What Role Do Tubulotoxic Chemicals Play In Renal Failure?
Exposure to tubulotoxic chemicals is a hidden risk factor for renal failure. Learn how these substances contribute to kidney damage and what you can do to avoid them.
Author:Suleman ShahReviewer:Han JuSep 11, 202420.2K Shares421.8K Views
There is increasing evidence that the exposure to tubulotoxic chemicals can lead to glomerulonephritis and renal failure.
Glomerulonephritis is seen as a serious immunologic disease of the glomeruli. However, it is considered an innocent disease as long as renal function is normal.
To prevent or to treat serious glomerulonephritis, it is therefore necessary to know what causes renal failure.
For many years, the interest has been focused on various immunological reactions, either:
- between foreign antigens that arrive into the glomeruli after having reacted with circulating antibodies and complement; or
- between autologous anti-kidney antibodies and various kidney cells or membranes
In addition, severe proteinuria has been considered noxious for the tubular cells. However, there are a host of contradictory observations.
The Role Of The Immunological Processes
If the immunological reactions in the glomeruli are the cause of renal failure, directly or indirectly, there should exist an association between the number of glomerular immune complexes (ICs)or the degree of glomerular damage and renal function, but it is not so.
Greater amount of glomerular ICs are often seen in the following animals with normal renal function and normal urine:
- sheep
- steers
- guinea pigs
- horses
- mice
- rabbits
Although their renal function and their urine are normal, these patients may have such deposits as well:
- those with malignancies
- alcoholic liver disease
- essential hypertension
A single injection of a foreign antigen into experimental animals results in the production of circulating and glomerular ICs.
However, no renal damage is seen apart from mild and transient proteinuria unless:
- the animals are injected with Freund’s adjuvant (FA); or
- the foreign antigen is injected repeatedly
In accordance, most cases of human glomerulonephritis following an acute infection may heal without permanent damage of the kidneys, but:
- renal failure may be seen in patients with chronic infections; or
- if the patients are exposed to tubulotoxic chemicals
Experimental glomerulonephritis can also be produced in rats by autologous anti-brush border or anti-podocyte antibodies, either:
- by immunization with rat kidney cells (active Heymann nephritis); or
- by injecting rabbit anti-rat brush border antibodies into rats (passive Heymann nephritis)
These models are used as an argument for the idea that serious glomerulonephritis is caused by immunologic mechanisms.
However, without Freund’s adjuvant, autologous anti-kidney antibodies do not produce more than mild and transient proteinuria.
In passive Heymann nephritis, injected heterologous rabbit antibodies bind to the glomerulus immediately, but no harm is produced until a few days later, when the autologous anti-rabbit Ig antibodies lead to complex formation in situ.
However, this model cannot be used as an argument for an immunologic mechanism, as the presence of heterologous antibodies is most unlikely in human glomerulonephritis.
Similar objections are relevant as regards experimental anti-glomerular-basement (GBM) nephritis.
Glomerulonephritis is produced by injecting heterologous or homologous anti-GBM antibodies, but without Freund’s adjuvant, no renal damage is seen.
The innocence of anti-GBM antibodies in human glomerulonephritis also appears from the fact that they can be found:
- in the circulation of animals and human beings with normal renal function
- in kidneys transplanted to patients with terminal anti-GBM nephritis without causing any harm
The Missing Link
Obviously immunologic reactions in the kidney do not produce renal failure by themselves.
In most animal experiments, the crucial factor is Freund’s adjuvant (FA), a mixture of mycobacteria emulsified with mannide monooleate in hydrocarbon oil.
There is general agreement that the role of Freund’s adjuvant is to enhance the immunological reactions, which is partly true, because many hydrocarbons interfere in an unpredictable and unfortunate way with the immune system.
However, there is much evidence that the chemical factors alone are able to produce renal failure, both in animal and human glomerulonephritis.
Several authors have demonstrated that an injection of Freund’s adjuvant without antigen causes typical signs of glomerulonephritis in experimental animals including:
- proteinuria
- tubulointerstitial damage
The changes are less severe compared with experiments that include immunization, but much worse using immunization alone.
Most patients with post-streptococcal glomerulonephritis (PSGN)recover with no sequels. Exceptions are seen in epidemics in oil-producing areas, such as South Trinidad and Maracaibo in Venezuela.
Here, epidemics of PSGN are not only frequent, but PSGN often progresses to renal failure.
Exposure to toxic compounds may be the trigger in many cases, but if the exposure is accidental and of short duration, the glomerulonephritis may heal without sequels.
In a study of 15 patients with acute PSGN, 6 of them had been exposed to hydrocarbons between the infection and the acute onset of the PSGN, and 4 had been exposed in their occupation for several years.
At follow-up those who were no longer exposed had regained normal renal function, whereas three of the four who still were exposed had:
- proteinuria
- a decreased glomerular filtration rate (GFR)
A few of 15 age-matched and sex-matched controls, who had been infected with nephritogenic streptococci without developing glomerulonephritis, had insignificant exposure only and unrelated to the streptococcal infection.
There is much evidence that tubular damage plays an important role in the development of renal failure in glomerulonephritis, both in animals and in man.
The following are tubulotoxic:
- mercury
- gold
- lithium
- silicon
- penicillamine
- selenium
- most hydrocarbons
Numerous reports and experiments have documented that they may produce serious glomerulonephritis as well.
Immunologic processes may participate, because these chemicals also disturb the immune system.
Hydrocarbons
The most common and the best-studied factor is hydrocarbon exposure.
When Stephen W. Zimmerman, Ken Groehler, and Gregory J. Beirne published a case-control study of patients with terminal renal failure and controls without renal disease matched for age and gender, publication of several case reports followed, and serious interest in the subject was raised.
Their study was published in 1975 by the journal The Lancet.
Zimmerman et al. found that almost all patients with glomerulonephritis had been exposed to toxic substances, mainly hydrocarbons, but only a few of the controls.
Since then, 20 case-control studies of patients with glomerulonephritis and healthy control individuals or patients with various non-renal diseases have been published.
With one exception, these studies have shown that the degree of hydrocarbon exposure of patients with acute or early chronic glomerulonephritis was the same compared with the controls.
Whereas patients with chronic and, in particular, terminal renal failure were significantly more exposed.
The exception was a nationwide, population-based case-control study of 926 patients with renal failure, 222 of whom had glomerulonephritis, and 998 control subjects matched for age and gender.
In that study, no difference was found with regard to the degree of renal failure between exposed and unexposed patients, including those with glomerulonephritis.
Therefore, the authors of that study, which was published in 2004 by the Journal of the American Society of Nephrologyand with C. Michael Fored as lead author, claimed that organic solvents have no adverse effect on the development of renal failure.
The study had several biases, however, such as:
1. Statisticians, who were not blinded to the patient’s case-control status, interviewed the subjects. Occupational hygienists were only involved, if the patient reported exposure to solvents.
2. A kidney biopsy specimen was available in only 61% of the patients.
3. The diagnoses of underlying renal disease were based on routine clinical evaluation.
4. As the study included patients from all the hospitals in the country, some of the diagnoses must have been made by non-nephrologists.
Because all other studies have shown that exposure is most pronounced in patients with terminal renal failure, the most serious bias was the exclusion of:
- patients who had died before the interview
- patients who were too ill to be interviewed
- patients who had received a kidney transplant
A strong argument for hydrocarbons being the cause of renal failure in glomerulonephritis is that renal function improves if the exposure is discontinued.
In one study, 50 patients were followed for 7-8 years. Nine of 26 were heavily exposed, but none of 24 moderately or rarely exposed had end-stage renal disease at follow-up.
In another study, 68 patients were followed up for 5 years; 21/29 among those, whose disease had progressed, had been exposed to hydrocarbons, but only 5/39 among those with stable renal function.
In a third study, the patients were asked to discontinue their exposure.
Although renal function was lower and blood pressure was higher initially, the course was more favorable in 15 patients who discontinued exposure than in 15 who did not.
Case-control studies may be subject to recall bias.
This problem was solved in a study of the occupations of 124 patients with glomerulonephritis according to a public census.
Compared with the general population in the catchment area of the hospital, occupations with occasional, inevitable, and heavy and inevitable exposure were significantly higher (p< 0.001).
In addition, 15 of the 49 patients with an unexposed occupation had been in an occupation with heavy exposure before the public census.
Experimental Evidence
That glomerulonephritis can be produced by chemicals alone without immunization has been demonstrated in at least 29 experiments on rats, mice, and guinea pigs exposed to:
| 4’-fluoro dimethyl benzanthracene | mixed organic solvents |
| bromoform | petrol |
| carbon tetrachloride | styrene |
| diacetyl-benzidine | trichloroethylene |
| dibromochloromethane | trimethylpentane |
| dinitrochlorobenzene | white spirit |
| maleic vinyl ether anhydride | xylene |
Most types of glomerulonephritis have been produced including:
- proliferative and focal segmental proliferative glomerulonephritis
- extra capillary glomerulonephritis
- anti-GBM (glomerular basement membrane) disease
- anti-TBM (tubular basement membrane) nephritis
- IgA nephritis
- minimal change nephropathy
- focal segmental glomerulosclerosis(FSGS)
Tubular damage was noted in all experiments; renal function was measured in eight and was decreased in five.
In the studies, where the animals were examined at different times during or after the exposure, the tubular changes were observed immediately, whereas the glomerular deposition of immune complex (IC) and complement appeared late in the course.
The Mechanism
Tubular damage in human glomerulonephritis is seen as a result of decreased renal blood flow due to obstruction of the glomerular capillaries.
However, several authors have measured the renal blood flow in acute glomerulonephritis.
Moreover, there has been a general agreement that it is unchanged or reduced only to a small extent, even in patients with renal failure
The role of glomerular damage is also contradicted by the findings in focal glomerular sclerosis (FGS).
This glomerulonephritis type is almost always associated with tubulointerstitial damage.
As obstruction of a juxtamedullary, but not of a cortical glomerulus, results in the formation of a vasa recta connecting vas afferens with vas efferens, tubular damage in FGS should be confined to the cortex, which it is not.
That the primary event is tubular damage is more likely because FGS is seen in many non-glomerular renal diseases with tubulointerstitial damage.
In accordance a highly significant correlation has been found in chronic glomerulonephritis between glomerular filtration rate (GFR) and the extent of tubular damage, but a much weaker correlation, if any at all with the degree of glomerular damage.
The crucial role of tubular damage is supported by the finding that patients with glomerulonephritis and decreased GFR have tubular proteinuria correlated with the degree of renal failure.
A large number of clinical and experimental observations have also shown that even pronounced membranous glomerulonephritis (MGN) may appear without proteinuria or renal failure.
Also, despite severe glomerular changes in patients with diabetic nephropathyor renal amyloidosis, no elevation of serum creatine is seen in the absence of tubulointerstitial damage.
It is a common view that the tubular cells are damaged by severe proteinuria.
However, the glomerulonephritis type with the most pronounced proteinuria has minimal change in nephropathy.
Also, patients with this disease most often have a normal GFR without tubular proteinuria or other signs of tubular damage, even after many years.
The crucial role of the tubulointerstitial changes is also illustrated by a meta-analysis of nephritis caused by treatment with non-steroidal anti-inflammatory drugs (NSAID).
In 97 case reports of NSAID-nephropathy, six different types of glomerulonephritis were reported.
Treatment time was strongly associated with the diagnoses:
a. The mean time of those with acute tubulointerstitial nephritis was 1.7 months.
b. For those with minimal change, it was 8.2 months.
c. For those with membranous glomerulonephritis, it was 39 months.
Treatment time was strongly associated with the number of glomerular immune complex (IC), but inversely associated with GFR and the degree of interstitial damage.
A probable mechanism behind renal failure is that tubular degeneration and cortical interstitial fibrosis, the usual findings after exposure to tubulotoxic chemicals, lead to post-glomerular capillary resistance.
The decline of the glomerular blood flow may further glomerular trapping of circulating macromolecules, which explains why the tubular changes in the animal experiments and in NSAID-nephropathy appear before the glomerular immune deposits.
In accordance, both GFR and tubulointerstitial damage in patients with glomerulonephritis are associated with degree of hydrocarbon exposure.
If exposure to tubulotoxic chemicals may cause renal failure in patients with glomerulonephritis, such exposure should have a similar effect in other renal diseases as well, and this is also what has been observed.
In a case-control study of 272 men and women with chronic renal failure (CRF) of all types and 272 controls matched for age, sex, and region of residence, significantly increased risks of CRF were found for exposure to:
| chromium | oxygenated hydrocarbons |
| grain dust | silicon-containing compounds |
| lead | tin |
| mercury | welding fumes |
Grain dust contains high amounts of silicon.
The frequencies of various occupational exposures were especially high among patients with diabetic nephropathy.
The latter is in support of a study published in 1994 by the journal Diabetic Medicine, with Muhammad M. Yaqoob as lead author.
Yaqoob et al. found a higher level of hydrocarbon exposure in patients with incipient particularly in those patients with overt diabetic nephropathy compared with diabetic patients with normal renal function.
Immunosuppressive Treatment
The standard treatment of glomerulonephritis is the use of immunosuppressive drugs.
Most trials have compared various types of such drugs.
There are only a few randomized, controlled trials where immunosuppression has been compared with placebo, and several of them have failed.
Most important is that possible exposure to nephrotoxic chemicals has not been investigated in any trial.
It is therefore impossible to know whether:
- improvement is due to the drugs used; or
- to cessation of the patient’s exposure
Conclusion
There is much evidence that renal failure, in most cases of glomerulonephritis, is caused by exposure to tubulotoxic chemicals and that such exposure may be deleterious in other kidney diseases as well.
Several studies of glomerulonephritis associated with hydrocarbon exposure have reported improvement of renal function after cessation of the exposure.
It is reasonable to assume that improvement may be achieved also by cessation of exposure to other tubulotoxic chemicals and in other kidney diseases.
It should therefore be mandatory to ask all the patients with renal failure about possible toxic exposure and to suggest cessation of such exposure.
Experienced occupational hygienists should perform the interviews because many doctors are unfamiliar with the working conditions of their patients, and several patients are unaware of their exposure.
Therefore, more studies and clinical trials should be made that will focus on tubulotoxic chemicals in renal failure.
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
Each article at World Wide Journals is a piece of this ongoing quest, blending analysis with personal reflection. Whether exploring quantum frontiers or strumming chords under the stars, my aim is to inspire and provoke thought, inviting you into a world where every discovery is a note in the grand symphony of existence.
Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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