New Treatments For FSGS -ASN Conference

FSGS 

Nephron
Idiopathic focal and segmental glomerular sclerosis or FSGS is one of the most common causes of non diabetic kidney disease in the world and also one of the least satisfying to treat due to the difficulty with initiating and maintaining a durable remission. For decades the standard of treatment has been steroid therapy in high doses given either daily or every other day. This results in significant toxicity which includes the development of diabetes mellitus, osteoporosis, personality changes, weight gain, easy bruising etc. Yet these negative effects of steroid therapy are outweighed significantly by the result of not treating FSGS as the disease will usually progress to end stage renal disease (with a requirement for dialysis and transplantation). Even after transplantation there is a risk of recurrence of the disease within hours after surgery in some patients.

If ever there was a nephropathy in need of new treatment options it would be FSGS.

NEW OPTIONS

• Oral dexamethasone for FSGS

Oral dexamethasone was found to be as effective as steroid therapy, not superior however. The side effect profile is very similar. It is unlikely that further studies will change the outlook for dexamethasone as an alternative therapy

• Rituximab

Rituximab in FSGS has had a stormy course with the safety of rituximab as a therapeutic option under scrutiny due to deaths from a rare condition known as plemorphic multifocal leucoencephalopathy. The first cases were seen in patients with lupus treated with rituximab. Response rates to rituximab have varied in different studies implying that perhaps there are certain patient specific factors which predispose for response to rituximab. The key for the future of rituximab will be identifying patients with FSGS who are likely to respond.

• Rosiglitazone

This drug is primarily used in the treatment of type 2 diabetes where it acts to reduce insulin resistance and enhance glucose uptake into skeletal muscle. The drug however has an antifibrotic effect which may be useful in FSGS this drug is currently undergoing phase I trials.

• Adalimumab

This drug is an inhibitor of tumour necrosis factor one of the major cytokines (hormone produced by cells that affect other cells ) that induces inflammation. Inhibition of TNF is a possible pathway for treating FSGS. The FONT II study will look at the efficacy of adalimumab in patients with FSGS.

• Retinoids

Wikipedia defines retinoids as " A class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth. Retinoids have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes."

What that essential translates to is that retinoids are a group of molecules that alter the expression of a variety of genes some of these genes are important to the proliferation of cells within the kidney and may play a role in the mechanism of FSGS. Trials with accutane (a retinoid currently used for treatment of acne) are currently at phase II.

• Perfinidone

Which has been shown to be helpful in diabetic nephrosclerosis has shown some efficacy in FSGS as well. The drug is capable of altering the rate of decline of kidney function in FSGS however it does not induce remission. It also does not alter proteinuria.

So some hope exists for improving the treatment of FSGS but it is still early days for almost all of the above.

ASN conference day 2

 Some rights reserved by Michael in San Diego, California 

The conference has been extremely crowded so far with some talks having to close doors due to inability to accommodate any more people after all sitting and standing room has been exhausted. So I have turned to the poster sessions in attempt to connect with some of the breaking research which is yet to be published. When they are eventually published the data presented in posters may be the source of the next oversubscribed big session at ASN next year.

Dr. Mita M shah et. al. sought to answer the question as to whether the immune system in older patients becomes less responsive. If this is true then older patients who receive transplants will need less medication. This would be an important finding because immunosuppressive medications have side effects which worsen lipid profile and may place a group already at risk for cardiovascular disease at further risk of increased events.

In the study that is yet to be published 158 stable patients were followed for roughly 6.5 years post transplant. The end result was that there was no basis for discontinuing or decreasing immunosuppressives  in older patients. In fact doing so may decrease graft survival.

Dr. Abdelaziz En-Nia presented a poster on polymorphism within the HLA-DR gene promoter and the predictive effect on post transplant kidney rejection and cardiovascular events. This is novel research that suggests that the HLA-DR locus that is routinely tested for prior to transplantation may be involved in the cardiovascular outcome post transplant. Cardiovascular disease mortality being one of the major causes of death after transplantation. Being able to isolate a subset of patients on a genetic basis who are more prone to cardiovascular disease will allow more aggressive therapy for the patients that need it most post transplantation which may translate into survival.

Dr. G Dreyer et. al presented a poster on the variation of Vitamin D levels in a multi ethnic renal transplantation population. The basis of the study was the fact that vitamin D deficiency is highly prevalent in patients after renal transplantation. This being important because of the risk of increased infections in patients with vitamin D deficiency and immunosuppression.

The unpublished results suggest that vitamin D levels vary considerably by ethnic group post transplant when other factors are controlled or accounted for. South Asians and Black patients having the lowest levels of vitamin D.

Research of Gudrun E Norby and others from Oslo in Norway have shown that SLE transplanted patients have equal survival of the transplanted kidney as other patients. However patients with SLE are at higher risk of death after tranplantation most likely from cardiovascular disease. This increased risk of cardiovascular disease in patients with SLE has been described before in the SLE patients with and without cardiovascular disease.

Highlights of the American Society of Nephrology Conference Day 1.

 Some rights reserved by Michael in San Diego, California 

After a whirlwind 12 hours of connecting flights I have finally arrived in San Diego to attend this years American Society of Nephrology conference.

The opening session of the 42nd annual conference was kicked off with an engrossing lecture by Nobel Prize winner Dr. Roger Tsien MD.

Dr Tsien gave an overview of his prize winning research on labeling of molecules with photo-labile elements and fluorescent techniques which allow direct visualization of processes which could only previously be imagined. The highlight of his presentation was his novel use of color as a tool and guide for surgeons. By injecting molecules that bind to cancer cells or their products, cancer cells can be made to glow any color that he chooses. This allows the operating surgeon to see the extent of the tumor in realtime allowing the possibility of more complete resection of tumors and thus increasing the chances of cure.

The possibilities opened by this research are amazing, almost any molecule can be tagged by his method and then linked to a marker of his choosing. Gadolinium for instance can be applied as a marker instead of a light emitting compound if the true extent of the tumor needed to be visualized on MRI.

Also of note........

The John P Peters Award was awarded to William E Mith MD, FASN for a lifetime of work in renal nutrition, muscle protein catabolism and acidemia induced muscle protein metabolism.

The Outcome of three major studies are expected to be revealed this year.

FAVORIT - The purpose of this randomized clinical trial is to determine if lowering homocysteine levels in renal transplant recipients with a multivitamin will reduce the occurrence of cardiovascular disease outcomes.

ROADMAP - ROADMAP is a randomized, double-blind, placebo-controlled, parallel-group, multi-center Phase III study being conducted at 262 collaborating centers in 19 European countries. The primary goal of the study is to test the hypothesis that treatment of T2DM patients with 40 mg of olmesartan medoxomil will prevent or delay the occurrence of microalbuminuria in comparison to a regimen that excludes agents that directly block the RAS. The secondary objective is to test the hypothesis that treatment with olmesartan medoxomil has a positive effect on cardiovascular and renal morbidity and mortality.

TREAT - Will evaluate whether treatment of anemia with Aranesp (darbopoietin) reduces cardiovascular events in patients with chronic kidney disease and with type 2 diabetes.

One of the most interesting papers mentioned today in the presidents opening address was the localization of increased risk of non-diabetic kidney disease in African Americans to the Myh9 gene locus. This finding may finally explain why African Americans are at increased risk of kidney disease and ultimately lead to understanding the mechanism of this increased risk thus guiding more specific therapy for patients with the gene.

Stay tuned the conference has only just begun....

Insulin Resistance and Kidney Disease, some thoughts.

Insulin molecule courtesy wikipedia.

Insulin resistance is a term many doctors and scientists are already familiar with. However not that many patients have a concept of exactly what is meant by resistance to insulin. Other than its role in the causation of type 2 diabetes, Ginsberg considers insulin resistance a major underlying abnormality driving cardiovascular disease, the major cause of morbidity and mortality in much of the world.

Although most of the research produced thus far focused on the role of insulin resistance in diabetics, it is now apparent that insulin resistance is important in its own right.

Insulin resistance is a syndrome that has been linked to increased risk for cardiovascular disease. However its effect is believed to act via promoting dyslipidemia, hypertension, hypercoagulability, and atherosclerosis.

In terms of kidney disease it has been shown by other authors that insulin resistance correlated linearly with decline in renal function. Independent variables related to insulin resistance were bicarbonate and Apo A-1/B levels in patients with chronic kidney disease. Low serum bicarbonate has been implicated in increased bone disease of renal failure and poor cardiac function as well increasing the pace of progression to end stage renal disease an effect that can be ameliorated in part by the prescription of bicarbonate. It would therefore not surprise me if insulin resistance were associated in some future study with increased progression to end stage renal disease. The Treatment of insulin resistance will likely then be a significant issue for patients with kidney disease.

Rosiglitazone is an oral drug that reduces the amount of sugar (glucose) in the blood. It is used for treating patients with type 2 diabetes. It is one of the few drugs currently available capable of reducing insulin resistance. The drug itself is not without side effects, there have been warnings issued regarding a propensity for the development of heart failure in some patients on this drug.

Type 2 diabetic patients on dialysis may derive benefits from this drug both in terms of glucose control as well as reduced insulin resistance. While the question of the safety of rosiglitazone among patients on dialysis still remains to be fully answered, a study of 24 patients on CAPD treated with rosiglitazone has revealed interesting evidence that the drug has no long term negative effects on cardiac function in CAPD patients. Although the study was small, it is somewhat reassuring that the drug may also be safe in patients with lesser degrees of kidney failure.

Once the drug is deemed safe in patients with kidney disease it would be interesting to see a randomized control trial sufficiently powered to determine if rosiglitazone has any impact on the progression of renal disease. If the answer is no then insulin resistance may just be another marker of the inflammatory state that is uremia instead of a driver of progression in and of itself.

Peritoneal Dialysis and Encapsulating Peritonitis

Copyright © 2012 by American Roentgen Ray Society
Sclerosing encapsulating peritonitis.

Peritoneal dialysis relies on the peritoneal lining as a surface for the exchange of substances during dialysis. However the peritoneal membrane was never intended to be used for this purpose. The goal of peritoneal dialysis research is to find the least traumatic and disruptive method of ensuring efficient dialysis occurs for as long as possible before the peritoneal lining is "worn out". The greatest advance in this area would entail some method that allows the membrane to continue to function indefinitely.

One of the unsolved problems remains the absence of any clear way to predict the peritoneal membrane will react under the same circumstances from patient to patient. For instance some patients are able to withstand recurrent infections with very little structural alterations to the peritoneum while others have to be switched to hemodialysis  after one or two episodes of peritonitis.

Arguably the most feared complication of PD is an entity known as encapsulating peritoneal sclerosis (EPS) or sclerosing encapsulating peritonitis. This condition is multifactorial and thankfully quite rare with dialysis induced EPS being rarer still.



Identifiable causes include

• Post surgical.


• Medication with Beta blockers.


• Cirrhosis with ascites.


• Generalized Peritonitis of any cause.


• Peritoneal dialysis.

Encapsulating peritoneal sclerosis is characterized by inflammation of the peritoneal lining with progressive scarring and shrinking of the area of the peritoneum, since the peritoneum surrounds the intestines the intestines are slowly compressed into a tight mass of tissue surrounding by strong fibrotic bands.

Because the bowel is now packed into a very small space obstruction of the bowel becomes more common. Symptoms include abdominal pain and retention of fluid in the abdomen.

The etiologies of EPS secondary to PD include

• severe and/or nonresolving peritonitis, especially that due to Staphylococcus aureus, fungi, and Pseudomonas sp, and especially in the long-term patient.

• Increased duration of PD has been assumed by some to be a risk factor for EPS.

• Acetate-buffered PD solutions


• certain β-blocking agents


• the use of in-line bacterial filters


• exposure to certain antiseptics or disinfectants. (chlorhexidine)

It is noted by Perl Bargman and Chan that "in more than half the patients who develop EPS, the diagnosis is made after transfer to hemodialysis (HD)."

It is therefore necessary to maintain a heightened state of suspicion for this condition in patients who have peritoneal membrane failure and have to be transferred to HD. Be particularly suspicious if unexplained gastrointestinal signs occur such as abdominal pain intermittent obstruction and ascites.

The earlier the diagnosis is made the better the outcome. Antiinflammatory medications may be helpful in the early stages later on surgical therapy with nutritional support at a centre that is specialized in this condition is required.

Cannulation Technique may Improve Fistula Survival

AV FISTULA

An AV fistula is the access of choice in patients starting dialysis. The use of AV fistula first is associated with less risk of infection which is a significant cause of morbidity and reduced survival in dialysis patients.

The technique used to cannulate a fistula is essentially the method used by the HD nurse to insert the venous and arterial needle into the fistula so that an adequate blood flow for the process of dialysis can occur.

However as noted by Van Loon et. al. "Little is known about cannulation of the vascular access (VA), such as the number of successful cannulation procedures, frequency of complications caused by cannulation, and VA failure."

The above investigators then went on to publish the results of a study conducted in incident dialysis patients who were followed for 6 months after the first successful cannulation with 2 needles.

Data collection included patient characteristics:

• Comorbidities


• Medication.

Vascular access characteristics:

• Type of VA and location


• Vein diameter


• Length of the cannulation route


• Maturation period.

The study took place between 2005 and 2007 in 10 Dutch dialysis facilities and ultimately included 120 patients.

For AV fistulas with a short cannulation route (small area for insertion of the needle) outcomes were negatively affected compared to those that had a longer area for cannulation.

Significant predictors of vascular access failure were previous use of central vein catheters and previous use of single needle dialysis.

The conclusion of the investigators was that "The present study demonstrated that during the first 6 months of a newly placed VA, a huge number of cannulation-related complications such as miscannulation, use of CVC, and SN dialysis are encountered."

So although fistula first is the logical choice in new patients, there are two important points that need to be noted. The fistula should be created in a manner that it is easily cannulated hence reducing cannulation errors and vascular access failure, according to this study the length of the cannulated limb of the fistula is very important in this regard.

Two cannulation technique is a wild card variable that is likely to vary widely from centre to centre based on differing levels of competence and experience between HD staff. The importance of cannulation has now been shown, the next step is standardizing techniques for cannulation and investigating access survival with different techniques and approaches to determine which technique or combination of techniques is best.

Stem Cells Provide Hope In Alport Syndrome.

ALPORTS
Hepinstall's Pathology of the Kidney, 6th Edition

Alport syndrome is a genetic defect of type 4 collagen, a major structural component of the glomerular basement membrane. Which is in turn the major structural component that defines the function of the filtration apparatus of the kidney. Defects of this important component of glomerular function results in various abnormalities. In Alport syndrome patients progressively lose renal function due to inflammation of the kidney. There is currently no known cure for this condition.


Researchers in Boston however have published a paper that seeks to lay the foundation of a possible future treatment. Their research focuses on a lab induced variant of Alport syndrome in rats and its subsequent treatment with stem cells derived from the bone marrow of healthy rats. The results so far suggest that the damage caused by the mutant type of collagen in Alport syndrome is repaired by infusion of both bone marrow derived stem cells from rats as well as human stem cells.


The findings are fairly exciting because there was benefit to be had even in advanced disease. The missing collagen being synthesized and introduced into the abnormal basement membranes subsequently resulting in reorganization of the structural components of the basement membrane and improved kidney function.


The technical aspects have yet to be worked out sufficiently to even provide a best guess timeline for possible human trials but the ground is fruitful for further research.


Where is the renal stem cell indeed?

Muscle Cramps In Dialysis Treated By Vitamin E

muscle cramp

photo Credit:happeningfish

Cramping of the muscles while undergoing dialysis is one of the most frequent complaints of dialysis patients. It occurs in up to 20% of dialysis sessions.

• Risk factors for cramping includes high weight gain in between dialysis sessions.


• Having low serum calcium or derangement of sodium and potassium.


• Intradialytic hypotension may also present with cramping of the muscles.

While many corrective actions may taken during the treatment to treat the cramps, it may be found that this interrupts treatment time and can reduce clearances and achieved ultrafiltration especially if sodium chloride is used repeatedly to treat the episodes of cramping.

Recently an article published in the American Journal of Therapeutics has shown that vitamin E maybe effective at preventing cramping during dialysis.

The basis for the study was that many reports previously suggested that vitamin E (vit. E) may be effective for the prevention of HD-associated cramps.

• The investigators decided  to perform a selected controlled trial of supplementary vit. E for treatment of patients who are known to have frequent cramping episodes during and after dialysis.


• They compared the number of attacks of muscle cramps with the patient's baseline over a specific period of time.


• The study was admittedly small with only 19 HD patients. Patients were treated 400 IU of VIT E daily for 12 weeks.

THE RESULT

• The frequency of muscle cramps decreased significantly during vit. E therapy, and, at the end of the trial, vit. E led to cramp reductions of 68.3%.  With no adverse effects.


• The study was not definitive however due to its small size. The fact that vitamin E had no significant side effects at the doses suggests this may be worth trying if you have very severe cramps that is if your nephrologist agrees and you have addressed all the risk factors mentioned above.

Large Kidneys What Do They Mean?

Usually kidney disease is associated with small kidneys. The process that shrinks the kidney is scarring otherwise known as fibrosis which is the end point of any damage to the kidney. However from time to time a disease process will come along that causes enlargement of the kidney as it proceeds to damage the kidney. Some of the diseases that may cause this are as follows.

• Infiltrative diseases such as sarcoidosis and amyloidosis both cause this. Amyloidosis is a disease of the blood which bears certain similarities with multiple myeloma and may coexist with this condition. There is deposition of large quantities of abnormal protein in amyloidosis which are laid down around the blood vessels and other structures of the kidney leading to abnormal function.


• HIV kidney disease is associated with kidneys that are larger than expected for the degree of kidney failure that exists.


• In acute renal failure due to acute tubular necrosis or a severe inflammation of  the kidneys.


• In diabetic kidney disease there is enlargement of the organ in the early stages of diabetic kidney disease. However the kidney subsequently shrinks to roughly normal size by the time end stage renal disease occurs. The finding of normal size kidneys in patients with chronic renal failure is therefore not uncommon.


• Polycystic kidney disease as expected.

Other problems in Polycystic Kidney Disease

[caption id="attachment_642" align="alignright" width="199" caption="Polycystic Kidney Disease"][/caption]

Autosomal Dominant Polycystic Kidney Disease has several manifestations which are not confined to the kidney. These manifestations include the following.
It is very common for patients to have cysts on other organs of the body. The most common organ to find cysts other than in the kidney is the liver. Cysts in the liver may produce pain and patients may have bleeding into these cysts however the liver function is not usually affected. However in patients who have the recessive type of polycystic kidney disease usually seen in children there may be fibrosis of the liver. Cysts may also be found in the pancreas intestine and in the muscles.

Patients with polycystic kidney disease may also have a floppy heart valve known as mitral valve prolapse. This is usually detected as an unsual sound heard when a physician listens to the heart beat.

Symptoms of Mitral valve prolapse tend to develop gradually and include.

• A racing or irregular heartbeat.


• Dizziness or lightheadedness.


• Difficulty breathing.


• Fatigue.


• Chest pain.

However the vast majority of patients with mitral valve prolapse have no symptoms, lead perfectly normal lives and will never know they have this condition.

Patients with polycystic kidney disease may also have dilation of the main artery the aorta this is called an aneurysm. Symptoms of an aortic aneurysm include a pulsatile mass within the abdomen and abdominal pain. If the aortic dilatation involves the aortic valve they may have a more serious presentation including acute heart failure.

The dilatations of blood vessels are a feature of polycystic kidney disease and may also occur in the brain and heart. When occurring in the brain patients are at increased risk of stroke. Stroke may occur at any age although usually a devastating complication the aneurysm may be detected by a special type of MRI. The question however is who should receive screening for these aneurysms and when. Few Guidelines exist however a reasonable approach would be to screen patients who have a family history of stroke, patients who have to be on a blood thinner for any reason or who have an acquired disorder of clotting that would increase their risk of bleeding and those with severe hypertension as that increases the risk of bleeding.

Older Dialysis Patients May Not Derive Benefit from Dialysis

[caption id="attachment_636" align="alignright" width="300" caption="Dialysis in the Elderly "][/caption]

Recently I asked the question can you be too old for dialysis. Then today I noticed a news release based on an article published in the new England Journal of Medicine which suggests that elderly patients living in nursing homes may not be deriving significant benefit from dialysis. I had feedback on my own article, which suggested the very concept of limiting dialysis based on age is repulsive. Let me make it quite clear, that it was never my intention to suggest such a thing.

My point remains that in order for a treatment to be offered, it must be shown to be of benefit to the patient. The first rule of medicine is ...at least do no harm. In the case of dialysis the elderly population is not as frequently studied survival numbers as well as quality of life data is limited. Dialysis is quite an undertaking at any age. However in elderly patients the situation is complicated by issues with immobility and transport to and from the dialysis centre.

If it is indeed true that after the initiation of dialysis in nursing home residents the functional decline that occurs is unchecked by dialysis then we must ask ourselves why are we dialysing this group of patients. Who stands to benefit from their dialysis if it is not them directly then who?

Functional status decline after commencing dialysis is based on the presence of multiple conditions which precede the initiation of dialysis, these conditions are not correctable in the majority of cases and in themselves represent a form of end stage disease of organs other than the kidney. Not only may dialysis not benefit patients which such a high burden of disease but I would go further to say that the fluid shifts which occur in standard hemodialysis may theoretically cause further harm depending on the co-morbidities present.

The point is not to deny any patient group dialysis based on any non modifiable variable such as age but to better be able to advise patients and their families about realistic outcomes when initiating dialysis in all patient groups. Right now the data in the elderly population is sparse and we are just now beginning to see some indication of what the true position maybe.  I for one am looking forward to reading the correspondence that this paper in the New England Journal of medicine is sure to bring.

Treatment Options In Goodpastures.

Kidney (Photo credit: Joshua Schwimmer)

Overview of Goodpastures Syndrome.

A rapidly progressive form of kidney disease associated with antibodies directed against the structural components of the functional subunits of the kidney and the lung. The disease therefore gives rise to both lung and kidney pathology a situation termed pulmonary renal syndrome.

The exact cause is unknown. It is considered an autoimmune disorder (other autoimmune disorder's that affect the kidney include Lupus Nephritis). The bodies own immune system is responsible for targeting both lung and kidney tissues. The initial immune system activation may occur in response to viral infection or even the inhalation of toxin from the environment such as inhaling gasoline. Smoking increases the risk of the disease it is most likely to occur in men from ages 16 to 61.

It is possible to be predisposed to good pastures syndrome based solely on your genes. It is therefore possible to have family members with the same problem. The disorder is however relatively rare.


Symptoms of Goodpastures.

The predominant symptoms of Goodpastures syndrome includes cough productive of bloody sputum due to bleeding within the lungs from the inflammation caused there. The kidney disease produced usually has symptoms such as swelling fo the feet or around the eyes retention of fluid and elevated blood pressure with or without headaches. There is lethargy and weakness associated with decreased appetite if the condition has been going on long enough. The nonspecific symtpoms of weakness and lethargy loss of appetite are due to the systemic nature of the disease as well as the anemia associated with it. The anemia is frequently multifactorial, due both to iron loss due to the loss of blood in the lungs as well as kidney disease. Because of episodes of bleeding into the lungs there may be episodic shortness of breath which may be due both to retention of fluid from kidney failure as well as blood filling the spaces within the lung for gas exchange.


Treatment Options.

The mainstay of treatment of Goodpastures is early recognition followed by plasmapherisis (a process of removal of the immune system components of blood) and administration of cytotoxic medication, (medication targeted against rapidly dividing cells of the immune system) and steroid therapy.

Goalfinder immune-system-action (Photo credit: gfinder)

On the horizon are some interesting therapeutic options.


A monoclonal antibody known as ox-8 is the latest experimental drug with efficacy in experimental good pastures disease in rats. It is deemed effective in the prevention and treatment of experimental inflammation of the kidney in rats. We will be hearing more about this one in the future.


Because goodpastures is caused by activity of the native immune system against the collagen forming the structural component of the filtration apparatus of the kidney it is possible to treat the disease by turning off the immune reaction against that specific structural component which is collagen. This has been accomplished in rats utilizing nasally administered collagen which induces tolerance. When tolerance occurs the immune system accepts a previous enemy as a friend and does not attack. This would effectively turn off the immune response against the kidney if it can be achieved in humans


Much basic research is needed and continues to be done looking at goodpasture's disease. Although a rare disease the mechanisms of tolerance and autoimmunity governing the pathology of this condition if properly understood and targetable would herald a new day in the treatment of many other kidney diseases of similar etiology.

Chinese Herbal Medicine and Kidney Stones

Chinese Herbs.
image http://www.acupuncturehealingbristol.co.uk/id41.html

Kidney stone pain or ureteric colic is perhaps the most feared symptom of urolithiasis. People who experience it at its worst will do anything that they have been told will help in the passing kidney stones. Because of this fact there are many questionable products on the market which claim to pass kidney stones or dissolve kidney stones. From time to time I have reviewed some of the more prominent preparations.

There is a natural tendency to discount what we don't understand or were not trained to understand. I am no exception to this rule, having not been trained in traditional herbal medicine in a country where it is practiced. However I do believe the current upsurge in published studies utilizing traditional medicine has allowed for a bridging of knowledge between two worlds which are destined to collide. Clearly herbal medicine represents an area where there are opportunities to be exploited in development of new pharmaceutical agents. While practitioners of herbal medicine stand to gain valuable insight into the possible drug interactions which may occur between established pharmaceuticals and herbal preparations.

Therefore I was excited to note the following study published in the Brazilian Journal of Urology as recorded in the pubmed database. The purpose of the study was to assess the evidence based literature supporting the use of traditional Chinese medicine Kampo herbal and acupuncture in stone disease management.


Kampo literally means medicine from China and its a traditional japanese therapeutic system.

Kampo is said to have little or no side effects. If proven then this would be a significant advantage over traditional therapies for long term treatment of chronic kidney stones.
The herbs of Kampo are Chorei-to, Wullingsan, Kin Quan Cao, Nia Shi Mixture


Chorei-to
A mixture of herbs for nephritis and kidney stones. This mixture of herbs when examined together did not prevent formation of calcium phosphate crystals in an experimental model however individual herbs in the mixture had possible beneficial effect. Takusya decreased tissue calcium concentration and reduced tissue calcium oxalate in rat kidneys. Overall the constituents may increase solubility of calcium oxalate which is a good thing. The effect was not particularly strong in the experiments done.


Wullingsan

A combination of herbs thought to act as a diuretic. In laboratory studies wullingsan was able to reduce the rate of nucleation or the start of stone formation at specific dosages, however at higher doses the extract increased stone formation.


Jin Quan Cao
The main anti stone ingredient is called DS-T, it is believed to block urinary calcium excretion by either inhibiting the endogenous synthesis of 1-25(OH)2D from 1-alphaD3 in the kidney or by inhibiting the action of 1-25(OH)2D on increased intestinal absorption of Ca.

Niao Shi Mixture (NSM)

For more than 30 years, NSM has been used clinically at Guanganmen Hospital (Beijing, China) to treat urinary calculus and is very effective at preventing hydroxyproline stones.


Most of the studies were done in animals or in purely experimental models. It is possible that the herbs studied could have had a more pronounced and universally positive effects in humans. Properly designed studies of individual component vs placebo and separate components will be needed to produce the level of evidence needed for these preparations to be accepted into the western model of medicine. However the positive effects are intriguing to say the least


Previous review of Indian Herbal Medicines for Kidney stones
Previous review of URIFLOW

Green tea and Kidney Cancer News

Image by Dano

An abstract from the Journal Oncology Reports. has brought Green Tea back into the news yet again.

EGCG (epigallocatechin gallate), the major antioxidant found in green tea, has been shown to inhibit the growth of many tumor cells even inducing the tumor cells to spontaneously die by a process known as apoptosis. EGCG can inhibit one of the enzymes involved in DNA synthesis and repair and thus cause reactivation of genes that lead to this effect. The gene responsible is known as TFPI-2, a member of the Kunitz-type serine proteinase inhibitor family. Previous studies demonstrated that the expression of TFPI-2 and invasiveness of renal cell carcinoma had a negative correlation. TFPI-2 may induce tumor cell apoptosis in renal cell carcinoma. Lower expression of TFPI-2 in renal cell carcinoma may be induced by EGCG in green tea. This may explain the finding of the investigators where EGCG was shown to inhibit growth and induces apoptosis in renal cell carcinoma cell line. Although tests of invasiveness and metastasis did not indicate any significant differences between control and treatment group. The results suggest that EGCG inhibits growth and induces apoptosis in renal cell carcinoma through overexpression of TFPI-2 . This is the first report showing that EGCG is likely to be an effective agent for renal cell carcinoma.

Green tea's story continue to impress me.

Lupus and Kidney disease..What is Lupus Nephritis?

Lupus nephritis
http://www.kidneypathology.com/English_version/Case_8.html

Lupus nephritis an ominous name for a condition that most people would not have heard of. Chances are if you know the entity to which I am referring you either have this disease or know someone who does.

Lupus nephritis is the name given to inflammation of the kidney because of lupus. There are several flavors of Lupus nephritis and they are graded from 1 to 6 based on testing of kidney tissues. The prognosis of lupus nephritis is tied to the class of the disease. With Class I disease having the best prognosis while class 4 and 5 disease and combinations thereof having the worst overall prognosis.

Estimates are that up to 50% of patients who have lupus will have some manifestation of lupus nephritis over the course of their illness. To understand Lupus Nephritis we must first understand some of the key points surrounding lupus itself.

HOW DOES LUPUS OCCUR

Systemic lupus is an autoimmune disease.

The native immune system attacks normal tissue as it would a foreign invading organism.

The reason for this is not yet fully known.

Majority of problems are related to INFLAMMATION within the tissues affected.

The kidney is very vulnerable to inflammation

The organ receives a very high blood flow

Inflammatory cells are easily transported through the blood to the organ.

The consequences of this inflammation, results in several distinct syndromes.

Organ involvement in Lupus

SYNDROMES ASSOCIATED WITH LUPUS NEPHRITIS

Nephrotic syndrome.

Nephritic syndrome.

Acute renal failure

Chronic renal failure

Nephrotic syndrome

A constellation of symptoms and signs which include swelling and passage of high level of protein in the urine associated with high levels of cholesterol.

The nephritic syndrome

The presence of either visible or microscopic amount of blood in the urine in conjunction with elevated blood pressure and fluid retention. There is also usually some retention of waste products in the blood on screening tests of kidney function

Acute renal failure

A sudden decrease in the ability of the kidney to perform its main functions

The excretion of nitrogenous waste products.

The excretion of excess acid.

The excretion of excess fluids.

[caption id="attachment_597" align="alignright" width="300" caption="Lupus antibodies NLM ADAM "][/caption]
Chronic renal failure

This is better termed chronic kidney disease.

A gradual loss of renal function taking place over 3 months or more.

Symptoms of renal failure may be present

Weakness

Lethargy

Fatigue

Vomiting

Fluid retention

Loss of appetite.

If the diagnosis is suspected by your physician it may be confirmed only by a series of tests.

• Measurement of electrolytes and urea and creatinine.


• Measurement of creatinine clearance.


• Measurement of 24 hour protein excretion.


• Analysis of the urine sediment.


• General investigations targetted at the activity of systemic lupus.


• dsDna antibody.


• Complement levels.


• CRP and ESR.

Based on the history and clinical findings plus the results of investigations so far


A clinical syndrome may be diagnosed

• Nephrotic syndrome.


• Nephritic syndrome.


• Acute renal failure.


• Chronic renal failure.

The treatment of lupus nephritis however depends on The HISTOLOGICAL CLASS of disease and the CLINICAL SYNDROME.

Histology is the study of tissues, usually carried out under the microscope.
Samples of tissue are obtained by a procedure known as biopsy. Biopsy may be

1. Open biopsy requiring general anaesthesia and major surgery.


2. Closed biopsy usually done under ultrasound guidance.

CLASS I

Essentially normal.

CLASS II (mesangial)

A localised Mild increase in the cells seen.

CLASS III (focal proliferative)

A diffuse or widespread increase in cells of immune origin and kidney origin. But large areas of normal or mild disease still apparent.
CLASS IV (diffuse proliferative).

As above but almost no areas of mild disease or normal kidney tissue on biopsy.

CLASS V (membranous)

May or may not have an increased number of cells. However there are deposits of abnormal protein apparent within the kidney.

CLASS VI (sclerosing).

Scarring of the kidney usually results when the above classes have progressed beyond the ability to respond to treatment.

TREATMENT OF LUPUS NEPHRITIS

Class I disease
Usually no treatment above what is required to maintain lupus in remission.

Class II disease
May require treatment with increased doses of steroids. Usually responds promptly to therapy and is easily treated.

Class III disease
May behave like Class II disease or Class IV disease.

Class IV disease
Aggressive disease that easily and rapidly progresses without aggressive treatment.

Class V disease.
Pure Class V disease is controversial.
Class V disease with features of class IV is treated as IV
Class V disease with features of III is treated as III or IV.

Class VI disease
Prevent further deterioration of renal function and if signs of chronic renal failure are also present then prepare for dialysis.

• The NIH has the most complete follow up data for severe lupus nephritis defined as Class IV And Class V with features of Class IV.

• Their data suggested that survival with Cyclophosphamide was 90 percent at 10 years.


• With Azathioprine alone 60 percent at 10 years.


• Prednisone alone 20 percent at 10 years.

New treatment options for therapy with lupus are being studied daily.

Iron, EPO Anemia and Kidney Disease

Iron Anemia and kidney disease

 Some rights reserved by Newbirth35
Spiegel and Chertow in the Clinical Journal of the American Society of Nephrology have taken a look at the direction we are heading in the treatment of anemia in ESRD based on a few recent studies.

Their commentary is particularly interesting because it brings to light a new possible threat, the injudicious use of iron in the absence of sufficient safety data.

They highlight several clinical controversies still facing patients in the dialysis population. Controversies that stem from recently done studies which have questioned the optimal hemoglobin range for correction of anemia and the absence of any long term safety data for IV iron therapy.

It is suggested that economic factors may further complicate the use of such agents based on the reimbursement model, the drive for profit in dialysis providers and marketing pressures from big Pharma.

Several unanswered questions remain that are likely to be further muddled before the situation becomes more clear. What is the best marker of an adequate iron load? Serum ferritin has been shown to be a poor marker. It is well established that serum ferritin is a better marker of overall inflammation than of iron stores in patients on dialysis. If the administration of iron to patients with high serum ferritin is thought to produce a benefit in terms of reduction of ESA dosage, then economic pressure to see the administration of iron in patients with high serum ferritin may cause the adoption of protocols that have a limited safety track record. The interplay of iron, ESA and reimbursement policy is something to watch for in upcoming industry news.

Exercise and Kidney Disease

Stretching Out (Photo credit: Tyne & Wear Archives & Museums)

Exercise has proven health benefits in the normal population. These benefits are tied in some instances to weight loss. However the health benefits of exercise exceed that of weight loss alone. In a recent press release the American Society of Nephrology has made the statement "getting off the couch could could lead to a longer life for kidney disease patients." Based on a study which will be published in the Clinical Journal of the American Society of Nephrology (CJASN).

The mortality among patients with CKD is driven unexpectedly by cardiovascular disease implying that the function of these two organs although quite different on paper, are closely related on some more fundamental level that is not readily apparent. Although there are many theories as to how this may occur. The one that I consider the most likely to be true suggests that cardiovascular disease in chronic kidney disease is modulated primarily by inflammation and as pro-inflammatory states go CKD is pretty bad.

I think the findings of this study are to be expected, there is absolutely no evidence to suggest that patients with kidney disease would not derive benefit from exercise. Where this study is likely to have a significant impact is in the promotion of a healthy lifestyle choices among patients with kidney disease. Too frequently patients with CKD are sedentary a finding echoed by the investigators of this study.

Patients on dialysis are particularly prone to the ill effects of a sedentary lifestyle. The fact that dialysis usually occupies in the region of 12 hours out of the productive week usually leads to less exercise among this patient group. In addition to that there is the question of co-morbidities which may prevent exercise and a general feeling of fear and lack of confidence in exercising among some patients to contend with and already you see that this is likely to be an uphill struggle.

Unfortunately patients on dialysis are at very high risk of cardiovascular disease and as such they have the most to benefit from exercise. Consider for example that the traditional role of cholesterol as a risk factor for cardiovascular disease in the normal population is not as strongly supported in the dialysis population, add to that the still murky roles of non traditional risk factors such as PTH and phosphate and you will understand that a traditional risk factor such as lack of exercise may very well be a blessing and one of the most easily and cheaply modifiable targets for intervention.

[caption id="" align="alignnone" width="308" caption="Dialysis Exercise"][/caption]

There are machines available that will allow patients on dialysis to pedal against increasing resistance while having dialysis. These should be more widespread, patients on dialysis are essentially a captive audience for such an intervention. They are safe in the vast majority of patients and allow for previously sedentary time 4 hours three times a week to be used as part of the requirements for exercise. Even 20 minutes per dialysis session of resistance cycling is likely to have a positive effect.

Maybe as a result of this study we will see dialysis chairs with attached bicycles and spinning instructors becoming a part of the dialysis process. At least I hope so.

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.