History of renal anaemia
As far back as 1836 Richard Bright noted that renal failure patients “lost the healthy colour of their countenance”.
Just 3 years later, Robert Christison described “the proportion of haemotosin in the blood is invariably and greatly reduced” in patients with severe “disease of the kidnies” (sic)
The symptoms of anaemia, pale skin and palpitations, were known from the Middle Ages, but erroneously attributed to “love sickness” as they were most often seen in young unmarried women. Even then, however, it was understood that iron had a part to play for the recommended treatment for this love sickness was iron filings in wine or marriage!
In 1852 Justus von Liebig proposed the idea that blood contained an iron compound that could bind with oxygen and then release it in the tissues where it was needed. This iron compound is, of course, haemoglobin. Not long after, it was recognised that the symptoms of anaemia (pallor, lightheadedness) were caused by lack of oxygen. So they worked out that the red cells contained haemoglobin that carried the oxygen to the tissues. A shortage of red cells was going to lead to a shortage of oxygen and the symptoms of anaemia.
It was known that red blood cells did not live as long in renal failure but that alone seemed insufficient to explain the anaemia seen with chronic renal disease.
It took a rather bizarre experiment in the early 20th century to reach the hypothesis that a hormone was responsible for triggering the manufacture of red blood cells: they took serum from bleeding rabbits and injected it into healthy rabbits who promptly responded by making lots more red blood cells. This hormone was initially named “haematopoietin” but later changed to “erythropoietin” (EPO) in recognition that it only affected the red cell lines, the erythrocytes.
Renal patients seemed to produce insufficient amounts of EPO in response to anaemia.
In 1957 the kidneys were identified as the major site of EPO production. It was another 14 years though until they managed to isolate some (from an anaemic sheep) and yet another 14 before they were able to produce it on a large scale.
In 1985 a patient on dialysis received the first treatment with EPO. Recombinant human erythropoietin was made in 1987 and received FDA approval in US for use in chronic renal failure patients on dialysis.
Then followed debate on when it should be used (to prevent or treat the anaemia), whether iron was also necessary (either orally or intravenously) and what the target haemoglobin level should be.
To begin with EPO use was in dialysis patients and those approaching end stages of renal impairment. However it is known that the prevalence of anaemia in early stages of renal disease is around 12% (de Lusignan, 2005) and so there is an argument for using EPO earlier.
This might not apply to patients with ADPKD.
In 1989 it was demonstrated that in patients with polycystic kidney disease the interstitial cells produce EPO independent of oxygen concentrations. (Eckardt, 1989) This has led to the belief that PKD patients have higher levels of EPO. More recent studies have confirmed this and found that around the cysts is an accumulation of proteins called HIFs that trigger the EPO manufacturing process. So it is common to find higher red cell counts and even an excess (polycythaemia) in ADPKD patients.
Whether this is a good thing or not is still debated. One study looking at use of ESAs such as EPO in PKD patients concluded that a haemoglobin (Hb) above 13 per se was not in itself a risk factor, but those who had many EPO injections and a higher Hb did not do so well as those who naturally achieved an Hb of 13, without the ESA injections. (Shah, 2012).
This suggests that treating PKD patients with EPO needs to be very closely monitored and as yet the best balance between treatment and over treatment has not yet been defined. It is definitely not always the case of “more is better” when it comes to haemoglobin, erythropoietin and PKD.
Eckardt’s research on EPO in PKD
He had 18 patients with ADPKD, 12 on haemodialysis and 6 approaching end stage renal failure. He took cyst fluid from over 300 cysts (some from kidneys in situ and others just after nephrectomy). The concentration on EPO from the cyst fluid were found to be unrelated to oxygen pressure in the cysts. He concluded : single interstitial cells juxtaposed to proximal tubular cysts may produce EPO independent of the oxygen pressure inside the cysts, which ameliorates the anemia during end-stage polycystic kidney disease.
Ten years after Eckardt, a group (Zeier, 1996) found higher erythropoietin concentrations in patients with PKD who were on renal replacement therapy. They believed that not being anaemic was a protective factor for cardiovascular disease and partially explained the better survival of ADPKD patients on renal replacement therapy.
The renal interstitium
The renal interstitium is defined as the intertubular, extraglomerular, extravascular space of the kidney. It is filled with cells, extracellular matrix, and interstitial fluid. It contains fibroblasts, flattened cells found in many connective tissues, which give structural support and also make the extra cellular matrix (a kind of gluey filler). Some of these fibroblasts produce EPO in response to decreased oxygen tension in the surrounding tissue. Although the liver makes around 10% of human EPO when the kidney is damaged the liver cannot compensate for the falling kidney EPO production. There have been problems in experimenting with these mechanisms because as yet nobody has been able to grow kidney fibroblasts that produce EPO. To date the EPO-producing liver cells have been used to study the physiology but they are subtly different. Giving anaemic patients exogenous EPO is expensive and carries risks so a better understanding of the physiology might enable control of the natural production of EPO.
Current use of EPO
EPO or other erythrogenic treatments (erythrocyte stimulating agents or ESAs) are for the treatment of anaemia associated with chronic kidney disease. It comes in refilled syringes, the EPO ones containing from 1000 units to 10,000 units. The dose starts at 50 units per kg body weight, given 2-3 times per week. The injection is subcutaneous if not on dialysis or IV if on haemodialysis. This is adjusted until the target haemoglobin is reached and then a maintenance dose is used. Contraindications include hypersensitivity to any of the constituents and uncontrolled high blood pressure.
Monitoring while on EPO should include blood pressure, haemoglobin (not to exceed 12g/dl), ferritin and iron saturation (to ensure sufficient iron is stored for making new red cells). B12 and parathyroid levels are also checked as EPO works less effectively when these are abnormal. Minor side effects include headaches but more concerning are possible thrombotic events, which is why the target haemoglobin level may be less than a healthy adult would have. EPO may interact with ACE inhibitors (anti hypertensives) and cyclosporine.
Of course a renal transplant will go some way to correcting the anaemia, but low haemoglobin is still found in post transplant patients and is linked with poorer outcomes. This is where ADPKD patients however may have the advantage – with a tendency to higher haemoglobin levels after transplants we do have better survival rates compared with non-ADPKD transplants.
Bright R. Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine. Guys Hospital Report, 1836. 1, 338-379
Cameron JS. Towards the Millenium: the history of renal anaemia and the optimal use of epoeitin. Nephrol Dial Transplant. 1999. 14, suppl 2, 10-21
Christison R. On granular degeneration of the kidnies and its connexions with dropsy inflammations and other diseases (sic). Black. Edinburgh. 1839.
Eckardt KU, Mollmann M, Neumann R, Brunkhorst R, Burger HU, Lon- nemann G, et al. Erythropoietin in polycystic kidneys. J Clin Invest (1989) 84:1160–6. doi:10.1172/JCI114280
Shah, A., Molnar, M. Z., Lukowsky, L. R., Zaritsky, J. J., Kovesdy, C. P. and Kalantar-Zadeh, K. (2012), Hemoglobin level and survival in hemodialysis patients with polycystic kidney disease and the role of administered erythropoietin. Am. J. Hematol., 87: 833–836. doi: 10.1002/ajh.23255
Zeier et al. Autosomal dominant polycystic kidney disease—the patient on renal replacement therapy Nephrology. Dial. Transplant. (1996) 11 (supp6): 18-20. doi: 10.1093/ndt/11.supp6.18
Zeisberg M, Kalluri R. Physiology of the renal interstitium. Clin J Am Soc Nephrol. 2015 October 7; 10(10): 1831–1840. doi: 10.2215/CJN.00640114