FATIMA UNIVERSITY MEDICAL CENTER

DEPARTMENT OF INTERNAL MEDICINE

SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Hematologic,
Endocrine, Neurologic
& Dermatologic
Part 1: 7 October
Classification &
Cardiovascular Aspects of
Aspects of CKD
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I
 FATIMA UNIVERSITY MEDICAL CENTER
DEPARTMENT OF INTERNAL MEDICINE
SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Hematologic
Aspects of CKD
Classification &
Part 1: 7 October Cardiovascular Aspects of
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I
OBJECTIVES
1. To enumerate the causes of Anemia
in CKD
2. To identify possible choices in the
Anemia management
3. To determine other blood problems
identified among CKD patients

3
 Anemia / Reduced Erythrocyte Mass
• One of the most clinically significant complications of CKD
• Severity and prevalence go together with progression of CKD
• Anemia is relatively uncommon in earlier stages (stages G1–3) of CKD
• Prevalence begins to increase significantly with an eGFR below 60
mL/min/1.73 m2
• Often more severe among patients with CKD and diabetes mellitus
 Anemia
• Reduction below normal range for Hgb concentration and hematocrit
• Results in reduced oxygen carrying capacity and delivery to the body’s
tissues and organs
• WHO & KDIGO:

Hgb <13g/dl for adult men Hgb <12g/dl for adult women
 Overview of Pathogenesis of Renal Anemia

• Renal anemia is typically an isolated normochromic, normocytic anemia with

no leukopenia or thrombocytopenia

• Both RBC life span and the rate of RBC production are reduced

• The normal bone marrow has considerable capacity to increase the rate of
erythropoiesis, however, this EPO-induced compensatory increase in
erythrocyte production is impaired in CKD.
 Erythropoeitin
• Produced primarily by the liver in the fetal period
• After birth, mainly produced in the kidneys (specifically peritubular
fibroblasts, located in the renal cortex) – Brenner
• Synthesized by the renal peritubular interstitial fibroblast-like cells
(primary source) and hepatocytes (lesser degree) - KDIGO
• Major regulator of production of erythrocytes by interaction with
specific EPO receptors (EPO-Rs) on bone marrow erythroid
progenitors
• Cofactors: iron, vitamin B12, and folic acid
• Modulated by the delivery of oxygen from the circulating
erythrocytes
Renal Anemia Relative
EPO
Deficiency
• Normocytic, normochromic
anemia Shortened
• Slightly hypochromic
Drugs Red cell
Survival
anemia, with insufficient
production of erythrocytes

Marrow Blood
Fibrosis Loss
Renal
Anemia

Aluminum Uremic
Inhibitors of
Overload Erythropoeisis

Iron
Folic Acid, Metabolism,
Vitamin D, Hepcidin,
Zinc Anemia of
Deficiency Chronic
Disease
 1. Relative Erythropoietin Deficiency
• Serum EPO concentrations are generally equal to or higher than those in patients without
CKD
• Even with advanced CKD, the ability to produce EPO is preserved and some degree of
responsiveness to lower Hgb is retained.
• However adequacy of EPO rise relative to the anemia is insufficient
• Become more a function of GFR than of Hgb concentration when the GFR drops below
around 40 mL/min/1.73 m2
• Mechanism of blunted EPO response: disturbed oxygen-sensing mechanism
2. Shortened Red Cell Survival
• Uremic red cells: more fragile to osmotic stimuli
• Glutathione deficiency - not able to mount an effective response to oxidative stress
• Carnitine deficiency

3. Blood Loss
• Coagulopathy of CKD - major role in the occult blood loss via gastrointestinal bleeding
• Blood loss due to the dialysis procedure: estimated the blood loss due to hemodialysis to
be between 1 and 3 L/year (Each milliliter of blood contains approximately 0.5 mg of iron)
4. Uremic Inhibitors of Erythropoeisis
• Cytokines such as TNF-α, IL-1, IL-8, IL-12, and INF-γ may impair erythroid
proliferation via multiple mechanisms
• Cytokine-induced apoptosis
• Downregulation of EPO-Rs
• Impaired production of other factors, such as stem cell factor
• Direct toxic effects on progenitors.
5. Iron Deficiency, Hepcidin & Anemia of Chronic Disease
• Hepcidin: negative regulator and key
regulator of iron homeostasis
• Reduce duodenal, iron absorption,
heme iron recycling and iron
mobilization from macrophages
• High iron = high hepcidin
• Hepcidin is a central regulator of
systemic iron homeostasis
5. Iron Deficiency, Hepcidin & Anemia of Chronic Disease
• In CKD
• Elevated hepcidin in dialysis
• Progression or severity of anemia in patients
with nondialysis-requiring CKD (ND-CKD)
seems to be associated with higher serum
hepcidin concentrations
• EPO therapy leads to a reduction in serum
hepcidin values that correlates with the bone
marrow response
• Use of antihepcidin compounds may
restore iron availability in and improve the
effectiveness of ESA therapy
6. Folic Acid, Vitamin D & Zinc Deficiency
• Net loss of folate is associated with dialysis
• Best assessed by measuring RBC folate because the plasma assay is
affected by recent dietary intake and overestimates the true
prevalence of folate deficiency
• Vitamin D supplementation (50,000 IU/month) in patients on
dialysis did not result in changes in Hgb concentrations
• A Zn supplementation trial has shown measurable improvements in
Hgb concentration
7. Aluminum Overload
• Altered iron metabolism
• Direct inhibition of erythropoiesis
• Disruption of red cell membrane function and rheology
• In dialyzed patients: most notable hematologic effect of aluminum overload is microcytic
• EPO responsiveness is reduced
• Improvement of anemia has also been shown in patients with the use of chelation therapy with deferoxamine

8. Marrow Fibrosis
9. Drugs
• (RAAS) inhibitors
• Angiotensin II has direct facilitating effects on erythroid progenitor cells, which are inhibited by these
compounds
• AcSDKP, an endogenous inhibitor of erythropoiesis, accumulates in patients treated with angiotensin-
converting enzyme (ACE) inhibitors
 Pathogenesis of Renal Anemia

• Subtle changes in blood oxygen content induced by anemia,

stimulate the secretion of EPO through a widespread system of
oxygen-dependent gene expression.

• hypoxia-inducible transcription factors (HIFs) -> HIF-1, HIF-2

• production of HIF-1α and HIF-2α is largely independent of

oxygen, but their degradation is related to cellular oxygen
concentrations.

• HIF-2 -> primarily responsible for the regulation of EPO

production.
 Pathogenesis of Renal Anemia

• The mechanisms impairing renal EPO production in diseased kidneys

remain poorly understood
• The production capacity for EPO remains significant, even in CKD

MAIN PROBLEM : failure of EPO production to increase in

response to chronically reduced hemoglobin (Hb)
concentrations
 Pathogenesis of Renal Anemia

EPO stimulates RBC production by

binding to homodimeric EPO receptors 1.Inhibition of RBC production by
unknown uremic inhibitors of
erythropoiesis may contribute to the
Binding of EPO to its receptors pathogenesis of renal anemia
salvages these progenitor cells and the
erythroblast generation from
apoptosis 2.There is inhibition of EPO production and EPO efficacy, reduced
iron availability, mediated through inflammatory cytokines

-> hepatic release of hepcidin in states of inflammation

cell division and maturation into RBCs. it simultaneously blocks iron absorption from the gut and promotes iron
sequestration in macrophages.
 Regulation of Erythropoiesis by HIF

Key players
• HIF
• Von Hippel Lindau
protein
• Steady-state:
• Ubiquitin protein
EPO concentration at
degradation system
approximately 10 to 30 U/L
• Anemia or hypoxia:
EPO concentrations as much
as 10,000 U/L.
 How do we test for Anemia?

CKD WITHOUT ANEMIA CKD WITH ANEMIA

(not being treated with ESA)

When clinically indicated and: When clinically indicated and:

Annually - CKD 3  Every 3mos – CKD 3-5ND, CKD

Twice per year - CKD 4-5ND 5PD
Every 3mos - CKD 5HD and CKD  Monthly – CKD 5HD
5PD
Evaluation of Anemia
 Evaluation of Anemia

• KDIGO guidelines recommend the ff tests for the initial evaluation of anemia:

CBC, w/c includes Hb concentration, red cell indices, WBC count and differential,
platelet count
• Severity of anemia

Absolute reticulocyte count

• high in patients with active blood loss/hemolysis
• Low in hypoproliferative erythropoiesis with anemia
 Evaluation of Anemia
Serum ferritin levels (assess iron stores)
• Acute phase reactant hence may be elevated in inflammatory states
• Check CRP if no clinical evidence of infection
• <30ug/l – severe iron deficiency, predictive of absent iron stores in
marrow
• >300ug/l – most have shown normal bone marrow iron stores

Serum TSAT (measure availability of iron for erythropoiesis)

 Evaluation of Anemia

Vitamin B12 and folate

• Uncommon but impt treatable causes of anemia, <10%
of HD patients
• Macrocytic RBCs
• Consider nutritional deficit
• Folate deficiency – check serum folate
Evaluation of Anemia
 Oral vs Intravenous?

• GOALS OF IRON THERAPY

• Prevent iron-deficient erythropoiesis
• Achieve and maintain target Hb levels
• Reduce ESA doses in pts rcvng ESA tx

• KDIGO Guidelines for adult patients with

NDD CKD and anemia not on iron or ESA
therapy
• Trial of IV iron or 1-3month trial of oral
iron
 Iron Treatment on CKD non HD

• In CKD ND pts, may give iron IV or oral

• Advantage of IV iron over oral is small -> Hgb difference of 0.31g/dL
• Oral Iron -> 200mg of elemental iron/day
• Most commonly used ferrous sulfate but other iron preparations
can be used
• If goals of iron supplementation are not met w/in 1-3mos ->
consider IV iron
 Iron Treatment on CKD 5HD, 5PD

• In CKD 5HD pts, IV route is preferred

• led to a greater increase in Hgb, lower ESA dose, or both.

• CKD 5PD pts – limited data but IV iron is superior to

oral iron
 Iron Treatment

• IV IRON
• May be given as a single large dose or as repeated smaller doses
• Common practice – initial course of 1000mg IV iron
• may be repeated to increase hgb level or allow a decrease in ESA dose;
if TSAT remains <30% and ferritin <500

• Serum ferritin and TSAT levels should not be measured until at least one
week has elapsed since the most recent prior IV iron dose.
 Iron Status Evaluation

• Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy

• Falling TSAT/ferritin – may reflect ongoing blood loss

• Increasing TSAT/ferritin – may indicate excess; may stop or reduce iron
• Increasing ferritin but stable/declining TSAT – evaluate for
infection/inflammation
 Iron Status Evaluation

• Test iron status more frequent (TSAT and ferritin):

• initiating or increasing ESA dose
• blood loss
• monitoring response after a course of IV iron
• in circumstances where iron stores may become depleted
 Iron Status Evaluation

• Monitor patients for 60 minutes after the initial dose of IV iron

• WOF Hypotension, dyspnea, anaphylaxis

• Avoid IV iron to patients with active systemic infections

• theoretical and experimental evidence to suggest that iron administration may worsen an existing
infection but clinical evidence is lacking.
• Clinical judgement if there is immediate need to IV iron in the setting of an active infection
 Consider QOL prior to initiation of ESAs

KDIGO Class 1B recommendation

• In initiating and maintaining ESA
therapy, we recommend balancing the
potential benefits of reducing blood
transfusions and anemia-related
symptoms against the risks of harm in
individual patients (e.g., stroke, vascular
access loss, hypertension)
 ESA Initiation

• Address all correctable causes of anemia (including iron deficiency and inflammatory
states) prior to initiation of ESA therapy.
• Use ESA therapy with great caution, if at all, in CKD patients with active malignancy— in
particular when cure is the anticipated outcome (history of stroke or malignancy)
TREAT TRIAL
higher death rate from cancer in darbepoetin vs placebo
Absolute risk of stroke attributable to high hgb/ darbepoetin was 8% with hx of stroke vs
1% in w/out hx of stroke.
ESA Initiation in Adult CKD ND Patient
 Initiating ESA in Adult CKD 5D

Start ESA therapy when Hgb is between 9-10 g/dL to

Hb > 9 – 10 g/dL
avoid having the Hgb fall below 9.0 g/dL

Individualization of therapy
 some patients may have improvements in QOL at higher Hb
concentration and ESA therapy may be started above 10.0 g/dl
 ESA Maintenance Therapy

• ESAs not be used to maintain Hb concentration above 11.5 g/dl

• Individualization of therapy will be necessary as some patients may have improvements in

QoL at Hb concentration above 11.5 g/dl and will be prepared to accept the risks. (Not
Graded)

• ESAs not be used to intentionally increase the Hb concentration above 13 g/dl. (1A)
 ESA Dosing

• Determine the initial ESA dose using the patient’s Hb

concentration, body weight, and clinical
circumstances. (1D)
• Rate of increase in Hgb concentration of 1 to 2g/dl per month
• AVOID a rise in Hgb >2 g/dl over 4 weeks
• Higher Hb levels require lower initial ESA doses
• In patients with a history of CVD, thromboembolism or seizures,
or HPN, initial doses should be in the lower range
 ESA Initiation

• Determine the initial ESA dose using the patient’s Hb

concentration, body weight, and clinical circumstances. (1D)
• Rate of increase in Hgb concentration of 1 to 2g/dl per month
• AVOID a rise in Hgb >2 g/dl over 4 weeks
• Higher Hb levels require lower initial ESA doses
• In patients with a history of CVD, thromboembolism or seizures, or HPN,
initial doses should be in the lower range
 ESA Dosing

Increase Epo alfa or beta every 4 weeks

• ESA dose adjustments be made based (3x20iu/kg)
on the patient’s Hb concentration, rate
of change in Hb concentration, current
ESA dose and clinical circumstances. If hgb > 11.5g/dl, reduce dose by 25%
(1B)
If Hb continues to increase, hold ESA until
• Decreasing ESA dose in preference to Hgb begins to decrease
withholding ESA when a downward
adjustment of Hb concentration is reinitiate therapy at a dose approximately 25%
needed. (2C) below the previous dose
 ESA Dosing

• Alternatively, may repeat the Hb determination again in a

shorter interval (e.g., weekly) and interpret any further rise,
before considering holding the dose.

 If the Hb increases by more than 1.0 g/dl (10 g/l) in any 2-

week period, the dose should be decreased by approximately
25%
 ESA Administration

• For CKD 5HD patients and those on hemofiltration or HDF

therapy -> can use either intravenous or subcutaneous
administration of ESA. (2C)

• For CKD ND and CKD 5PD patients -> subcutaneous

administration of ESA (2C)
 ESA Administration
• Frequency of administration
• Epoetin-alfa efficacy decreases when the dosing is extended from 3 times
weekly to once-weekly administration
• Long-acting ESAs, darbepoetin -> maximum efficacy when given every 2
weeks
• Methoxy polyethylene glycol-epoetin-beta (CERA) -> maximum efficacy
every 4 weeks.
• When converting a patient from one ESA to another the pharmacokinetic
and pharmacodynamic characteristics of the new ESA need to be taken
into consideration.
 Type of ESA

• no evidence that any given ESA brand is superior to another

• a number of different types of short-acting or long-acting

ESAs are available worldwide
 Types of ESA

• EPOETIN
• EPO ALFA and BETA
• Half life 6-8hours
o DARBEPOETIN ALFA
Longer half life then rhEPO – 48 hours
No significant difference b/w IV or SQ route
• CERA “Continuous erythropoietin receptor activator”
Half life of 130 hours IV/SQ; less frequent injections
 ESA Administration
• Frequency of monitoring
• During the initiation phase of ESA therapy, measure Hb
concentration at least monthly. (Not Graded)
• During the maintenance phase:
• For CKD ND pts, measure Hb concentration at least every 3
months. (Not Graded)
• For CKD 5D patients, measure Hb concentration at least
monthly. (Not Graded)
 Evaluation for Pure Red Cell Aplasia
• Investigate for possible antibody-mediated PRCA when a patient
receiving ESA therapy for more than 8 weeks develops the following
• Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0 g/dl per week OR requirement of
transfusions at the rate of approximately 1 to 2 per week, AND
• Normal platelet and white cell counts, AND
• Absolute reticulocyte count less than 10,000/ml

• STOP ESA therapy in patients who develop antibody-mediated

PRCA.
• Peginesatide -> tx for patients w fith antibody-mediated PRCA. (1B)
• initiated at a dose of 0.05 to 0.075 mg/kg body weight by subcutaneous
injection every 4 weeks
ESA use in CKD and CVD Outcomes
 Evaluating Iron Therapy & ESA use
• Results from these trials resulted in the FDA boxed warning for ESA use
• Use of iron therapy increased as a result
• Important to achieve balance between iron therapy and ESA use to improve
QOL and avoid AEs with either agent
• Assess for inflammation through iron parameters
 When to Transfuse???
• Avoid when possible in :
• Chronic anemia – minimize risks related to their use
• Pts for Organ transplantation – minimize risk of allosensitization

• May consider transfusion if:

• ESA therapy is ineffective (BM failure, ESA resistance)
• The risk of ESA therapy may outweigh its benefits (malignancy, stroke)

Decision to transfuse with non-acute anemia should not be based on any

arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia.
When to transfuse
 When to Transfuse???
URGENT TREATMENT OF ANEMIA
When rapid correction of anemia is required to stabilize the patient’s
condition (e.g., acute hemorrhage, unstable coronary artery disease)
When rapid pre-operative Hb correction is required
When to Transfuse??!
When to Transfuse??!
When to Transfuse??!
 Disorders of Hemostasis in CKD
• Elevated bleeding time

Thrombastenia
• Diminished aggregation
response to ADP and
epinephrine
• Reduced ristocetin-induced
platelet agglutination

Most consistent abnormality in platelet Endothelial

• Effect of repeated platelet function in uremia is an impaired production of NO, a
powerful platelet
activation interaction of platelets with the inhibitor, has been
• Removal of younger
vascular subendothelium noted to be increased
platelets with greater
function
• Impairment of platelet Dialysis More important Content of
function from a secondary pathogenic factor in serotonin and
effect of activated associated platelet dysfunction may
ADP is reduced in
leukocytes platelet be the effect of uremic
plasma on platelet uremic platelet
dysfunction responsiveness granules
 Treatment of Uremic Platelet Dysfunction
First aspect of treatment to correct uremic platelet dysfunction is provision of adequate
dialysis
Treatment of anemia with rhEPO - most effective treatment of uremic platelet
dysfunction
• Most likely related to the associated changes in blood flow, with platelets moving
closer to the vessel walls
• Also possible that EPO treatment itself may directly affect platelet function:
increase in young circulating forms of platelets, with improved functional
characteristics - > increase in young circulating forms of platelets, with improved
functional characteristics
• Improved platelet intracellular calcium mobilization, increased expression of GPIb,
and repaired platelet signal transduction
Treatment of Uremic • Little vasopressor activity and only rarely induces hyponatremia
• The mechanism of improved platelet function is not completely
Platelet Dysfunction known, but enhanced release of larger vWF multimers by
endothelial cells probably plays an important role.
Desmopressin • Development of tachyphylaxis caused by the depletion of the
endothelial stores of vWF multimers

Cryoprecipitate • Reserved for Life threatening bleeding

• MOA: Unknown but may be related to the inhibition of vascular NO production

Estrogen • May be related to the inhibition of vascular NO production

• Fibrinolytic Inhibitor
Tranexamic Acid • Short term (6 days)/ Long term (3 months)
 Hypercoagulability in CKD
• Prothrombotic, hypercoagulable state, • Oxidized plasma albumin has also been
which may play a role in the implicated in generating a prothrombotic
atherosclerotic/ cardiovascular state via CD-36-mediated platelet
complications activation
• Symptomatic venous thromboembolism • No significant differences in
is moderately increased thromboembolic or hemorrhagic
• ESA therapy may further increase complications in CKD patients treated
thromboembolic complications with warfarin or NOACs
• Indolic uremic solutes have also been • Omit heparinization when dialyzing
implicated in the procoagulant patients on chronic anticoagulation
phenotype of uremia therapy with vitamin K antagonists
Heparin-Induced Thrombocytopenia

An acute thrombotic event in a All heparin-based

thrombocytopenic patient on
maintenance hemodialysis or therapies should be
unexpected occlusions of the
extracorporeal circuit should
discontinued
prompt a search for possible HITPresence of
antibodies to the
platelet factor 4–
heparin (PF4-H)
Use of direct complex Warfarin should not be
considered until the
thrombin inhibitors resolution of
or factor Xa thrombocytopenia and
inhibitors for neither should prophylactic
platelet transfusions
anticoagulation
White Cell Function in CKD
Leukocyte
Leukocyte
Functional
Activation
Impairment

Use of particular dialyzers and dialysates has been

associated with intradialytic leukocyte activation Dysfunctional immune response in patients
and enhanced oxidant stress, which may with CKD - Enhanced susceptibility to bacterial
exacerbate the underlying activated inflammatory or viral infections
state

Advanced oxidation protein products Reduced response to

(AOPPs) carried mostly by serum
albumin hepatitis B vaccine

Can trigger neutrophil activation and respiratory burst,

which can be reduced in vitro by N-acetylcysteine Impaired phagocytosis by neutrophils
Erythocytosis in CKD patients

ADPKD Post KT

Renal
Renal
Stenosi
Tumor
s
 1. Polycystic Kidney Disease
• Degree of anemia in ADPKD is less severe than for other causes of CKD
• Although patients with ADPKD on dialysis usually require treatment
with ESAs
• Occasionally may become polycythemic
• EPO concentrations up to twofold higher
• Cyst wall interstitial cells have been shown to express EPO mRNA and
cysts derived from proximal but not distal tubules contain increased
concentrations of bioactive erythropoietin
• Cyst expansion results in pericystic hypoxia -> enhanced production of EPO in
cystic kidneys is probably due to local hypoxia and mediated via HIF activation
• Regional hypoxia also appears to stimulate cyst growth, primarily via increased
fluid secretion into the cyst lumen
 2. Post Transplant Erythrocytosis
• Transplantation is usually followed by full correction of renal anemia
• 10% to 20% erythrocytosis - more likely to occur in patients with normal kidney function
• Increased plasma EPO concentrations: selective venous catheterization studies suggest that
the native kidneys are the main source of increased EPO
• unclear how the secretion rate is enhanced after transplantation
• Treatment:
• RAASi: most effective therapy
• No evidence that angiotensin acts directly on EPO- producing cells, but there are several ways through
which RAAS blockade may inhibit erythropoiesis
• Angiotensin II leads to preferential constriction of efferent glomerular arterioles -> increases the ratio of
filtered sodium -> Na is the main determinant of renal oxygen consumption -> increased o2
consumption -> less o2 in the peritubular capillaries -> enhanced EPO secretion
• Reversed by RAASi
• discontinuation of diuretics, theophylline, and phlebotomy
3. Renal Artery Stenosis
• Rarely associated with erythrocytosis
4. Renal Tumor
• 5% of patients with renal carcinomas have erythrocytosis
• One-third of tumor-associated erythrocytosis is caused by renal
cancer
• Associated with mutations of the VHL gene that interfere with its
ability to target HIF for proteasomal degradation
 Anemia Erythrocytosis

CBC, Retic, TIBC, Fe, TSAT, Ferritin ADPKD Post KT Renal Renal
Stenosis Tumors

Iron ESA Transfusion WBC Problem

Oral IV EPO α EPO ß CERA Hematologic WBC WBC Functional

Aspects of Activation Impairment
CKD

Disorder of
Plan for KT? Coagulation

Platelet Dabigatran Rivaroxaban Apixaban

Problem

Heparin – Induced Thrombasthenia

Thrombocytopenia Dialysis Associated
Platelet Dysfunction

Desmopressin Estrogen Cryoprecipitate Tranexamic

 FATIMA UNIVERSITY MEDICAL CENTER
DEPARTMENT OF INTERNAL MEDICINE
SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Endocrine
Aspects of CKD
Classification &
Part 1: 7 October Cardiovascular Aspects of
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I
OBJECTIVES
1. To enumerate the altered hormones
in CKD
2. To connect the effect of decreased
kidney function to these hormones
and their axis

71
True or false
The kidneys are part of the endocrine
system
 True or false
The kidneys have endocrine function

The kidneys produce three important hormones:

erythropoietin, calcitriol (1,25-
dihydroxycholecalciferol ) and renin
The Endocrine System
Pancreatic Alteration
• Uremic Insulin Resistance

Hypothalamopituitary Axis
• Thyroid Hormone Alteration
• Growth Hormone Alteration
• Adrenal axis alteration

Gonadal Alteration
• Prolactin Alteration
• Effects on Female CKD Patients
• Effects on Male CKD Patients
Which of the following are common factors in the
uremic phenotype that have been proposed to
mediate/contribute to insulin resistance?
a. Dyslipidemia and increased fat mass
b. Protein-energy wasting and inflammation
c. Anemia and acidosis
d. Vitamin D deficiency and hyperparathyroidism
e. All options
 Insulin – Resistance in CKD

• Reduced biologic effect for any given blood

concentration of insulin
• Common in CKD

• Impaired tissue sensitivity to insulin is the primary cause of

insulin resistance in uremia
• INFLAMMATION: A reduced level of insulin receptor
phosphorylation
 Uremic Insulin Resistance
• Impaired tissue sensitivity to insulin- primary cause of insulin resistance in
uremia
• Both hyperparathyroidism and vitamin D deficiency may mediate insulin
secretory abnormalities
• Hyperinsulinemia promotes tubular sodium retention, decreases urinary uric
acid clearance, and upregulates the RAAS, all established risk factors for
hypertension
• Uremic dyslipidemia: characterized by hypertriglyceridemia, reduced HDL
cholesterol, increased VLDL and LDL
• Abnormalities improve concomitantly with the correction of IR and glucose intolerance
after the intravenous administration of 1,25(OH)2D therapy
 Insulin – Resistance in CKD
Body’s Resistance to Insulin

Compensatory Increase in Production and secretion of Insulin

by the Pancreas = HYPERINSULINEMIA

Concomitant inadequate secretion of insulin = ABNORMAL

GLUCOSE TOLERANCE -> DIABETES MELLITUS
Insulin – Resistance in CKD
 Insulin – Resistance in CKD
Treatment

Regular exercise and lifestyle modification

(ACE) inhibitor treatment appears to improve insulin sensitivity and may

reduce the risk of type 2 diabetes mellitus in CKD

INDIVIDUALIZED TREATMENT WITH ORAL HYPOGLYCEMIC

AGENTS, GLP-1 AGONISTS OR INSULIN
 The Thyroid & CKD

The most common thyroid hormone disturbance in

CKD

a. Subclinical hyperthyroidism
b. Subclinical hypothyroidism
c. Low T3
d. Low T4
 Thyroid Hormonal Alterations in CKD

• The kidney is involved in

the metabolism and
clearance of thyroid
hormones.
• A decline of kidney function
is accompanied by a
characteristic disturbance
in thyroid physiology
 Thyroid Hormonal Alterations in CKD

NEGATIVE feedback
KIDNEY: Clearance of Iodide mechanism blocking thyroid
hormone production

Plasma Iodide Retention in

CKD Low T3 levels in Uremia =
Appropriate compensatory
response to reduce
energy expenditure and minimize
protein catabolism
 Thyroid Hormonal Alterations in CKD

• Low T3 Syndrome (reduced T3 in the presence of normal

TSH and T4): 70% of ESRD
• Subclinical Hypothroidism: 18% PD, 22% HD Patients
 Thyroid Hormonal Alterations in CKD

THRYROID DYSFUNCTION THYROID DYSFUNCTION IN

IN UREMIA OTHER CHRONIC ILLNESSES
Low T3 from diminished Increased conversion of T4
conversion of T4 to T3 in to the metabolically
the periphery inactive reverse T3 (rT3)
 Thyroid Hormonal Alterations in CKD
CONSEQUENCES WHEN DO WE TREAT LOW T3/SUBCLINICAL
HYPOTHYROIDISM?
•Increased risk of mortality
• Potential unfavorable effects of thyrotoxicosis:
•Fatigue, Impaired quality of life tachycardia, loss of skeletal muscle and bone,
•Impaired Cardiovascular Response, heart failure
increase rates of heart failure • Key therapeutic approach for the successful
management of nonthyroidal illness in CKD:
•Ovulatory Dysfunction/Infertility
restore thyroid hormone deficiencies and
•Low T3 Syndrome = Lower Graft maintain thyroid hormones within the normal
Survival in KT range
 Thyroid Hormonal Alterations in CKD
WHEN DO WE TREAT LOW T3/SUBCLINICAL HYPOTHYROIDISM?
•TSH > 10 mU/L: Treat due to risk of progression to overt hypothyroidism, myocardial infarction,
atherosclerosis
•TSH 7.0 to 9.9 mU/L
•Treat patients age 65 to 70 years with TSH 7.0 or higher
•TSH Upper limit of normal to 6.9 mU/L
•Treat patients <65 6o 70 years with symptoms of hypothyroidism
•High titers of anti-TPO
•Infertility or attempting pregnancy: T4 replacement in women with subclinical hypothyroidism who are
trying to conceive
True or false
Growth hormone levels in CKD are
reduced
True or false
Growth hormone levels in CKD are
reduced
 Growth Hormone in CKD

• Resistance to the actions of CONSEQUENCE

Disturbances in the GH/IGF-1
GH and IGF-1 system in CKD = growth
• Due to decreased GH retardation, Protein Energy
receptors and/or post–GH Wasting and sarcopenia, and
receptor progression (i.e., loss of
• Decreased IGF-1 synthesis kidney function in CKD).
 Growth Hormone in CKD
• The growth hormone (GH)/insulin-like growth factor 1 (IGF-1)
system: Anabolism, body growth, and body composition

• Regulates a range of metabolic processes for the growth of cells

and tissues in the body

• GH induces protein synthesis and nitrogen retention and impairs

glucose tolerance by antagonizing insulin action, lipolysis:
protein stores rather than fat Tissue are preserved
 Growth Hormone in CKD

CHILDREN • ADULTS
Recombinant human GH (rhGH) is • Individualized
an approved treatment for growth • Risks:
failure in children. • Hypertension
GH therapy should be considered in • Hyperglycemia, Diabetes
children with CKD who have a height • fluid retention
less than 2 standard deviations • Colonic polyps, colonic malignancy
(SDs) below the mean • Some mice models: Increased sclerosis =
Progression of CKD
 Growth Hormone in CKD

Which of the following is NOT a possible adverse

reaction to growth hormone (GH) treatment in
children?
a. Fluid retention
b. Intracranial hypertension
c. Hypoglycemia
d. Hyperglycemia
 Prolactin in CKD

Hyperprolactinemia in CKD is understood as a

consequence of reduced renal clearance

CONSEQUENCES:
• Galactorrhea and infertility due to the inhibition of
gonadotropin secretion
• Women: amenorrhea
• Men: erectile dysfunction and
 Prolactin in CKD
• MINIMIZE OR AVOID Drugs that further stimulate prolactin
production
• Antidopaminergic medications
• Metoclopramide
• Cimetidine
• Neuroleptics
 Adrenal Gland
• Adrenocorticotropic hormone (ACTH) was used 60 years ago for the
treatment of nephrotic syndrome in children but was gradually
replaced by synthetic glucocorticoid analog
• Antiproteinuric, lipid-lowering, and renoprotective properties, which are
not fully explained by its steroidogenic effects
• Aldosterone increases oxidative stress and promotes vascular
inflammation
• Salt overload → increased aldosterone secretion→ aldosterone
causes hypertrophy and fibrosis in the heart
• Prevented by the administration of mineralocorticoid receptor (MR)
antagonists
 Adrenal Gland
• Dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulfate (DHEA-S) – Low
in CKD
• Associated with the progression of glomerular
injury in men with type 2 diabetes mellitus
 Gonadal Dysfunction in CKD

Successful conception
with pregnancy is rare in
women with ESKD
 Gonadal Dysfunction: Women
• Elevated Prolactin, FSH, LH are usual findings in uremia
• Disturbances in menstruation and fertility →
Amenorrhea
• Menstrual cycle typically remains irregular after the
initiation of dialysis.
• Characterized by the absence of cyclic gonadotropin and
estradiol release
• Anovulation and subsequent infertility
• Decreased libido and reduced ability to reach orgasm
 Gonadal Dysfunction: Women
• Successful conception with pregnancy is rare in women with
ESKD
• Pathologic endometrium morphology - proliferative changes
in 30% and atrophic changes in almost 25%
• Premature menopause, approximately 4.5 years earlier on
average than their healthy counterparts
• Hypogonadism - linked with sleep disorders, depression,
urinary incontinence and, in the long term, osteoporosis,
impaired cognitive function, and increased cardiovascular risk
 Treatment of Gonadal Dyfunction in Women
• Education about sexual function in • It is not clear whether unopposed
estrogen stimulation (due to
the setting of CKD, adequate anovulatory cycles) predisposes
dialysis delivery, and treatment of women with CKD to endometrial
underlying depression hyperplasia or endometrial cancer -
• Hypoactive sexual desire disorder routine gynecologic follow-up is
recommended
(most commonly reported • Vaginal atrophy and dyspareunia -
problem) - testosterone topical estrogen cream and vaginal
replacement therapy, kidney lubricants
transplantation (most effective) • Uremic women who are menstruating
- birth control
• Chronic anovulation and lack of • Estradiol hormonal replacement therapy
progesterone secretion → to restore regular menses and improve
sexual function in premenopausal
menorrhagia - Oral progesterone
 Gonadal Dysfunction: Men
Causes of hypogonadism in CKD
• Hyperprolactinemia
• Comorbid conditions (e.g., PEW, obesity, diabetes mellitus,
hypertension)
• Medications that may influence gonadal function (e.g., ACE
inhibitors, ARBs, spironolactone, ketoconazole,
glucocorticoids, statins, cinacalcet)
• Increase LH, FSH, LH/FSH ratio
• Rarely normalize and often progress despite dialysis
 Gonadal Dysfunction: Men
• Kidney transplant may restore normal sexual activity,
although some features of reproductive function may
remain impaired
• Decreased libido, erectile dysfunction, oligospermia and
infertility, osteopenia and, to some extent, osteoporosis,
sarcopenia and anemia
• Treatment - optimal delivery of dialysis and adequate
nutritional intake, as well as screening for depressive
symptoms
 FATIMA UNIVERSITY MEDICAL CENTER
DEPARTMENT OF INTERNAL MEDICINE
SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Neurologic
Aspects of CKD
Classification &
Part 1: 7 October Cardiovascular Aspects of
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I
OBJECTIVES
1. To know ways on how to prevent
occurrence of stroke in CKD patients
2. To enumerate different neurologic
conditions encountered among CKD
patients

108
 Stroke

Disorders of
Sleep Cognitive
Disorders Function
Neurologic
Conditions
in CKD

Neuropathy Seizure
 Stroke

Sudden onset of focal neurologic symptoms resulting from an interruption

in blood supply to a corresponding area of the brain.

ISCHEMIC OR HEMORRHAGIC

STROKE MORTALITY RISKS IN CKD: INCREASED SIXFOLD TO TENFOLD

Stroke
 Stroke Risk Factors & Prevention in CKD
Treatment of hypertension in the general population reduces stroke risk by an
average of 40%
Each 10-mm Hg increase in mean blood pressure = 11% increased risk for
stroke

Dietary Approaches to Stop Hypertension (DASH) diet

Rich in vegetables, fruits, and low-fat dairy products when combined with
reduced sodium intake (<2g/day), can lower blood pressure by 11.5 mm
Hg systolic
higher sodium and lower potassium intake = heightened risk for stroke

Correct Anemia: increased risk of vascular events

Stroke Risk Factors & Prevention in CKD
 Stroke Risk Factors & Prevention in CKD
• Risk factor: Levels of albuminuria more than 30 mg/g = increase risk for
BOTH ISCHEMIC AND HEMORRHAGIC Stroke

• Even absent intradialytic hypotension, hemodialysis has been shown to cause

cerebral hypoperfusion.

• Atrial fibrillation increases the risk for stroke by 2.5 to 4.5 times

• In patients with noncardioembolic stroke or TIA, guideline recommends

antiplatelet agents to reduce the risk for recurrent stroke
 Chronic confusional state
• Impairment in memory and at least one
Acute confusional state Disorders of other cognitive domain, such as language,
• recent onset of fluctuating awareness
• impairment of memory and attention
Cognitive orientation, reasoning, or executive
functioning
• disorganized thinking Function • must be severe enough to interfere with
daily activities and independence

Disequilibrium
Dementia
Syndromes

Uremic Dialysis Chronic

Dialysis
Encephalopath Cognitive
Dysequilibrium Dementia
y Impairment
 1. Uremic Encephalopathy
Signs and symptoms
• Characterized by lethargy and confusion in early stages and can progress to seizures and/or coma
• Other neurologic signs - tremor, myoclonus, or asterixis
Pathophysiology
• Kidney injury may activate cytokines that cross the blood–brain barrier or activate other messengers that
contribute to neuronal dysfunction
• Retention of uremic solutes may trigger both the inflammatory reaction and the neuronal dysfunction
• Guanidine compounds, including guanidinosuccinic acid, methylguanidine, and homoarginine, induce
seizures, possibly through their effects on N-methyl-d-aspartate (NMDA) receptors and/or by modulating
calcium channels
• Anemia and secondary hyperparathyroidism are proposed risk factors
Treatment
• Initiation or intensification of renal replacement therapy - resolution of symptoms typically occurs within
days
• Modest dietary protein restriction may be appropriate in certain settings
 2. Dialysis Disequilibrium
• Seen during or shortly after the first several dialysis treatments
• Has also been reported in patients undergoing peritoneal dialysis and maintenance
hemodialysis
Symptoms: headache, visual disturbance, nausea, or agitation, and in severe cases, delirium,
lethargy, seizures, and coma
Patholophysiology: Primarily attributable to brain edema
• Rapid removal of urea (and other water-soluble, rapidly diffusible solutes) by dialysis leads to a solute
gradient between the blood and brain, in turn leading to influx of water into the brain.
• decrease in intracellular pH and formation of idiogenic osmoles (osmolytes) within the brain contributes
to the development of cerebral edema when an osmolar gradient develops during dialysis
Prevention - reducing the efficiency dialysis, increasing the dialysate sodium concentration,
and administering mannitol
 2. Dialysis Disequilibrium
H20

LAG IN OSMOLAR SHIFT BETWEEN THE

BLOOD AND THE BRAIN = REVERSE UREA
RAPID REMOVAL OF UREA AND EFFECT= OSMOSIS DRIVES WATER INTO
SMALL SOLUTES IN THE BLOOD THE BRAIN = CEREBRAL EDEMA
2. Dialysis Dysequilibrium
2. Dialysis Disequilibrium: Mannitol

A short HD session (2 hours)

with a low blood flow (200
ml/min) and a urea
reduction ratio goal of 0.4
is recommended as the
initial prescription for
patients at risk for DDS
 2. Dialysis Disequilibrium: Mannitol
H20

LAG IN OSMOLAR SHIFT BETWEEN THE

BLOOD AND THE BRAIN = REVERSE UREA
RAPID REMOVAL OF UREA AND
EFFECT= OSMOSIS DRIVES WATER INTO
SMALL SOLUTES IN THE BLOOD
THE BRAIN = CEREBRAL EDEMA
 2. Dialysis Disequilibrium
PROXIMAL TUBULE / THIN DESCENDING
LUMEN LIMB OF LOH BLOOD
Mannitol Water
H20 permeable
H20
cell
membrane
H20 Mannitol
H20

Water
H20 permeable H20
Mannitol
cell
membrane
H20
 3. Dialysis Dementia
• First described in the 1970s, occurred almost exclusively among patients on
hemodialysis rather than peritoneal dialysis
• Epidemic forms occur in geographic clusters and are strongly associated with
aluminum contamination of dialysate
Symptoms: neuropsychiatric symptoms, osteomalacia, myopathy, and anemia
• Exacerbated by hemodialysis or by administration of chelating agents such as
deferoxamine or desferrioxamine, presumably due to mobilization and redistribution of
tissue aluminum into the brain
Treatment: Chelation therapy is indicated despite the caveats noted earlier
because there is no other effective method for removal of aluminum
 4. Chronic Cognitive Impairment
Evaluation and Management
• In addition to cognitive function testing, laboratory testing for vitamin B12 deficiency
and hypothyroidism is recommended for all patients with suspected dementia
• Intensification of the dialysis regimen is not routinely recommended due to
nondefinitive findings from two clinical trials.
• Two classes of medications – for treatment of Alzheimer type and vascular dementia
• Cholinesterase inhibitors: mild-to-moderate dementia
• Memantine (NMDA receptor antagonist): moderate-to-severe Alzheimer dementia, vascular
dementia
• Require dose modification
• A key aspect of dementia management is the assessment of patient safety and ability to
perform self-care functions, comply with medical regimens, and participate in medical
decision making
 Seizure in ESKD
• In adults with ESKD receiving maintenance dialysis, seizures are reported to
affect between 2% and 10%
• Uremia lowers the seizure threshold
• Characteristics
1. Uremic encephalopathy - generalized tonic-clonic or myoclonic seizures, partial motor
seizures
• Definitive treatment involves the institution of renal replacement therapy
• (AEDs) with low dialytic clearance
2. Dialysis disequilibrium - occur during or immediately after hemodialysis treatment
3. Drugs and intoxication - drugs and/or their metabolites may lower the seizure threshold
in patients with ESKD
• Meperidine, acyclovir, penicillin, cephalosporins, theophylline, metoclopramide, and lithium
• Ingestion of star fruit has been linked with seizures in patients with ESKD
 Seizure in CKD…
What will you think of???
• Stroke
• Subarachnoid hemorrhage
• Head trauma Uremia lowers
• Intracranial tumor
• Systemic illness such as meningitis the seizure
• Drug intoxication threshold
• Metabolic disorders: hypoglycemia,
hypocalcemia, and hypomagnesemia.
 Neuropathy in CKD
Which is true about uremic polyneuropathy?

a. Proximal to distal, asymmetric

b. Involves the upper extremities more than the lower
extremities
c. Sensory symptoms precede motor symptoms
 Neuropathy in CKD
Which is true about uremic polyneuropathy?

a. Proximal to distal, asymmetric (DISTAL, SYMMETRIC)

b. Involves the upper extremities more than the lower
extremities (LOWER>UPPER)
c. Sensory symptoms precede motor symptoms

WHY IT OCCURS: Retention of a number of uremic solutes,

including parathyroid hormone, myoinositol, and other
“middle molecules,” has been correlated with motor nerve
conduction velocity
 Neuropathy in CKD
Uremic polyneuropathy
• Distal, symmetric, mixed sensorimotor polyneuropathy
• Lower extremities more than the upper extremities
• Sensory symptoms typically precede motor symptoms
• Some authorities consider restless legs syndrome (RLS) part of the clinical spectrum of uremic
polyneuropathy
• Correlated uremic solutes - parathyroid hormone, myoinositol, and other “middle molecules”
Mononeuropathy
• Typically involve compression or ischemia of the ulnar or median nerves
• Attributable to dialysis-related (β2-microglobulin) amyloidosis or ischemic mononeuropathy associated
with an arteriovenous fistula
Autonomic neuropathy
• Orthostatic or dialysis-associated hypotension and impotence
 Sleep
Disorders in
CKD

Periodic Limb
Restless Leg
Sleep Apnea Movements
Syndrome
of Sleep
 1. Sleep Apnea
• Sleep apnea: prevalence of sleep apnea was 4x higher in
patients on dialysis
• Upper airway occlusion - Pharyngeal narrowing has been
demonstrated in patients on dialysis: pharyngeal water content
and rostral overnight fluid shifts, impaired upper airway muscle
tone resulting from uremic neuropathy
• Central ventilatory control - hypocapnia resulting from adaptation
to chronic metabolic acidosis
• Treatment - CPAP is the primary therapy
 2. Restless Leg Syndrome
• Urge to move the legs associated
with feelings of discomfort or
paresthesias
• Occur during periods of inactivity
and are alleviated by movement
• Pathogenesis - associated with
disrupted dopaminergic
function
• Iron is a cofactor for dopamine
production
• Iron deficiency has been
implicated
2. Restless Leg Syndrome: Treatment
Mild or moderate symptoms: lifestyle
modification
• Good sleep hygiene
• Elimination of exacerbating substances such as
antidepressant medications, caffeine, nicotine, and
alcohol
Severe symptoms: dopaminergic therapy is first-
line therapy
• Levodopa, Ropirinole
• Side effects such as daytime worsening of symptoms
may occur with continuous use
• Second line agents: carbamazepine or gabapentin,
and benzodiazepines
• Kidney transplantation and short daily hemodialysis,
but not conventional dialysis, appear to have a
beneficial effect on symptoms
• In a clinical trial of 25 patients requiring
hemodialysis, RLS symptoms were reduced with
 3. Periodic Limb Movement of Sleep
• Characterized by sudden and repetitive jerking movements
of the lower extremities during sleep
• Common among patients on dialysis and associated with
daytime sleepiness, low quality of life, and, in one study,
an increased risk for mortality
• Pathogenesis unknown
• Kidney transplantation has been reported to reduce the
frequency and improve symptoms of daytime sleepiness
 Stroke

Same Risk Factors

Cardiovascular &
Neurologic Events

Embolism
 FATIMA UNIVERSITY MEDICAL CENTER
DEPARTMENT OF INTERNAL MEDICINE
SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Dermatologic
Aspects of CKD
Classification &
Part 1: 7 October Cardiovascular Aspects of
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I
OBJECTIVES
1. To identify the most common
dermatologic manifestation of CKD
2. To enumerate different skin
conditions seen among CKD patient

138
Skin Manifestations in CKD
• Skin manifestations of end-stage
renal disease are diverse, with
pruritus being very common
• Calciphylaxis - high morbidity
and mortality
• Range morphologically from a
broken-up, lacelike pattern of pink
to purple erythema early on
(reticulated vascular pattern) to
ulcers, with black eschars in later
stages
 Skin Manifestations in CKD:
1. Pruritus
Pruritus is more common in patients with ESRD disease than in
those with acute kidney injury (AKI)
• Up to 90% of patients undergoing hemodialysis may experience
pruritus
• HD > PD
• Can be localized or generalized
• Pruritus tends to be prolonged, frequent, and intense
• Exacerbating factors include heat, nighttime dry skin, and sweat
• Other potentially pathogenic factors include the opioid system,
xerosis, elevated histamine, excess uremic toxins, peripheral
neuropathy, and hyperparathyroidism
 Skin Manifestations in CKD
• Treatment of pruritus: antihistamines are not effective
• A therapeutic ladder
• 1st line: emollients and capsaicin
• 2nd line: ultraviolet light
• Phototherapy with ultraviolet B (UVB; 280−320 nm) - act by
suppressing histamine release or vitamin A levels in the epidermis,
which are known pruritogenic substrates
• Risk of skin cancer should be balanced
• 3rd line: oral gabapentin or intravenous nalfurafine may be
considered
Pruritus Treatment
Skin Manifestations in CKD
2. Xerosis
• Dry, rough, or shiny, may be
scaly or fissured, with a
cracked appearance
• May or may not be pruritic
• Mainstay of treatment is
hydration of the skin. For
pruritic cases, direct
treatment of the pruritus
may be helpful
Skin Manifestations in CKD
3. Acquired ichthyosis
• more than just dry skin because the skin develops patterned scale
• Histopathologic features – hyperkeratosis, occasionally epidermal
hypogranulosis
• Unknown pathogenesis
• Treatment: hydration of the skin.
4. Pigmentary alteration
• Most common alteration - yellowish tint (more common in hemodialysis
than peritoneal dialysis)
• Hyperpigmentation - secondary to increased melanin production as a
result of elevated levels of β-melanocyte–stimulating hormone
 5. Acquired Perforating Dermatosis
• Distributed predominantly on the legs and
arms, although the trunk and head may also be
involved. Individual lesions are crateriform,
umbilicated, or centrally hyperkeratotic papules
and nodules
• Severe pruritus
• May develop in crops and commonly resolve
with scarring after 6 to 8 weeks
 5. Acquired Perforating Dermatosis
• Histopathologic evidence of extrusion of
dermal material through an epidermal channel
is necessary for the diagnosis
• Proposed pathogenesis: increased fibronectin,
pruritus and scratching, epidermal
dysmaturation, and dermal deposition of
substances not excreted in renal failure
• Treatment of this disorder is difficult,
• Topical steroids, keratolytics, lubrication, and topical
or oral retinoids
• Narrow-band UVB
6. Calciphylaxis/ Calcific Uremic Arteriolopathy
• Most often in dialysis patients generally
with associated hyperparathyroidism or an
elevated calcium phosphate product
• Fatty areas of the thighs, abdomen, and
buttocks symmetrically, lower extremities
• Early lesions: pink-violaceous, broken-up
circles, firm plaques, solid purple-pink or
mottled, retiform purpura, erosions, or
subcutaneous nodules
• Occasionally, bullae may be seen. Early
lesions may progress to painful ulcers with a
black eschar
6. Calciphylaxis/ Calcific Uremic Arteriolopathy

• Histopathologic findings supportive of

calciphylaxis include medial calcification of
medium-sized vessels, with intimal hyperplasia
and thrombosis.
• Deficiencies in inhibitors of vascular
calcifications may play a role in CUA
pathogenesis, especially fetuin-A and vitamin
K−dependent matrix Gla protein.
• Treatment (supportive): wound care, pain
management, and modification of any risk
factors
• For nonulcerated lesions, systemic steroids may lead
to rapid healing
• Hypercoagulable state: anticoagulation may be
considered
 7. Metastatic Calcification
• Abnormal calcium phosphate product, with or without
hyperparathyroidism
• Usually affect periarticular areas and the fingertips
• Not all calcification in the skin is secondary to metastatic
calcification. Trauma may result in so-called dystrophic calcification.
Some systemic diseases, such as dermatomyositis, may be associated
with calcification of the skin.
• Treatment: focuses on normalizing calcium and phosphate levels.
• Foods that should be avoided include milk and milk products, certain
vegetables (e.g., broccoli, Brussels sprouts), oysters, salmon, beer, nuts, and
wheat germ
• Lesions are symptomatic, surgical removal may be considered.
 8. Porphyria Cutanea Tarda
• Up to 18%
• Deficient activity of the heme biosynthetic
enzyme uroporphyrinogen decarboxylase
(UROD) in the liver -> pathophysiology unclear
• Elevated levels of urinary uroporphyrin (if not
anuric) and fecal isocoproporphyrin
• Cause photodamage on exposure to light with
a wavelength near 400 nm
• Cutaneous findings - noninflamed blisters,
erosions, and crusts involving the dorsal hands
and forearms
• Blisters may heal with scarring or milia Immunofluorescent findings - granular to linear staining of
• Hypertrichosis on the face immunoglobulin G (IgG) and C3
• Hyperpigmentation and sclerodermoid plaques Treatment:
Sun avoidance and sun protection
Desferoxamine
Chloroquine
Small-volume phlebotomy
 9. Pseudoporphyria
• Presentation similar to that in porphyria cutanea tarda
• Noninflamed blisters on the extremities, especially the hands and forearms and other
sun-exposed areas
• Milia, scarring, and hyperpigmentation may result
• Hypertrichosis
• Normal levels of plasma uroporphyrin and red blood cell protoporphyrin – Differentiates
from porphyria cutanea tarda
• Histologic findings - similar to those of porphyria cutanea tarda
• Although the pathogenesis of pseudoporphyria is unclear, elevated aluminum levels were
found in a small study
 10. Eruptive Xanthomas
• Buttocks and proximal extremities
• Histopathologic examination of a
lesion reveals extracellular lipid and
foamy macrophages
• Associated with hyperlipidemia, such
as hypothyroidism and nephrotic
syndrome
• In nephrotic syndrome, the
xanthomas are likely secondary to
various lipid abnormalities
• Resolve spontaneously once lipid
levels are normalized.
 Skin Manifestations of CKD
11. Pseudo-Kaposi Sarcoma
• Vascular proliferation that mimics
Kaposi sarcoma near or over an
arteriovenous shunt
12. Iododerma
• In the setting of renal insufficiency or
failure, patients who receive iodide in
the form of intravenous contrast may
develop translucent papulonodular or
vegetative lesions of iododerma
• Histopathologically - marked epidermal
hyperplasia, with intraepidermal
pustules of neutrophils and sometimes
eosinophils
• Clinical and histopathologic exclusion
of infectious causes is required.
 13. Nephrogenic Systemic Fibrosis
• Exposure to gadolinium-based magnetic resonance imaging (MRI) contrast
agents in patients with abnormal renal function
• Impaired excretion of gadolinium-based contrast may allow more time for
gadolinium atoms to dissociate from their proprietary ligand molecule → bind
to other available anions (chiefly phosphates) → deposit peripherally →
effects on local tissue fibroblasts and/or circulating matrix stem cells termed
“circulating fibrocytes.”
• (FDA) recommends caution
• eGFR less than 30 mL/min/1.73 m2
• Undergoing dialysis
• With AKI - difficult to predict eGFR in a non−steady-state setting
 13. Nephrogenic
Systemic Fibrosis
Symptoms
• Bound-down, indurated skin on the
extremities
• Early in NSF, patients may have edema
and erythema that mimics cellulitis
• Joint contractures
• Yellow scleral plaques
Histopathologically
• Increased dermal and/or subcutaneous
fibroblast-like cells are seen
 13. Nephrogenic
Systemic Fibrosis
• Systemic disease may have
marked elevations in their
erythrocyte sedimentation rate
and serum C-reactive protein
level.
• Prevention is key – no reliable
treatment
• Management
• Renal transplantation: sometimes
helpful in halting progression and
occasionally reverses the disease
• Extracorporeal photopheresis
• Physical therapy
• Reports of imatinib
 14. Dialysis – Associated Steel Syndrome
• Usually involves the brachial area in patients
with diabetes
• Pallor or a reticulated pink to blue
discoloration of the skin surrounding
necrosis, ulceration, or gangrene
• Altered hemodynamics secondary to the
fistula result in decreased distal perfusion
• Risk factors - diabetes, vascular stenosis,
neuropathic disease, and calcifying sclerosis.
• Treatment - fistula ligation and/ or banding.
 Skin Manifestations of CKD
15. Metastatic renal cell carcinoma
• Common cutaneous sites for metastatic renal cell carcinoma are the trunk and scalp.
16. Dialysis-related amyloidosis
• More common presentations - carpal tunnel syndrome and destructive arthropathy
• Rare reports of immobile dermal nodules secondary to β2-microglobulin deposition,
most often affecting the buttock
17. AV shunt dermatitis
• Irritant contact dermatitis over their shunts
• Substituting normal saline for the cleansers (soaps, disinfectants, and alcohol) used to
clean the skin before hemodialysis was helpful
• Mild topical steroid
 Nail Manifestations of CKD
• Up to 40% of patients with renal
dysfunction have half-and-half nails
• May resolve spontaneously and is likely
secondary to melanin deposition in the nail
bed and plate.
• Fingernails are affected more commonly
than toenails.
• The nails have a white to normal proximal
half and a red-brown distal half.
 FATIMA UNIVERSITY MEDICAL CENTER
DEPARTMENT OF INTERNAL MEDICINE
SECTION OF NEPHROLOGY

Nephrology Hour:

and Chronic Disease

Classification &
Part 1: 7 October Cardiovascular Aspects of
CKD
Hematologic, Endocrine, 14 October 2022
Part 2: 14 October Neurologic & Dermatologic
Aspects of CKD James Vincent C. Legaspi,MD
Adult Nephrology Fellow, Level I