|MANAGING A SIDE EFFECT
|Year : 2018 | Volume
| Issue : 1 | Page : 39-44
Managing a side effect: Cyclosporine-Induced nephrotoxicity
Manasi Shirolikar1, Sushil Pande1, Milind Borkar1, Sachin Soni2
1 Department of Dermatology, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur, Maharashtra, India
2 Consultant Nephrologist, United CIIGMA Hospital, Aurangabad, Maharashtra, India
|Date of Web Publication||10-Jul-2018|
Dr. Sachin Soni
Consultant Nephrologist, United CIIGMA Hospital, Aurangabad, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Shirolikar M, Pande S, Borkar M, Soni S. Managing a side effect: Cyclosporine-Induced nephrotoxicity. Indian J Drugs Dermatol 2018;4:39-44
|How to cite this URL:|
Shirolikar M, Pande S, Borkar M, Soni S. Managing a side effect: Cyclosporine-Induced nephrotoxicity. Indian J Drugs Dermatol [serial online] 2018 [cited 2019 May 23];4:39-44. Available from: http://www.ijdd.in/text.asp?2018/4/1/39/236281
| Introduction|| |
Cyclosporine (CsA), an immunosuppressant, is a calcineurin inhibitor (CNI) which is specific for T-cells. It was discovered in Sandoz Laboratories in Basel, Switzerland by isolating it from the soil fungus Tolypocladium inflatum gams. Initially used for rheumatoid and psoriatic arthritis, it was later approved for prophylaxis of organ rejection. Dermatologists often prescribe CsA in the dose of 3–5 mg/kg/day for management of papulosquamous disorders, mainly psoriasis and autoimmune connective tissue disorders. It is also used off-label in atopic dermatitis. Nowadays, CsA is increasingly being used for the treatment of toxic epidermal necrolysis with good effects. Calne et al. used CsA following transplantation in a dose of 25 mg/kg and found unexpected nephrotoxicity that had previously not been seen in animal experiments. Most of the persistent renal dysfunction is seen when the drug is used for a long duration of time and when dose of CsA is >5 mg/kg/day, especially in patients of psoriasis. This is an important side effect that needs to be recognized at early stages to avoid chronic kidney damage or irreversible nephrotoxicity.
| Pathophysiology of Nephrotoxicity|| |
Renal dysfunction can be functional or structural. Functional impairment is further split into vascular dysfunction and tubular dysfunction. Vascular dysfunction is caused by vasoconstriction of the afferent glomerular arterioles, resulting in decreased renal glomerular filtration rate (GFR) and renal blood flow with decreased clearance of creatinine. Tubular dysfunction is characterized by decreased magnesium reabsorption, decreased uric acid excretion, decreased potassium and hydrogen ion secretion, and distal tubular acidosis. Hypomagnesemia, decreased bicarbonate concentration, hyperuricemia, and hyperkalemia may also result. There is no loss of urinary concentrating power, as is the case with other nephrotoxins.
Activation of the renin–angiotensin system (RAS), afferent arteriolar vasoconstriction, increased vascular resistance of afferent and efferent arterioles, and decreased GFR are seen., Activation of the RAS by CsA occurs by two mechanisms, a direct effect on juxtaglomerular cells  and indirectly through arterial vasoconstriction and reduced renal plasma flow. In addition to the RAS activation, it has been shown that CsA increases the vasoconstrictor factors – endothelin (ET) and thromboxane; and decreases the vasodilator factors – prostacyclin, prostaglandin E2, and nitric oxide (NO).,
CsA may also increase superoxide, upregulate angiotensin II receptors, and increase the concentration of calcium in smooth-muscle cells causing increased sensitivity to vasoconstrictive stimuli.,
Tubular changes also include isometric vacuolization of the proximal tubule.
Acute functional changes are typically reversible on withdrawal of CsA treatment.
Chronic nephrotoxicity is due to structural changes in renal blood vessels and renal tubules. This includes an obliterative microvascular renal injury (vasculopathy) and a tubulopathy.
Vasculopathy comprises glomerular or arteriolar thrombi (platelets or fibrin), arteriolopathy, and interstitial fibrosis with tubular atrophy. Nodular protein deposits cause narrowing or occlusion of the vascular lumen. Mucoid thickening of the intimal wall can also occur, leading to arteriolar hyalinosis, interstitial fibrosis (striped form), tubular atrophy, and glomerular sclerosis.
Tubular structural changes include single-cell necrosis and microcalcification of Tamme–Horsfall protein in the distal tubule. These changes are seen with higher doses of CsA and are, thus, uncommon these days.
While tubulopathic changes are reversible, vasculopathic changes are maintained in up to half of patients.,
CsA alters transcription of genes such as NO synthase, transforming growth factor beta (TGF-β), ET-1, Collagen I and IV, and Bcl-2 which are proposed to be involved in the pathogenesis of chronic nephrotoxicity. Thus, both immunosuppression and nephrotoxicity are closely related to the suppression of calcineurin.,
| Risk Factors for Cyclosporine Nephrotoxicity|| |
Individual susceptibility also plays a role in susceptibility to renal toxicity.
Systemic levels of cyclosporine
CsA has a relatively narrow therapeutic window. Thus, precautions must be taken to keep the dosage within a preset target range. However, maintaining CsA concentrations within these ranges often proves to be difficult due to high inter- and intra-individual pharmacokinetic variability. This is seen with Sandimmune® more often than with Neoral ®.,,
Local renal exposure to cyclosporine
Levels of CsA in the renal tissue are much higher than in blood., This, in addition to local renal factors, contributes to nephrotoxicity. These factors include the age of the recipient and the kidney (if transplanted), local renal P-glycoprotein, and the use of nonsteroidal anti-inflammatory drugs.,,, Thus, it could be predicted that younger patients with native kidneys or those with kidneys transplanted from younger donors could be less susceptible to CsA nephrotoxicity.
There have been many studies of the safety of long-term CsA therapy in dermatology with regard to nephrotoxicity.
A study of renal biopsy specimens obtained from 30 psoriasis patients treated with CsA showed that all patients treated for 2 years or longer had an abnormal kidney biopsy specimen, with pronounced glomerular sclerosis after 4 years of continuous treatment. A study of maintenance CsA for 3.5 years in psoriasis patients showed a moderate degree of interstitial fibrosis and glomerular scarring in two of 14 patients after 2.5 years, with minimal to mild change in all of the remaining 12 patients . One year later, there was progression of fibrosis in nine of the 12 patients still enrolled in the study. Similarly, 1 month after drug withdrawal, tubulointerstitial scarring and arteriolopathy was seen in 27% of renal biopsy specimens taken from 15 psoriatic patients who had received CsA (<5 mg/kg/day) for 30 months. These patients had marked increases in serum creatinine levels of >90% above baseline, and conversely, those showing no increase in serum creatinine levels did not have structural renal changes in 86% of cases. There was no correlation, however, with dose or treatment duration. In a study evaluating eight patients treated with a mean dose of 3.3 mg/kg/day for 5 years, renal biopsy specimens revealed tubular atrophy and arterial hyalinosis in six patients (75%), with interstitial fibrosis and obliteration of glomeruli. Again, the best predictor of permanent renal damage was a persistent increase in serum creatinine level 1 month after treatment withdrawal.
In psoriasis patients, nephrotoxicity is associated with longer use, higher cumulative and daily dosage, and acute increases in serum creatinine. Slight-to-moderate interstitial fibrosis was observed in patients treated for at least 1–2 years, while glomerular sclerosis or severe interstitial fibrosis were seen in some cases after 3 years or more. The functional significance and the reversibility of the structural changes have not been fully characterized in the available studies.
| Cyclosporine Nephrotoxicity and Hypertension|| |
Initiation and monitoring of antihypertensive therapy may be a reason why dermatologists have been apprehensive to include CsA in their clinical armamentarium. New-onset hypertension with CsA treatment has been reported in a wide range from 0% to 57% in different studies. A short-course of CsA therapy shows a decreased incidence of new-onset hypertension which is usually reversible on dose reduction or with antihypertensive medications. There seems to be a lower incidence of new-onset hypertension as seen in studies of adults with atopic dermatitis compared with studies of psoriasis patients receiving short-term CsA treatment. This may be due to a younger mean age in the cohort of patients recruited to atopic dermatitis studies; however, psoriasis patients may have a higher inherent risk of developing hypertension because of an increased incidence of obesity and the metabolic syndrome and therefore hypertension.,
In patients receiving long-term treatment, hypertension is more frequent. Longer-term studies have shown the persistence of hypertension posttreatment in up to 35% of patients.
The absence of an association between CsA dose and frequency of hypertension has been shown in other studies.,, Thus, there may be subset of patients with increased sensitivity to CsA, who are predisposed to hypertension even at low doses. Consequently, it has been suggested that CsA-induced hypertension should be managed by antihypertensive therapy rather than dose reduction.
| Prevention of Cyclosporine-Induced Nephrotoxicity|| |
CsA-induced nephropathy can be prevented by appropriate monitoring for the drug, avoidance of concomitant drugs, and giving proper drug interval.
Monitoring of serum creatinine, blood pressure, and various other parameters is to be done as shown in [Figure 1] and [Figure 2]. Fasting (fasting 12 h, in the morning, no preceding strenuous exercise) serum creatinine should be measured in a standardized manner on at least two separate occasions and repeated again if there is a discrepancy of >10 μmol/L between these measurements.,,, The average of these two values then serves as the baseline serum creatinine against which subsequent treatment values are compared.
|Figure 1: Management of renal toxicity during cyclosporine therapy proposed by Griffiths et al|
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Assessing CsA serum concentrations is a good tool to avoid CsA-induced side effects including nephrotoxicity. These are monitored mainly in transplant patients to avoid toxicity due to high concentrations of CsA and minimize possible organ rejection caused by low concentrations, because of the small therapeutic window. However, this has not been adopted or shown to be of benefit in monitoring efficacy or toxicity in dermatology patients.,, No correlation was established between immunosuppression and occurrence of adverse events., It can be used, however, if there is a query regarding patient adherence to treatment or to detect CsA levels above the recommended dosing range.
Avoidance of concomitant drugs increasing cyclosporine-associated nephropathy
CsA can delay the metabolism of multiple agents, including digoxin, simvastatin, prednisolone, diclofenac, and methotrexate, leading to increased concentration and toxicity of these drugs.
Drugs that may increase the risk of CsA-associated nephrotoxicity are shown in [Table 1].,
|Table 1: Drugs that may increase the risk of cyclosporine-associated nephrotoxicity|
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Since CsA nephropathy is strictly related to drug dose (>5 mg/kg/day) and treatment duration, ,, it has been proposed that the risk of renal toxicity during CsA treatment is reduced by the use of intermittent, short courses of the drug. The drug-free days allow renal recovery and restoration of normal renal function.
Strategies to reduce local renal susceptibility to calcineurin inhibitor toxicity
As vasoconstriction of the afferent arterioles appears to play a pivotal role in acute and chronic CNI nephrotoxicity, the potential role of vasodilatory agents for the avoidance of CNI nephrotoxicity cannot be underestimated. Various calcium channel antagonists such as nifedipine, verapamil, and diltiazem have shown their efficacy in reducing CNI nephrotoxicity in human studies.,,
Considering role of RAS activation in pathogenesis of CNI nephrotoxicity, therapeutic RAS inhibition appears an important approach. Beneficial effects have been observed in animal and human studies using losartan, lisinopril, and spironolactone.,,,
In rats as well as human studies, vasodilatory prostanoids like misoprostol showed beneficial effect in reducing CNI nephrotoxicity., L-arginine or molsidomine by virtue of NO generation has also shown promise in animal studies. Finally, other therapeutic approaches such as anti-TGF-β antibodies, statins, magnesium supplementation, and use of antioxidants , have shown some beneficial effect in amelioration of CNI nephrotoxicity.
| Treatment of Nephrotoxicity-Induced Manifestations|| |
Treatment of hypertension
- As there seems to be no relationship between the onset of hypertension and CsA dose, the introduction of antihypertensives may be more appropriate than dose reduction
- Calcium channel blockers of the dihydropyridine class (amlodipine or isradipine) are the antihypertensives of choice in CsA-mediated hypertension because of their vasodilating effect on the afferent arteriole, which may confer protection against nephropathy.,, Nifedipine can potentiate the gingival hypertrophy caused by CsA. Verapamil and diltiazem should be avoided as they interfere with serum CsA levels
- Angiotensin-converting enzyme inhibitors reduce CsA nephrotoxicity and improve the cardiovascular alterations observed in renal transplant recipients., However, some studies show a further decrease in GFR in CsA-treated hypertensive patients. Conversely, other studies have shown perindopril to be equally effective as amlodipine in lowering blood pressure without affecting GFR or effective renal plasma flow ,,
- The use of thiazide diuretics may increase nephrotoxicity 
- Potassium-sparing diuretics should also be avoided, as CsA can increase serum potassium.
Thus, CsA-induced nephrotoxicity can be prevented or treated effectively. This should allow dermatologist to use CsA in optimal and effective manner for various dermatology indications. Dermatologist should be vigilant to detect nephrotoxicity and should promptly seek nephrologist's opinion for further management of CsA-associated nephropathy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]