Inflammation and Kidney Disease

Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through Phagocytosis. (Photo credit: Wikipedia)

Inflammation is defined by medicine.net as a basic way in which the body reacts to infection, irritation or other injury, the key feature being redness, warmth, swelling and pain. Inflammation is now recognized as a type of nonspecific immune response. This is a definition that everyone who has ever had a cut or bruise can understand easily.

When one speaks of inflammation in kidney disease however the above definition will not adequately describe what is happening in a meaningful way. In fact the definition speaks primarily towards the outward manifestations of inflammation in the skin that have been known for centuries, redness warmth and pain.



However the other manifestations of inflammation within the organs of the body do not quite follow the same pattern as seen on the skin. Inflammation is caused by substances in the blood that are produced by cells of the immune system. It is the function of these cells to detect foreign invaders of the body and destroy them. This is accomplished by cells that detect the foreign invader as foreign and identify it to other groups of cells that are responsible for the actual destruction of the invader. When the invader is destroyed the cells involved form a memory of the event and the next time the invader attempts to gain entry the result is is a faster and stronger response.

The process requires quite a bit of crosstalk between cells of the immune system. These cells talk to each other by way of producing chemicals that act as signals that carry instructions to other cells. These chemicals go by many names but they are best called cytokines. Many of these cytokines are involved in producing the standard inflammatory reaction that is seen in the skin such as after a bee sting.

Various cells that participate in immune functions. Note that even though hematopoietic stemm cell, erythrocyte, maegakaryocyte and platelets are found in the blood, they do not participate in immune functions. (Photo credit: Wikipedia)

Interestingly the cells of the kidney, just like other organs, are capable of reacting to the levels of cytokines within the blood. The function of these cells may be altered by these cytokines. The cells of the kidney also produce cytokines as part of their daily functions as they need to talk to other cells as well in order to keep the whole machine running properly.

Problems arise when an inflammatory reaction takes place such as due to a bee sting, but the inflammation never quite stops. Usually once the inflammation has run its course the cells involved signal an end to the fight and things return to normal with the level of cytokines in the blood falling back to normal.



In circumstances where inflammation continues unchecked, the immune system becomes activated and cytokine levels remain high. This is called a pro-inflammatory state. When the body gets stuck in this state dysfunction of many organ systems can occur due to the high levels of cytokines telling cells that there is a war going on within it. This may actually be necessary if there was a severe chronic infection happening that required such a state. However frequently the pro-inflammatory state is not due to anything correctable by the pro-inflammatory state itself and hence it is not self limited.

The results can be devastating, including muscle loss as if one was malnourished due to effects of high levels of cytokines that produce muscle wasting. Increased risk of cardiovascular disease because the cells of the blood vessels are more likely to produce severe cholesterol plaques which obstruct blood flow to the heart. The blood vessels also have disturbances of function which prevent them from relaxing to allow adequate blood flow to organs that need it, such as the kidney or the exact opposite, too much relaxation, which prevents an adequate pressure head for distribution of blood. The cells of the bone marrow responsible for producing blood do not produce adequate blood cells in response to the signal to do so in the presence of excessive inflammation.

These problems have a striking resemblance to some of the problems being faced by people with kidney disease. There is anemia, muscle wasting and malnutrition and increased heart disease. This may imply that there is a relationship between chronic kidney disease and inflammation. Such a relationship has essentially been shown to exist by ongoing clinical research.

Thus inflammation, not the type that causes swelling pain and redness then goes away, but the chronic continuous activation of the immune system occurs in kidney disease and is responsible for much of the morbidity and death that occurs because of CKD.

Recently the authors of this study have shown that calcium and phosphate levels are important in determining the overall level of inflammation in patients with stage 3 to 4 kidney disease and beyond. What this means is that if calcium and phosphate levels are controllable in some way then the burden of disease produced by chronic inflammation in CKD may be reduced.

Too Old for Dialysis?

Patient receiving dialysis. ‪中文(繁體)‬: 正在接受血液透析的病患。 (Photo credit: Wikipedia)

Is there any such thing as being too old or too ill for dialysis?

That question is more than a little unfair.

A better question should be do the elderly derive benefit from dialysis?

If someone chooses not to take the option of dialysis what are their options?

How do these options compare in terms of outcome in the elderly population?

A logical argument for the commencement of any patient on dialysis is the premise that dialysis will increase the quantity and quality of life. Dialysis has known complications and can give rise to some morbidity itself. Therefore the benefits of dialysis must exceed the risks of the procedure for it to be the mainstay therapy that it is today. These statements in large part are grounded in scientific research. This research was done in populations that are representative of the population that was dialysed at the time. However the number of patients on dialysis above age 65 is growing rapidly. How does dialysis compare to the alternative in this age group.

What alternative could I possibly be referring to? Transplantation maybe? ....No. By alternative I refer to maximum conservative management or MCM. This is a wonderful phrase that means nondialysis management of renal failure that would usually require dialysis. This type of management scenario is vastly different from that seen in patients on renal replacement therapy. Guidelines such as K/DOQI and others are no longer as strictly applied. The focus is no longer placed on long term outcomes but is instead placed on making the patient as symptom free as possible without dialysis.

Patients may choose maximum conservative management based on religious beliefs or cultural reasons. Some people hate the very idea of dialysis. In my experience elderly patients who have relatives or friends who have been on dialysis are more likely to delay dialysis for as long as possible. Particularly if their dialysis unit is far away from their home and a large percentage of the day will be required just to travel back and forth.

Patients with a high burden of disease conditions are more likely to have a stormy course on dialysis. If there is no likely benefit in terms of quality of life maximum conservative management maybe offered to the patient with an option to dialyse at any time if they change their mind.

A recent paper in the Clinical Journal of the American Society of  Nephrology has recently brought this topic into focus. The conclusion of that study was "Dialysis prolongs survival for elderly patients who have ESRD with significant comorbidity by approximately 2 yr; however, patients who choose MCM can survive a substantial length of time, achieving similar numbers of hospital-free days to patients who choose hemodialysis." now this is likely to spur much debate in follow up issues of the Journal. But we must remind ourselves that when treating patients your first responsibility is to do no harm. In following this very first rule of medicine we must think about the individual's right to choose based on risk vs benefit for each patient.

Fat and renal failure

SYDNEY, AUSTRALIA - FEBRUARY 04: Clients do floor exercises at the NuYu Weight Loss Retreat on February 4, 2010 in the Hawkesbury Valley near Sydney, Australia. Nuyu is a live-in style retreat offering programs that run for up to 6 weeks addressing all aspects of healthy living including exercise, meal planning, emotional well being and boast a 80% success rate for long term weight management. The latest statistics from the Dietitians Association of Australia state that 62% - more than 13 million Australian adults - and 25% of Australian children are overweight or obese. (Image credit: Getty Images via @daylife)

The relationship between kidney disease and obesity is explored by a systematic review of the available evidence by Sankar et al. The key take home points from the article are as follows.

• Obesity is important because nearly 2/3 of american adults are overweight and 50% of this number are obese. Thus giving rise to a very large prevalence. Any health conditions tied to obesity are therefore going to be equally prevalent.

• Obesity increases the incidence of known risk factors for kidney disease such as hypertension, diabetes and dyslipidemia.

• Obesity is a unique independent risk factor for kidney disease.

• Chronic kidney disease is increasing. Currently 20 million americans have CKD.

• The number of patients requiring dialysis will increase exponentially over time.

• The contribution of obesity to ESRD is likely to be very signficant directly and indirectly via diabetes and hypertension.

• The effects of weightloss on progression to ESRD is not clear.

The authors found that weight loss may offer benefits to patients with kidney disease. Weightloss resulted in decreased protein in the urine as well as stabilisation of a measure of kidney function the GFR. The benefits were more pronounced in patients who had bariatric surgery. The current evidence is pointing to a role of weightloss via surgical methods if necessary to slow the progression of CKD. To speak to this point more studies with longer follow up will  be needed.


photo credit: Tobyotter

Stems Cells in Kidney Disease-The Renal Stem Cell

Diagram of stem cell division and differentiation. A - stem cell; B - progenitor cell; C - differentiated cell; 1 - symmetric stem cell division; 2 - asymmetric stem cell division; 3 - progenitor division; 4 - terminal differentiation (Photo credit: Wikipedia)

One of the challenges of medicine and the hope of all those who turn to practitioners of the art of medicine is the search for a cure, something that makes you whole again. It is for this reason that research surrounding stem cells and the potential therapies to be derived from stem cells inspires strong emotional responses from lay persons as well as experienced research scientists. The fact is that we have never been closer than we are now to being able to cure many types of diseases that were previously considered chronic. The converse however is that much work needs to be done, some of that work being fundamental basic research into the nature of cell replication and the mechanism of determination of cell roles that make one cell a stem cell and another cell not.

The kidney has been regarded as an organ incapable of true regeneration. This label has resulted in the doctrine that renal diseases are never truly totally reversible. In fact to support this argument we see where researchers have now made it known that child hood nephrotic syndrome secondary to minimal change disease, once considered one of the most reversible types of renal damage may alter the kidney for life in ways that we do not understand, predisposing for further kidney disease in the future. We note with some trepidation research that shows that patients hospitalized with acute renal failure, even with recovery of renal function have an unexpectedly high rate of progression to require dialysis in the years ahead. Is anything truly acute in kidney disease anymore?

When we speak to patients about their condition we are trained to avoid mentioning the word cure or reversal and lean more towards statements such as slow and retard progression of kidney disease. The impression we give is that chronic kidney disease tends to be an ominous relentless process that all of our technology and treatment methods combined will only slow.

This is why the promise of stem cell therapy for the kidney becomes so important. This explains why people will fly across the globe spending large sums of money for pseudoscientific therapy. It is because the proponents of pseudoscientific stem cell therapies make it their business to use the words that we are told not to, "cure", "reverses all damage", "regenerate", to name a few.

It therefore becomes vital to separate the pseudoscience from the science. That is exactly what Little and Bertram's article in the Journal of The American Society of Nephrology seeks to do while lighting the way for future research. Unfortunately the people in need of this knowledge are most unlikely to ever read it.

So where is the kidney stem cell, the one true cell that can become all other parts of the kidney. The cell that by itself if necessary will regrow the entire organ. Such a cell sadly has never been found and is unlikely to exist anywhere outside of science fiction. What does exist however is a cell with some classic features of a stem cell in that it may divide indefinately and has not been predetermined to become one specific type of cell only.

The hope is that cells of this nature will still be useful in kidney disease either by being able to replace diseased cells with new healthy cells or by just being in the same vicinity of diseased cells somehow produce chemicals that stimulate the diseased cells to shrug off the damage and get back to doing their job. One area of the kidney where the process of regeneration does occur is the tubule of the kidney. One of the most recognizable renal diseases and most common cause of acute renal failure is ATN, acute tubular necrosis. In this disease cells within the tubules of the kidney spontaneously die falling into the tubule and blocking them in the process. This causes renal failure, however in time brand new cells grow and replace the cells lost and the tubule is as good as new.

Diseases and conditions where stem cell treatment is promising or emerging. (See Wikipedia:Stem cell#Treatments). Bone marrow transplantation is, as of 2009, the only established use of stem cells. Model: Mikael Häggström. To discuss image, please see Template talk:Häggström diagrams (Photo credit: Wikipedia)

Where do these new cells come from? do they travel from the bone marrow from a stem cell source located there that produces the exact kind of tubule cell needed? Are they derived from the border of the glomerulus and the tubule implying a source of cells similar to stem cells within the kidney itself. Recently Appel et. al. have suggested the latter is actually the case. This may explain why the kidney cannot regenerate the tubule too many times. If this source or pool of "stem like" cells are used up with repeated acute diseases of the kidney then the kidney may lose its ability to regenerate. It is even possible that these cells are there to repair some of the natural damage of aging and by forcing them to be used in an episode of ATN we reduce the kidney's resistance to the wear and tear of the aging process.

Stem cell therapy is a very important evolving area of medical science. Understanding stem cells increases our understanding of many areas of medical physiology that had lagged behind the frontier of medicine. It is likely to continue to drive research at a rapid pace based on the perceived light at the end of the tunnel....the ability to use the word cure more readily and frequently.