NANOBACTERIUM SANGUINEUM & THE GU SYSTEM

B. Polycystic Kidney Disease (PKD):

PKD is the most common cause of renal failure in the US, with a yearly cost of $ 750 million.  PKD is an autosomal dominant genetic disease, with the inherited defect present in 1 in 400 of us, but penetrance is obviously variable.  Renal failure may occur during childhood, while on the other hand clinically silent PKD may be noted at autopsy, when a middle aged individual dies from an extra-renal cause.  In PKD, the renal tubules obstruct and enlarge, forming cystic structures, which crowd out and damage the still normally functioning renal tissue (fig. 1 – normal kidney and fig. 2 – PKD tissue).  Over time, the cysts enlarge, new cysts form, and renal function declines, then new cysts form, and so on.  Patients may present with renal insufficiency, hematuria, or abdominal pain from the enlarging cysts.  In PKD, cardiac and vascular lesions are a leading cause of death.  70% of PKD patients also harbor liver cysts; cerebral aneurysm is not uncommon, and polycystic patients are five times more likely than the unaffected to develop a kidney stone.  Histologic examination of the polycystic kidney demonstrates renal cell apoptosis, tubular obstruction, interstitial inflammation, and abnormal calcification.  Bacterial lipopolysaccharide can be recovered from cyst fluid.  PKD is associated with an inherited abnormality in polycystin, a protein thought to be involved in cell-bacteria binding.  Animal models of genetic or chemically induced PKD exist.  Here, the penetrance, or clinical expression of PKD, is influenced by co-existent infectious phenomena.  PKD predisposed animals, exposed to frequent infections, develop renal failure early in life, while animals raised in a germ free environment will maintain normal renal function longer.  The clinical expression of PKD thus appears to be an interaction between a genetic predisposition, an inflammatory autoimmune or hyperimmune reaction, and an infectious, trigger.

What agents, or agents, serve as the infectious trigger?  Hjelle analyzed cyst fluid, renal tissue, and urine obtained from 13 PKD patients, coincident to kidney explantation; in one patient fluid was aspirated from liver cysts.  5 patients were uremic, and explantation was being carried out concomitant to transplantation.  The other 8 were already on renal replacement therapy, either dialysis or by transplantation, and explantation was being carried out to address abdominal pain from the enlarging cysts.  Let’s look at Dr. Hjelle’s findings step by step.

        Bacterial endotoxin, or lipopolysaccharide, was present in at least one cyst fluid sample in all 13 patients, but in a greater percentage of cyst fluid samples, and at a higher concentration, in the sicker, still uremic patients.  20% of the cyst fluid samples obtained from the patients on renal replacement therapy contained lipopolysaccharide, at a concentration of .25 units/ml, while 40% of the fluid samples obtained from the uremic patients were positive, at a 7-fold greater concentration – this makes sense, as immune function is impaired in uremic individuals. 

While the cyst fluid was immunoreactive to monoclonal antibodies raised against C. pneumonia, structures resembling C. pneumonia were not observed in the polycystic tissue samples; only structures resembling N. sanguineum were seen.  Hjelle found that anti-C. pneumonia monoclonal antibodies, which should react to C. pneumonia and C. pneumonia alone, cross-reacted with N. sanguineum.  Monoclonal antibodies raised against N. sanguineum did not cross-react with C. pneumonia, nor did they react against E. coli or B. fragilis.  Antibodies to C. pneumonia thus pick up N. sanguineum, a carbonate apatite generating bacterium that can target, gain entry into, and then kill human cells.  A high titer of anti-C. pneumonia antibody is often found in the sera of patients with coronary disease, and is associated with an increased event rate, but C. pneumonia is only infrequently visualized within specimens of atherosclerotic plaque.  C.  pneumonia does not cause tissue calcification.  C. pneumonia has only rarely been cultured from atherosclerotic plaque.  Puskas, in a paper to be abstracted in a latter section, has demonstrated that human atherosclerotic plaque is immunoreactive to anti-N. sanguineum monoclonal antibodies, and that EDTA pretreatment enhances this immunoreactivity, and that N. sanguineum can be cultured from the calcified atherosclerotic plaque.  Up until now, research has focused on C. pneumonia as the “H. pylori of atherosclerosis”, based upon its immunologic signature.  Could it be that the  anti-C. pneumonia antibodies, upon which so much faith has been based, are really antibodies to N. sanguineum?

            Hjelle found that the Nanobacteria cultured from the cyst fluid and polycystic tissue specimens remained virulent, able to invade mammalian cells in tissue culture.  Nanobacterial antigen was present in the urine of all of the male PKD patients, and in14% of the female patients.  Urine obtained from 30% of healthy male and 10% of healthy female control subjects was also N. sanguineum immunopositive. 

  The plot thickens.  How often will a CT scan or abdominal ultrasound reveal a simple or “benign” renal or hepatic cyst?  We typically ignore them as a normal variant finding.  Why? – Because they are idiopathic?  Hjelle aspirated fluid from a simple renal cyst in a healthy individual, and guess what, the fluid grew out N. sanguineum.  Liver cyst fluid recovered from a PKD patient was positive as well.  Urine and blood obtained from a 23-year-old Finnish male with rapidly enlarging cysts but still normal renal function grew out N. sanguineum, the growth of which could be halted by tetracycline (while tetracycline is bacteriostatic to most bacteria, at .3 μg/ml it is bacteriocidal to N. sanguineum).  Hjelle also pointed out that 40% of biopsy specimens obtained from patients with renal failure, not due to PKD, will contain structures resembling N. sanguineum, and that 80% of non-PKD renal failure patients will develop cysts.  While N. sanguineum can be recovered from the blood of 5% of medical students and 15% of blood donors, N. sanguineum can be identified in the blood of 80+% of end stage renal disease patients. 

C. Thoughts and Hypotheses:

            Compared to individuals with normal renal function, dialysis patients are 20 times as likely to develop obstructive coronary disease, and their cardiac echo studies frequently demonstrate mitral annular and aortic valve calcification, all of which progress more rapidly than in individuals with intact renal function. Why does renal disease predispose to cardiovascular disease?  Or does cardiovascular disease also predispose to kidney disease?  Why does renal disease predispose to cardiovascular calcification?  Three reasons come to mind.  First, renal insufficiency is typically accompanied by difficult to treat hyperhomocysteinemia.  Second, renal insufficiency compromises excretion of ADMA, the physiologic antagonist of arginine; the resultant elevated ADMA to arginine ratio blocks nitric oxide synthesis, and thus promotes vascular wall oxidative stress and endothelial dysfunction. 

  Third, and pertinent to our discussion, it appears that the timely clearance of free-floating Nanobacterium sanguineum from the blood (also carried inside or on RBC’s remember) depends on intact renal function.  As renal function declines, Nanobacteria hang around longer in the blood, invade the vascular wall, producing inflammation and calcification within the vascular wall, a disease state that we call calcific atherosclerosis.  Individuals with PKD appear to be genetically predisposed to hypersensitivity reactions to renal Nanobacterial infection and to make cysts instead of stones.  The Nanobacteria produce tubular cell apoptosis; the tubules obstruct, the body tries to wall of the area of biofilm and infection, cysts form and dilate, compromising function of the remaining renal cells.  As renal function deteriorates, the ability to clear Nanobacteria deteriorates, more tubular cells are invaded and killed, more cysts form, and eventually the kidney fails. Currently, nearly all PKD patients will eventually require dialysis or kidney transplantation.

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