KIDNEY DISEASE

What is kidney disease?

Any condition leading to restricted blood flow through the kidney can result in damage to kidney tissue. Some medicines may also be toxic to the kidney. Acute kidney failure is a sudden decline in kidney function, leading to an increase in concentrations of urea, creatinine and other substances that the kidney normally eliminates from the body. Although often reversible and self-limiting, uncorrected acute kidney failure can be fatal. Chronic kidney disease results in a significant reduction in a range of important functions of the kidney. Its causes include high blood pressure, diabetes, inflammation and scarring of the kidney, urinary obstruction and various inherited disorders. It results in the excretion of protein in the urine (albuminuria), and measurement of this can give an indication of disease extent. It eventually progresses, usually over a period of years, to end-stage renal disease (also known as renal failure), which is fatal if not treated by dialysis or kidney transplantation. Weakening of the bones, due to disturbances in calcium, phosphate and parathyroid hormone levels, is a frequent complication of chronic kidney disease.

Who does kidney failure affect and what is the cost?

Kidney Research UK has estimated that around 34,000 people are receiving treatment for kidney failure in the UK, a number that is rising by 8 per cent annually. Around half of them have had a kidney transplant and are receiving anti-rejection treatment, while others are being given regular dialysis, of whom about half undergo peritoneal dialysis and the remainder haemodialysis. There were 1,783 kidney transplants performed in the United Kingdom in 2004/05, with about 6,900 people on the waiting list. The total prevalence of chronic kidney disease may be as much as 50 times that of treated kidney failure, as there may be no obvious symptoms initially and hence it may be undetected in its earlier stages.

Impaired kidney function is more common in the elderly. A study of 50-75 year olds in two London GP practices showed that 6 per cent of those with hypertension also had kidney disease, as did 12 per cent of those with diabetes and 17 per cent of those with both hypertension and diabetes. People of South Asian and African Caribbean origin are 3-5 times more susceptible to kidney disease.

Kidney disease represents a significant burden on the NHS budget, estimated at 2 per cent of total spending. The annual cost to the NHS of managing diabetic kidney disease alone has been estimated at £765 million, while the average annual cost of haemodialysis is over £20,000 per patient. The initial cost for transplantation is similar. It is thus very desirable, from both an economic and a humanitarian point of view, to develop ways of preventing the occurrence and progression of kidney disease and to diagnose it early.

Present treatments and shortcomings

In acute kidney failure, salt balance has to be maintained with diuretics and vasodilators to allow the damaged kidney time to recover. Established acute kidney failure needs intensive nursing to deal with excess potassium, increasing tissue acidity, possible infection, and problems of nutrition. Dialysis may be necessary, but can be stopped when kidney function has recovered.

In chronic kidney disease, many patients will have high blood pressure and/or diabetes and these should be treated. The anti-hypertensive ACE inhibitors and angiotensin receptor blockers (ARBs) have been shown to be able to slow the progress of kidney disease associated with diabetes and hypertension and some are authorised for this purpose. These include the ACE inhibitors captopril (Bristol-Myers Squibb) and lisinopril (Zestril, AstraZeneca and Carace, Bristol-Myers Squibb) and the ARBs irbesartan (Aprovel, BMS/Sanofi) and losartan (Cozaar, Merck Sharp & Dohme). Tight control of blood glucose level is also beneficial for slowing the progression of kidney disease in diabetes (diabetic nephropathy).

A low protein diet is used to help control urea levels, and anaemia will be treated with erythropoietin (Eprex, Janssen-Cilag or Neorecormon, Roche) given by injection three time a week, or with a longer-acting variant (Aranesp, Amgen) given once a week. Raised cholesterol levels are very common and are treated using statins to reduce the risk of cardiovascular events such as strokes and heart attacks.

Bone disease caused by kidney disease is treated by reducing blood phosphate level through dietary restriction and with phosphate-binding agents (e.g. Renagel, Genzyme) that prevent absorption from the gut, and by giving vitamin D analogues such as alfacalcidol (One-Alpha, Leo) or calcitriol (Rocalcitrol, Roche) to correct low blood calcium. At the same time, cinacalcet (Mimpara, Amgen) may be given to lower parathyroid hormone levels, which slows down bone breakdown and remodelling.

Regular dialysis or transplantation are used to treat end-stage disease, which is otherwise fatal. Transplantation has been greatly aided by medicines such as cyclosporin (Sandimmun, Novartis), tacrolimus (Prograf, Astellas) and more recently, mycophenolate mofetil (Cellcept, Roche) (see Transplantation).

What's in the development pipeline?

A variety of new phosphate-binders are in development. Lanthanum carbonate (Fosrenol, Shire) has completed trials, Mitsubishi's colestilan is in Phase 3, Zerenex (Keryx BioPharma) is in Phase 2 and Ilypsa's ILY101 is in Phase 1.

Roche has developed CERA, which stimulates red cell production and may need to be given only once every 2-4 weeks. Another red cell stimulator in development is AF-37702 (Hematide, Affymax), a synthetic peptide that is in Phase 2 trial. Also under review is oral paricalcitol (Zemplar, Abbott) for control of hyperparathyroidism. Meanwhile AstraZeneca is evaluating whether rosuvastatin (Crestor) can reduce the number of heart attacks, strokes and cardiovascular deaths among those on dialysis.

A diverse range of agents is being studied for use in diabetic nephropathy. At the Phase 2 stage, BioStratum has Pyridorin, Exelixis is trialling XL784, Eli Lilly is studying ruboxistaurin (Arxxant), sanofi-aventis is investigating AVE 7688 (Ilepatril) and Speedel is studying SPP301. At Phase 1 are alagebrium (Alteon) and FG-3019 (FibroGen).

Lastly, there are several treatments being explored for the kidney inflammation (nephritis) seen in the autoimmune disease systemic lupus erythematosus. The established immunosuppressant tacrolimus (Astellas) has been developed in this indication, as has Abetimus (Riquent, La Jolla Pharmaceuticals). Abetimus reduces the body's production of antibodies that are thought to be involved in causing this condition. At Phase 3, Genentech is conducting a trial of rituximab (MabThera) GSK has belimumab, licensed from HGS, and Roche is studying mycophenolate mofetil (CellCept) for the same condition.

The longer-term future

The kidney is a complex, vital and sensitive organ. Taking about a quarter of the heart's output of blood at rest, it is intimately connected with the health of the cardiovascular system. In view of the large numbers of people potentially affected by impaired kidney function, it is encouraging that the level of research to provide new medicines in this area is high. Treating kidney disease effectively to reduce progression over time will ease pressure on transplantation and expensive end-stage care such as dialysis.

FOR FURTHER INFORMATION CONTACT:

National Kidney Federation
6 Stanley Street
Worksop
Nottinghamshire, S81 7HX
Phone: 0845 601 0209 (Helpline)
Website: www.kidney.org.uk

British Kidney Patient Association
Bordon
Hampshire, GU35 9JZ
Phone: 01420 472 021
Website: www.britishkidney-pa.co.uk