Kidney disease can lead to patients needing either dialysis or even a transplant. Research by pharmaceutical companies has resulted in many medicines to help prevent kidney damage and make transplant safer.
Kidney disease has many causes and takes many forms, but any condition leading to restricted blood flow through the kidney can result in damage to its tissue. Acute kidney failure is a sudden decline in the function of the organ, leading to an increase in concentrations of urea, creatinine and other substances that the kidney normally eliminates from the body. Some medicines may also be toxic to the kidney.
Although it is often reversible and self-limiting, uncorrected acute kidney failure can be fatal. Chronic kidney failure results in a significant reduction in a range of important functions of the kidney. Its major causes include diabetes, hypertension, long lasting inflammation and scarring (pyelo- and glomerulonephritis) after bacterial infection. Urinary obstruction and inherited disorders such as polycystic kidney disease are less common causes of chronic kidney failure. End-stage liver disease leads to a very serious clinical state of renal failure which is difficult to treat.
At present, more than 250,000 patients in Europe are on treatments with kidney dialysis machines. About half of them can expect to receive a kidney transplant combined with anti-rejection treatment, a number that has more than doubled over the past 15 years. Of those who are being given regular dialysis, about half undergo peritoneal dialysis and the remainder haemodialysis. There were 10,644 kidney transplants performed in the European Union in 2001, with over 50,000 people on the waiting-list. Impaired kidney function is more common in the elderly and may go undetected in its earlier stages.
If this trend were to continue, national governments would need to spend between three and five per cent of their annual healthcare budgets on renal replacement therapies. It is thus highly desirable, from an economic as well as a humanitarian point of view, to develop ways of preventing the occurrence and progression of kidney disease and to diagnose it early.
In acute kidney failure, salt balance has to be maintained and the remaining function sustained with diuretics and vasodilators to allow the damaged kidney time to recover. Established acute kidney failure requires close monitoring to deal with emerging electrolyte balance issues, including excess potassium and increasing tissue acidity. Patients should also be monitored for possible infection and problems of nutrition. Dialysis may be necessary, but can be stopped when kidney function has recovered.
In chronic kidney failure, many patients will have high blood pressure and should be treated appropriately. A low-protein diet is used to help control urea levels, and anaemia will be treated by regular injections of erythropoietin.
Chronic kidney failure will also lead to secondary hyperparathyroidism with problems of maintaining blood levels of phosphorus, calcium, parathyroid hormone, and calcium-phosphorus products. To avoid defective bone formation, phosphate binders are given to reduce phosphate absorption in conjunction with vitamin D sterols which may raise blood calcium and phosphorus levels.
On the other hand, hyperphosphataemia occurs in many patients with kidney disease, especially those on dialysis. High blood phosphorus concentrations trigger various complications caused by phosphorous interaction with blood calcium or parathyroid hormone. These make patients more prone to calcium deposition in soft tissues such as the coronary arteries, increasing the risk of ischaemic heart disease.
To treat this condition, an oral calcimimetic compound is available. The medicine increases the sensitivity of calcium receptors on the parathyroid gland to calcium level in the blood, thus reducing levels of parathyroid hormone, phosphorus, calcium and calcium-phosphorus products. In the treatment of secondary hyperparathyroidism, this oral calcimimetic modulates the calcium-sensing receptor which regulates parathyroid hormone secretion.
The anti-hypertensive ACE inhibitors have been shown to be able to slow the progress of kidney disease associated with diabetes and hypertension and many are authorised for this purpose.
Regular dialysis or transplantation is used to treat end-stage disease, which is rapidly fatal. Transplantation has been greatly aided by medicines which suppress the body’s own immune system to avoid rejection. Several new medicines for kidney transplantation have recently been introduced. They include monoclonal antibody products, which block the IL-2 receptor involved in kidney rejection, the calcineurin inhibitors and a mTOR inhibitor.
ACE inhibitors have been shown to slow progression of kidney disease and now another class of anti-hypertensive medicines, the angiotensin 2 receptor blockers (ARBs), has been shown to be similarly effective in recent major trials. This class of new medicines was found to be effective in lowering microalbuminaemia - a sign of early phase kidney disease and for prevention of progression of kidney disease in diabetes.
Phase 2/3 clinical studies are underway to assess the safety and activity of newly developed phosphate binding compounds in patients with chronic kidney disease who are on haemodialysis. Some projects at an earlier stage include trials of immunosuppressive agents in the autoimmune kidney disease lupus nephritis and the study of an adenosine A₁ receptor antagonist in kidney disease. To treat anaemia in patients with kidney disease, several red cell stimulators are in development which may be given only once every two to four weeks.
Up to 40 per cent of patients with membraneous glomerulopathy (MG) reach end stage renal failure, making the condition one of its most common causes. Current treatment options include corticosteroids, alkylating agents, and calcineurin-inhibitors, but their use is controversial. Experimental data in MG suggests that B lymphocyte activation results in immunoglobulin deposition along the glomerular basement membrane, causing injury of kidney tissue and subsequent proteinuria. Based on the rationale that selective depletion of B cells may prevent this process, research groups are investigating in Phase 2 clinical studies whether a monoclonal antibody that is directed against B cells suppresses the synthesis of such immunoglobulins, which may lead to better outcomes in patients with MG.
Diabetes can cause an accumulation of proteins in the kidneys, leading to scar formation and eventual kidney failure. An experimental medicine which has been beneficial in other diseases involving scar formation, such as pulmonary fibrosis, may be able to slow scar formation in diabetic kidney disease as well, possibly prolonging kidney function. This molecule is in Phase 2 clinical trials.
Another approach to influencing the inflammatory process in diabetic kidney disease is the use of Antioxidant Inflammation Modulators (AIMs) that are being considered to restore organ function by inducing the cytoprotective transcription factor Nrf2. In people with diabetes, fat cells produce cytokines and mobilise free fatty acids which induce insulin resistance.
Resulting high blood sugar levels and increased cytokine production induce reactive oxygen and nitrogen species, which in turn induce vascular inflammation and endothelial dysfunction. This process creates a vicious cycle of inflammation, vasoconstriction, and ischaemia, the end result of which is sclerosis in the kidney and other blood vessels. By inducing Nrf2 and suppressing inflammation, researchers hypothesise that this cycle of inflammation and sclerosis can be eliminated. This project is in Phase 2 clinical trials.
Endothelin is a macromolecule produced both by blood vessels and the kidneys. Higher than normal levels of endothelin are thought to contribute to progression of kidney disease and proteinuria. By using medicines that block the effects of endothelin, it is thought that both progression and proteinuria can be reduced. Endothelin receptor antagonists are being investigated in Phase 1/2 clinical trials to ascertain whether these compounds improve kidney function.
The kidney is a complex, vital and sensitive organ. Taking about one quarter of the heart’s output of blood at rest, it is intimately connected with the health of the cardiovascular system. As has been seen with ACE inhibitors and ARBs, medicines that normalise the working of the heart may also have beneficial effects on the kidney.
The prevention of other underlying causes of kidney disease, like polycystic renal disease, is also under study; here, one approach is the use of antisense oligonucleotides which target the c-myc oncogene.
Given the level of research to provide new medicines in this area, the prospects for treating kidney disease should continue to improve, easing pressure on transplantation and expensive end-stage care such as dialysis.