dialysis: a case-based clinical review and update j. …

DIALYSIS: A CASE-BASED CLINICAL REVIEW AND UPDATE

J. Kevin Tucker, Associate Physician

Department of Medicine, Renal DivisionBrigham and Women’s Hospital Assistant Professor of Medicine

Harvard Medical School

J. Kevin Tucker, MD

• Birmingham-Southern College

• Cornell University Medical College (Weill Cornell)

• Medicine Residency at Massachusetts General Hospital

• Nephrology Fellowship at University of Alabama at Birmingham

• Assistant Professor of Medicine at HMS• Clinical focus: CKD, Hemodialysis, Peritoneal

Dialysis

• Medical Education

Disclosures

• Nothing to disclose

Objectives

• Use case scenarios to review dialysis-related clinical problems

• Review controversies in dialysis management

• Discuss anemia management, volume control, medications in dialysis, bone disease, and dialysis-relate emergencies

Case 1

A 72-year-old man with ESRD on HD, diabetes mellitus type 2, and peripheral arterial disease is admitted with a diabetic foot ulcer. He has a hemoglobin of 7.8 g/dL on admission. He has had no evidence of GI bleeding.

Case 1Past Medical History

• ESRD

• Diabetes mellitus type 2

• Hypertension

• Colon cancer s/p partial colectomy 5 year prior; no metastatic disease

• TIA

Case 1 Outpatient Medications

• Amlodipine 10 mg daily

• ASA 81 mg daily

• Calcitriol 0.25 ug 3x/weekly

• Labetalol 300 mg bid

• Lisinopril 10 mg daily

• Pravastatin 40 mg daily

• Renal multivitamin daily

• Iron gluconate 125 mg weekly

Anemia Labs

• Hemoglobin 7.8 g/dL

• T-sat 33%

• Ferritin 1352 ug/L

Case 1 Question (Audience Response):

What would you do next in managing this patient’s anemia?

A) Do nothing. The patient is asymptomatic.

B) Add an ESA.

C) Transfuse to a hemoglobin of 10-11 g/dL.

D) Refer to hematology for an anemia evaluation.

Case 1 Explanation

The patient’s hemoglobin will continue to decline such that he will ultimately need transfusion. He has not been on an ESA because of the remote history of colon cancer. The risks of repeated transfusion are greater than the risk of an ESA in this setting.

KDIGO Recommendations

Special considerations with ESAs in dialysis

• Cancer

• Stroke

• Vascular access thrombosis

ESAs and Cancer

• Beginning in 2010, the FDA required that ESAs be prescribed to cancer patients under its risk evaluation and mitigation strategy program• Requires additional education for healthcare providers who prescribe and

dispense ESAs

• Requires documentation that patients understand ESA-related risks

Source Cancer Type Concomitant Therapy

# of patients randomized

ESA Treatment

Hemoglobin Stopping

Value g/dL

Adverse Outcome

Henke et al 2003

Head and neck

Radiotherapy 351 Epoetin beta (300 IU/kg 3x/week)

> 14 (women)> 15 (men)

Locoregional progression

Hedenus et al 2003

Lympho-proliferative

cancers

Chemotherapy 349 Darbepoietinalfa (2.25

ug/kg/week)

> 14 (women)> 15 (men)

Shortened overall survival

Leyland-Jones et al 2005

Metastatic breast cancer

Chemotherapy 939 Epoetin alfa (40000 U/wk)

> 14 Overall survival vs

placebo

Overgaard et al 2007

Locally advanced head and

neck

Radiotherapy 522 Darbepoietinalfa (150 ug/week)

> 15.5 Increased risk in local-regional failure

PREPARE Breast cancer Chemotherapy 733 Darbepoietinalfa (4.5

ug/kg/2 wk)

> 13 Shortened overall survival

Bennett CL et al JAMA 2008; 299: 914-924

What is the evidence for an increased risk of cardiovascular events?

• CHOIR

• TREAT

The CHOIR Study

Singh AK et al. N Engl J Med 2006;355:2085-2098

Mean Monthly Hemoglobin Levels (Panel A)and Mean Weekly Doses of Epoetin Alfa (Panel B)


Probabilities of the Primaryand Secondary End Points


Treat Study

• Randomized study involving 4038 subjects with diabetes, anemia, and CKD

• 2012 subjects randomized to receive darbepoetin to achieve a hemoglobin of 13 g/dL

• 2026 randomized to placebo with rescue darbepoeitin given when hemoglobin less than 9 g/dL

• Primary outcomes: death or a CV event and death or ESRD

Pfeffer M et al. N Engl J Med 2009;361:2019-2032

Mean Hemoglobin Levels through 48 Months among Patients Who Were Assigned to Receive Darbepoetin Alfa or

Placebo

Pfeffer M et al. N Engl J Med 2009;361:2019-2032

Kaplan-Meier Estimates of the Probability of the Primary and Secondary End Points: Note Panel E

Association between Hemoglobin Level and Dose of Darbepoetin Alfa, According to the Level of Response to

the First Two Doses

Solomon SD et al. N Engl J Med 2010;363:1146-1155

Rates of Primary End Points

Solomon SD et al. N Engl J Med 2010;363:1146-1155

Is a higher hemoglobin better in dialysis patients?

Probability of Death or a First Nonfatal Myocardial Infarction in the Normal-Hematocrit and Low-Hematocrit Groups

Besarab A et al. N Engl J Med 1998;339:584-590

Are ESAs Associated with vascular access thrombosis?

Churchill et al J Am Soc Nephrol 1994; 4:1809-1813

FDA changes to the ESA labelJune 2011• For patients with CKD on dialysis:

• Initiate ESA treatment when the hemoglobin level is less than 10 g/dL

• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of ESA.

• When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly.

• For patients who do not respond adequately over a 12-week escalation period, increasing the ESA dose further is unlikely to improve response and may increase risks.

New drugs to treat anemia of chronic kidney disease

• HIF prolyl hydroxylase inhibitors• Stabilize the HIF complex

• Stimulate endogenous EPO production• Orally administered

Gupta N and Wish JB. Am J Kidney Dis 2017; 69: 815-826

HIF-PH Inhibitors Under Development

Drug Dosing Frequency

Roxadustat 3x/week

Vadadustat Daily

Daprodustat Daily

Molidustat Daily

Vadadustat in Anemia of CKD

• Recent publication of two papers in NEJM • Vadadustat in treating anemia of CKD in dialysis-dependent CKD

• Incident dialysis patients

• Prevalent dialysis patients

• Vadadustat in treating anemia of non-dialysis CKD• Prior EPO treatment

• EPO naïve

K Eckardt et al. N Engl J Med 2021;384:1601-1612

Change from Baseline Hemoglobin

K Eckardt et al. N Engl J Med 2021;384:1601-1612

Cardiovascular Safety in the Two Trials

Summary of Vadadustat Trials

• Dialysis-Dependent CKD• Vadadustat was non-inferior to EPO with respect to correction of anemia

• Vadadustat was non-inferior with respect to cardiovascular safety

• Non-Dialysis-Dependent CKD• Vadadustat was non-inferior to EPO with respect to correction of anemia

• Vadadustat did not meet non-inferiority criteria with respect to cardiovascular safety

Case 1 Outcome

• Using a patient-centered approach, risks and benefits were discussed.

• Based upon that discussion, a low, fixed dose of darbepoietin was started.

• Patient had a good response, with his hemoglobin rising to 10-11 g/dL.

Case 2

A 62-year-old man with ESRD secondary to scleroderma is admitted to the hospital with shortness of breath.

Past Medical History

• ESRD

• Scleroderma

• COPD

• Peripheral arterial disease

• Recurrent pleural effusion

• Malnutrition

Case 2Hospital Course• Diagnosed with pulmonary emboli → started on IV heparin

• Pneumonia treated with cefepime

• Ileus

• GI bleeding

• Sacral wound

Dermatology Consult

Dermatology Recommendations

• “Please start patient on IV acyclovir for HSV infection. Recommend touching base with pharmacy for appropriate dosing in HD patient”

• “Can transition to valacyclovir at discharge. Treatment duration will be until lesions heal”

• Patient started on acyclovir 5 mg/kg q 24 hours

Altered Mental Status

• Four days later patient develops altered mental status

• Sent for stat head CT

• Upon return from head CT, patient is anxious and confused and says, “I died down there.”

Case 2 Question (Audience Response)

What is the most likely explanation for the patient’s altered mental status?

A) Inadequate dialysis

B) Cefepime

C) Acyclovir

Altered mental status in a dialysis patient

Always think about medications

• Acyclovir

• Cefepime

• Narcotics

• Gabapentin

• Amantadine

• Baclofen

Acyclovir neurotoxicity

Clinical features of acyclovir neurotoxicity

• Disturbances in consciousness

• Seizures

• Myoclonus

• Coma

• Death delusions• “Le delire de negation” or Cotard’s syndrome

• A more specific neuropsychiatric symptom

Gentry JL and Peterson C. Am J Med 2015; 128: 692-694

Diagnosis and Management

• Diagnosis may be confirmed by measurement of metabolite 9-carboxymethoxymethylguanine

• Discontinuation of drug

• Hemodialysis

Case 3

A 57-year-old woman with ESRD secondary to multiple myeloma dialyzes 3.5 hours three times weekly. Her dry weight is 42.5 kg. Her average interdialytic weight gain is 1.7 kg, but she has occasional IDWG up to 4 kg. She has had two hospitalizations over the last six months for shortness of breath and pulmonary edema. She has frequent episodes of cramping during her dialysis treatments. She occasionally skips treatments and often cuts her treatments short. She dialyzes with a high-flux polysufone dialyzer (Optiflux 160). Her dialysate Na+ is 140 mEq/L, K+ 2.0 mEq/L, and HCO3- 35 mEq/L.

Case 3Past Medical History

• ESRD

• Multiple myeloma

• Hypertension

• Secondary hyperparathyroidism

• Anemia

Case 3Medications• Gabapentin 100 mg po 3x/week

• Renal multivitamin 1 po daily

• Cinacalcet 30 mg po daily

• Darbepoietin 20 ug IV weekly

Case 3Labs

Case 3Blood pressure report


What is the next best step to improve this patient’s fluid management?

A) Increase her dialysate sodium to 145 mEq/L

B) Increase dialysate calcium to 3.5 mEq/L

C) Increase time on dialysis

D) Change to a larger surface area dialyzer

Case 3 Explanation

• Increasing her dialysate sodium may exacerbate the issue of excessive IDWG.

• Increasing the dialysate calcium sometimes help with hypotension, but that is not the issue in this case.

• A larger surface area dialyzer will help urea clearance, but that is not the issue in this case.

• Longer time on dialysis may help to reduce cramping, allow her to reach her dry weight, and lower the UF rate.

Issues with this patient

• Excessive IDWG

• Missing treatments

• Cutting treatments short• Cramping

• Hypotension

• High UF rates

What is the UF rate?

• Fluid removed per body weight per unit time expressed in mL/kg/hour

• Pre-weight 47.1 kg

• Fluid removal 2.6 kg

• 2600 mL/47.1kg/3.5 hours= 15.8

Online UFR calculators

http://www.homedialysis.org/ufr-calculator

Why worry about UFR?

https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/Downloads/Proposed-PY-2019-measure-specs_6-24-15.pdf

Relationship between UFR and mortality

High ultrafiltration rates may be associated with higher all-cause and CV mortality

Flythe JE et al Kidney Int 2011; 79: 250-257

Case 4

A 60-year-old man with a history of end stage renal disease on hemodialysis for 15 years is admitted for back pain and hand pain. One week prior to presentation, he developed an exacerbation of chronic back pain, prompting a visit to the Emergency Department.

Case courtesy of Dr. Ignacio Portales-Castillo

Case 4• Evaluation revealed severe thoracic and lumbar

pain, central and paraspinal, exacerbated by coughing and movements, with no radiation and no leg weakness or sphincter incontinence.

• He also reported ongoing severe pain on his palm and middle three fingers of left hand with paresthesias, irrespective of dialysis treatments.

• ROS also notable for left shoulder pain.

Case 4: Past Medical History

• End stage renal disease on HD x 15 years• HD 3x/week

• HD Rx: 4 hours/High flux polysulfone/Qb 450/Qd 800/2.0K+, 2.5Ca++

• spKt/V 1.7

• Hypertension

• Pulmonary hypertension

• Hepatitis C (treated)

Case 4: Medications

• Amlodipine 10 mg daily

• Cinacalcet 60 mg daily

• Metoprolol tartrate 50 mg bid

• Oxycodone 5 mg PRN

• Sevelamer carbonate 800 mg po qAC

Case 4: Physical Examination

• T 37 degrees C; BP 130/84 mm Hg; HR 74

• Lungs clear

• RRR, normal S1 and S2

• No peripheral edema

• Left arm AVF collapses with elevation

• Left hand with 4/5 grip strength

Case 4: Laboratory studies


• Calcium 9.3 mg/dL

• PO4 4.3 mg/dL

• PTH 384 pg/mL

• Alkaline phosphatase 102 IU/L

• Albumin 4.0 g/dL


What is the most likely unifying diagnosis to explain the patient’s back, shoulder, and wrist pain?

A) Infection-associated inflammatory arthritis

B) Uncontrolled hyperparathyroidism

C) Dialysis-associated amyloidosis


What do you think is the most likely unifying diagnosis to explain the patient’s back, shoulder, and wrist pain?

A) Infection-associated inflammatory arthritis

B) Uncontrolled hyperparathyroidism

C) Dialysis-associated amyloidosis

Case 4 Explanation

The patient has no evidence of an infection. His PTH is modestly elevated, and the alkaline phosphatase does not suggest high bone turnover. The combination of back pain, shoulder pain and wrist pain with probable carpal tunnel syndrome in this long-term dialysis patient is most suggestive of dialysis-associated amyloidosis.

Imaging

• Progressive vertebral endplate erosion of T5-T6 since 2014

• Minimal endplate changes without paravertebral fluid collection or disc changes

2014 2019 2019 T2

Dialysis-associated spondyloarthropathy

Radsource.com

Carpal Tunnel Syndrome

Fenves AZ et al Am J Kidney Dis 1986; 7:130-134

Carpal Tunnel Syndrome

Incidence of CTS in TaiwanIncidence of Carpal Tunnel Syndrome in Taiwan

Tsai CH et al Annals of Plastic Surgery 2020; 84 (1S) S100-S106

Dialysis-Related Spondyloarthropathy

• Severe narrowing of the intervertebral disc

• Erosins and geodes of the adjacent vertebral plate

• Absence of significant osteophytosis

Nishi S et al Ren Replace Ther 2019; 5

Relationship with dialysis vintageRelationship to Dialysis Vintage

Winchester JF et al Adv in Ren Replace Ther 2003; 10: 279-309

Role of b-2 microglobulin clearanceRole of b2-Microglobulin Clearance

Dember LM and Jaber BL Seminar Dial 2006; 19: 105-109

Dialysis-associated amyloid becoming less common?

Dialysis-associated amyloidosis becoming less common?

Treatment Options -Lixelle Column

Kazama JJ et al. Nephrology Dial Transplant 2001; 16 Suppl 4: 31-35

Treatment Options: Lixelle Column

Case 5

You are the medical director of an ambulatory dialysis clinic. The charge nurse notes that an unusually large number of patients have had a significant (4-5 g/dL) drop in hemoglobin. Potassiums are higher than usual, and indirect bilirubin is elevated in the majority of patients.


Which element in the water treatment system needs to be investigated?

A) RO system

B) Carbon filters

C) Deionizers

D) Sediment filters

Case 5 Explanation

Hemolysis should be suspected in this case because of the hyperkalemia and hyperbilirubinemia.

Hemolysis occurring in multiple patients in a dialysis clinic is suggestive of dialysate contamination by chlorine or chloramine, which should be removed by the carbon filter.

Symptoms/signs of hemolysis in dialysis patients• Hypertension

• Chest pain

• Abdominal pain

• Nausea/vomiting

• Shortness of breath

• Back pain

• Diarrhea

• Generalized erythema

• Port-wine appearance of blood in venous line

Spry L Seminars in Dialysis 12:205, 1999

Management

• When hemolysis is suspected on dialysis:• Blood pump should be stopped.

• Blood lines clamped.

• Potassium rich blood should not be reinfused.

• Tubing should be saved to check for defects.

• Dialysate sample should be kept for analysis.

Dialysis-related causes of hemolysis

• Copper

• Chlorine, Chloramine

• Nitrates, nitrites

• Overheated dialysate

• Hypo-osmoloar dialysate

• Kinked or defective tubing

• Formaldeyhde

Other causes of hemolysis

• Medications

• G6PD deficiency

• Hypersplenism

• Sickle cell anemia and other hemoglobinopathies

• Hypophosphatemia

Multistate Outbreak of Hemolysis, 1998

• 30 patients in 3 states developed hemolysis with or without chest pain, shortness of breath, nausea, or abdominal pain, while on hemodialysis

• 2 deaths were associated with this outbreak.

MMWR 47: 483-484

Nebraska outbreak of hemolysis

• Case defined as• Hypertension (increase in SBP of > 30 mm Hg above baseline)

• Evidence of hemolysis (+ “pink test”)

• 13 of 118 patients at two dialysis centers in Lincoln met the definition

• Onset of symptoms occurred at a median of 120 minutes (range 20-272) into the session.

• Case patients ranged in age from 46 to 84.

• All patients were dialyzed using the same tubing lot.

Maryland outbreak of hemolysis

• 12 of 298 patients at four hemodiaysis clinics developed abdominal pain, nausea, and/or erythroderma.

• All had evidence of hemolysis upon hospital admission.

• Symptom onset: 114 minutes (range 22-227) into the treatment.

• All were dialyzed with tubing from the same lot.

Multistate outbreak of hemolysisInvestigation

• Examination of implicated blood tubing revealed narrowing of the aperture through which blood was pumped during the treatment.

• Analysis of water at one of the hemodialysis centers in Nebraska was within normal limits for chlorine, chloramine, endotoxin, bacteria and trace elements as defined by AAMI standards.

Hemolysis due to Chloramine Contaminated Dialsyate

Hemolysis due to Chloramine Contaminated Dialysate• Approximately 100 patients were exposed to chloramine

contaminated dialysate at an oupatient clinic when the water treatment system failed.

• Most patients developed hemolytic anemia, and 41 patients required transfusion.

• The carbon filter was replaced, and there was no further evidence of chloramine contamination.

Case 6

SJ is a 68-year-old woman with a 5-year history of ESRD and a long history of EtOH abuse. She has been sober for the last year. She frequently misses dialysis and when she does attend her sessions, she signs off earlier than her prescribed time.

Case 6

She presents to the Emergency Department complaining of weakness and nausea. She has not dialyzed for one week.

Case 6: Physical Examination

• Thin elderly woman weighing 44 kg

• BP 180/80 mm Hg; HR 100; T 96.5 degrees F

• Basilar crackles

• Regular rhythm with no pericardial friction rub

• Soft, nontender abdomen; normal bowel sounds

• 1+ pitting lower extremity edema

• Tortuous and aneurysmal left arm AVF

• Normal mental status

Case 6: Labs

• K+ 6.1 mEq/L

• CO2 16 mEq/L

• BUN 150 mg/dL

• Creatinine 10.1 mg/dL

• PO4 7.2 mg/dL

• Calcium 7.3 mg/dL

• Albumin 3.2 g/dL

• EtOH undetectable

• WBC 5.2 K/uL


• Platelets 190K

Case 6

• Fellow’s dialysis prescription:• F80

• 4 hours

• Qb 400

• Qd 800

• 2.0 K+

• UF to dry weight

Case 6: Outcome

• About 2 hours into her treatment, the patient has a generalized tonic-clonic seizure. Dialysis is terminated.

• Seizure breaks with a dose of intravenous lorazepam.


What is the most likely explanation for this patient’s seizure?

A) Brain tumor

B) Dialysis disequilibrium

C) Uremic encephalitis

D) CO2 retention

Cerebral edema: most severe outcome

Bagshaw SM et al 2004; BMC Nephrol. 5: 9

Dialysis disequilibrium

• A set of neurologic signs and symptoms that may occur in patients undergoing HD.

• Symptoms may be mild (headache, restlessness) to severe (disorientation, seizures).

• Pathophysiology• Changes in cerebral osmolality

• Changes in CSF pH (decrease in pH during HD)

Arieff AI Kidney Int 1994; 45: 629-635

Dialysis disequilibrium

• Greater risk in patients with pre-existent neurologic disease• Stroke

• Head trauma

• Malignant hypertension

Bagshaw SM et al 2004; BMC Nephrol. 5: 9

Prevention of dialysis disequilibrium

• Start “gentle”• Low Qb

• Low Qd

• Smaller dialyzer

• Osmotic agents (mannitol)

dialysis: a case-based clinical review and update j. …

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