Renal Replacement Therapy and Transplantation

Renal replacement therapy has a vital role in the treatment of severe acute renal failure and end stage chronic renal failure (ESRF). Three choices for renal replacement therapy are available for patients with ESRF:

• Conservative care and symptom control
• Dialysis (either peritoneal or haemodialysis)
• Kidney transplant (from a living or cadaveric donor)

The outcome of renal transplantation has steadily improved. Survival one year after transplantation is more than 88% for cadaveric grafts and 95% for grafts from living donors.¹

• Dialysis may not improve quality of life in patients with extensive co-morbidities. Very elderly patients may not even have the length of their lives prolonged by dialysis.
• In these circumstances, many patients opt for symptom control without dialysis, using erythropoietin, vitamin D analogues, dietary control, antipruritics and antiemetics as necessary. Such patients often have significantly better quality of life, fewer hospital admissions (e.g. from dialysis-related complications), and are more likely to die finally at home rather than in hospital than patients receiving dialysis.
• Conservative care still involves active management of the complications of renal failure. Patient and carer participation in care provision and a multidisciplinary team approach including nurses, doctors and counsellors are crucial to effective patient management and support.

Chronic renal failure

• When to start dialysis in patients with chronic renal failure remains controversial, and should depend on the patient's views and wishes. In general, patients usually begin dialysis when their GFR reaches 10 mL/minute, or 15 mL/minute if they are diabetic (i.e. stage 5 chronic kidney disease (CKD)).
• There is no good evidence that starting dialysis earlier is of any benefit to patients, but if dialysis is delayed for too long, patients can become very malnourished. Early referral for specialist renal care before renal replacement therapy is required can significantly delay the need for dialysis, and reduce early morbidity and mortality - ie when GFR falls below 30 mL/minute (stage 4 CKD).
• Treatment of end-stage renal disease with dialysis has a high mortality rate and low quality of life. Increasing the dialysis dose above the currently recommended levels of three times weekly haemodialysis does not decrease the mortality rate. Short daily haemodialysis or daily home nocturnal haemodialysis are promising alternatives. Both improve quality of life and control of blood pressure and anaemia.²

Indications for dialysis in acute renal failure

• Presence of clinical features of uraemia (e.g. pericarditis, gastritis, hypothermia, fits or encephalopathy)
• Fluid retention leading to pulmonary oedema: inability to reduce excess volume with diuretics with urine volume under 200 mL in 12 hours
• Severe hyperkalaemia (potassium above 6.5mmol/L) unresponsive to medical management
• Serum sodium above 155mmol/L or below 120 mmol/L
• Severe acid-base disturbance (pH under 7.0) that cannot be controlled by sodium bicarbonate
• Severe renal failure (urea greater than 30 mmol/L, creatinine greater than 500 micromol/L.
• Toxicity with drugs that can be dialysed.

• Haemodialysis involves pumping blood from the body through an artificial kidney in which the blood is surrounded by a solution of electrolytes (the dialysate), whose concentration can be varied precisely. Solutes present in the blood at high concentration (e.g. urea, potassium, creatinine) diffuse into the dialysate and are removed. Blood is drawn from an arteriovenous fistula and then circulated through the dialyser and returned into the fistula. Heparin is constantly infused.
• Changing the concentration of solutes in the dialysate can alter the electrolyte composition of the blood, e.g. raising the dialysate calcium above the serum concentration can increase serum calcium in patients with hypocalcaemia.
• Ultrafiltration is used to regulate the distribution of water between the blood and dialysate. The volume of water to be removed from the patient's blood can be controlled by altering the pressures on either side of the membrane separating the blood from the dialysate.
• Patients are exposed to vast volumes of water so the danger from impurities is high. High-flux dialysis requires the use of ultrapure water.
• Patients need very good vascular access, which is obtained by creating a fistula between a peripheral artery and vein (usually radial or brachial), or a permanent plastic catheter inserted into an internal jugular or subclavian vein. The fistula takes several weeks to mature and should ideally be fashioned 3-6 months before starting haemodialysis.
• Haemodialysis can be carried out in a hospital centre or in the patient's home. Dialysis for chronic renal failure is usually performed three times each week for about 4 hours. Some patients opt for daily haemodialysis (usually 6 days/week), which provides the best control of fluid balance and biochemistry, but is very intensive.
• Complications of haemodialysis:
  • Access related: local infection, endocarditis, osteomyelitis, creation of stenosis, thrombosis or aneurysm
  • Hypotension (common), cardiac arrhythmias, air embolism
  • Nausea and vomiting, headache, cramps
  • Fever: infected central lines
  • Dialyser reactions: anaphylactic reaction to sterilising agents
  • Heparin-induced thrombocytopenia, haemolysis
  • Disequilibration syndrome: restlessness, headache, tremors, fits and coma

• A dialysate is infused into the peritoneal cavity and the blood flowing through peritoneal capillaries acts as the blood source.
• Ultrafiltration is controlled by altering the osmolality of the dialysate solution and thus drawing water out of the patient's blood. This can be achieved with glucose or other large molecular weight solutes in the dialysate. The glucose load may cause poor diabetes control and weight gain.
• A catheter is inserted into the patient's peritoneum under local or general anesthetic, which remains in place permanently and through which dialysate is infused. The waste solutes are removed by exchanging the peritoneal fluid for a fresh solution.
• Patients can be trained to perform continuous ambulatory peritoneal dialysis (CAPD), which usually involves four exchanges of about 20 minutes spaced throughout the day. Alternatively, an automated peritoneal dialysis can be used to do a number of exchanges overnight while the patient is asleep, then with only one or two daytime exchanges required.
• Peritoneal dialysis can be performed at home, at work or while on holiday. It therefore allows a high degree of independence and control but a great deal of support is still required.
• Contraindications to peritoneal dialysis: intra-abdominal adhesions and abdominal wall stoma. Obesity, intestinal disease, respiratory disease and hernias are relative contraindications.
• Complications of peritoneal dialysis:
  • Peritonitis, sclerosing peritonitis
  • Catheter problems: infection, blockage, kinking, leaks or slow drainage
  • Constipation, fluid retention, hyperglycemia, weight gain
  • Hernias (incisional, inguinal, umbilical)
  • Back pain
  • Malnutrition

• A kidney transplant provides the best long-term outcome for patients with end stage renal failure. The kidney may come from a cadaveric donor (85-90%) or from a living donor.
• All patients with ESRF should be considered for a transplant. Age is not a major determinant of outcome, but the presence of comorbid disease adversely affects survival.
• Ischaemia times for the donor kidney:
  • Warm ischaemia: time between death and chilling plus time out of ice at transplantation. Maximum allowable time before irreversible damage is 1 hour.
  • Cold ischaemia: time in ice, usually maximum is 30 hours.
• Patients do not generally have their native kidneys removed, and the transplanted kidney is placed extraperitoneally in the iliac fossa.
• Patients require frequent follow-up after discharge (two or three times each week initially).
• Patients will be treated with various immunosuppressant drugs, which may include ciclosporin, azathioprine, mycophenolate mofetil, tacrolimus, sirolimus or prednisolone. These drugs must be taken for life and require careful monitoring.
• Adding interleukin-2 receptor antibodies to ciclosporin based immunosuppression reduces episodes of acute rejection at six months by 49%.⁴
• Patients need to be followed up for life and this includes annual screening for cancers, drug toxicity and cardiovascular disease.
• Contraindications for transplantation:
  • Cancer
  • Active infection
  • Uncontrolled ischaemic heart disease
  • Acquired immunodeficiency disease with opportunistic infections
  • Active viral hepatitis
  • Extensive peripheral vascular disease
  • Mental incapacity
• Benefits of transplantation:
  • Can stop dialysis
  • Improved quality of life with normal diet and activity, relaxation of fluid restriction
  • Reversal of anaemia and renal bone disease
• Risks of transplantation:
  • Immediate operative complications (local infection, pain, pneumonia, deep vein thrombosis)
  • Immediate graft failure
  • Arterial or venous thrombosis in the transplant
  • Infections (viral, bacterial, fungal)
  • Cancer (skin, lymphoma)
  • Side effects of immunosuppressive drugs
• Complications of transplantation and subsequent immunosuppression treatment:
  • Postoperative problems, e.g. deep-vein thrombosis, pulmonary embolism and pneumonia.
  • Opportunistic infections: viral, particularly herpes simplex in the first four weeks and then CMV later, fungal and bacterial
  • Malignancies (especially lymphomas and skin cancers)
  • Drug toxicity, bone marrow suppression
  • Recurrence of the original disease in the transplant
  • Urinary tract obstruction
  • Cardiovascular disease, hypertension, dyslipidaemia
  • Graft rejection:
    • Hyperacute: occurs within minutes of insertion. Is now rare due to more accurate cross matching. Requires removal of graft.
    • Accelerated: aggressive mainly T-cell mediated crisis can occur within a few days in patients previously sensitised. Presents with fever, swollen transplanted kidney and rapidly increasing serum creatinine. Can be salvaged with high dose steroids plus antilymphocyte antibodies but long-term survival is affected.
    • Acute cellular: occurs in around 25% of patients usually in 1-3 weeks but can occur up to 12 weeks. Clinical signs are fluid retention, rising blood pressure and rapid increase in creatinine. Treatment is with intravenous steroids after diagnosis by biopsy. Latest induction regimens can reduce incidence of acute rejection to 10%.
    • Chronic: presents with a gradual rise in serum creatinine and proteinuria, resistant hypertension. Graft biopsy shows vascular changes, fibrosis, and tubular atrophy. It is not responsive to increasing immunosuppression therapy.
• Prognosis:
  • Over 90% of transplants should be working 1 year after surgery. A cadaveric transplant has a mean survival of 15 years, and a living transplant about 18-20 years.
  • Acute rejection and early graft loss are becoming increasingly less common.
  • Cadaveric donor renal transplantation, more human leukocyte antigen (HLA) mismatches, increased donor age, cold ischemia time greater than 24 hours, African American recipient, and a history of diabetic nephropathy all increase the risk of graft failure, return to dialysis and death.⁵
  • Most patients with a renal transplant will die from cardiovascular disease.