Fluorosis and Renal stones
NOTE: THIS IS AN ONLINE E LOGBOOK TO DISCUSS OUR PATIENT'S DE-IDENTIFIED HEALTH DATA SHARED AFTER TAKING HIS / HER /GUARDIAN'S SIGNED INFORMED CONSENT. HERE WE DISCUSS OUR INDIVIDUAL PATIENT'S PROBLEMS THROUGH A SERIES OF INPUTS FROM THE AVAILABLE GLOBAL ONLINE COMMUNITY OF EXPERTS INTENDING TO SOLVE THOSE CLINICAL PROBLEMS WITH COLLECTIVE CURRENT BEST EVIDENCE-BASED INPUT
ABSTRACT: Fluorosis a crippling disease is a public health problem with a worldwide distribution and endemic in at least 25 countries with India reporting approximately 25 million people presently affected by fluorosis and 66 million are at risk of developing fluorosis, including children of age 14 years. Here we discuss a case of skeletal fluorosis with a complaint of anuria. We also discuss how fluorosis and how lack of family support crippled this man.
CASE:
PATIENT HISTORY: The patient was a toddy climber by profession. In the year 2002 patient visited a physician due to colicky pain which was diffuse throughout the anterior abdominal wall, with radiation to
his back. The pain was exacerbated by walking and relieved with rest. He was diagnosed with having renal calculi in the right kidney which was operated on and removed. In the year 2007, he fell while climbing a toddy tree and fractured the shaft of his right femur for which ORIF was done. After that he used to walk with support for a few months, then he became normal again but gave up toddy climbing. In the year 2012, he fractured his tibia for which no treatment was done. Later in the year 2012 patient once had a feeling of lightheadedness or dizziness, for which he visited a local physician and was diagnosed with hypertension Since then on regular medication( tab. Ampong 5mg PO/OD) for the same. In the year 2013, he fell in his home and fractured his hip joint for which again no treatment was done. From then onwards he is unable to walk even with support and is bedridden. Gradually, he c/o pain and stiffness in his knee joints which further compelled him to reduce trying to move his joints. In the year 2015 patient developed FIXED FLEXION DEFORMITY grade III of both knees with bilateral knee pain. He started smoking at the age of 25 years and used to smoke 9 bidis/day but stopped 15 years ago due to family pressure and deteriorating health. History of occasional alcohol consumption. He had stopped drinking bore water in 2012 after public awareness program by Govt.
On 02.02.22 a 65-year-old man visited our hospital in Narketpally, Nalgonda with complaints of anuria since 12pm 01.02.22, with c/o urinary urgency and incomplete voiding of urine, along with the sudden onset of shortness of breath grade 2, paroxysmal nocturnal dyspnea -ve, orthopnea -ve, no chest pain. He complains of decreased appetite in the last few weeks, irregular bowel since last month, a burning sensation since last few days, and abnormal micturition since 1 wk.
FAMILY HISTORY: It was noted that his wife is also suffering from fixed flexion deformity though with no known history of renal caliculi or some noteworthy problem. We also took into account the fact that his attendant(son) reported that many old people from their community are suffering from fixed flexion deformity.
GENERAL EXAMINATION AT THE TIME OF ADMISSION: The patient is conscious, coherent, cooperative, well oriented to time, place, person. Signs of pallor and pedal edema are present. Mild fever spike. No icterus, cyanosis, clubbing, lymphadenopathy was seen. Both his knees were flexed and at 90 degrees which he was unable to extend, making him unable to move without a wheelchair. Signs of dental enamel molting. His neck was floating midway in the air as if someone kept an imaginary pillow below his head. He is unable to rest his head on the bed and complained of immobility, stiffness, and pain while trying to do any kind of neck movement. The attendant said he has been bedridden like that for the past 10 years.
VITALS :-
TEMPERATURE - 98.6 F
PULSE - 100 BPM
RR - 16 CPM
BP - 160/90 mmHg
spO2 - 98 % @ ROOM AIR
GRBS: 106mg/dl
CVS - S1S2 heard, no murmurs, Apex beat heard over 6th ICS 2cm outside midclavicular line.
CNS - Intact
RS:- Dyspnea present; BREATH SOUNDS - Vesicular; B/L IAA, ISA crept present
PER ABDOMEN: soft, non-tender
CHIEF COMPLAINT: c/o anuria since the day before admission
TREATMENT HISTORY: Tab. Amlong 5 mg PO/OD continuing, Sx for renal calculi, Sx for femur fracture.
TESTS PERFORMED:
ECG report showed little sinus tachycardia.
NCCT - KUB(PLAIN): i) Bilateral ureteric calculi causing moderate hydroureteronephrosis
ii) Vesical calculi with diffuse wall thickening
iii) Left renal calculi 4mm size
iv) Minimal bilateral perinephric fat stranding
v) Prostatomegaly
vi) Diffuse bony sclerosis of visualized bones likely suggestive of renal osteodystrophy
RFT :
Test Result Normal Range
- Urea #58mg/dl 17 - 50
- Creatinine #3.0mg/dl 08 - 1.3
- Uric acid 6.3mg/dl 3.5 - 7.2
- Calcium #7.8mg/dl 8.6 - 10.2
- Phosphorus 2.9mg/dl 2.5 - 4.5
- Sodium 144mEq/L 136 - 145
- Potassium 3.7mEq/L 3.5 - 5.1
- Chloride 99mEq/L 98 - 107
HAEMOGRAM :
Test Result Normal Range
- Hb #7.4gm/dl 13.0 - 17.0
- TC 6,900cells/cumm 4000 - 10000
- Neutrophils 65% 40 - 80
- Lymphocytes #19% 20 - 40
- Eosinophils 06% 01 - 06
- Monocytes 10% 02 - 10
- Basophils 00% 0 - 2
- PCV #23.1vol% 40 - 50
- MCV 86.8ft 83 - 101
- MCH 27.8pg 27 - 32
- MCHC 32.0 31.5 - 34.5
- RDW-CV #15.0% 11.6 - 14.0
- RDW-SD 47.9fl 39.0 - 46.0
- RBC count #2.66millions/cumm 4.5 - 5.5
- Platelet count 1.79lakhs/cu.mm 1.5 - 4.1
i) RBC - normocytic normochromic
ii) WBC - within normal limits
iii) Platelets - Adequate in no. and distribution
iv) Hemoparasites - No hemoparasites seen
v) Impression - Normocytic normochromic anemia
URINARY PROTEIN(24 hrs) :
Test Result Normal Range
- 24 hrs urinary protein 454.7mg/day <150mg/day
- 24 hrs urine volume 1,800ml
COMPLETE URINE EXAMINATION(CUE)
Test Result Normal Range
- Colour Pale Yellow Pale Yellow
- Appearance Clear Clear
- Reaction Acidic 5.0 - 9.0
- SP Gravity 1.010 1.001 - 1.035
- Albumin + Negative
- Sugar Nil Negative
- Bile salts Nil Negative
- Bile Pigments Nil Negative
- Pus cells 1 - 2 0-5/HPF
- Epithelial Cells 3 - 4 0-5/HPF
- RBCs 2 - 3 0-2/HPF
- Crystals Nil Nil
- Casts Nil Nil
- Amorphous Deposits Absent Nil
- Others Nil Nil
USG REPORT:
i) B/L gross HUN
ii) B/L grade II RPD
iii) Left renal calculi
iv) Increased texture of kidneys
CHEST X - RAY REPORT
PROVISIONAL DIAGNOSIS: AKI secondary to? Acute urinary retention
TREATMENT:
DAY - 1
IV FLUIDS 2 U NS & 2 U RL @ 100 ML / HR
INJ LASIX 40 MG IV / BD ( indication - excess fluid buildup due to LVF )
INJ PAN 40 MG IV / OD
Nebulization with Duolin and Budecorct 8th hourly( indication - mild URTI )
DAY - 2
S: One session of hemodialysis ( indication of dialysis - anuria )
0: TEMP - Afebrile
BP - 130/90 mmHg
PULSE -86 bpm
RR - 20 CPM SPO2 98% @ RA
CVS -S1S2+, NO MURMURS
RS - BAE +
PA - SOFT, NON TENDER
A: AKI ON CKD??? WITH LEFT RENAL CALCULUS SIZE 4MM B/L HYDRONEPHROSIS
P:
1) Inj. AUGMENTIN 500mg / IV/BP
2) Inj. LASIX 40mg/IV/BD
3) ORAL FLUIDS ~2L.
4) Inj. PAN 40mg /IV/OD
5) Neb with DUOLIN & Budecort 8th hourly
6) Tab. AMLONG 5mg PO/OD
STRICT I/O CHARTING
DAY 3
S: Urine output increased -1700ml
O: ONE SESSION OF HEMODIALYSIS DONE ON 3/02/2022
TEMP - Afebrile
BP - 130/90 mmHg Pulse 82 BPM
RR - 20 CPM
SPO2 - 98% @ RA
CVS - S1S2+, no murmurs
RS - BAE +
PA - soft, non-tender
A: Acute Kidney Injury?? secondary to Benign Prostatic Hyperplasia? urethral stricture? with left renal calculi size 4mm B/L hydronephrosis
P
1) Inj. Meropenem 500mg / IV/BD
2) Inj. LASIX 40mg/IV/BD
3 ORAL FLUIDS ~2L.
4) Inj. PAN? 40mg /IV/OD
5) Nebulisation with Duolin & Budecort 8th hourly
6) Tab. Amlong 5mg PO/OD
STRICT VO CHARTING
DAY - 4
S: Urineoutput Improved, No fresh Complaints
0: ONE SESSION OF HAEMODIALYSIS WAS YESTERDAY (Total - 2 Dialysis )
TEMP - AFEBRILE
BP - 130/70 MMHG
PULSE - 96 BPM
CVS -S1S2+, NO MURMURS
RS - BAE +
PA - SOFT, NON TENDER
A: PostRenal AKI Secondary to B/L Ureteric Calculi
- Moderate Hydrouretero Nephrosis with left Renal Calculi
P :
1) Inj. Meropenem 500mg IV/BD
2) Inj. LASIX 40mg/IV/BD
3 ORAL FLUIDS ~2L.
4) Inj. PAN 40mg /IV/OD
5) Neb with DUOLIN & Budecort 8th hourly
6) Tab. AMLONG 5mg PO/OD
Strict Input-output charting
DAY - 5
S: Urine output Improved, Patient complaining Of Loss Of Appetite, No Fever Spikes
0 : Haemodialysis (Total - 2 Dialysis ) .
Output - 1800ml
Input - 1600ml
TEMP - Afibrile
BP - 130/80 mmhg
PULSE - 96 BPM
CVS -S1S2+, no murmurs
RS - BAE +
PA - Soft, non-tender
A: PostRenal Acute kidney injury Secondary to B/L Ureteric Calculi and Bladder Calculi
- Moderate Hydrouretero Nephrosis with left Renal Calculi
- Ossification of the Posterior longitudinal ligament / Diffuse idiopathic skeletal hyperostosis
P:
1) Inj. Meropenem 500mg IV/BD
2) Inj. LASIX 40mg IV/BD
3 ORAL FLUIDS ~2L
4) Tab. AMLONG 5mg PO/OD
Strict Input-output charting
FINAL DIAGNOSIS: i) Postrenal Acute Kidney injury secondary to B/L ureteric calculi and bladder calculi
ii) Moderate hydroureteronephrosis with left renal calculi. iii) Ossification of the Posterior longitudinal ligament / Diffuse idiopathic skeletal hyperostosis
COMMENT: The patient was recommended Sx to remove renal, ureteric, and bladder stones, but we were not given consent by the patient's attendant. The patient was discharged after treating his chief complaint of anuria.
CASE DISCUSSION :
As we can see this patient is suffering from recurrent renal stones, multiple fractures( indicating weakness of his bones ) from time to time, so in this discussion, we will try to find if there is any correlation between his recurrent renal stones, weak and brittle bones and whether fluorosis can lead to all these problems by gathering and reviewing various articles.
First what lead us to suspect chronic fluorosis?
The patient complains of neck ache, stiffness, rigidity, generalized skeletal discomfort, fixed flexion deformity of his knee joints leading to restricted movement with associated gastric complaints and
hails from areas endemic to fluorosis. History of multiple fractures indicating weakness of bones.
Skeletal Fluorosis should be strongly suspected in any person with
features of stiffness, rigidity, restricted movements at the spine and joints,
bone and joint pains, and who has been residing continuously for >6 months in
a fluorosis-endemic area. The clinical investigations for the
confirmation of the diagnosis include the following:
- Haemoglobin%: Anaemia due to reduced erythropoietin activity secondary to fluorosis induced osteosclerosis of medullary cavities (In our patient Hb - 7.4gm/dl, RBC - 2.66 million/cumm)
- Renal function tests: These may show impaired urea clearance, decreased glomerular filtration rate, increased blood urea nitrogen (In our patient urea - 58 mg/dl)
- Radiographic features: Increased bony density(osteosclerosis) compact bone thickening, bamboo spine(ankylosing spondylitis), periosteal bone formation. ossification of the attachments of tendons, ligaments, ossification of the post. longitudinal ligament. All of which was seen in our patient.
So, how can chronic fluorosis lead to fractures?
What we learned via reviewing literature...
Prolonged
ingestion of fluoride through drinking water, in excess of the daily
requirement of 1.5 mg/L as the upper limit (as set by the WHO) is associated with
dental and skeletal fluorosis. Signs of skeletal fluorosis become evident on the consumption of 8–10 ppm of fluoride in drinking water for approximately 10
years or more. Our patient is residing in a fluorosis endemic area and had been drinking bore water since birth, only stopping 10 years back.
Vague, diffuse aches, muscle weakness,
chronic fatigue, and stiffness of joints with decreased range of motion are
common initial symptoms. These symptoms may be dismissed as
functional but may, in fact, be early signs of fluoride damage to tendinous
insertions and ligaments as well as joint capsules. During later stages, calcification of the
bones takes place, osteoporosis in long bones, and symptoms of osteosclerosis
where the bones become denser and develop abnormal crystalline structure. In advanced stages, bones and joints become
weak rendering movement difficult and painful. Fusion of vertebrae is observed
in many areas of the spine. The greatest changes are observed in the
spine, particularly in the cervical region. Kyphosis with limited
spinal mobility, flexion contracture of lower extremities, and restricted chest
wall expansion occur. The “Poker back” spine (kyphosis) is a late
manifestation of skeletal fluorosis wherein the entire spine becomes one
continuous column of bone. In the final stage, the patient is left
crippled. The main mechanism
of skeletal fluorosis is the fluoride incorporation into the bone
hydroxy-apatite, altering the size and structure of its crystals. The
fluorapatite formed decreases the mechanical competence of the bone, resulting
in abnormal structure and poor quality of bone with an increased risk of fractures.
Diving a bit deeper...
Fluoride can
demonstrate biphasic actions (i.e., mitogenic at low concentrations and toxic at
higher concentrations). Fluoride
inhibits a unique fluoride‐sensitive phosphotyrosine phosphatase (PTP) in osteoblasts,
which results in a sustained increase in the tyrosine phosphorylation level of
the key signaling proteins of the MAPK mitogenic transduction pathway, leading
to the potentiation of the bone cell proliferation initiated by growth factors. The fluoride acts in coordination with aluminum to form fluoroaluminate, which
activates a pertussis toxin‐sensitive Gi/o protein on the bone cell membrane, leading to activation of cellular protein tyrosine kinases (PTKs), which in turn leads to
increases in the tyrosine phosphorylation of signaling proteins of the MAPK
mitogenic signal transduction pathway, ultimately leading to a stimulation of
cell proliferation.
The main mechanism
of skeletal fluorosis is the fluoride incorporation into the bone
hydroxy-apatite, altering the size and structure of its crystals. The
fluorapatite formed decreases the mechanical competence of the bone, resulting
in abnormal structure and poor quality of bone with an increased risk of fractures.
Diving a bit deeper...
Fluoride can act
on osteoblasts and osteoclasts in vivo and in vitro. NaF is an anabolic agent capable of increasing
bone mass, although the mechanism for its action remains unclear. While NaF may
increase bone mass, the newly formed bone appears to lack normal structure and
strength. In trabecular bone, fluoride results in an increase in bone volume
and trabecular thickness without a concomitant increase in trabecular
connectivity. It is this lack of trabecular connectivity that reduces bone
quality despite the increase in bone mass.
All of these explain how fluorosis leads to his skeletal deformity.
Our next question...Can fluorosis somehow increase the chance of renal stone formation?
What we learned from various articles...
The World Health Organization is acutely aware
that fluoride is a kidney toxin, recently citing the finding that approximately
100,000 individuals in the Assam region in India have been taken ill with kidney failure, stiff joints, and anemia as a result of high
natural levels of fluoride in the water [WHO 2015]. Similar results have been
found in other parts of India [Hindu 2017] and Sri Lanka [Dharmaratne 2015].
Among major adverse effects on the kidneys from excessive consumption of fluoride are
•
immediate effects on the tubular area of the kidneys, inhibiting the tubular reabsorption;
•
changes in urinary ion excretion by the kidneys
•
disruption of collagen biosynthesis in the body, causing damage to the kidneys and other organs; and
•
inhibition of kidney enzymes, affecting the functioning of enzyme pathways.
In another research, 20 urinary stones were taken from patients at a Russian hospital with ion chromatography and conductivity detection. They detected fluoride ions in 80% of the stones, at concentrations of 0.01–4.0mg per gram of stone.
The vast majority of the stones contained very small concentrations of fluorides, below 0.1mg per gram of stone, but two of the stones had fluoride concentrations above 0.5mg. This indicates that the formation of these stones may have been promoted by high concentrations of fluorides in the patients’ urine, perhaps due to the patients ingesting lots of water containing added fluoride or even lots of fluoride toothpaste.[“In our previous experiment using rats, fluoride was reported to cause renal calcification, whose mechanism was deduced to be due to an increase in parathyroid hormone (PTH) secretion. However fluoride-induced renal calcification that was independent of PTH has not been understood well in the nephron of fluoride-treated animals. Thus, we examined the effect of sodium fluoride on intracellular calcium mobilization in a normal rat kidney epithelial cell line (NRK-52E cells). The calcium accumulation was found to be remarkably increased by the addition of sodium fluoride (NaF). The elevation of [Ca2+]i was demonstrated to be due to calcium entry through nifedipine-sensitive calcium channels.”
SOURCE: Murao H, et al. (2000). Sodium fluoride increases intracellular calcium in rat renal epithelial cell line NRK-52E.Biol Pharm Bull. 23(5):581-4.]
This study shows that there was no
association at higher concentrations, and the test of trend indicated a linear trend was not
present.In another investigation, a case-controlled study was conducted on 824 school children aged 8–15 years, where drinking water
was contaminated with fluoride. This study showed chronic kidney damage to be higher in the affected
children, other than fluorosis, and significantly higher urinary fluoride as
compared to the control area children.Another cross-sectional study conducted on
239 adults (18–77 years old) by monitoring four early kidney injury biomarkers
(ALB, Cys-C, KIM-1, and OPN) related to environmental fluoride exposure,
indicated possible tubular dysfunction due to fluoride exposure, that might
increase susceptibility to the future development of CKD.
The vast majority of the stones contained very small concentrations of fluorides, below 0.1mg per gram of stone, but two of the stones had fluoride concentrations above 0.5mg. This indicates that the formation of these stones may have been promoted by high concentrations of fluorides in the patients’ urine, perhaps due to the patients ingesting lots of water containing added fluoride or even lots of fluoride toothpaste.
SOURCE: Murao H, et al. (2000). Sodium fluoride increases intracellular calcium in rat renal epithelial cell line NRK-52E.Biol Pharm Bull. 23(5):581-4.]
This study shows that there was no association at higher concentrations, and the test of trend indicated a linear trend was not present.
After going through these articles we conclude that high fluoride can act as a predisposing factor for renal stones.
CONCLUSION: Our patient emphasizes the importance of considering fluoride as an explanation for osteosclerosis and in diagnosing skeletal fluorosis especially in those who are at high risk from environmental or occupational exposure. Data gathered from different sources do suggest that fluoride may behave as a mild promoter of urinary stone formation by (a) excretion of insoluble calcium fluoride, (b) increasing oxalate excretion, and (c) mildly increasing the oxidative burden, although more extensive research needs to be done to consolidate the fact and understand it's mechanism.
MY EXPERIENCE AS AN ELECTIVE STUDENT:
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