figure 8: Chronic paronychia

Figure 9: Pityriasis versicolor

Figure 10: Icthyosis in patient with CKD

Figure 11: Follicular hyperkeratosis in patient with CKD

Figure 12: Planter hyperkeratosis in patient with CKD

Figure 13: Alopecia in patient with CKD

Figure 14: Chronic leg ulcer in CKD patient

ASSOCIATION BETWEEN CUTANEOUS MANIFESTATIONS AND STAGES

OF CKD

Table 7 shows that the proportion of cutaneous manifestations increased progressively with worsening kidney function. In stage 3 CKD, 53.5% of the patients had cutaneous manifestations, while 58.3% of patients with stage 4 CKD had cutaneous manifestations. The highest proportion of 61.0% was seen in patients with stage 5

CKD. However, the progressive increase in the proportion of cutaneous manifestations with the stage of CKD did not reach statistical significance.

The association between specific cutaneous manifestations and the stage of

CKD is shown in table 8. Some of the specific cutaneous manifestations such as xerosis, hyperpigmentation, half and half nail, and pallor increase progressively with stage of CKD but did not reach statistical significance. Pruritus which was also noted to decrease with worsening of kidney function was also not statistically significant.

Fungal infections and icthyosis, despite having 50% of their presentation in patients with stage 4 CKD, did not show a significant statistical association with the stage of CKD.

The association of cutaneous manifestations seen only in stage 3 such as alopecia, mee’s lines and chronic leg ulcer also were not statistically significant.

Similarly, the association of cutaneous manifestations seen only in stage 4 such as bacterial infection and those seen only in stage 5 such as follicular hyperkeratoses, plantar hyperkeratoses, arteriovenous shunt dermatitis and uraemic frost were not statistically significant.

.Table 7: Association between the stages of chronic kidney disease and the presence of cutaneous manifestations

Stages of chronic kidney disease Cutaneous manifestations

Present Absent

frequency percentage frequency percentage

Stage 3 23 53.5 20 46.5

Stage 4 21 58.3 15 41.7

Stage 5 25 61.0 16 39.0

Total 69 57.5 51 42.5

X2 = 0.496 df=2 p-value= 0.780

Table 8: Association between the stages of chronic kidney disease and the

presence of specific cutaneous manifestations

Stage 3 Stage 4 Stage 5 p. value cutaneous Frequency %within Frequency %within Frequency %within manifestations disease disease disease Xerosis 8 25 11 34.4 13 40.6 0.671 Pruritus 8 50 5 31.3 3 18.8 0.426 Hyperpig- 3 20 5 33.3 7 46.7 0.634 mentation Half and half 3 23.1 4 30.8 6 46.2 0.518 Pallor 3 23.1 4 30.8 6 46.2 0.518 Fungal infection 3 37.5 4 50 1 12.5 0.312 Icthyosis 2 25 4 50 2 25 0.932 Folicullar 0 0 0 0 3 100 0.060 Hyperkeratosis Alopecia 2 100 0 0 0 0 0.252 Mee’s line 2 100 0 0 0 0 0.252 Chronic leg ulcer 1 100 0 0 0 0 0.378 Plantar 0 0 0 0 1 100 0.336 Hyperkeratosis Arteriolar Shunt 0 0 0 0 1 100 0.336 Dermatitis Bacterial 0 0 1 100 0 0 0.504 infection Uraemic frost 0 0 0 0 1 100 0.336

CHAPTER SEVEN

DISCUSSION

The prevalence of cutaneous manifestations among patients with CKD in this study was 57.5% (fig. 1). This is within the prevalence range of 50-100% reported in literatures. 1-4 Falodun et al3 reported 89.1% while Thomas E A et al1 reported 97.9%.

These showed that cutaneous manifestations are common in patients with chronic kidney disease. The sub-categories of patients with CKD who were involved in the study are in stage 3, 4 and 5 of CKD. About 53.5% of stage 3 patients had cutaneous manifestations, 58.3% of stage 4 patients had cutaneous manifestations, while 61.0% of patients in stage 5 had cutaneous manifestations. The proportion of patients with cutaneous manifestations progressively increased with worsening kidney function from stage 3 to stage 5 but did not reach statistical significance. The increasing proportion of cutaneous manifestations with stage could be because of the increased duration of illness in later stages of illness thereby allowing sufficient time for changes in the skin to occur.

Seventy six males (63.3%) participated in the study while the females constituted 36.7%. The ratio of females to male in this study was 1:1.7. In a similar study by Thomas et al, fewer number of females participated in their study with female to male ratio of 1:3.7. Young and middle aged patients constituted the largest proportion of patients who participated in the study, with 70% of the patients between the ages of 21 years and 60 years. In the study by Thomas et al, patients in the middle age category constituted the largest proportions of patients in their study. This is because CKD is common in young and middle aged patients as has been depicted in

57 previous stidies.5,6 Ninety one (75.8%) patients were managed conservatively while twenty nine (24.2%) were managed by haemodialysis (fig. 2).

Xerosis remained the most commonly observed skin change in patients with

CKD.26 In this study 26.7% of patients had xerosis making it the commonest cutaneous manifestation in this study as well. The patients presented mainly with xerosis on the extremities (fig. 3). This might be due to an added effect of climate and environment since the extremities are often exposed. This could cause local effect of dehydration. Other factors responsible for xerosis include, reduced size of eccrine sweat glands and sebaceous glands, the use of diuretic treatment, and the increase in plasma and skin vitamin A and its carrier retinal binding protein.4,86,87 Fluid is also thought to shift away from the dermis following fluid mobilization by dialysis.99

Thomas et al1 reported a prevalence of 66.7% while Falodun3 reported that 60% of his patients presented with xerosis. The relatively low frequency obtained in this study may not be unconnected with the fact that the totality of skin manifestation was lower though xerosis remained the commonest manifestation.

The proportion of patients with xerosis increases progressively with worsening of CKD. The proportions of xerosis observed in stages 3, 4, 5 were 25%, 34.4% and

40.6% respectively. The increasing proportion of xerosis may be as a result of increased use of diuretic as renal function worsens and the added use of haemodialysis which can cause fluid shift away from the dermis. Despite the progressively increasing proportion of xerosis, the test of association did not show significant variation between the number of patients with xerosis and the stages of

CKD

Pruritus was the second commonest skin change in this study with 13.3% of the patients presenting with it. This was closely related to the frequency of pruritus reported in a review by Ponticell C et al,36 where they reported 15-40% of patients with CKD presenting with pruritus. Thomas et al1 also report a frequency of 43.4% while Falodun et al3 report 26.7%.

The patients presented with generalized pruritus of mild to moderate severity.

There were no associated plaques or nodules. While the cause of pruritus in CKD is largely unknown, some hypotheses have been put forward to explain it. The immune hypothesis was supported by the findings that C - reactive protein and interleukin-6 level are elevated in the plasma of patients with CKD. 17,39 The improvement of pruritus with ultraviolet light B (UVB), immunosuppressive drugs like tacrolimus also favoured immune hypothesis. Opioid hypothesis is the second hypothesis postulated to explain pruritus in CKD patients. Increased activity of opioid u-receptor, and decreased regulation of opioid k-receptor in thought to cause pruritus in CKD. 41,43

Other factors believed to play some roles in the aetiology of pruritus in CKD patients include increased parathyroid hormones, histamine release by increased dermal mast cells and xerosis. The frequency of xerosis (26.67%) noted in this study might also have contributed to the frequency of pruritus. 47

While xerosis increased progressively with worsening kidney disease, on the contrary, the proportion of patients with pruritus progressively decreased with worsening kidney function from stage 3 to stage 5 but did not also reach statistical significance. Large amount of mast cells are present in the dermis of patients with

CKD. Release of histamine by these mast cells also contributes to pruritus.

Erythopoetin has been documented to decrease plasma histamine concentration, thereby reducing pruritus.9 The increasing use of erythropoietin as kidney function worsens may therefore explain the progressive decline in the proportion of pruritus observed in this study.

Diffuse hyperpigmentation (fig. 4) was observed in 12.5% of patients in this study. This prevalence is within the documented range reported in previous studies.

Prevalence of 7.5-43% have been reported in previous studies.1,3,26 Mild diffuse hyperpigmentation may not be readily noticed in black skin as in the Caucasian skin.

This may cause the observed frequency to be less than the actual frequency of diffuse hyperpigmentation. Self-reporting of hyperpigmentation by patients ‘‘since it has to be compared with usual level of pigmentation’’ may also altered the actual frequency of hyperpigmentation noted in this study.

Brown diffuse hyperpigmentation and yellow-grey discolourations were not seen in this study. This could be because they were either absent or because the study population was predominantly a Fitzpatrick skin type VI with high pigmentation, thereby altering the typical presentation. The inability of the kidney to excrete beta- melanocyte stimulating hormone ( - MSH) leading to accumulation of melanin and chromogens in basal layer and superficial dermis causes hyperpigmentation in patients with CKD.4,26,82

A review of the variation in hyperpigmentary changes between stages 3, 4 and

5, shows 20% of the pigmentary changes in stage 3, 46.67% in state 4 and 33.3% in stage 5. The test of association between the stages of CKD and hyperpigmentary

60 changes (p-value 0.634) was not significant. This shows that the presence of hyperpigmentary changes was not significantly altered by the stage of CKD.

A number of nail changes were observed in this study, with half and half nail being the most common (fig. 5,6). Although the exact cause of half and half nail in

CKD is not known, it is however known that there an increase in the number as well as increased wall thickening of the capillaries.33 Half and half nail occurred in 10.8% of the patients involved in this study. Prevalence of 15-50% was reported by Lubach et al88 among patients on chronic hemodialysis. Pico et al83 reported that nail changes increased in prevalence with respect to time of dialysis and was significantly more pronounced in the haemodialysis group. This may explain the slightly lower prevalence of 10.8% observed in this study as it reflected the prevalence among all the patients rather than a subpopulation of those on haemodialysis alone. This study showed increasing proportion of half and half nail with the stages of CKD, however the increase was not statistically significant.

The prevalence of pallor seen in this study was 10.8% which is low compared with other studies. The cause of pallor in patients with CKD includes decrease production of erythropoietin by the kidneys, and increased haemolysis.4,26 It was also observed that the patients on dialysis which constitutes 24.2% were given erythropoietin routinely and as well as haematinics such as parenteral or oral iron and multivitamins. With increased likelihood of anaemia in stage 5 CKD patients compared to stages 3 and 4, the low prevalence of pallor may also be partly explained by the high proportions of stages 3 and 4 patients recruited for the study (fig 2). The observed frequency of pallor may therefore be reduced as some of the patients have

61 had their anaemia corrected through these supplements. Although pallor was also noted to increase with worsening kidney disease, the variations in its occurrence did not reach statistical significance.

Cutaneous infections arising from fungal infections affected 6.7% of the patients while 0.8% of patients had bacterial infections. The spectrum of fungal infections seen in this study included tinea unguium, tinea pedis, pityriasis versicolor

(fig. 7,8,9) which was similar to that reported by Udayakumar et al.26 However, this study recorded lower frequency of infections probably because the study population was not limited to haemodialysis population, and also because it excluded patients who have diabetic mellitus who may have increase propensity to acquiring infections.

Impaired cellular and humoral immunity predisposes to cutaneous infections in patients with CKD.35 The patients with nephrotic syndrome who tend to have more impairment in humoral immunity were mainly in stage 1 and II of CKD and they were not recruited for this study. Similarly, diabetes mellitus patients with greater propensity for impaired cellular immunity were also not recruited for this study. The exclusion of these two categories of patients could explain the relatively low proportion of cutaneous infections seen in this study.

The distribution of fungal infections between the stages showed that patients in stage 3 CKD had 37.5% of the burden of fungal infection. Stage 4 had 50% while the remaining 12.5% occurred in stage 5 CKD. The observed variation between fungal infection and the stages of chronic kidney disease was not statistically significant.

Similarly, bacterial infections did not vary significantly with the stage of chronic kidney disease. Since bacterial and fungal infections have common pathogenic

62 mechanism of defective humoral and cellular immunity in patients with CKD, similar pattern of association with stages of CKD may be expected. The observed associations were however not statistically significant.

In addition to xerosis, other abnormalities of keratinization that were seen in this study included icthyosis, follicular hyperkeratosis and plantar hyperkeratosis

(fig. 10,11,12). Icthyosis was documented in 6.67% of the studied patients. Acquired icthyosis had been noted in patients with chronic kidney disease.4 Acquired icthyosis being severe form of skin dryness had similar pathogenesis with xerosis as discussed above. A total of 8 patients with icthyosis were seen in the study, with 25% in stage 3,

50% in stage 4 and remaining 25% in stage 5. Icthyosis also did not vary significantly with the stage of CKD.

A few patients with CKD presented with keratosis pilaris – like lesion.26 This findings are not at variance with the findings in this study where 2.5% of the patients had follicular hyperkeratosis. Increased plasma and skin content of vitamin A and its carrier, retinol-binding protein in uraemic patients have also been implicated in the pathogenesis of follicular hyperkeratosis as with other abnormalities of keratinization.4,86,87 The association between follicular hyperkeratosis and the stages of CKD were not statistically significant.

Hair changes in CKD include hair loss which could be due to telogen effluvium “following ill health”, xerosis, pruritus and drugs such as heparin, antihypertensives and antilipids94,27. Other hair changes include colour change and shaft abnormalities (such as twisting flattening, irregular diameter) which can be detected by election microscopy26, 27, 89, 90. In this study, diffuse alopecia (fig. 13) was

63 found in 1.7% of patients with CKD. Hair changes have been reported in 10-30% of

CKD patients who are on dialysis.26 The relatively low frequency of hair changes seen in this study may be because of duration on maintenance dialysis. The impact of drugs such as heparin will be more obvious as the duration on maintenance dialysis increases. This is less likely in this environment where dialysis is expensive and unaffordable by majority of patients. The two cases of alopecia seen were among patients with stage 3 CKD. There was no significant association between alopecia and stages of CKD.

Mee’s lines were also observed in 1.7% of the patients. Udayakumar et al26 reported a higher prevalence of 7% among haemodialysis patients. Other nail changes due to infections observed were Tinea unguium, acute and chronic paronychia. The two cases of mee’s lines seen were among patients with stage 3 CKD. There was no significant association between Mee’s lines and stages of CKD.

Chronic leg ulcer (fig. 14) was observed in only a patient (0.8%). The probability that the ulcer was a chance occurrence is not unlikely as it was observed in only a patient who had stage 3 CKD. The ulcers were symmetrically and posteriorly located on the lower half of the legs. Skin biopsy showed keratinizing stratified squamous epithelium with pseudoepitheliomatous hyperplasia, acanthosis, parakeratosis and hypergranulosis. The sub-epithelium showed proliferation of fibro- collagenous tissue and increased inflammatory lymphocytes. No atypical cells were present. These features are consistent with chronic leg ulcers. Although calciphylaxis has been reported as a cause of non-healing ulcer by Arshdeep et al,100 the tissue histology of the ulcer in this study was consistent with chronic ulcer rather than

64 specific features of calciphylaxis. Specific stain for calcium such as alizarin was however not done. The low prevalence of chronic leg ulcer seen in this study is consistent with other studies since calciphylaxis is a relatively rare cutaneous manifestation in patients with CKD and the incidence has been reported to be less than 1% in patients with CKD.19,32The imbalance between inducers and inhibitors of calcification has been known to cause calciphylaxis.62 Increase in the amount of inducers such as osteopontin, morphogenic protein-4, and reduction in the amount of inhibitors such as fetuin A, and osteoprogerin lead to calciphylaxis.63,64,65 Other attributed causes of calciphylaxis include changes in calcium and phosphate metabolism, increased use of vitamin D analogues, hyperparathyroidism and decrease in protein C and protein S.32 Factors noted to predispose to calciphylaxis which include white race, diabetes mellitus and prolonged duration of renal replacement therapy,19-22 were however, not present in this study, thereby reducing the prevalence.

Although, abnormalities of veins leading to venous ulcer may also be considered as the primary cause of the chronic leg ulcer, venous ulcers have also been strongly associated with cutaneous calcification which in CKD may also be linked to calciphylaxis.101,102 Two patients with sickle cell disease who were involved in the study did not have chronic leg ulcer despite the increased risk posed by sickle cell haemoglobinopathy.

Only one patient with stage 5 CKD presented with plantar hyperkeratosis giving a frequency of 0.8%. This condition has also been reported in CKD patients by

Cawley et al84 and Bencini et al.85 Increased plasma and skin content of vitamin A and

65 its carrier, retinol-binding protein in uraemic patients have also been implicated in the pathogenesis of plantar hyperkeratosis as with other abnormalities of keratinization..4,86,87 Association between plantar hyperkeratosis and the stages of

CKD also was not statistically significant.

Arteriovenous shunt dermatitis occurs at the site of arteriovenous fistula. It arises due to irritant contact dermatitis from soaps or cleansing agents, disinfectant, and alcohol. Irritant dermatitis is dependent on both concentration of substance and duration or frequency of exposure to contact. Arteriovenous shunt dermatitis was seen in one patient. This gives a frequency of 0.8% among patients with CKD. The prevalence of 8% was reported in patients on chronic haemodialysis by Goh et al.95

The probable reasons for the low prevalence in this study could be the absence of arteriovenous shunts in most of the patients, and the low frequency of dialysis attributable to the high cost of the procedure and the low socio-economic status of affected patients.

Arteriovenous shunt dermatitis usually occurs at the site of shunt in patients with CKD on haemodialysis.95 The occurrence of arteriovenous shunt dermatitis was not observed to vary significantly with the stages of CKD in this study. Reports on shunt dermatitis have been limited to patients on chronic haemodialysis with shunts in place. 95

Uraemic frost occurs when the blood urea nitrogen level exceed 250-

300mg/dl4. Urea concentration in sweat is increased and after evaporation, there is deposition of urea crystals on the skin surface. A patient with stage 5 CKD had uraemic frost in this study. The availability of dialysis, and the relatively high level of

66 urea at which it occurs makes uraemic frost less common as observed in the study.

Although this study did not show a statistically significant association between presence of uraemic frost and stages of CKD, uraemic frost may be commoner in the later stages of CKD since urea is also higher in these stages. This may also explain why the only documented case in this study was in stage 5.

The association between the stages of CKD and cutaneous manifestations did not show significant variation as discussed above. This implied that there was no significant variation in cutaneous manifestations observed in haemodialysis dependent (stage 5) patients and the rest of the patients. The reason why stage 5 CKD patients may not demonstrate statistically significant patterns of cutaneous manifestations in this study could be because there were few patients on maintenance haemodialysis and the short duration in which they been on dialysis. This could however change if a larger population of haemodialysis patients is studied.

Arteriovenous shunt dermatitis was discussed above as a cutaneous manifestation seen only in haemodialysis patients with arteriovenous shunt. Other cutaneous changes specific to haemodialysis reported in literatures like bullous disease of haemodialysis,15 Acquired perforating dermatoses,25,93 and pseudokaposi’s sarcoma,94 were not found in this study. Some of the reasons adduced to their absence may be because of their low prevalence in haemodialysis population where bullous disease of haemodialysis was reported in 5% of patients on haemodialysis,15 and acquired perforating dermatosis in 10% of patients on dialysis.11,13,25,93 Other probable reasons accounting for absence of these cutaneous changes included the fact that most

67 of our patients cannot afford dialysis long enough to develop haemodialysis specific cutaneous manifestations.

CONCLUSION

The occurrence of cutaneous manifestations is high among patients with chronic kidney disease with a prevalence of 57.5% observed in this study. As with several other studies, xerosis was the commonest skin changes observed in these patients.

The patterns of cutaneous manifestations were not observed to vary with the stages of chronic kidney disease in this study. However, shunt dermatitis was noted as a cutaneous manifestation occurring only in stage 5 CKD patients with arteriovenous fistula.

RECOMMENDATIONS

The study demonstrated a high burden of cutaneous manifestations in patients with chronic kidney disease. In view of this, the following recommendations are hereby suggested;

1. All patients with chronic kidney disease should be examined for identification

and treatment of cutaneous changes by their attending physician.

2. More studies on the relationship between the stages of CKD and the cutaneous

manifestations are advised. This will enable the unfolding of more knowledge

about the exact relationship between the stages of CKD and associated

cutaneous manifestations.

REFERENCES

1) Thomas EA, Pawar B, Thomas A. A prospective study of cutaneous

abnormality in patients with chronic kidney disease. Indian J Nephrol.

2012;22(2):116-20

2) Otike-Odibi BI, Olumide YM, Oresanya FA. Pattern of cutaneous

manifestations of end stage renal disease in Lagos metropolis. Nigerian

Journal of Dermatology. 2012; 1(2):7-10

3) Falodun O, Ogunbiyi A, Salako B, George AK. Skin changes in patients with

chronic renal failure. Saudi J Kidney Dis Transpl. 2011;22(2):268-72

4) Nunley JR. Dermatologic manifestations of renal disease [document on the

Internet]. Medscape Online; 2014 Jan 23 [cited 2015 Feb 7]. Available from:

http://emedicine.medscape.com/article/1094846-overview

5) Afolabi MO, Abioye-Kuteyi EA, Arogundade FA, Bello IS. Prevalence of

chronic kidney disease in a Nigerian family practice population. SA FamPract.

2009;51(2):133

6) Hallan SI, Coresh J, Astor BC, Asberg A, Powe NR, Romundstad S, et al.

International comparison of the relationship of chronic kidney disease

prevalence and ESRD risk. J Am SocNephrol. 2006;17:2275-84

7) Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al.

Prevalence of chronic kidney disease in the United States. JAMA.

2007;298:2038-47

8) Stevens BR, Fleischer AB, Piering F, Crosby DL. Porphyria cutanea tarda in

the setting of renal failure. Arch Dermatol. 1993; 129:337

9) De Marchi S, Cecchin E, Villalta D, Sepiacci G, Santini G, Bartoli E. Relief of

pruritus and decreases in plasma histamine concentrations during

erythropoietin therapy in patients with uremia. N Engl J Med. 1992;326:969

10) Sarkell B, Patterson JW. Treatment of porphyria cutaneatarda of end-stage

renal disease with erythropoietin. J Am AcadDermatol. 1993;29:499

11) Patterson JW. The perforating disorders. J Am Acad Dermatol.1984;10:561

12) Rapini RP, Hebert AA, Drucker CR. Acquired perforating dermatosis. Arch

Dermatol. 1989;125:1074

13) Morton CA, Henderson IS, Jones MC, Lowe JG. Acquired perforating

dermatosis in a British dialysis population. Br J Dermatol.1996; 135:671

14) Goh CL, Phay KL. Arterio-venous shunt dermatitis in chronic renal failure

patients on maintenance haemodialysis. Clinical and Experimental

Dermatology. 1988;13:379–81

15) Gilchrest BA, Rowe JW, Mihm MC Jr. Bullous dermatosis of hemodialysis.

Annals of Internal Medicine.1975; 83: 480–3

16) Sandoval M, Ortiz M, Díaz C, Majerson D, Molgó M. Cutaneous

manifestations in renal transplant recipients of Santiago, Chile. Transplant

Proc. 2009;41(9):3752-4

17) Patel TS, Freedman BI, Yosipovitch G. An update on pruritus associated with

CKD. Am J Kidney Dis. 2007;50: 11-20

18) Narita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, et al. Etiology and

prognostic significance of severe uremic pruritus in chronic hemodialysis

patients. Kidney Int. 2006; 69: 1626-32

19) Janigan DT, Hirsch DJ, Klassen GA, Macdonald AS. Calcified subcutaneous

arterioles with infarcts of the subcutis and skin ('calciphylaxis') in chronic

renal failure. Am J Kidney Dis. 2000; 35: 588-97

20) Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR.

Calciphylaxis: natural history, risk factor analysis, and outcome. J Am

AcadDermatol. 2007; 56: 569-79

21) Rogers NM, Teubner DJO, Coates PTH. Calcific uremic arteriolopathy:

advances in pathogenesis and treatment. Semin Dial. 2007; 20: 150-7

22) Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis CL, et al.

Risk factors and mortality associated with calciphylaxis in end-stage renal

disease. Kidney Int. 2001; 60: 324-32

23) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,

classification and stratification. Am J Kidney Dis. 2002;39:S1-S266

24) Bricker NS, Morrin PA, Kime SW., Jr The pathologic physiology of chronic

Bright’s disease. An exposition of ‘intact nephron hypothesis’. Am J Med.

1960;28:77-98

25) Farrell AM. Acquired perforating dermatosis in renal and diabetic patients.

Lancet.1997; 349:895

26) Udayakumar P, Balasubramanian S, Ramalingam KS, Lakshmi C, Srinivas

CR, Mathew AC. Cutaneous manifestations in patients with chronic renal

failure on hemodialysis. Indian J DermatolVenereolLeprol. 2006; 72: 119-25.

27) Hajheydari Z, Makhlough A. Cutaneous and mucosal manifestations in

patients on maintenance hemodialysis. Iran J Kidney Dis. 2008; 2: 86-90.

28) Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al.

Pruritus in haemodialysis patients: International results from the Dialysis

Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant.

2006; 21: 3495-505

29) Mistik S, Utas S, Ferahbas A, Tokgoz B, Unsal G, Sahan H, et al An

epidemiology study of patients with uremic pruritus. J

EurAcadDermatolVenereol. 2006; 20: 672-8

30) Dyachenko P, Shustak A, Rozenman D. Hemodialysis-related pruritus and

associated cutaneous manifestations. Int J Dermatol. 2006; 45: 664-7

31) Glynne P, Deacon A, Goldsmith D, Pusey C, Clutterbuck E. Bullous

dermatoses in endstage renal failure: porphyria or pseudoporphyria? Am J

Kidney Dis. 1999; 34: 155-60

32) Wilmer W, Magro CM. Calciphylaxis: emerging concepts in prevention,

diagnosis, and treatment. Semin Dial. 2002; 15: 172-86

33) Lindsay PG. The half-and-half nail. Archives of Internal Medicine.

1967;119:583–7

34) Cowper SE. Nephrogenic Systemic Fibrosis [ICNSFR Website]. 2001-2013.

Available at http://www.icnsfr.org. Accessed Feb 7 2015.

35) Minnaganti VR, Cunha BA. Infection associated with uremia and dialysis.

Infect Dis Clin North Am. 2001; 15: 385-406

36) Ponticelli C, Bencini P L. Uremic Pruritus. A review. Nepron. 1992;60(1):1

37) Szepietowski JC, Schwartz RA. Uremic pruritus. Int J Dermatol. 1998;37:247

38) Ståhle-Bäckdahl M. Uremic pruritus. SeminDermatol. 1995 ;14:297

39) Keith-Reddy SR, Patel TV, Armstrong AW, Singh AK. Uremic pruritus.

Kidney Int. 2007; 72: 373-77

40) Garcia-Bravo R, Rodriguez-Pichardo A, Camacho F. Uraemic follicular

hyperkeratosis. Clinical and Experimental Dermatology. 1985; 10: 448–54

41) Umueuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T, et al.

Involvement of central µ-opioid system in the scratching behavior in mice, and

the suppression of itch by the activation of µ-opioid system. Eur J Pharmacol.

2003; 477: 29-35

42) Kimmel M, Alscher DM , Dunst R, Braun N, Machleidt C, Kiefer T, et al.

The role of micro-inflammation in the pathogenesis of uremic pruritus in

haemodialysis patients. Nephrol Dial Transplant. 2006;21: 749-55

43) Garssen J, Gruijl D, Dijk V, Loveren HV, Vandebriel RJ , Wolvers DA,et al.

UVB exposure-induced systemic modulation of TH1- and TH2-mediated

immune responses. Immunology. 1999; 97: 506-14

44) Kumagai H, Saruta T, Matsukawa S, et al. Prospects for a novel kappa-opioid

receptor agonist, TRK-820, in uremic pruritus. In: Yosipovitch G, Greaves

MW, Fleischer JA, McGlone F, editors. Itch, Basic Mechanisms and Therapy.

New York, NY: Dekker; 2004. p. 279–286

45) Wikstrom B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, et al.

Kappa-opioid system in uremic pruritus: multicenter, randomized, double

blind, placebo-controlled clinical studies. J Am SocNephrol. 2005;16: 3742-47

46) Cho YL, Liu HN, Huang TP, Tarng DC. Uremic pruritus: roles of

parathyroid hormone and substance P. J Am AcadDermatol. 1997;36: 538-43

47) Szepietowski J, Thepen T, van Vloten WA, Szepietowski T, Bihari IC.

Pruritus and mast cell proliferation in the skin of haemodialysis patients.

Inflamm Res 44 (Suppl 1) 1995: S84-S85

48) Fantini F, Baraldi A, Sevignani C, Spattini A, Pincelli C, Giannetti A.

Cutaneous innervation in chronic renal failure patients: an

immunohistochemical study. ActaDermVenereol. 1992; 72: 102-5

49) Morton CA, Lafferty M, Hau C, Henderson I, Jones M, Lowe JG. Pruritus

and skin hydration during dialysis. Nephrol Dial Transplant. 1996;11: 2031-6

50) Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gamma-linolenic

acid on refractory uremic pruritus. Am J Kidney Dis. 2006; 48: 69-76

51) Wsik F, Szepietowski J, Szepietowski T, Weyde W. Relief of uraemic

pruritus after balneological therapy with a bath oil containing polidocanol

(BalneumHernal Plus): an open clinical study. J Dermatol Treat. 1996;7: 231-3

52) Szepietowski JC, Szepietowski T , Reich A. Efficacy and tolerance of the

cream containing structured physiological lipids with endocannabinoids in the

treatment of uremic pruritus: a preliminary study. ActaDermatovenerol Croat.

2005; 13: 97-103

53) Breneman DL, Scott Cardone J, Blumsack RF, Lather RM, Searle EA,

Pollack VE. Topical capsaicin for treatment of hemodialysis-related pruritus.

Journal of the Academy of Dermatology. 1992;26: 91–4

54) Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. A prospective

proof of concept study of the efficacy of tacrolimus ointment on uremic

pruritus (UP) in patients on chronic dialysis therapy. Nephrol Dial Transplant.

2004; 19: 1895-901

55) Gilchrest BA, Rowe JW, Brown RS, Steinman TI, Arndt KA. Ultraviolet

phototherapy of uremic pruritus. Long-term results and possible mechanism of

action. Ann Intern Med. 1979; 91: 17-21

56) Gunal AI, Ozalp G, Yoldas TK, Gunal SY, Kirciman E, Celiker H. Gabapentin

therapy for pruritus in haemodialysis patients: a randomized,

placebocontrolled, double-blind trial. Nephrol Dial Transplant.

2004;19:3137-39

57) Pauli-Magnus C, Mikus G, Alscher DM, Kirschner T, Nagel W, Gugeler N, et

al. Naltrexone does not relieve uremic pruritus: results of a randomized,

double-blind, placebo-controlled crossover study. J Am SocNephrol.

2000;11:514-9

58) Pederson JA, Matter BJ, Czerwinski AW, Llach F. Relief of idiopatic

generalized pruritus in dialysis patients treated with activated oral charcoal.

Ann Intern Med. 1980; 93: 446-8

59) Silva SR, Viana PC, Lugon NV, Hoette M, Ruzany F, Lugon JR . Thalidomide

for the treatment of uremic pruritus: a crossover randomized doubleblind trial.

Nephron. 1994; 67: 270-3

60) Webster SB, Dahlberg PJ. Bullous dermatosis of hemodialysis: case report and

review of the dermatologic changes in chronic renal failure. Cutis.

1980;25:322–6

61) Worth RL. Calciphylaxis: Pathogenesis and therapy. J Cutan Med Surg.

1998;2:245

62) Shroff RC, Shanahan CM. The vascular biology of calcification. Semin Dial.

2007;20:103-9

63) Griethe W, Schmitt R, Jurgensen JS, Bachmann S, Eckardt KU, Schindler R.

Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis. J

Nephrol. 2003; 16: 728-32

64) Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an

early perspective. Am J PhysiolEndocrinolMetab. 2004; 286: 686-96

65) Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, et al. The

serum protein α2-Heremans-Schmid glycoprotein/fetuin-A is a systemically

acting inhibitor of ectopy calcification. J Clin Invest. 2003; 112: 357-66

66) Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H.

Parathyroidectomy promotes wound healing and prolongs survival in patients

with calciphylaxis from secondary hyperparathyroidism. Surgery.

2001;130:645-51

67) Guerra G, Shah RC, Ross EA. Rapid resolution of calciphylaxis with

intravenous sodium thiosulfate and continuous venovenous haemofiltration

using low calcium replacement fluid: case report. Nephrol Dial Transplant.

2005;20:1260-2

68) Hanafusa T, Yamaguchi Y, Tani M, Umegaki N, Nishimura Y, Katayama I.

Intractable wounds caused by calcific uremic arteriolopathy treated with

bisphosphonates. J Am AcadDermatol. 2007;57: 1021-5

69) Basile C, Montanaro A, Masi M, Pati G, De Maio P, Gismondi A. Hyperbaric

oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol.

2002;15: 676-80

70) Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE.

Scleromyxedema-like cutaneous diseases in renal-dialysis patients. Lancet.

2000;356:1000

71) Cowper S E, Su LD, Bhawan J, Robin HS, LeBoit PE, Nephrogenic

fibrosing dermopathy. Am J Dermatopathol. 2001;23:383

72) Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez

SA. Description of twelve cases of nephrogenicfibrosingdermopathy and

review of the literature. Semin Arthritis Rheum. 2006; 35: 238-49

73) DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging

threat among renal patients. Semin Dial. 2006; 19: 191-4

74) Evenepoel P, Zeegers M, Segaert S, Claes K, Kuypers D, Maes B, et al.

Nephrogenicfibrosingdermopathy: a novel, disabling disorder in patients with

renal failure. Nephrol Dial Transplant. 2004;19: 469-73

75) Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based

contrast agents: a summary of the medical literature reporting. Eur J Radiol.

2008;66: 230-4

76) Penfield JG, Reilly RF Jr. What nephrologists need to know about gadolinium.

Nat ClinPractNephrol. 2007; 3: 654-68

77) Edward M, Fitzgerald L, Thind C, Leman J, Burden AD. Cutaneous mucinosis

associated with dermatomyositis and nephrogenicfibrosingdermopathy:

fibroblast hyaluronan synthesis and the effect of patient serum. Br J Dermatol.

2007;156: 473-9

78) Edward M, Quinn JA, Mukherjee S, Jensen MB, Jardine AG, Mark PB, et al.

Gadodiamide contrast agent 'activates' fibroblasts: a possible cause of

nephrogenic systemic fibrosis. J Pathol. 2008;214: 584-93

79) Schroeder JA, Weingart C, Coras B, Hausser I, Reinhold S, Mack M, et al.

Ultrastructural evidence of dermal gadolinium deposits in a patient with

nephrogenic systemic fibrosis and endstage renal disease. Clin J Am

SocNephrol. 2008;3: 968-75

80) Kucher C, Xu X, Pasha T, Elenitsas R. Histopathologic comparison of

nephrogenic fibrosing dermopathy and scleromyxedema. J CutanPathol.

2005;32:484-90

81) Digby S, Macduff E, Blessing K, Holmes S. Nephrogenic systemic fibrosis: a

histopathological study of eight cases of a recently described entity.

Histopathology. 2008;52: 531-4

82) Gilkes JJH, Eady RAJ, Rees LH, Munro DD, Moorhead JF. Plasma

immunoreactive melanotrophic hormones in patients on maintenance

haemodialysis. Br Med J. 1975; 656–8

83) Pico MR, Lugo-Solinos A, Sanchez JL, Burgos-Calderon R. Cutaneous

alterations in patients with chronic renal failure. International Journal of

Dermatology,1992;31: 860–3

84) Cawley EP, Hoch-Ligeti C, Bond GM. The eccrine sweat glands of patients

in uremia. Archives of Dermatology.1961; 84: 51–6

85) Bencini PL, Montagnino G, Citterio A, Graziani G, Casati S, Ponticelli C.

Cutaneous abnormalities in uremic patients. Nephron. 1985; 40(3): 316–21

86) Kelleher J, Humphrey OS, Homer D, Davison AM, Giles GR, Losowsky MS.

Vitamin A and its transport proteins in patients with chronic renal failure

receiving maintenance haemodialysis and after renal transplantation. Clinical

Science.1983; 65: 619–26

87) Vahlquist A, Berne B, Danielson BG, Grefberg N, Berne C. Vitamin A

losses during continuous ambulatory peritoneal dialysis. Nephron.

1985;41:179–83

88) Lubach D, Strubbe J, Schmidt J. The ‘half and half nail’ phenomenon in

chronic hemodialysis patients. Dermatologica.1982; 164:350–3

89) El Matri A, Ben Ayed H. (1990). Turning blond hair in haemodialysis

patients. 11th Intermational Congress of Nephrology; Tokyo; 1995 Jul 15–20.

Abstract 242A

90) Bencini PL, Graziani G, Crosti C. Hair shaft abnormalities in uremia, a SEM

study. Preliminary report. European Journal of Dermatology. 1992;2:119–21

91) Jacobs C, Brunner FP, Brynger H, Chantler C, Donckerwolcke RA, Hathway

RA, et al. Malignant diseases in patients treated by dialysis and transplantation

in Europe. Transplantation Proceedings. 1981;13: 729–32

92) Kelly MA, O'Rourke KD. Treatment of porphyria cutanea tarda with

phlebotomy in a patient on peritoneal dialysis. J Am Acad Dermatol.

2001;44:336

93) Saray Y, Seçkin D, Bilezikçi B. Acquired perforating dermatosis:

clinicopathological features in twenty-two cases. J EurAcadDermatolVenereol.

2006;20: 679-88

94) Goldblum OM, Kraus E, Bronner AK. Pseudo Kaposi’s sarcoma of the hand

associated with an acquired, iatrogenic arteriovenous fistula. Archives of

Dermatology. 1985;121:1038–40

95) Goh CL, Phay KL. Arterio-venous shunt dermatitis in chronic renal failure

patients on maintenance haemodialysis. Clinical and Experimental

Dermatology. 1988;13:379–81

96) Servais G, Daens S, Guillaume MP, Cumps J, Duchateau J, Peretz A.

Diagnostic specificities and sensitivities of anti dsDNA, anti-membrane DNA

and anti-nucleosomes autoantibodies. Scand J Clin Lab Invest Suppl.

2001;235:61-7

97) Hochberg MC. Updating the American College of Rheumatology revised

criteria for the classification of systemic lupus erythematosus. Arthritis Rheu.

1997;40(9):1725

98) Cockroft D, Gault MK. Prediction of creatinine clearance from serum

creatinine. Nephron.1976;16: 31–41.

99) Weiss T, Windthorst C, Weiss C, Kreuzer J, Kubler W. Acute effects of

haemodialysis on cutaneous microcirculation in patients with peripheral

arterial occlusive disease. Nephrol Dial Transplant. 1998;13:2317-21

100) ArshdeepTindni, Kumar G, Mukta Panda. Non-healing painful ulcers and role

of sodium thiosulphate: A case report. Cases J. 2008:178 Publish online sept

23,2008

101) Chave TA, Varma S, Knight AG. Dystrophic calcinosis cutis in venous

ulcers: a cause of treatment failure. Br J Dermatol 2001; 145:364-365

102) Miedinger D, Daikeler T. Images in clinical medicine. Chronic venous

insufficiency and dystrophic subcutaneous calcification. N Engl J Med 2008;

358:e10

103) Cochran WG. 1963.Sampling Techniques, 2nd Ed.,New York:Jonh Wiley and

Sons,Inc.

APPENDIX I

PROFORMA

CUTANEOUS MANIFESTATIONS IN PATIENTS WITH CHRONIC KIDNEY DISEASEAT OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX ILE-IFE, NIGERIA

1. Serial number……………………………………………………………….. 2. Hospital No:………………………………………..……...…………………. 3. Age (as at last birthday) :…………………………………………………… 4. Sex ; male ……………………..female………………………………. 5. Occupation:………………………………………………………..……. 6. Educational qualification ; None…..Primary…..Secondary…..Tertiary….. 7. Family history of CKD………………………………………………… 8. Date of diagnosis of CKD……………………………………………………. 9. Duration of illness:……………………………………………..…..………… 10. Cause of CKD:………………………………………………………………. 11. Weight ………… …………………………….…………………………….. 12. Height ………………………………………………………...... 13. Electrolyte, urea and creatinine………………………….………………… ………………………………………………………………………………... 14. GFR( Cockcroft-Gault formula) creatinine clearance={(140-age) x weight(kg) x (0.85 if female) x (1.212 if black)} / {0.813 x serum creatinine (umol/L)}97…………………..………………………………………………. 15. Stage of CKD……………………………………………..………………….. 16. Full Blood count……………………………………………………………… 17. Urinalysis……………………………………………………………….……. 18. Treatment type -conservatives - haemodialyis (less than 3 sessions a week )

-haemodialyis ( 3 sessions a week) -transplant 19. Fasting blood sugar…………………………2HPP………….…………….. 20. Anti-double stranded DNA…………………………………………………… 21. HIV screening………………………………………………………...……… 22. Liver Function Test…………………………………………………..……… …...... 23. SKIN CHANGES YES NO DESCRIPTION A. Pruritus B. Calcification / Calciphylaxis. C. Acquired Perforating Dermatoses D. Bullous Skin Disease E. Nephrogenic Fibrosing Dermopathy F. Pigmentary Changes 1. Hyperpigmentation 2. Hypopigmentation 3. Yellow Grey Discoloration 4. Pallor. G. Cutaneous Dryness ( Xerosis) H. Plantar Hyperkeratosis I. FollicularHyperkeratosis J. Half and Half nail YES NO DESCRIPTION K. Terry nail L. Muerke’s lines M. Mee’s line N. Splinter hemorrhage O. Alopecia P. Shunt dermatitis

Q. PseudoKaposi sarcoma R. Other skin changes /diagnoses. 24. Histology of skin…………………………………………………………… 25. Renal and liver ultrasound scan…………………………………………… ……………………………………………………………………………… 26. Past history of skin disease ………………………………………………… 27. Past history of use of topical steroids………………………………………

APPENDIX II

APPENDIX III

INFORMED CONSENT SHEET

CUTANEOUS MANIFESTATIONS IN PATIENTS WITH CHRONIC

KIDNEY DISEASE AT OBAFEMI AWOLOWO UNIVERSITY TEACHING

HOSPITAL COMPLEX (OAUTHC) ILE-IFE, NIGERIA

Client’s Agreement

I have read the information provided above/have had it read to me. I have had the opportunity to ask questions and my questions have been answered to my satisfaction. I agree that blood investigations as outlined in the proforma be carried out on me with collection of 5mls of my blood. I also agree that small part of my skin, be cut out or scrapped (skin biopsy and skin scrapings) for investigations. I have the right to withdraw from the study at any time.

Yes No

…………………………………………………….. …………… Signature/Thumb print of research respondent Date

…………………………………………………….. …………… Signature/Thumb print of person obtaining consent Date