1. A 35-year-old man with CKD 5 received a kidney transplant 5 weeks ago. He is on triple immunosuppression (CNI-based). Excellent kidney function on discharge (S Cr 98 µmol/L). He was given simvastatin 40 mg OD as a treatment of hypercholesterolaemia. Shortly after commencing simvastatin, he noticed a change of the colour of urine (coca-cola-like, see below on the right compared to the control on the left) and generalised musculoskeletal pain and tenderness. This was also associated with deterioration of the kidney function (s Cr 123 µmol/L).
- What is your working diagnosis?
- What are the investigations required to confirm your diagnosis?
- Explain the link between his medications and this condition?
Dear All
We need to address the management plan of this case.
Also, what is the preferable statin in the transplant population?
Do you think that simvastatin was the best statin?
What statin do you use for CKD and renal transplant patients at your workplace?
It’s a case of drug induced Rhabdomyolysis. Mostly induce by Statin effect on the myocytes, as its blood level is reaching a toxic level due to the inhibitory effect on the hepatic enzyme CYP3A4 by CNI.
serum and urine myoglobin measurement are mandatory to confirm the diagnosis.
Rhabdomyolysis associated AKI is a commonly encountered basically secondary to ATN and vasoconstrictive effect of the myoglobin, which is usually impacting the tubules after overwhelming the capacity of Megaline and Tubulin receptors in proximal segments of the nephrons, Making tubular casts by binding to tubular protein Tom-Horsfall protein
Risk factors:
Higher doses of Statins
Hypothyroidism.
Vitamin D deficiency.
CNI, particularly Cyclosporin.
Management:
Acute management is to stop Statin medication, and over-diuresis of the patient with normal saline 500 ml/hour, to reduce the concentration of the myoglobine in tubular fluid and prevent further damage induced by the sheer amount of the filtered myoglobine.
sodium bicarbonate might be effective as well.
novel medications that prevent the binding of Myoglobin and Tom-Horsfall protein might be useful as well.
Long term strategy:
To use Statin which is not utilizing CYP3A4 such as Fluvastatine and Pravastatine. Furthermore, they are associated with lesser risk on the inducing Rhabdomyolysis.
On the other hand, switching Cyclosporin to Tacrolimus is linked to a lesser risk of Rhabdomyolysis.
If hyperlipidemia is still reported then starting small doses of Rosuvastatin 5 mg, Atorvastatin 10 with close monitoring of the CPK is the norm.
In our practice, Pravastatin, is the statin recommended as first line of therapy, however, its failed in most of the times to control the hyperlipidemia triggered by the immunosuppressant, therefore switching to Atorvastatin or Rosuvastatin escalating dose, with monitoring of CPK is common practice.
Reference:
Statins: Actions, side effects, and administration
Robert S Rosenson, Statins: Actions, side effects, and administration.www.uptodate.org
Hi Dr Jebur,
I like your scientific contents. When you type headings and sub-headings, please type in bold or underline so that it is easier to read your write-up.
Dear Professor,
In our institute:
For Post Transplant Patients:
HI Dr Vali,
It is so nice to see you referring to your own institutional experience.
We need to address the management plan of this case.
Also, what is the preferable statin in the transplant population?
Rosuvastatin (Crestor) is one of the most potent statins and is currently widely prescribed.
Do you think that simvastatin was the best statin?
What statin do you use for CKD and renal transplant patients at your workplace?
I like your logical approach and well structured reply. Ajay
Thanks alot for you Prof Sharma
atorvastatin, simvastatin, and lovastatin are not used in CKD and transplant patients
but pravastatin, fluvastatin, and rosuvastatin are used safely because they are not metabolized by 3A4 isoenzymes
simvastatin was not a good option
management plan
1- stop statin
2- management of AKI fluid challenge
3-if there is any clinical indications or lab indications for dialysis we should proceed
4-if cyclosporine given , need to be stopped and replaced by tacrolimus and adjusted according to serum creatinine level
5-we can use methylprednisolone as a cover to avoid any risk of acute rejection which may associated due to inadequate immunosuppressive doses
6-after recovery, cardiology consultation for treatment of hypercholesterolemia by safe type of statin
Patrick A. Torres, John A. Helmstetter, Adam M. Kaye, Alan David Kaye. Rhabdomyolysis: Pathogenesis, Diagnosis, and Treatment. Ochsner J. 2015 Spring; 15(1): 58–69.
Thankyou Riham but remember that Tac. is metabolized by the same enzyme so using another statin as Fluvastatin which is metabolized byCYP2c9 is a better choice.
Diagnosis :
Most probably is statin induced rhabdomyolysis with AKI
2. To confirm diagnosis:
• CK , ALT , AST
• Serum K , phosphorus , uric acid
3. The relation to the current medications:
Simvastatin interact with CNI especially cyclosporine and compete on hepatic CYT p enzyme especially when using simvastatin with large dose
Management:
-stop simvastatin
-good hydration 1-2 lit/ hour maintaining Uop 200-300 ml /hour
-alkalinization with sodium bicarbonate
-The best drugs used as lipid lowering
rosuvastatin ( crestor)
Flavastatin , pravastatin
we can change cyclosporine to Tacrolimus
First of all, stop simvastatin.
For patients with rhabdomyolysis, initiate isotonic saline at a rate of 1 to 2 L/hour. The rate is adjusted to target a goal urine output of approximately 200 to 300 mL/hour while avoiding volume overload.
For patients with severe rhabdomyolysis in whom a diuresis has been established with volume administration, IV sodium bicarbonate infusion can be given.
Also, what is the preferable statin in the transplant population?
Fluvastatin 40 mg daily. But we can use any drug with adjusted dose like:
•Fluvastatin 40 mg daily
•Atorvastatin 10 mg daily
•Rosuvastatin 5 mg daily
•Pravastatin 20 mg daily
•Simvastatin 20 mg daily
Do you think that simvastatin was the best statin?
No. It is not preferable drug with cyclosporin, or it should be given in lower dose
What statin do you use for CKD and renal transplant patients at your workplace?
We usually use Atorvastatin
https://www.uptodate.com/contents/prevention-and-treatment-of-heme-pigment-induced-acute-kidney-injury-including-rhabdomyolysis?search=rhabdomyolysis%20treatment&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H25399035:~:text=Prevention%20and%20treatment,MD%2C%20MSc%2C%20FASN
https://www.uptodate.com/contents/statin-muscle-related-adverse-events?search=simvastatin%20interaction%20with%20cyclosporin&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3#:~:text=Statin%20muscle%2Drelated,Givens%2C%20MD%2C%20MSCE
Thankyou
We need to address the management plan of this case.
Also, what is the preferable statin in the transplant population?
Do you think that simvastatin was the best statin?
What statin do you use for CKD and renal transplant patients at your workplace?
Thankyou
Management plan of this case:
first stop the statin continue other treatment plan, IV hydration with N/S at a rate of 1-2 L/hr to keep urine out put 200-300 ml/hr. then the fluid should be tiutrated accordingly avoiding volume overload, then diuretic could be employed. IV isotonic bicarbonate can be used to keep urine ph>6.5 in some cases.
hypocalcemia should not be corrected until it became symptomatic, hyperkalemia management with kayexalate , hyperurecemia if uric acid > 8mg/dl with allopurinol 300 mg.
what is the preferable statin in the transplant population?
Pravastatin, Pitavastatin, Fluvastatin and Rosuvastatin are the preferable statins in kidney transplant patients.
However Rosuvastatin is usualy not used as it has recently been associated with proteinuria and renal failure at higher doses from the FDA, which is of concer in post kidney transplant recipient.
Do you think that simvastatin was the best statin?
No, it has a high drug-drug interaction index
What statin do you use for CKD and renal transplant patients at your workplace?
We use Atorvastatin in low dose for our CKD patients, in transplanted patients we usauly do not start statin until not controlled lipid profile with life style modification and not before the 6th month post transplantation.
References:
UpToDate-
Riella LV, Gabardi S, Chandraker A. Dyslipidemia and its therapeutic challenges in renal transplantation. Am J Transplant. 2012 Aug;12(8):1975-82. doi: 10.1111/j.1600-6143.2012.04084.x. Epub 2012 May 11. PMID: 22578270.
Can you elaborate more on Rusovastatin (creator),?proteinuria and CKF!
Shin JI, Fine DM, Sang Y, Surapaneni A, Dunning SC, Inker LA, Nolin TD, Chang AR, Grams ME. Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria. J Am Soc Nephrol. 2022 Jul 19;33(9):1767–77. doi: 10.1681/ASN.2022020135. Epub ahead of print. PMID: 35853713; PMCID: PMC9529194.
In my country pravastatin used to treat high cholesterol level.
References:
Thank you
Well done
Thnxs prof
Management:
The preferable statin in renal transplant patients is pravastatin, as it is the only statin that is not metabolised by the cytochrome P450 system, so no risk of interaction with CNI.
Simvastatin is not a good choice to renal transplant patients as it is subjected to drug-drug interaction.
At my institution, we usually use Atorvastatin.
Very good
thanks
Simvastatin is known to have the highest incidence of rhabdomyolysis. So simvastatin would not have been the best choice for a statin for this patient.
Use of hydrophilic statins like pravastatin and Rosuvastatin has been associated with a lower incidence of rhabdomyolysis. Pravastatin has been associated with the least incidence of rhabdomyolysis. However, it is not a very potent statin.
For this patient we can use rosuvastatin.
Atorvastatin inhibits CNI metabolism and can increase the levels of the CNIs and the CNIs can also increase the levels of atorvastatin – therefore, if the patient is on atorvastatin and CNIs the CNI levels must be carefully monitored and the patient advised that if he develops myalgias he should come to the hospital immediately
For CKD patients we use atorvastatin after a recent study showed an increase in proteinuria in CKD patients using high dose rosuvastatin
Thankyou can you have a reference for rouvastatin and proteinuria?
Thank you Professor
The reference is:
JASN September 2022, 33 (9) 1767-1777
Thankyou Hussein I went through it but 2 points:
dose was 40 mg!!!
GFR was<30
the usual dose is 10/20.
Management plan
Discontinue simvastatin or reduce dosage to 50% , i.e., 20 mg in this patient.
Check activity of AST and ALT, and CK when restarting statin therapy
Change to different statin – recommendations include atorvastatin and fluvastatin.
Educate patient about their symptoms and the relation with drug so that they can report if any reactions occur further.
Preferable statin
CKD patients statin
We commonly use Atorvastatin at our centre.
References
Thankyou
The managing in this case it discontinuing the medications which are causing the side effects. The simvastatin must be discontinued.
Once the cause has been eliminated then a positive response must be seen but the patient must be continued with fluid therapy to try to achieve a urine output of about 200 ml/hour. The fluid preferable is the saline solution.
The blood test must be done to monitor the kidney function to see if the AKI is improving.
All other nephrotoxic medications must be adjusted and those with no vital importance should be discontinued.
Simvastatin is not the best statin and there are others that are superior and they are rosuvastatin and Lipitor
The preferable statin that can be used is atorvastatin, rosuvastatin, Fluvastatin, and pravastatin.
The statin that is used in patients with CKD more frequently is atorvastatin. Crestor is available but a bit costlier. Simvastatin is also used but at a lower scale.
Thank you
_ preferable statin is pravastatin or rusovastatin. Or at least use atorvastatin with small dose 10_20 mg/day with close monitoring of CNI trough level and development of rhabdomyolysis side effect.
_ simvastatin is not the preferred option, especially on such very high dose 40 mg !!
_ at our hospital, we use atorvastatin 10 mg for most of cases, except when receiving cyclosporin we use rosuvastatin.
_ pravastatin is best option with CNI combination, but unfortunately not available in Egypt
Thank you
Management is stop statin and good hydration and alkalization of urine and dialysis
atorvastatin improved GFR in patients with CHD ( according to studies), and rosuvastatin
Thank you
lipid abnormalities are frequent after kidney transplantation. With Cyclosporin, the interaction of statins is frequent. CysA increases the level of nearly all statins as they all share the same pathway ( simvastatin, atorvastatin, and lovastatin are metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) enzyme system). On the other hand, clearance of pravastatin, fluvastatin, and rosuvastatin do not rely upon CYP3A4. still, CysA increases their level.
After Tacrolimus, the interaction was found to be less.
The patient is probably on Cyclosporin, so simvastatin was not a good option. We need to change to Tacrolimus if on Cyclosporin.
(https://www.uptodate.com/contents/kidney-transplantation-in-adults-lipid-abnormalities-after-kidney-transplantation?search=lipid%20renal%20transplantation&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H2127895739)
For CKD, controversy is present. In patients on Hd, generally, drugs are continued but not first initiated (based on data from 4D and aurora) but in general, in predialysis patients, drugs are started with dose reduction. Atorvastatin 20 mg, rosuvastatin 10 mg (in normal population or in stage 1-2 CKD normal dose is up to 80 for atorvastatin and 10 mg for Rosuvastatin)
the detailed dose can be seen in the table: (https://www.uptodate.com/contents/lipid-management-in-patients-with-nondialysis-chronic-kidney-disease?search=statins-and-chronic-kidney-disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1)
Thank you
The following 3 factors may help us in the decision when using statin in CKD especially in the setting of transplantation
First is renal drug clearance, and renal dose adjustment
Second the effect of statin on renal functions and proteinuria
Third is the metabolism by CYP 3A4 (CNI drug-drug interactions)
Conclusion
References
1. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385:351.
2. Frayling TM. Statins and type 2 diabetes: genetic studies on target. Lancet 2015; 385:310.
3. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Int Suppl 2013; 3:263.
4. de Zeeuw D, Anzalone DA, Cain VA, et al. Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial. Lancet Diabetes Endocrinol 2015; 3:181.
5. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation 2005; 111:3051.
6. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012; 126:617.
-Initial treatment for rhabdomyolysis is aggressive isotonic fluid administration to facilitate myoglobin clearance, but adequate kidney function will be needed to clear pigment and associated intracellular contents in the urine.
-Concurrent treatment with statins and CNI, particularly cyclosporine, should be conducted with caution with lower doses of statins due to rhabdomyolysis high risk Tacrolimus drug-drug interactions are less severe and less common in comparison with cyclosporine.
-Since simvastatin and cyclosporine are metabolised both through the cytochrome P 450 3 A4 pathway thereby causing rhabdomyolysis .
Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by different cytochromes and they rarely get into drug-drug interaction so can be used.
Ezetimibe as an alternative in the case of statin intolerance on the inability to
reach a therapeutic dose.
PCSK9 Inhibitors, Inclisiran, Bempedoic Acid are newly introduced drugs to reduce LDL ,C
Reference
-Chmielnicka, K.; Heleniak, Z.; Dębska-Ślizień, A Dyslipidemia in Renal Transplant Recipients,Transplantology 2022, 3, 188–199
Management plan:
Stop Simvastatin first.
I.v fluid to maintain hydration and wash out of myoglobin.
Short term dialysis may require
Atorvastatin, Rosuvastatin are preferable.
No, I think no.
At our workplace, we usually practice Atorvastatin and Rosuvastatin.
Management of rhabdomylosis and AKI :
-stop the cause ( medication ) and search for safe alternative
-IV hydration 1-2 L/day
-if any electrolytes disturbance to treat medically or if dialysis needed
What statin do you use for CKD and renal transplant patients :
In literatures other statins used are : rosuvastatin , flavastatin
plan of management?
first intravenous fluid normal saline 1.5 liters per hour to maintain 200 ml/hour urine output .alkalization of urine keeps urine PH more than 6.5.
preferable statins are rosuvastatin or atorvastatin.
simvastatin is not a good option.
in our center we use rosuvastatin
Management includes discontinuing the simvastatin. Fluid therapy with 1-2-liter normal saline per hour is recommended to create 200 ml urine output per hour. Urinary alkalization by sodium bicarbonate infusion is helpful.
Preferable statins are pravastatin and fluvatatin. Simvastatin is not the best option.
We usually use atorvastatin 10-20 mg/day because of cost and availability.
1- We need to address the management plan of this case.
Rhabdomyolysis management :
1) Assess the ABCs (A irway, B reathing, C irculation),
2) provide supportive care as needed.
3) Ensure adequate hydration, and record urine output.
4) Insert a Foley catheter for careful monitoring of urine output.
5) Identify and correct the inciting cause of rhabdomyolysis (eg, toxins- statin ).
recommendations for the treatment include:
1) Fluid resuscitation.
2) Prevention of end-organ complications ( acute renal failure [ARF]).
3) Other supportive measures include correction of electrolyte imbalances.
4) Obtain an ECG to monitor effects of hyperkalemia and other electrolyte disturbances.
Serial physical examinations and laboratory studies are indicated to monitor for compartment syndrome, hyperkalemia, acute oliguric or nonoliguric renal failure, and disseminated intravascular coagulation (DIC).
2- Also, what is the preferable statin in the transplant population?
The preferable statin in transplant patients are pravastatin and rosuvastatin.
3- Do you think that simvastatin was the best statin?
No it is not the best choice as it is not the preferred statin in kidney transplantation.
4- What statin do you use for CKD and renal transplant patients at your workplace?
Atorvastatin in CKD patient and rousuvastatin in transplant patient .
What is your working diagnosis?
This is a drug related rahbdomylsis. It occurs after statin therapy frequently
What are the investigations required to confirm your diagnosis?
To confirm:
Myoglobin in urine
In urine analysis: it gives positive dipstick in absence of RBCs in urine microscopy
Electrolytes: potassium and uric acid and low calcium
Explain the link between his medications and this condition?
The link is the use of Cytochrome inhibitor (C3A4) (Cyclosporine) with simvastatin in high dose
the management plan:
stop the offending drugs
revise the trough level of cyclosporine
hydration (with urine output target 2ml/kg/ hour)
urine alkalinaization
cation for electrolytes
use of other statins i.e., pravastatin or other new drugs PCS inhibitors
Also, what is the preferable statin in the transplant population?
rosuvastatin or pravavstatin
Do you think that simvastatin was the best statin?
no it is one of the most associated with rhabdomyolysis
What statin do you use for CKD and renal transplant patients at your workplace?
rosuvastatin or atorvaststin
The main hypothesis is rhabdomyolysis due to the use of simvastatin, or even increased serum concentration of cyclosporine leading to acute kidney injury.
Cyclosporine dosage is necessary to assess whether it could be an adverse effect. However, what happened is probably related to simvastatin promoting rhabdomyolysis. It is necessary to measure creatine kinase, liver enzymes. We can perform renal USG to assess acute kidney injury.
There are few studies, but the drug interaction between cyclosporine and statins is already known in the sense of causing an increase in the plasma concentration of statins and also their metabolites, although the opposite may exist (increase in the concentration of cyclosporine and its metabolites), but in smaller proportion.
This interaction happens because both drugs are metabolised by cytochrome P450 (CYP)3A4.
REFERENCES:
– Asberg A. Interaction between cyclosporine and lipid-lowering drugs. Drugs 2003;63:367-78
– Muck W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999;65:251-61
– Izar, Maria Cristina de Oliveira. Hypolipidemic treatment under special conditions: posttransplant and/or immunosupressive therapy. Arq. Bras. Cardiol. 85 (suppl 5) • Out 2005 • https://doi.org/10.1590/S0066-782X2005002400013
Diagnosis : AKI secondary to statin.
Investigations.
serum CK, VBG, Urine for myoglobulin. Urine microscopy.
Ultrasound doppler kidney graft
Management:
1) Hydration. Keep patient euvolumic.
2) Stop offending medications eg statin.
3) Avoid nephrotoxic medications.
4) Monitor renal profile.
Rhabdomyolysis
Ø Elevated CPK
Ø Myoglobinuria
Ø Electrolyte abnormalities: hyperkalemia (potassium levels may increase by >1.0 vs. 0.3 mmol/L/d from baseline compared with other nonhypercatabolic AKI), hyperphosphatemia (release from injured muscle cells), hypocalcemia (due to calcium phosphate deposition into injured muscles, reduced bone sensitivity to parathyroid hormone), hyperuricemia, and metabolic acidosis.
Ø Transaminitis (elevated intramyocyte aspartate aminotransferase [AST], alanine aminotransferase [ALT], LDH, and aldolase) in rhabdomyolysis, but not in hemolysis
Statin induce Rhabdomyolysis
The main step in management is stop the medication and hydration
Rhabdomyolysis caused by statins per se, or due to interaction with CNI
Urine dipstick positive for blood with no RBCs in microscopy
creatinine kinase>>> elevated>> mostly in thousands
electrolyte imbalance including hyperkalemia, hyperphosphatemia, hypocalcemia and hyperuricemia
elevated serum creatinine due to precipitation of myoglobin th tubules and direct toxic injury from myoglobin
simvastatin metabolism by CYP3A4, CNI is CYP3A4 inhibitor, concomitant use of both increase the level of simvastatin resulting in injury to skeletal muscle and release of myoglobin
it is supportive, including
1- stop the offending medication
2- fluid replacement maintaining high urine output
3- alkalization of urine with sodium bicarbonate
4- ECG monitoring with management of electrolyte imbalance mainly hyperkalemia
This is a case of drug induced Rhabdomyolysis .
The offending drug was statin which has a toxic effect on the myocytes when the drug level reaching the toxic level while using with the CNI’s that have an inhibitory effect on the hepatic enzyme.
Rhabdomyolysis cause AKI due to the damage effect of myoglobulin on the tubular cells.
The diagnosis is confirmed by serum and urine myoglobin measurement in edition to increased hepatic enzymes, high LDH, high CPK , hyperkalaemia , hyperphosphatemia , high Uric acid .
The risk factors include old age ,female sex , hypertension, hypothyroidism, low BMI.
Plan of management include:
This is a case of rhabdomyolysis caused by a CNI-simvastatin drug-drug interaction involving the same isoenzyme, CYP3A4. Urine color indicates myoglobinuria, and a recent increase in creatinine indicates AKI.(1)
Investigations to confirm the diagnosis:
Serum creatinine kinase: >5 times the upper limit of normal and usually greater than 5000 units/L
Urinalysis: suggestive of myoglobinuria
Other associated abnormalities:
Electrolyte abnormality: Hypocalcemia, hyperkalemia, hyperphosphatemia
LFTs:increase AST,ALT (non specific for muscle or liver injury) and normal GGT and bilirubin level (specific for liver injury)
Metabolism of statins:
CYP3A4 isoenzyme: simvastatin, atorvastatin, and lovastatin sharing a common metabolism pathway as CNI are particularly susceptible to drug-drug interactions with CNI, posing a risk of serum statin elevation and subsequent acute toxicities (2).
Alternative metabolic pathway: pravastatin, pitavastatin, fluvastatin and rosuvastatin do not carry a similar risk of drug–drug interactions with CNI (2).
Preferable statin in CKD: Atorvastatin
Preferable statin in kidney transplant recipient: Rosuvastatin
Management:
Stop Simvastatin
Promote diuresis with isotonic saline at a rate of 200 to 300ml/hr
Correct Hyperkalemia or hyperphosphatemia if present
Other Goals: Urine ph>6.5 and Blood ph<7.5
Reference:
Diagnosis : Statin-induced rhabdomyolysis,
Risk factor here is the using of CNI
co-administration of statin with CNI especially cyclosporin increase risk of rhabdomyolysis, as statin is metabolized by cytochrome P450CYP3A4 and CNI inhibit it causing increased level of statin
Not all statins
some statins ( atorvastatin, simvastatin and lovastatin) undergo phase one metabolism by cytochrome P450 3A4, while other statins ( pravastatin, fluvastatin and rosuvastatin) are not metabolized by 3A4 isoenzymes
Investigation
monitor the serum ck level , 5 times above the normal reference range
urine myoglobin will show erythrocyte positivity on urine dipstick because the orthotoluidine portion of the dipstick turns blue in the presence of myoglobin.
Management plan
1.Stopping of simvastatin and using one of (pravastatin, fluvastatin and rosuvastatin)2.Agressive hydration at rate 500 ml/h saline solution alternated every hour with 500 ml/h of 5% glucose solution with 50 mmol of sodium bicarbonate for each subsequent 2-3 L of solution.3.A urinary output goal is 200 ml/h , urine pH > 6.5 and plasma pH < 7.5.4.monitor level of Cyclosporine or shift to Tac
Torres PA, Helmstetter JA, Kaye AM, Kaye AD. Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J. 2015 Spring;15(1):58-69.
What is your working diagnosis?
Rhabdomyolysis secondary to statin therapy
What are the investigations required to confirm your diagnosis?
· Serum Creatine kinase
· Evidence of myoglobinuria through routine urine dipstick combined with microscopic examination of the urinary sediment.
· other enzymes indicative of muscle injury are typically elevated with rhabdomyolysis (eg, aldolase, aminotransferases, lactate dehydrogenase). (1)
Explain the link between his medications and this condition?
The greatest risk of developing a statin-related myopathy appears to be associated with taking concomitant other medications that interferes with statin metabolism, rendering the statin dose more toxic and thus increasing the risk of rhabdomyolysis. these include: fibrates, antifungals, macrolides, and fusidic acid. drugs that inhibit cytochrome p450-3A4 (CYP3A4), reduce the metabolism and consequently increase the serum concentration of CYP3A4-metabolized statins: Clarithromycin, Erythromycin,Telithromycin, Clotrimazole, Itraconazole, Fluconazole, Ketoconazole, Voriconazole, Atazanavir, Darunavir, Lopinavir, Ritonavir, Tipranavir, Diltiazem, Verapamil, Amiodarone, Ciclosporin, Ranitidine, Sertraline, Tamoxifen(3)
factors which predispose a person to develop statin-induced rhabdomyolysis are older age, frailty, multisystem diseases, and multiple medications. Hypothyroidism, impaired liver function, and impaired kidney function are also thought to increase the incidence of statin-induced myopathy.(2)
1- up to date
2- Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiother Can. 2014 Spring;66(2):124-32. doi: 10.3138/ptc.2012-65. PMID: 24799748; PMCID: PMC4006404.
3- Ezad S, Cheema H, Collins N. Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxf Med Case Reports. 2018 Mar 14;2018(3):omx104. doi: 10.1093/omcr/omx104. PMID: 29593874; PMCID: PMC5853001.
What is your working diagnosis?
Statin induced rhabdomyolysis
What are the investigations required to confirm your diagnosis?
Urine dip: Blood +, Negative RBCs under microscopy.
Serum CK: higher than 5 times of upper normal.
High K, PO4, low Ca, deranged liver enzymes.
Management: stop simvastatin, IV hydration aiming good diuresis 100-200 ml/h, HD can be considered if oligo-anuric.
Explain the link between his medications and this condition?
Interaction between simvastatin (metabolized by CYP3A4) and CNI.
If he is on Cyclosprin, switch to Tacrolimus
Fluvastatin, Pravastatin, Rosuvastatin and Atorvastatin are the recommended statins after renal transplantation.
Statin induced rhabdomyolysis complicated with AKI
1- Urine analysis : positive myoglobulin with NO RBC
2- Serum Myoglobulin level
3- Electrolytes level : hypocalcemia , hyperkalemia , hyperphosphatemia
4- Kidney function : Cr , Bun
5- high CPK level : for diagnosis and follow up
6- liver function test
Drug-drug interaction between cyclosporin and simvastatin , as Cyclosporine inhibit CYP3A mediated metabolism of simvastatin and also decrease the hepatic intake of this medication which lead to 2-10 times fold increase in its level and more prone to AKI and rhabdomylosis
1- Stop the Simvastatin
2- Hydration with normal saline- with aim to keep urine output at > 200 ml/hr
3- Maintain electrolyte balance
4- If indicated then we can start renal replacement therapy.
Fluvastatin
Atorvastatin
Q1- What is your working diagnosis?
Most probable diagnosis in this scenario is drug induced Rhabdomyolysis. it is well known that there is drug–drug interaction between cyclosporin and statin ( same interaction is not present with tacrolimus)
Q2- What are the investigations required to confirm your diagnosis?
1) Urinalysis- urine microscopy show no RBC at the same time the dip stick for hemoglobin will be positive.
2) Plasma centrifuging may help to distinguishing between hemoglobin and myoglobin by that fact that myoglobin does not precipitate but it becomes supernatant.
3) Other investigation include: plasma myoglobin level (high), creatine phosphokinase(high), serum uric acid level(high),serum phosphate (high),serum potassium(high), serum calcium (low).
Q3- Explain the link between his medications and this condition?
Pharmacokinetic studies confirm that ciclosporin interacts with all statins to increase the plasma levels of the statin. Ciclosporin is an inhibitor of CYP3A4 as well as several membrane transporters, including OATP2 and P-glycoprotein5. This interaction rise the risk of statin toxicity which may end by rhabdomyolysis. Studies demonstrate pharmacokinetic differences between cyclosporine and tacrolimus, particularly with regard to inhibition of 2 hepatic transporters: P-glycoprotein and organic anion transporting polypeptide (OATP). Compared with cyclosporine, tacrolimus does not affect these transporters, does not enhance statin exposure, and does not increase statin-associated safety events.
References :
1) Daniel R Migliozzi , Nicole J Asal , Clinical Controversy in Transplantation: Tacrolimus Versus Cyclosporine in Statin Drug Interactions, sage journals, 2020 Feb;54(2):171-177. doi: 10.1177/1060028019871891.
2) Kahwaji JM, Dudek RR. 2006. How can we manage hyperlipidemia and avoid rhabdomyolysis in transplant patients? Permanente Journal 10: 26-8.
The management in this case essentially is discontinuation of medications which are the underlying cause of the side effects; simvastatin must be discontinued.
Once the cause has been eliminated then improvement follows but the patient must be well hydrated to achieve a urine output of about 200 ml/hour. The favorite fluid is the saline solution.
Monitoring the kidney function is done to follow the improvement of AKI..
All other nephrotoxic medications must be adjusted and with discontinuation of unnecessary medications.
Simvastatin is not the best statin and there are others that are superior and they are rosuvastatin and Lipitor
The commonly used statins are atorvastatin, rosuvastatin, fluvastatin, and pravastatin.
The statin that is used in patients with CKD more frequently is atorvastatin. Simvastatin is also used but at a lower rate.
Q1- The diagnosis is drug-induced rhabdomyolysis because of drug interactions between simvastatin and cyclosporine. Both are metabolized by CYP3A4.
Q2- Laboratory tests are needed to confirm the diagnosis. Creatine phosphokinase (CPK) is released from muscles and is highly increased. Urine myoglobin, AST, ALT, uric acid, electrolytes, BUN and creatinine are needed, too.
Q3- Cyclosporine and simvastatin have drug interaction. Both are metabolized by CYP3A4 and cyclosporine increases level of simvastatin. Fluvastatin and pravastatin are the preferred statin while using CNIs.
This patient has drug induced rhabdomyolysis due to statin, simvastatin is metabolized by CYP3A4 enzyme which is inhibited by CNI and may lead to toxic effects from simvastatin.
investigations include urine dipstick positive for blood with urine analysis showing no RBCs on microscopic examination, positive urinary myoglobin, elevated serum CK, LDH, potassium, phosphate, AST and ALT and decreased serum calcium.
Management is supportive include stoppage of the offending drug, adequate hydration and hemodialysis when indicated as in presence of intractable hyperkalemia.
Jansuz Gumprech et al .Simvastatin-induced rhabdomyolysis in a CsA-treated renal
transplant recipient.Sci Monit. 2003 Sep;9(9):CS89-91.
Postrenal transplant with rhabdomyolysis is most probably drug induced by simvastatin in the presence of musculoskeletal pain and muscle tenderness and associated with Coca-Cola appearance of the urine.
do urine dipstick no RBCs of few less than 5 and the presence of myoglobulin.
elevated creatinine kinase 5 times from the normal range.
full blood count including differential and platelet count. If there is a possible infection or hemolysis, also elevated liver enzyme.
kidney function test (increase serum creatinine), serum calcium, phosphate, potassium, and potassium and VBG to detect and correct any metabolic acidosis
statin, including atorvastatin and simvastatin, are metabolism by the hepatic cytochrome p4503A4(CYP3A4) enzyme system and is also responsible for the metabolism of cyclosporine and sirolimus, cyclosporine increases blood levels of statin regardless of the pathway of statin metabolism and causes rhabdomyolysis.
pathogenesis of statin-associated muscle symptoms(SAMs)
1-genetic factors.
2-human leukocyte antigen
3-multi-omic network
Risk factors for statin-induced myopathy:
1-drug interaction such case cyclosporine.
2- pre-existing neuromuscular disorder.
3-hypothyroidism.
4-Vit D deficiency.
5- calcium channel blocker medication.
6-HIV and HCV protease inhibitor.
7-Grape fruit.
Reference
UpToDate
Drug induced Rhabdomyolysis.
urine and blood myoglobin, CPK, LFTs, URIC ACID, LDH, CALCIUM, PHOSPHATE, and POTASSIUM.
Good hydration, stop statins, switch cyclosporin to tacrolimus.
Management
REFERENCES
1. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: Pathophysiology and diagnosis. Eur J Intern Med 2007; 18:90.
2. Lemahieu WP, Hermann M, Asberg A, et al. Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. Am J Transplant 2005; 5:2236.
3. Katsakiori PF, Papapetrou EP, Goumenos DS, et al. Tacrolimus and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: An interaction study in CYP3A5 non-expressors, renal transplant recipients. Indian J Pharmacol 2011; 43:385.
4. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012; 126:617.
).
Most likely is Rhabdomyolysis due to:
Cyclosporine is a potent inhibitor of simvastatin metabolism, and may therefore facilitate simvastatin-induced rhabdomyolysis.
use of statins and cyclosporine should be avoided.
Investgation:
1/myalgias clincaly.
2/red to brown urine due to myoglobinuria.
3/elevated serum muscle enzymes(CK).
inhabitary effect on the hepatic enzyme by CNI.
note:
i write my answer as out side then copy it here.
What is your working diagnosis?
a case of rhabdomyolysis and myoglobinuric acute graft failure induced by the use of statin in transplant patient.
The risk of development of rhabdomyolysis and myoglobinuric acute graft failure is higher than general population in renal transplant recipients with concomitant use of cyclosporine A and statin
The adverse effects of statins mainly concentrate on liver and muscle, these adverse effects are dose-dependent and reversible.
Myalgia and fatigue are seen in 2% to 7% of cases and tenderness of muscles, weakness and myopathy with more than 10 fold increase of creatine kinase are seen in 0.01% to 0.5% of cases .
Rhabdomyolysis characterized by severe CPK increase, muscle necrosis and renal failure due to myoglobinuria may develop very rarely (0.15 fatal case in 1 million uses.
Explain the link between his medications and this condition?
Atorvastatin, lovastatin and simvastatin are primarily metabolized through the cytochrome P 450 3 A4 pathway.
The risk of adverse effects increases and important drug reactions may develop when they are used together with drugs metabolized through this pathway such as fibrates, cyclosporine, macrolite antibiotics, digoxin and warfarin.
treatment maily by stopping simvastatin and good hydration with isotonic saline at 1-2L/hr with monitoring of urine output , Bp ,cvp and CK level.
Correction of electrolyte abnormalities and sodium bicarbonate for alkalization of urine .
Switch simvastatin to Atorvastatin ,pravistatin,fluvastatin or Rosuvastatin .
Tacrolimus is more preferred in transplant patients with hyperlipidemia
What are the investigations required to confirm your diagnosis?
-CPK anc CK-MB
-urine analysis
-myoglobin, urea,creatinine,and uric acid
-AST, ALT,lactate dehydrogenase (LDH).
– sodium, potassium,calcium.
-albumin, hemoglobin.and cbc
-cyclosporine level.
Böbrek Nakilli Hastada Simvastatin Kullanımına Bağlı Gelişen Akut RabdomyolizSimvastatin Induced Acute Rhabdomyolysis in a Renal Transplant Patient
What is your working diagnosis?
Rhabdomyolysis secondary to medication ( most likely Simvastatin)
What are the investigations required to confirm your diagnosis?
Blood test like renal function , electrolytes ( hyper K hypo Ca ) liver function and most important CK
Urine test to check myoglobinuria m proteinuria
Explain the link between his medications and this condition?
Cyclosporine inhibit CYP3A mediated metabolism of simvastatin and also decrease the hepatic intake of this medication which lead to 2-10 times fold increase in its level and more prone to AKI and rhabdomylosis
Uptodate
What is your working diagnosis?
This is likely due to Simvastatin induced rhabdomyolysis with acute kidney injury .
What are the investigations required to confirm your diagnosis?
These will include-
Urine analysis- will be positive for myoglobin, not much RBCs
Serum Myoglobin levels.
Renal functions, Electrolytes, ALT and AST , Urate, Creatine kinase
Explain the link between his medications and this condition?
Cyclosporine has drug interaction with Simvastatin as both are metabolized by CYP 3A4. The toxic doses of Simvastatin can cause damage to myocytes with resulting Rhabdomyolysis. Cyclosporine has inhibitory effect on CYP 3A4 with resulting toxic level of Simvastatin .
Myoglobin can lead to ATN and vasoconstriction leading to AKI. Fluvastatin and Pravastatin are safe as they use different metabolic pathways. atorvastatin at 10 mg D can also be used.
Atorvastatin is the best statin in CKD.
For renal transplant patients Fluvastatin may be ideal
The management will include-
Stop the Simvastatin
Hydration with normal saline- with aim to keep urine output at > 200 ml/hr
Urinary Alkalanization by adding soda bicarb to fluids.
Maintain electrolyte balance
If indicated then we can start renal replacement therapy.
TAC bas immune suppression in case of hyperlipidemia.
What is your working diagnosis?
This is most likely a picture of rhabdomyolysis due to simvastatin and complicated with AKI.
What are the investigations required to confirm your diagnosis?
· Urinalysis will reveal a positive result for blood(myoglobin pigment) but no true RBCs on urine microscopy.
· High level of CK and AST.
· Low potassium, low calcium, high phosphorus.
· Metabolic Acidosis on ABG.
Explain the link between his medications and this condition?
CsA is known to have drug-drug interaction with simvastatin as both are metabolized by the hepatic enzyme CYP3A4.
Plan of management:
· To stop the offending agent(Simvastatin).
· Aggressive hydration to induce diuresis, aiming at UOP of > 200 ml/hr.
· Addition of sodium bicarbonate to running IV fluids may be of benefit(Urinary alkalinization helps washing myoglobin pigment).
· Correction of electrolytes abnormality if present.
· RRT as indicated.
Regarding lipid lowering agent in CKD, the best are: FLUVASTATIN AND PARAVASTATIN. RUSUVASTATIN AND ATORVASTAIN CAN BE USED IN SMALLER DOSES.
What is your working diagnosis?
We are dealing with drug induced rhabdomyolysis
simvastatin 40 mg + Cyclosporine
Note that Cyclosporine immunosuppressant is an inhibitor of CYP3A4 at therapeutic doses; therefore, simvastatin, lovastatin, and pitavastatin should be avoided.
What are the investigations required to confirm your diagnosis?
laboratory findings such as elevated serum creatine kinase (CK) and urine myoglobinuria confirm the diagnosis of rhabdomyolysis.
KFT
ALT ,AST
Serum electrolytes and uric acid
Explain the link between his medications and this condition?
Pharmacokinetic studies confirm that cyclosporin interacts with all statins to increase the plasma levels of the statin.
Cyclosporine is an inhibitor of CYP3A4 as well as several membrane transporters, including OATP2 and P-glycoprotein5. The metabolic pathways of statins include CYP3A4, OATP2 and P-glycoprotein .
It has been suggested that the risk of myopathy is lower with non-lipophilic statins because of their inability to enter muscle cells and to alter membrane structure.
Fluvastatin, pravastatin and rosuvastatin may be considered as alternatives as they are not as extensively metabolized by CYP3A4 and therefore less likely to result in rhabdomyolysis but still require careful monitoring .
management plan of this case
The standards of care for rhabdomyolysis include urine alkalization, aggressive intravenous fluids, and in some cases, short-term dialysis.
We need to stop simvastatin and wait for stabilizing the condition then to calculate the risk of cardiovascular diseases for this patient and if he needs statins he should take Fluvastatin, pravastatin and rosuvastatin as mentioned above.
In CKD patient we can use atorvastatin in low dose . And we can use Fluvastatin, pravastatin and rosuvastatin.
– In the presence of Coca-Cola colored urine(reported in 3.6% of the cases), muscle pain and tenderness associated with a new AKI, the most likely diagnosis is statin induced Rhabdomyolysis Caused by Simvastatin.
– The classic triad is myalgia, muscle weakness and myoglobinuria is observed in < 10% of cases
· What are the investigations required to confirm your diagnosis?
– Rhabdomyolysis ranges from an asymptomatic illness with just increase in CK to life threatening conditions associated with AKI, electrolyte imbalance up to DIC.
– Work-up to confirm the diagnosis include:
1) Full clinical examination focusing on neuro muscular examination to check for muscle pain ,tenderness and weakness.
2) The gold standard is to check creatinine kinase level(CK): values higher than 5 times the upper limit of than the upper limit of the reference range is commonly used. It is more sensitive and has longer half-life than the serum myoglobin level(1.5 days vs 2-4 hrs only)
3) urine myoglobin level: it results in positive urine dip stick and negative urine microscopy results.
4) Checking other electrolytes and enzymes that are released from the muscle injury. So we will encounter high K, phosphate, urate, AST, aldolase, LDH and low calcium level.
5) Check cyclosporine or tacrolimus trough level
– 60% of statin induced rhabdomyolysis is due to drug interaction when other co-administered drugs are metabolized by CP450.
– In the FDA adverse event reporting system (FEARS), Rhabdomyolysis was highest with simvastatin 36% and less common with Atorvastatin and pravastatin (12%), Lovastatin(6%) and Fluvastatin (2%)
– Statins act by competitive inhibition of HMG-CoA. However, their physio-chemical properties vary.
– Some statins like simvastatin, atorvastatin and lovastatin undergo phase I metabolism by cytochrome P450 3A4 and are called 3A4 substrates, while other statins like pravastatin, fluvastatin, and rosuvastatin) are not metabolized by the 3A4 isoenzyme.
– 3A4 isoenzyme is responsible for the metabolism of >50% of marketed pharmaceuticals. Administration of 3A4 inhibitors with a statin leads to significantly increased plasma statin levels, in turn leading to considerable statin toxicity.
– Drugs that are 3A4 inhibitors and are often prescribed with statins include fibrates calcium channel blockers, histamine H2 antagonists, antibiotics (eg, clarithromycin), antifungals (eg, itraconazole), antidepressants, antiretroviral drugs (eg, protease inhibitors), and immunosuppresives (eg, cyclosporine).
– Similarly, Law and Rudnicka showed that the incidence of rhabdomyolysis was higher for patients receiving lovastatin, simvastatin, and atorvastatin and lower for those receiving fluvastatin and pravastatin. They postulated that the reason is that lovastatin, simvastatin, and atorvastatin are metabolized by cytochrome P450 3A4 while fluvastatin and pravastatin are not.
The common risk factors for statin induced Rhabdomyolysis are:
– Use of high doses
– Advanced age
– Female sex
– DM
– Renal or hepatic insufficiency
Back to the management of our index case:
– Stop Simvastatin being the provoked cause
– IV fluid hydration aiming for a urine out-put of 200-300 ml/hr(some controversy of whether to use normal saline or sodium bicarbonate).Careful monitoring of the patient fluid status is of great importance, RRT may be indicated if the patient remains oligo-anuric with progressive worsening of the rnal functions.
– Monitor renal functions and electrolytes(only manage symptomatic hpocalcemia.
as rebound increase in the serum calcium occurs later)
– As KDIGO recommended the use of statin therapy in all kidney transplant patients to reduce cardiovascular risks. Accordingly, Statins can be re-introduced after resolving of rhabdomyolysis. The preferable statins are Fluvastatin or pravastatin as mentioned above and they can be introduced in smaller doses.
– The interaction of statins is less with Tacrolimus compared with cyclosporine, so, it is recommended to switch from Cyclosporine to Tacrolimus.
– References:
–
-This is a case of Rhabdomyolysis caused by the combination of simvastatin and CNI based immunosuppressive triple therapy.
-The investigations include
creatine phosphokinase (CPK) , creatine kinase–MB (CK-MB), myoglobin level , urea, creatinine ,urine analysis , myglobinuria, electrolytes ;Na ,K ,Ca PO4, ALT ,AST and CNI level.
-Statins lowers hyperlipidemia through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase,it rarely casues rhabdomysolsyis and myoglobuinuirc graft failure but the risk is higher with the concomitant use of CNI.
Atorvastatin,lovastatin and simvastatin are primarily metabolized through the cytochrome P 450 3 A4 pathway. The risk of adverse effects increases and important drug reactions can occur when they are used together with drugs metabolized through this pathway as cyclosporine.
Reference
-Atalay H et al. Simvastatin Induced Acute Rhabdomyolysis in a Renal Transplant Patient. Turkish Nephrology, Dialysis and Transplantation Journal 2009 . Vol. 18, No, 2, Page 100-102
Simvastatin induced Rhabdomyolysis.
Urine RME
S. CPK
S. LDH
S. Electrolyte
S. Creatinine
Drug drug interaction with simvastatin snd CNI
Very abbreviated reply, dear DrTufael.
There are no references!
Diagnosis :
Statin induced Rhabdomyolysis
(coca-cola-like urine + generalised musculoskeletal pain and tenderness + Rising KFTs )
with history of use of Statins (simvastatin )
Pathophysiology :
About 60% of cases of statin-induced rhabdomyolysis are attributable to medication interactions as some statins (atorvastatin, simvastatin, and lovastatin) undergo phase I metabolism by cytochrome P450 3A4 and are called 3A4 substrates, while other statins (pravastatin, fluvastatin, and rosuvastatin) are not metabolized by the 3A4 isoenzyme .
Numerous medications, including fibrates (especially gemfibrozil), calcium channel blockers, histamine H2 antagonists, antibiotics (such as clarithromycin), antifungals (such as itraconazole), antidepressants, antiretroviral medications (such as protease inhibitors), and immunosuppressants are 3A4 inhibitors (eg, cyclosporine).
What are the investigations required to confirm your diagnosis?
CK : The measurement of plasma CK is the gold standard for laboratory diagnosis. A concentration 5 times the top limit and A concentration of >5,000 IU/L is strongly associated with the development of kidney injury, and a level of CK regarded predictive of the chance of developing ARF
Electrolytes
Hyperkalemia , Hyperphosphatemia and Hypocalcemia
· Others :
· AST , ALT , Serum aldolase
Lactate dehydrogenase (LDH)
Myoglobin :
Blood Myoglobin has a half-life of 1-3 hours and is eliminated from plasma within 6 hours, measurements of plasma myoglobin are unreliable.
A positive result may assist confirm the diagnosis, but myoglobin levels that are not examined at the appropriate time may yield a false-negative result. Therefore, urine myoglobin measurements are preferred.
Management plan :
2- The cornerstone of therapy is extracellular volume expansion, which must to start rapidly : administer isotonic fluids at a rate of approximately 400 mL/h (may be up to 1000 mL/h based on type of condition and severity) and then titrate to maintain a urine output of at least 200 mL/h
3- Prevention of Acute Renal Failure :
Aklalization of urine :
Due to the fact that acidic urine is required to cause ATN, alkalizing urine is thought to be beneficial. Cast formation may be less likely as a result of alkalinization (ferrihemate and myoglobin).
4- Correction of Electrolyte, Acid-Base, and Metabolic Abnormalities
Treatment of hyperkalemia :
IV sodium bicarbonate,
glucose, and insulin;
oral or rectal sodium polystyrene sulfonate
Correct hypocalcemia only if the patient has cardiac dysrhythmias or seizures
Hyperphosphatemia and hyperuricemia are not clinically significant, and they almost rarely need to be treated.
References :
Al-Ismaili Z, Piccioni M, Zappitelli M. Rhabdomyolysis: pathogenesis of renal injury and management. Pediatr Nephrol. 2011 Oct;26(10):1781–1788.
Rowan CG, Brunelli SM, Munson J, et al. Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in the Health Improvement Network. Pharmacoepidemiol Drug Saf. 2012 May;21(5):494–506.
Khan FY. Rhabdomyolysis: a review of the literature. Neth J Med. 2009 Oct;67(9):272–283
I like your well structured reply.
young man with CKD 5 post renal transplantation 5 weeks ago, on CNI based triple therapy was started on simvastatin 40mg OD. He developed cola like urine and impaired kidney function cr 123.
young man with CNI based IS and started on statin has high risk for drug induced rhabdomyolysis due to drug and drug interaction.
risk factors for statin induced rhabdomyolysis
1- drug -drug interaction- Omar and Wilson et al reported 50% of cases are caused by drug -drug interaction
2-increases statin dosage associated with increased incidence of rhabdomyolysis
3- age above 65 years- Schech et al reported that statin users above 65 are 4 times higher risk of hospitalisation for rhabdomyolysis compared to those who younger
4- comorbidities- such as pre existing renal impairment, liver diseases
5- strenuous exercises
What are the investigations required to confirm your diagnosis?
I would like to do:
1- TDM for CNI – to make sure the level is within the therapeutic level
2- CK level- will be elevated in rhabdomyolysis
3- Ca/PO4 level – calcium will be low and phosphate will be high
4- urine microscopic examination – rbc cast
5- ABG – to avoid metabolic acidosis which will lead to cast formation
Explain the link between his medications and this condition?
Cyclosporin is an inhibitor of the cytochrome P450 isoenzyme 3A4 ( CYP3A4) and possibly OATP2 and P – Glycoprotein, which are involved in the biliary excretion of statins
Lovastatin, simvastatin and atorvastatin – metabolized by CYP3A4 and likely to be excreted to the bile, which cause the increment serum concentration when used together with CyA.
Fluvastatin – metabolised by CYP2C, but also extensively excreted in the bile , causing increased CyA concentration
Pravastatin and Rosuvastatin – not metabolised by CYP3A4 .
Our patient might be using CyA as one of IS, which caused increased simvastatin level.
How to manage rhabdomyolysis
What is the preferred statin in the transplant population?
switching to a hydrophilic and not metabolised by CYP3A4 such as pravastatin and rosuvasatin when used with CyA will be better option
In my centre, we use atorvastatin and rosuvastatin as preferred statin in CKD cohort.
In post transplantation cohort, we also use atorvastatin and rosuvastatin replacing all the simvastatin that started by periphery hospitals or clinics
1-Nisa safitri et al 2021
2-Joseph M Kahwaji et al 2006
I like your well structured reply.
– Mostly a case of rhabdomyolsis with AKI 2ry to use of simvastatin with drug drug interaction between cyclosporine & simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
· What are the investigations required to confirm your diagnosis?
– Urine analysis : positive haematuria by dipstick & negative for RBCS by microscopy .
– CPK levels : will be high
– Elevated AST levels
– Hypocalcaemia , hyperkalaemia , hyperphosphatemia & acidosis
· Explain the link between his medications and this condition?
– drug drug interaction between cyclosporine & simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
· the management plan of this case :
– stop simvastatin
– aggressive hydration by normal saline
– correct hypocalcaemia
– HCO3 only if acidosis
– Dialysis only if indicated as supportive measure
– Shift to tacrolimus .
– Pravastatin & Fluvastatin will be better choices
I like your well structured reply. But, there are no references!
This scenario involves a recent transplant recipient on CNI, MMF and steroids with simvastatin. The patient developed generalized musculoskeletal pain and coca-cola colored urine with elevation of serum creatinine.
The working diagnosis is rhabdomyolysis, due to statins – interacting with CNI (CYP3A4 inhibitor), leading to elevated serum concentration of simvastatin (1,2).
The muscle pains/ tenderness is due to accumulation of statins in the muscle and muscle fragility (3). The cola-colored urine is due to myoglobulinura (4). The rise in serum creatinine is due to precipitation of myoglobin in the renal tubules leading to obstruction and consequent oliguria.
Serum creatinine kinase (more than 5 times the upper limit of normal) and detection of myoglobin in urine and serum (although present in initial phase of injury) will help in confirming the diagnosis of rhabdomyolysis (5). Absence of RBCs in urine analysis in presence of blood/heme in urine (4). Other biochemical changes seen include elevated serum potassium, phosphorus, uric acid, creatinine, LDH and SGOT (4). Serum calcium will be low initially and rise later.
The concomitant use of simvastatin, an HMG-CoA reductase inhibitor, with calcineurin inhibitors (CYP3A4 inhibitor) causes increased serum concentration of the statin, leading to its accumulation in muscles and muscle fragility responsible for the muscular symptoms (2,6).
Management:
Management in this scenario will include cessation of the statin, hydration using intravenous fluids (to maintain a urine output of >300ml/hour) and urinary alkalinization (4). Indication of renal replacement therapy is if severe AKI requiring dialysis (refractory hyperkalemia, metabolic acidosis, encephalopathy or fluid overload).
References:
1) Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiother Can. 2014 Spring;66(2):124-32. doi: 10.3138/ptc.2012-65. PMID: 24799748; PMCID: PMC4006404.
2) Ezad S, Cheema H, Collins N. Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxf Med Case Reports. 2018 Mar 14;2018(3):omx104. doi: 10.1093/omcr/omx104. PMID: 29593874; PMCID: PMC5853001.
3) Tournadre A. Statins, myalgia, and rhabdomyolysis. Joint Bone Spine. 2020 Jan;87(1):37-42. doi: 10.1016/j.jbspin.2019.01.018. Epub 2019 Feb 6. PMID: 30735805.
4) Cabral BMI, Edding SN, Portocarrero JP, Lerma EV. Rhabdomyolysis. Dis Mon. 2020 Aug;66(8):101015. doi: 10.1016/j.disamonth.2020.101015. Epub 2020 Jun 10. PMID: 32532456.
5) Gupta A, Thorson P, Penmatsa KR, Gupta P. Rhabdomyolysis: Revisited. Ulster Med J. 2021 May;90(2):61-69. Epub 2021 Jul 8. PMID: 34276082; PMCID: PMC8278949.
6) Safitri N, Alaina MF, Pitaloka DAE, Abdulah R. A Narrative Review of Statin-Induced Rhabdomyolysis: Molecular Mechanism, Risk Factors, and Management. Drug Healthc Patient Saf. 2021 Nov 8;13:211-219. doi: 10.2147/DHPS.S333738. PMID: 34795533; PMCID: PMC8593596.
I like your well structured reply.
Statin induced rhabdomyolysis:(muscle pain,tea colored urine and rise in creatinine after starting statins)
‘Investigations required to confirm diagnosis:
1-‘Dipstick urine and microscopic urine examination (so blood positive by dipstick and No RBCs by microscopic exam).
2-CPK level
Management: should be by IVF and maintaining good UOP,sometimes alkalinization of urine by using IV sodium bicarb ,follow RFT and CPK and stop simvastatin .
Link between medication and rhabdomyolysis:
1-Drug-drug interaction between statins and CNI more severe with cyclosporine than tacrolimus .
2-According to KDIGO guidelines statins should be used in transplant patients in a dose less than CKD
initiate statin therapy with lower doses than the doses suggested by Kidney Disease: Improving Global Outcomes (KDIGO) to prevent possible side effects, such as one of the following regimens:
•Fluvastatin 40 mg daily
•Atorvastatin 10 mg daily
•Rosuvastatin 5 mg daily
•Pravastatin 20 mg daily
•Simvastatin 20 mg daily
in patients who cannot tolerate statins >ezetimibe or statin/ezetimibe combination is a good option ,PSCK9 inhibitors e,g evolocumab, alirocumab are not used because there is insufficient evidence on their risks and benefits in kidney transplant patients.
In our center we usually use Atorvastatin
I like your well structured reply. But, there are no references!
we give atorvastatin in our practice
This statin induced muscle toxicity and rhabdomyolysis although generally the risk is low.
the cause of statin induced rhabdomyolysis remains obscure but muscle toxicity has generally been attributed to deficiencies of synthetic products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway.
other investigations include:
1- serum K+ level
2- creatinine kinase enzyme level
3- lipid levels
4- liver function test
5- thyroid hormones level
Treatment include:
1- stopping this simavastatin which is the most one causing rhabdomyolysis
2- good hydration
3- alkalinization of the urine to minimize precipitation of myoglobin in the renal tubules
I like your reply, though it is very brief. But, there are no references!
Rhabdomyolysis secondary to statin therapy
Clinically
Rhabdomyolysis is characterized clinically by the classic triad of
Myalgias
red to brown urine due to myoglobinuria elevated serum muscle enzymes (including creatine kinase
The degree of muscle pain and other symptoms varies widely.
Laboratory
The hallmark of rhabdomyolysis is :-
– Elevation in CK and other serum muscle enzymes.
Serum CK levels at presentation are usually at least five times the upper limit of normal, but range from approximately 1500 to over 100,000 international units/L.
-Urine findings and myoglobinuria
Myoglobin, a heme-containing protein, is released from damaged muscle in parallel with CK.
It appears in the urine when the plasma concentration exceeds 1.5 mg/dL
Visible changes in the urine only occur once urine levels exceed from approximately 100 to 300 mg/dL, although it can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL
Myoglobin has a half-life of only two to three hours, much shorter than that of CK (36 hours). Because of its rapid excretion and metabolism to bilirubin, serum myoglobin levels may return to normal within six to eight hours.
Both hemoglobin and myoglobin can be detected on the urine dipstick as “blood”; microscopic evaluation of the urine generally shows few red blood cells (RBC)
Proteinuria may also be seen, due to the release of myoglobin and other proteins by the damaged myocytes
-Routine lab tests:-
Complete blood count, including differential and platelet count
Blood urea nitrogen, creatinine, and routine electrolytes including potassium
Calcium, phosphate, albumin, and uric acid
Electrocardiography
CRP
Drug-drug interactions may be responsible for rhabdomyolysis in some individuals. The nature of the interactions varies. As an example, some drugs interfere with the clearance of statins and lead to elevated plasma levels; offending agents
include macrolide antibiotics erythromycin and clarithromycin), cyclosporine, gemfibrozil, and some protease inhibitors used in the treatment of HIV infection.
For all statins, the risk of muscle injury is greater at higher doses.
Cyclosporine is an inhibitor of CYP3A4, CYP2C9, and the hepatocyte membrane efflux transporter organic anion transport protein (OATP), which regulates hepatic uptake of fluvastatin, rosuvastatin, and pitavastatin. Coadministration of cyclosporine can increase concentrations of fluvastatin twofold and rosuvastatin and pitavastatin by 3- to 10-fold or more
Cyclosporine has been safely administered with fluvastatin doses of up to 40 mg/day Rosuvastatin and pitavastatin are dose-limited or contraindicated with cyclosporine, respectively.
Management
When rhabdomyolysis is suspected, regardless of the underlying etiology, one of the most important treatment goals is to avoid acute kidney injury.
Because of the possible accumulation of fluids in muscular compartments and the associated hypovolemia, fluid management is imperative to prevent prerenal azotemia.
Azotemia is prevented primarily by aggressive hydration at a rate of 1.5 L/h.
Another option is 500 mL/h saline solution alternated every hour with 500 mL/h of 5% glucose solution with 50 mmol of sodium bicarbonate for each subsequent 2-3 L of solution.
A urinary output goal of 200 mL/h, urine pH >6.5, and plasma pH <7.5 should be achieved.
Notably, urinary alkalization with sodium bicarbonate or sodium acetate is unproven, as is the use of mannitol to promote diuresis.
Drugs such as statins that are known to be a risk factor for rhabdomyolysis should also be immediately stopped. Fasciotomy may be required in compartment syndrome to limit damage to muscles and kidneys.
Drugs doses
In patients receiving a statin, we initiate statin therapy with lower doses than the doses suggested by Kidney Disease: Improving Global Outcomes (KDIGO) to prevent possible side effects, such as one of the following regimens:
•Fluvastatin 40 mg daily
•Atorvastatin 10 mg daily
•Rosuvastatin 5 mg daily
•Pravastatin 20 mg daily
•Simvastatin 20 mg daily
●Target dose – For transplant recipients who are not on cyclosporine, doses may be increased, if the patient does not report side effects, in order to achieve the following final target doses: fluvastatin 80 mg daily, atorvastatin 20 mg daily, rosuvastatin 10 mg daily, pravastatin 40 mg daily, or simvastatin40 mg daily. These regimens have been shown to be beneficial in the CKD population in clinical trials.
For transplant recipients who are receiving cyclosporine, special caution is warranted. Cyclosporine inhibits the hepatic metabolism of many statins, resulting in higher blood levels. Thus, for patients who are on cyclosporine, we suggest continuing to use the lower doses listed above (ie, fluvastatin40 mg daily, atorvastatin 10 mg daily, rosuvastatin 5 mg daily, pravastatin 20 mg daily, and simvastatin 20 mg daily).
In our center we use Atorvastatin.
Reference
1- UP TI DATE
2-Rhabdomyolysis: Pathogenesis, Diagnosis, and Treatment
Patrick A. Torres, MD,1 John A. Helmstetter, MD,1 Adam M. Kaye, PharmD,2 Alan David Kaye, MD, PhD1,3
The Ochsner Journal 15:58–69, 2015
Ó Academic Division of Ochsner Clinic Foundation
I like your well structured reply.
What is your working diagnosis?
Myoglobinuria resulting from rhabdomyolysis, a complication of statins, of which simvastatin is an example.1 Rhabdomyolysis is among the best-recognized and the most feared complications of statins, and cerivastatin gives the worse form of rhabdomyolysis.2 The lysed skeletal muscles release excess myoglobin into the blood stream which spills over into the urine and passed out simulating haematuria.1 Other skeletal proteins and sarcoplasmic contents of the skeletal muscle that can be released into the serum are creatinine kinase, AST, ALT and electrolytes (potassium).1
Rhabdomyolysis also presents as generalized muscular pain and tenderness and muscle weakness of the proximal musculature.
Myoglobin is a dark-red, monomeric heme protein that contains iron in its ferrous (Fe+2) form. It is easily filtered by the glomerulus and is rapidly excreted into the urine. Plasma levels of myoglobin rapidly fall. When large amounts of myoglobin enter the renal tubule lumen, it interacts with the Tamm-Horsfall protein and precipitates; this is a process facilitated by acidic pH. Tubule obstruction principally occurs at the level of the distal tubule. In addition, reactive oxygen species generated by damage to both muscle and kidney epithelial cells promote the oxidation of ferrous oxide to ferric oxide (Fe+3), thus generating a hydroxyl radical. Both the heme moieties and the free iron-driven hydroxyl radicals may be critical mediators of the direct tubule toxicity, which mainly occurs in the proximal tubule.
Thus, the precipitation of myoglobin in the renal tubules with secondary obstruction, tubular toxicity, or both constitutes the primary causes for acute kidney injury during myoglobinuria. A higher volume of urine flow and a higher urine alkalinity prevent myoglobin from precipitating.
Why myoglobinuria is positive for urine dipstick suggesting as if there is blood in urine ?
Urine dipstick is positive for blood when there is myoglobinuria because of porphyrin ring in myoglobin (one in each molecule) and haemoglobin ( 4 in each molecule). Peroxidase like action of porphyrin makes dipstic test positive.
How can we mitigate further renal injury?
Please explain underlying physiology when explaining the necessary steps. Isotonic saline boluses of 20 mL/kg should be initially administered, with repeat boluses depending on the hydration status of the patient. This should be followed by continued hydration with IV fluids given at a rate of 2-3 times maintenance. Urine output goal of 2-3 mL/kg/h is the key objective. IV hydration should be continued until the CK level is consistently less than 1000 U/L, the urine clears, and the patient is able to maintain adequate oral hydration. Raising the pH of the urine to >6.5 can be facilitated by adding sodium bicarbonate to the fluids. Alkalinisation of the urine has been postulated to minimize the breakdown of myoglobin into its nephrotoxic metabolites and to reduce crystallization of uric acid, thereby decreasing damage to tubule cells.
What are the investigations required to confirm your diagnosis?
Urinalysis may test positive to blood, but, urine sediment microscopy will not reveal haematuria. Serum creatinine kinase will be elevated five times above the upper limit. Acute tubular necrosis can give rise serum urea, creatinine, hyperkalaemia, metabolic acidosis, and hypocalcaemia.
Explain the link between simvastatin and this condition?
Simvastatin is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.3 The exact mechanism by which statins cause rhabdomyolysis is uncertain. Rhabdomyolysis is dose dependent and the risk can increase by a concomitant ingestion of other medications that can inadvertently increase serum level of statins by inhibiting cytochrome P450 (CYP)3A4 system, an enzyme that is required for the metabolism of statins.4 . In this scenario, a concomitant use of CNI can potentiate the rhabdomyolysis complication of the simvastatin.
Describe the role of statins in the management of renal transplant recipient?
A. Statins reduce cardiovascular mortality in the general population and by extension; it should do same in ESRD patients or among renal transplant recipient.5, 6 Dyslipidemia is known as a nonimmunologic risk factor associated with chronic allograft nephropathy following kidney transplantation.
B. Extra-lipid effects of statins include anti-inflammatory, anti-proliferative and immunomodulatory actions.7-9
C. Statins may specifically benefit renal transplant recipients by modulating the thrombotic and fibrogenic processes, the endothelial function, and the effect on inflammatory and immune responses–both dependent and independent of inhibition of the HMG-CoA reductase enzyme.7, 8, 10, 11
References
1. Ezad S, Cheema H, Collins N. Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxf Med Case Reports 2018; (3): omx104.
2. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001; 2(5): 205–207.
3. Sakamoto K, et al. Mechanism of statin-induced rhabdomyolysis. J Pharmacol Sci. 2013.
4. .Neuvonen PJ, Niemi M, Backman JT. Drug interaction with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81.
5. Younas N, Wu CM, Shapiro R, et al. HMG-CoA reductase inhibitors in kidney transplant recipients receiving tacrolimus: statins not associated with improved patient or graft survival. BMC Nephrology 2010, 11:5.
6. Cheung BM, Lauder IJ, Lau CP, Kumana CR: Meta-analysis of large randomized controlled trials to evaluate the impact of statins oncardiovascular outcomes. Br J Clin Pharmacol 2004, 57(5):640-651.
7. Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J: Anti-inflammatory and immunomodulatory effects of statins. Kidney Int 2003, 63(1):12-23.
8. Raggatt LJ, Partridge NC: HMG-CoA reductase inhibitors asimmunomodulators: potential use in transplant rejection. Drugs 2002, 62(15):2185-2191.
9. Kobashigawa JA: Statins in solid organ transplantation: is therean immunosuppressive effect?. Am J Transplant 2004, 4(7):1013-1018.
10. Kwak B, Mulhaupt F, Myit S, Mach F: Statins as a newlyrecognized type of immunomodulator. Nat Med 2000, 6(12):1399-1402.
11. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U: Statins selectively inhibit leukocytefunction antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001, 7(6):687-692.
Working diagnosis: AKI due to Simvastatin induced Rhabdomyolysis
Diagnosis: S. CPK ( High )
Here, combination with statin and CNI increase the risk of Rhabdomyolysis. Simvastatin increases the level of CNI by P – glycoprotein (MDR1) efflux transporter.
Thank you
Your answer is incomplete. See the index case
*This is a case of Rhabdomyolysis induced by statins.
*Diagnosis by : 1.Ck and CK MM. 2.urine analysis : pigmented casts due to myoglobin. 3.Hyperkalemia, hyperphosphatemia and low calcium, elevated Liver enzymes,LDH.
*Best Statins used in transplanted patients that not utilized CYP3A4 as Fluvastatin and Pravastatin, which associated with lower risk of rhabdomyolysis. It is better to switch from cyclosporin to tacrolimus which has lower rhabdomyolysis risk.
*Statins of cytochrome (CYP3A4) enzyme inhibitor as; CNI , calcium channel blockers as diltiazem increases rhabdomyolysis incidence.
*Drug / Drug interactions between statins and CNIs will increase statin concentrations in blood and will eventually can induce rhabdomyolysis.
*Treatment of statin induced rhabdomyolysis: 1. stop the offending drug and good hydration and alkalization of urine. if not responding then, Renal replacement therapy may be indicated.
Mostly This is a case of statin induced Rhabdomyolysis, which is characterized by muscle cell death which can result in acute kidney injury from pigment nephropathy.
A diagnosis of rhabdomyolysis can be made on the basis of the symptoms, acute renal failure and an elevated creatine kinase, aspartate aminotransferase concentration.
A combination of early diagnosis, continuous renal replacement therapy can be used for allograft salvage in a patient with rhabdomyolysis in the immediate post-kidney transplant period.
Also to stop the simvastatin
Managing Hyperlipidemia in Kidney Transplant Patients
Depending on a patient’s lipid profile,
dietary modification,
increased physical activity,
weight-reduction therapies.12,13
However, this is rarely enough to achieve target levels, and statin therapy should be initiated.
Studies have shown the efficacy and safety of low dose statin therapy in this population.2,11,12,14
In particular, an average daily dosage of 10 mg simvastatin and 20 mg lovastatin had proved efficacy with minimal adverse outcomes.13,15Fluvastatin and pravastatin have also proven to be of benefit in this population.3,16,17
References
°Article informationJ Surg Case Rep. 2018 Apr; 2018(4): rjy078.
Published online 2018 Apr 30. doi: 10.1093/jscr/rjy078
PMCID: PMC5941162
PMID: 29765590
Thank you
Thank you
1_ the most probable daignosis of the current case is simvastatin induced rhabdomyolysis with AKI (hemoglobinuria ).
2. To confirm diagnosis:
_ serum CK_MM will be elevated as a marker of muscle damage
_ serum K, phosphorus and uric acid will be elevated.
3. The relation to the current medications:
_ both CNI especially cyclosporin and simvastatin compete with each other on hepatic CYT p enzyme especially in such large dose 40 mg simvastatin, leading eventually to increased side effect of statin as rhabdomyolysis and also Risk of CNI induced nephrotoxicity.
_ so the best management of such case has 2 limbs:
a. During this acute event:
_ stop offending drug , shift to pravastatin (lipostat, but not available in Egypt) so we can use rosuvastatin
_ good hydration and alkalinization of urine with Na bicarbonate guided by blood PH.
b . Long term managemnt :
_ shift from cyclosporin to tacrolimus as it has lower risk of statin induced rhabdomyolysis.
_ best statin is pravastatin (lipostat) but not avialble in Egypt.
_ So we can use rosuvastatin, but it has weeker effect. So we can use atorvastatin but with small dose 10_20 mg/day with close monitoring of CNI trough level and education of the patient to seek medical advice if any muscle pain or change of urine color
Thank you
In this case first of all is to stop the offending dug simvastatin ,
then ,treat the AKI and prereanl azotemia with aggressive hydration aiming to pass urine of 200 to 300 ml/mint .
This patient developed AKI in the sitting of rhabdomylesis due statin therapy which lead to sever ATN and vasconstriction effect of myoglobin which lead to ischemic ATN .and sever tubular damage ,because of that the main management plan is depend on iv fluid of NS 500ml/hr with or without iv bicarbonate .
All ckd and transplant patient need to be on rusavastatin or fluvastatin .
in my country we use to use rosuvastatin mainly
Rhabdomyolyis secondary to simvastatin toxicity
– Urine analysis to r/o hematuria/ RBCs cast
– Urine myoglobin
– Serum LDH, CK, Bone profile
– Liver function test
– Stop accused drug ; simvastatin and follow the clnical response along with laboratory findings
• Explain the link between his medications and this condition?
Both CNI and statin are metabolized by cytochrome P450 therefore; each other medication can elevate the level of the other one with toxicity effect of either.
Reference
Gumprecht J, Zychma M, Grzeszczak W, Kuźniewicz R, Burak W, Zywiec J, Karasek D, Otulski I, Mosur M. Simvastatin-induced rhabdomyolysis in a CsA-treated renal transplant recipient. Med Sci Monit. 2003 Sep;9(9):CS89-91. PMID: 12960932.
Thankyou
– Rabdomyolysis induced acute kidney injury.
What are the investigations required to confirm your diagnosis?
– myoglobin in urine
-Urine PH
-CK CKMB
electrolytes.
the cause of rhabdomyolysis due statin used in this transplanted patient due to
●Glucocorticoids – Glucocorticoids alter lipoprotein metabolism to cause dyslipidemia, particularly elevated cholesterol levels, via multiple indirect pathways.
immunosuppresive medication as :
●Calcineurin inhibitors – Cyclosporine can directly cause posttransplant hypercholesterolemia, an effect that is independent of concurrent glucocorticoid use .
●mTOR inhibitors – mTOR inhibitors (sirolimus and everolimus) are frequently associated with dyslipidemias posttransplantation, particularly hypertriglyceridemia. The mechanism of action includes blocking insulin-stimulated lipoprotein lipase.
plan .
stop causative drug.
good hydration 12 L/day
alkalalization of urine
Can you choose another statin withe the Tac.
Paravastatin and fluvastatin is preferable agents
1- This is a case of statin induced rhabdomyolysis complicated by AKI .Statin induced rhabdomyolysis is a well documented complication of statin. Statins act through inhibiting HMG-CoA reductase as well as cytochrome p450-3A4.
predisposition factors for statin induced rhabdomyolysis are
– High initial dose of statin
-Concomitant use of other cytochrome p450-3A4 such as CNI , CaCB.
Investigations to confirm the diagnosis
– CBK total , CBK MB
-ALT , AST
-Electrolytes : hyperkalemia, hypocalcemia and hyperphosphatemia
– Urine analysis for myoglobinuria.
Management plan
1- supportive measures
– Oral and IV fliud therapy to maintain UOP 200-300 ml/h and alkalanization of the urine using NaHCO3 to reduce myoglobin deposition in renal tubules causin g tubular damage and obstruction.
– Correction of eelectrolytes specially hyperkamia.
– Hemodialysis when indicated.
2- simvastatin modification : shift to hydrophilic statins as pravastatin or rosuvastatin . If the CPK level is 5 folds higher than normal , statins should be stopped and replaced by another lipid lowering drug.
Ref:
Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. Int J Cardiol. 2014 Jun 1;174(1):83-9. doi: 10.1016/j.ijcard.2014.03.150. Epub 2014 Mar 28. PMID: 24726164.
Thankyou well done
Management of this case:
This patient is suffering from rhabdomyolysis due to simvastatin whose metabolism (cytochrome-P450 CYP3A4 or CYP2C9 isoenzymes) is inhibited by CNI based immunosuppression.
The management would be:
Problem of statins in kidney transplant:
Do you think that simvastatin was the best statin?
So, simvastatin is not correct statin to be used in kidney transplant patient on CNI based immunosuppression. The interaction of simvastatin and CNI leads to myopathy complications like rhabdomyolysis
what is the preferable statin in the transplant population?
So, pravastatin, pitavastatin, fluvastatin and rosuvastatin are the preferrable statins in kidney transplant patients as they have alternative metabolic pathways
What statin do you use for CKD and renal transplant patients at your workplace?
We, at out institute use Rosuvastatin at our institute.
Riella LV, Gabardi S, Chandraker A. Dyslipidemia and its therapeutic challenges in renal transplantation. American Journal of Transplantation. 2012 Aug;12(8):1975-82.
Torres PA, Helmstetter JA, Kaye AM, Kaye AD. Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J. 2015 Spring;15(1):58-69. PMID: 25829882; PMCID: PMC4365849.
Thankyou Exellent and clear
Thankyou well done to the point
This is a case of drug induced muscle injury that is Rhabdomyolysis leading to myoglobinuria.
Statins are also associated with a chronic myositis syndrome, characterized by muscle pain and weakness with or without evidence of clinically detectable rhabdomyolysis.
Risk factors:
The ‘classic’ triad of symptoms includes muscle pain, weakness and dark urine.
Early complications:
Late complications
INVESTIGATIONS AND MANAGEMENT
Explain the link between his medications and this condition?
Both cyclos[orine and statins are metabolised by CYP3A4 and this ave bilateral interactions. Statin levels are increased ,manifold leading to muscle injury.
NOTE: There is lot of heterogeneity among the studies conducted regarding role of statins after kidney transplantation on long term graft outcome and risk of CVD as per the Cochrane review and meta analysis but still simvuastatin 10mg equivalent is considered in at risk patients.
AHA STATEMENT:Combination therapy of cyclosporine, everolimus, or sirolimus with lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The coadministration of tacrolimus and lovastatin, simvastatin, and pitavastatin is potentially harmful and should be avoided. The dose of atorvastatin >10 mg/d when coadministered with cyclosporine, tacrolimus, everolimus, or sirolimus is not recommended without close monitoring of creatinine kinase and signs or symptoms of muscle-related toxicity.
REF;
12).
CsA is also mainly metabolized by CYP3A4, which is why a
bilateral interaction with most statins is likely. It has been
shown in studies that statins principally metabolized by
CYP3A4 (atorvastatin, lovastatin and simvastatin) tend to in-
duce increased CsA levels (6,13±16). CsA, on the other hand,
has a major impact on plasma concentrations of all statins,
resulting in a several-fold higher exposure compared with
non-CsA-treated controls
Thankyou but what is the plan in this patient.
what is the acceptable combination to use in a patient with dyslipidemia