Renal replacement therapy

Question 1

Types of renal replacement therapy

Answer 1

-Haemodialysis (in hospital treatment)
-Peritoneal dialysis (at home)
-Transplant

Question 2

Indications for renal replacement therapy in CKD

Answer 2

-Uraemic syndrome including anorexia, nausea, lethargy (eGFR <10)
-Fluid overload (intractable dependent oedema resistant to diuretics, pulmonary oedema, severe hypertension)
-Hyperkalaemia (Potassium resistant to dietary control and medical intervention)
- Metabolic acidosis (chronic acidosis resistant to bicarbonate therapy)
-Relative indications (intractable anaemia despite erythropoietin and iron/ hyperphosphatemia despite binders)

Question 3

Describe haemodialysis

Answer 3

-Most common form of renal replacement therapy, can be used in AKI

-PRE:
=At least 8 weeks before the commencement of treatment, the patient must undergo surgery to create an arteriovenous fistula, which provides the site for haemodialysis, infection risk
=Most commonly this is created in the lower arm up to a year before
=Gain access to circulation through central venous catheter (TUNNELLED LINE/ PERMCATH) or fistula (ATRERIOVENOUS FISTULA): require (200mlhr)s adequate vascular access
=Screen blood borne disease

-DURING:
=Regular filtration of the blood through a dialysis machine in hospital.
-Most patients need dialysis 3 times per week, with each session lasting 3-5 hours (reduction in urea over 65%)
=Bidirectional diffusion of solutes between blood and dialysate across semipermeable membrane down concentration gradient
=Anticoagulation

-LIFESTYLE
=Some patients may be trained to perform home haemodialysis so that they do not have to regularly attend hospital (50%)
=Careful adherence to diet and fluid restrictions between treatments fluid removal compressed into treatment periods so can cause symptoms and haemodynamic instability

Question 4

Describe peritoneal dialysis

Answer 4

-Another form of renal replacement therapy where the filtration occurs within the patient’s abdomen/ peritoneal cavity
-Dialysis solution is injected into the abdominal cavity through a permanent catheter (peritoneal dialysis catheter)
-The high dextrose concentration of the solution draws waste products from the blood into the abdominal cavity across the peritoneum.
-After several hours of dwell time, the dialysis solution is then drained, removing the waste products from the body, and exchanged for new dialysis solution.

=Requires an intact peritoneal cavity without major scarring from previous surgery
=Diet and fluid less restricted, peritonitis and catheter -related infections may occur
=Usually asymptomatic

Question 5

Two types of peritoneal dialysis

Answer 5

1. Continuous ambulatory peritoneal dialysis (CAPD) - as described above, with each exchange lasting 30-40 minutes and each dwell time lasting 4-8 hours. The patient may go about their normal activities with the dialysis solution inside their abdomen
   =2L, x4 daily
2. Automated peritoneal dialysis (APD) - a dialysis machine fills and drains the abdomen while the patient is sleeping, performing 3-5 exchanges over 8-10 hours each night

Question 6

What is in dialysate?

Answer 6

-Glucose (in variable amounts to remove excess fluid)
-Calcium and magnesium (to combat metabolic bone disease as failure to metabolise vitamin D)

Question 7

Describe renal transplantation

Answer 7

-Involves the receipt of a kidney from either a live or deceased donor.
-The average wait for a kidney in the UK is 3 years, though patients may also receive kidneys donated by cross-matched friends or family.
-The donor kidney is transplanted into the groin, with the renal vessels connected to the external iliac vessels.
-The failing kidneys are not removed.
-Following transplantation, the patient must take life-long immunosuppressants to prevent rejection of the new kidney.
-The average lifespan of a donor kidney is 10-12 years from deceased donors and 12-15 years from living donors.

Question 8

Complications of haemodialysis and their causes and treatment

Answer 8

-Site infection/ sepsis (vascular access devices)
=Blood cultures, Abx

-Pulmonary oedema (breathlessness, fluid overload)
=Ultrafiltration, fluid restriction, lower dry weight)

-Endocarditis
-Stenosis at site

-Haemorrhage (blood loss, hypotension as anticoagulation and venous needle disconnection)
=Stop, source, heparin-free treatment

-Hypotension (leg cramps, chest pain as fluid removal and hypovolaemia, collapse)
=Saline infusion, exclude cardiac ischaemia

-Cardiac arrhythmia (hypotension and chest pain/ potassium and acid-base shifts)
=Check K+ review dialysis prescription, stop dialysis)

-Air embolus (circulatory collapse as disconnected or faulty lines and equipment malfunction)
=Stop

-Anaphylactic reaction to sterilising agents (membrane or sterilising)
= Stop, change to different artificial kidney)

-Disequilibration syndrome (delirium and convulsions due to cerebral oedema)

-Stenosis at site

Question 9

Complications of peritoneal dialysis with their causes and treatments

Answer 9

-Peritonitis (cloudy drainage fluid, abdominal pain, systemic sepsis- entry of skin contaminants via catheter, bowel organism less common)
=Culture (staph epidermis, aureus, coagulase negative), intraperitoneal antibiotics (gram +ve and -ve cover: vancomycin + ceftazidime/ aminoglycoside added to dialysis fluid/ ciprofloxacin orally), catheter removal? No surgery needed usually

-Sclerosing peritonitis (intermittent bowel obstruction, malnutrition, scarring and damage to peritoneal membrane: fibrosis, peristalsis cannot occur) RARE
=Increase in exchange volumes, haem, surgery, tamoxifen

-Peritoneal membrane leaks (fluid leak from tunnel or pleural effusion, leak adjacent to catheter or communication)
=Temporary reduction in volume of dialysis fluid/ switch to haem

-Catheter infection
-Catheter blockage
-Constipation
-Fluid retention
-Hyperglycaemia
-Hernias
-Back pain
-Malnutrition

Question 10

Complications and contraindications of renal transplantation

Answer 10

-DVT/PE
-Opportunistic infection
-Malignancies (particularly lymphoma and skin cancer)
-Bone marrow suppression
-Recurrence of original disease
-Urinary tract infection
-Cardiovascular disease
-Graft rejection

Active malignancy, vasculitis and cardiovascular comorbidity are common contraindications to transplantation, with risk of recurrence of the original renal disease (generally glomerulonephritides) being a less common problem.

Question 11

Symptoms of renal failure not adequately managed by RRT

Answer 11

-Breathlessness
-Fatigue
-Insomnia
-Pruritus
-Poor appetite
-Swelling
-Weakness
-Weight gain/loss
-Abdominal cramps
-Nausea
-Muscle cramps
-Headaches
-Cognitive impairment
-Anxiety
-Depression
-Sexual dysfunction

Question 12

Acute examples for dialysis indications

Answer 12

-Uraemia: pericarditis, encephalopathy
-Fluid overload (acute pulmonary oedema)
-Hyperkalaemia (>6.5)
-Metabolic acidosis (pH <7.1)
-Bleeding diathesis considered due to uraemia induced platelet dysfunction

Question 13

Planning for renal replacement therapy

Answer 13

-Patient education
-Planned initiation of dialysis
-Pre-emptive transplant
-Vaccinations
-Social work
-Psychiatry

Question 14

Conservative treatment of CKD

Answer 14

-In older patients and those with multiple comorbidities, conservative treatment of stage 5 CKD, aimed at limiting the adverse symptoms of ESRD without commencing RRT, is increasingly viewed as a positive choice
-Patients are offered full medical, psychological and social support to optimise and sustain their existing renal function and to treat complications, such as anaemia, for as long as possible, with appropriate palliative care in the terminal phase of their disease.
-Many of these patients enjoy a good quality of life for several years. When quality of life on dialysis is poor, it is appropriate to consider discontinuing it, following discussion with the patient and family, and to offer palliative care.

-QOL
-Coexisting cardiovascular disease (more sensitive to fluid balance changes, predisposing hypotension during dialysis and rebound hypertension between- pulmonary oedema with fluid overload)
-Confusion (serum electrolyte composition- exacerbate)
-Provision of treatment (assistance)
-Survival on dialysis (poor)
-Transplantation (risk of surgery and immunosuppression)

Question 15

What is dialysis disequilibrium?

Answer 15

Delirium and convulsions due to cerebral oedema

Question 16

Overview of haemofiltration

Answer 16

-Employed continuously for long periods daily using a dual-lumen intravenous catheter
-Principally used in the treatment of AKI in patients who are haemodynamically unstable and who therefore may not tolerate the rapid fluid and electrolyte changes associated with intermittent haemodialysis
-Large volumes of water are filtered from blood across a porous semipermeable membrane under a pressure gradient. Solutes are removed via ‘solvent drag’ rather than by diffusion, therefore this method is less efficient at clearing urea and potassium than haemodialysis. Replacement fluid of a suitable electrolyte composition is added to the blood after it exits the haemofilter. If removal of fluid is required, then less fluid is added back than is removed
-higher rates of filtration may be of benefit in patients with sepsis and multi-organ failure. Issues concerning anticoagulation are similar to those for haemodialysis, but may be more problematic because longer or continuous anticoagulation is necessary.

Question 17

Describe haemodiafiltration

Answer 17

-Haemodiafiltration combines hemodialysis with approximately 20–30 L of ultrafiltration (with replacement of filtrate) over a 3–5-hour treatment.
-It uses a large-pore membrane and combines the improved clearance of medium-sized molecules observed in haemofiltration with the higher small-solute clearance of haemodialysis.
-It is sometimes used in the treatment of AKI, often as continuous therapy.
-It is increasingly employed in patients on chronic dialysis but is more expensive than haemodialysis and the long-term benefits are not yet established.

Question 18

Immunosuppression after renal transplant

Answer 18

Triple therapy: prednisolone; ciclosporin or tacrolimus; and azathioprine or mycophenolate mofetil.

-Calcineurin phosphatase Inhibitors (CNI) eg Tacrolimus (Adoport) and less frequently Cyclosporin (Neoral).
=Prevents IL-2 production required for full T cell activation.
=Nephrotoxic: blood level is monitored and the dose adjusted accordingly, aiming for higher levels early after transplant and reducing over time.
=Beware – many drugs interact with CNIs, and therefore always check before starting a new medication in someone with a transplant on a CNI
=Tacrolimus: lower incidence of acute rejection compared to ciclosporin also less hypertension and hyperlipidaemia
however, high incidence of impaired glucose tolerance and diabetes

-Anti-proliferative agents eg Mycophenolate Mofetil and Azathioprine.
=These drugs block DNA and RNA synthesis by interfering with purine synthesis.
=MMF specifically inhibits a pathway unique to lymphocytes.
=These drugs can cause marrow suppression, leading to anaemia, low white cell count and increased risk of infection and low platelet count

-Prednisolone
=Used both in high dose pulses to treat Acute rejection but also as a maintenance immunosuppressant for the first year.
=Doses are gradually reduced from 20mg/day in the first month to a maintenance 5mg/day.

Question 19

Common causes of renal allograft dysfunction

Answer 19

Hours to days
-Renal artery/vein thrombosis: Technically difficult surgery, Thrombophilia/SLE
-Ureteric anastomotic leak : Small bladder/anuria pre-transplant
-Delayed graft function (i.e. transplant does not start working immediately): Prolonged cold ischaemia time, Donation after circulatory death, Older, hypertensive donor with stroke as cause of death, high tacrolimus level
-Hyperacute rejection : Pre-formed anti-HLA antibodies, HLA mismatch, Previous transplant

Weeks
-Acute rejection (especially <3 months; can occur later with non-adherence/insufficient immunosuppression)
= Pre-formed anti-HLA antibodies, HLA mismatch, Previous transplant

Months
-BK virus nephropathy: Intensive immunosuppression, Ureteric stent use
-Renal artery stenosis: Donor disease, Injury at organ retrieval

Years
-Chronic allograft injury (often antibody-mediated): Previous acute rejections, Non-adherence/insufficient immunosuppression

Any time
-Tacrolimus/ciclosporin toxicity
=High doses/serum levels, Concurrent use of drugs that inhibit cytochrome P450 system
-Sepsis (opportunistic and conventional)
-Recurrence of disease:
-Early (FSGS/MCGN/aHUS)
-Later (IgA nephropathy/membranous glomerulonephritis)
(Primary FSGS and MCGN, Previous transplant recurrence)

Question 20

Early phase (6 months post-transplant) complications

Answer 20

-Very regular follow up with blood tests is required – at least weekly until week 12 to pick up early signs of graft dysfunction which may be asymptomatic.
-Causes include:
=Acute immune-mediated rejection (AR)
=Arterial or venous occlusion/thrombosis
=Ureteric stricture (usually ischaemic stricture)
=Drug toxicity – calcineurin phosphatase inhibitors, such as tacrolimus
=Infection – Bacterial and more transplant specific viral infections from donor eg. BK virus, CMV or EBV

-Because of the greater immunological risk (higher risk of acute rejection) at this stage patients are on higher doses of immunosuppressants which increases the risk of over-immunosuppression:
=Infection
==bacterial,
==fungal eg Pneumocystis pneumonia (PJP) caused by pneumocystis jirovecii-
==Viral - either primary infection or reactivation of latent viral infection in recipient eg CMV, EBV or polyoma virus (BK virus)-
==Protozoal infections - rare
=Nephrotoxicity of calcineurin phosphatase inhibitors
=Specific steroid related effects – corticosteroid-induced bone loss, post-transplant diabetes (secondary to steroids and Tacrolimus), weight gain
=Bone marrow suppression

Question 21

Middle phase (6 months +) post transplant complications

Answer 21

-50% of Cadaveric Renal transplants can be expected to last at least 15 years now, with even better outcomes for recipients of live donor kidney transplants
-The 2 main causes of graft loss over this period are:

=Death of the patient with a functioning graft – primarily due to cardiovascular disease (20 fold higher morbidity/mortality compared to the normal population), therefore risk reduction is important – smoking, BP, cholesterol, reducing steroid usage
=Malignancy - almost all types of tumour are increased in incidence in transplant recipients, in particular skin, lymphoma and most solid organ
tumours. Therefore cancer risk need to be mitigated - sun protection, cancer screening – testicular self-examination, cervical smears, mammography, FOB screening for bowel cancer and a high index of suspicion for lymphoma.

-Loss of graft due to Chronic Allograft nephropathy (CAN).
=Presents as a gradually rising creatinine (creeping creatinine)
=Histologically CAN consists of variable tubulo-interstitial fibrosis, arterial and arteriolar hyalinization, and glomerulopathy with duplication of basement membrane.
=The aetiology is mixed: hypertensive injury and injury arising from hyperfiltration; nephrotoxicity from CNIs which cause afferent arteriolar vasospasm and ischaemia leading to interstitial fibrosis and immune-mediated damage - we know that late acute rejection (AR)i.e. AR after 6 months, incompletely treated AR, chronic antibody mediated rejection, poorer matched kidneys and sub-clinical AR all increase risk of CAN.
=Prevention: good BP control (target 130/80 or below); minimising CNI toxicity by using sparing regimes; optimising matching and preventing AR, late AR, sub-clinical AR.

Question 22

The failing transplant (late phase)

Answer 22

-When eGFR <30mls/min, similar issues present to those with CKD 4/5: extracellular fluid expansion due to Na and Water retention causing oedema and hypertension, anaemia due to EPO deficiency, hyperparathyroidism.
=Symptoms of lethargy and poor appetite start to predominate.

-CKD complications need treatment: diuretics for fluid retention, erythropoietin for anaemia, controlling Ca and PO4 balance and preventing hyperparathyroidism
=The patient needs to receive counselling and education so that they can be prepared in good time for starting dialysis or receiving another transplant.
=The patient can be re-listed for transplantation if the likely benefits outweigh the risks and the patient has a reasonable life-expectancy (more likely than not to survive>5yrs)

Question 23

Management in renal transplant follow up

Answer 23

-Consequences of higher cardiovascular risk – peripheral vascular disease, ischaemic and valvular heart disease, cerebrovascular disease.
=tacrolimus and ciclosporin can cause hypertension and hyperglycaemia. Tacrolimus can also cause hyperlipidaemia. Patients must be monitored for accelerated cardiovascular disease.

-Approximately 25% of clinic patients will have diabetes.

-Heightened awareness of the possibilities of malignancy and skin surveillance for lesions.
=patients should be educated about minimising sun exposure to reduce the risk of squamous cell carcinomas and basal cell carcinomas

-Monitoring for the potential for recurrence of some primary renal diseases in the transplanted organ.

-Ongoing management of multi-system diseases that caused renal failure.

-Potential consequences of polypharmacy and occurrence of drug interactions particularly with CNIs.

-Holistic care including sign posting/ referral to psychological and social support if required.

-Immunosuppressive Rx: Nephrotoxic effects of tacrolimus and ciclosporin/graft rejection/recurrence of original disease in transplanted kidney

Question 24

Matching of organs in transplant

Answer 24

-Organs are normally ABO blood group compatible.
-Our tissue type is determined by the HLA antigens we have inherited from our parents.
=There are class I MHC antigens (HLA and HLA B) carried on all cells and MHC Class 2 antigens (HLA DR, DP and DQ carried on lymphocytes and endothelial cells).

-HLA matching is done at each of the 2 alleles for HLA A, B and DR for kidney transplantation.
-By convention, we report them as mis-matches eg 000 is a complete match while 222 is no match at all.
=Ideally a 000 or a beneficial match (100 or a 010, as DR mismatches are worst) do the best.
-Increasing mismatches result in poorer outcome in terms of shorter graft survival: available organs are allocated to the best matched recipient.

-Each time you are transplanted (or exposed by blood transfusion or pregnancy to foreign HLA antigens) you may develop ‘donor-specific antibody’ (DSA) to them. Developing these DSA could preclude any future transplant if you have DSA to the donor
antigens (termed ‘unacceptable’ antigens) so matching is important not only for the current graft outcome but for future grafts as well.

=Pregnancy
=Previous transplant
=Blood transfusion

Question 25

Management of rejection

Answer 25

-Anti-lymphocyte preparations (e.g. anti-thymocyte globulin, ATG) may also be used as induction, especially in higher risk cases.
-Acute cellular rejection is usually treated, in the first instance, by high-dose glucocorticoids, such as intravenous methylprednisolone on three consecutive days.
-ATG is also used for glucocorticoid-resistant rejection. Antibody-mediated rejection is more difficult to treat and usually requires plasma exchange and intravenous immunoglobulin