Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols?

Table 1 The modified Jadad scale[37]

Item evaluated	Finding	Score
Was the study described as randomized?	Yes	+ 1
	No	0
Was the method of randomization appropriate?	Yes	+ 1
	No	- 1
	Not described	0
Was the study described as blinded? (double-blind with score 1; single-blind with score 0.5)	Yes	+ 1
	No	0
Was the method of blinding appropriate?	Yes	+ 1
	No	- 1
	Not described	0
Was there a description of withdrawals and dropouts?	Yes	+ 1
	No	0
Was there a clear description of the inclusion/exclusion criteria?	Yes	+ 1
	No	0
Was the method used to assess adverse effects described?	Yes	+ 1
	No	0
Were the methods of statistical analysis described?	Yes	+ 1
	No	0

The randomised controlled trials are scored between 0 (which is the lowermost quality) and 8 (the uppermost quality). Scores between 4 and 8 mean the articles considered of good to excellent quality, while articles with score 0 to 3 are of poor quality[37]. A data extraction sheet was prepared for summarizing the essence of the included studies as well as the quality assessment of the study as presented in Table 2.

Table 2 Summary of randomised controlled trials articles

Ref.	Cases included	Aim of the study	Results and conclusions	Modified Jadad score
van Sandwijk et al[43], 2018	186 patients with follow up for about 2 yr	To compare ESW (day 3 post-transplant), triple therapy with low dose tacrolimus and standard tacrolimus dose triple therapy	All groups showed no statistically significant differences in patient survival, allograft survival, incidence of acute rejection and eGFR	6
			Steroid withdrawal group has better cardiovascular risk profile and lower rates of infection
Andrade-Sierra et al[44], 2016	71 patients with follow up for 12 mo	To compare the impact of ESW (day 5 post-operative) with maintenance steroid use.	One-year graft survival was comparable (87% versus 94% in controls)	4
			Steroid free group has higher eGFR and better blood pressure control with fewer anti-hypertensive drugs (8% versus 50%; P < 0.001).
Nagib et al[45], 2015	428 patients with follow up for 66 ± 41 mo	To investigate long term outcome of ESW (steroids used for three days only) in living donor kidney allograft recipients	Steroid avoidance in low immunological risk recipients was both safe and effective using basiliximab induction	4
			Long term follow-up showed decreased total cost with steroid-free protocol despite comparable immune suppressant cost, mostly secondary to lowering the burden of chronic comorbidities related to steroid use
Thierry et al[46], 2014	131 patients were followed for 30 mo	To evaluate the impact of SA in comparison to LSW	At the end of the study period, 32.4% of steroid avoidance patients and 51.7% of steroid withdrawal group were receiving oral steroids	6
			There were no significant differences in kidney functions, proteinuria, or documented rejection between both groups
Ponticelli et al[47], 2014	139 patients with follow up for 12 mo	Evaluating the short-term impact of LSW (3 mo post-transplantation)	Treatment failure was noted in 14.7% of steroid withdrawal group compared to 2.8% in the control group	6
			NODAT was reported in 13.2% of steroid withdrawal group compared to 1.9% in the control group
Krämer et al[48], 2012	421 patients with follow up for three years	The outcome of two different steroid-free regimens in comparison to the conventional triple immunosuppressive therapy	Despite the increased risk of early acute rejection with steroid-free protocols, the long-term patient and graft survival were comparable	6
			Steroid free regimens were associated with a better cardiovascular risk profile
Thierry et al[49], 2012	222 low risk, de novo kidney transplant recipients with follow up for 6 mo	Evaluation of the short-term outcome of SA after 500 mg methylprednisolone + IL-2 receptor antibody induction in comparison to conventional maintenance steroids	The short-term outcome in the form of patient survival, graft survival, the incidence of BPAR and GFR were similar in both groups. However, SA was associated with a lower incidence of CMV infection (12.5% versus 22.7%, P = 0.045)	6
Gheith et al[50], 2011	100 patients with a median follow up of twelve months	Assessing the cost-benefit of ESW (3 d post-transplant) in living donor kidney allograft recipients	Despite the comparable immunosuppressant costs, steroid avoidance was associated with significantly lower total costs by the end of the first year after transplantation	4
			The higher costs associated with steroid use was attributed to the cost of management of steroid-related comorbidities
Sandrini et al[51], 2010	96 patients were followed for up to 4 yr	To compare the efficacy of ESW (day 5) versus later withdrawal after 6 mo of transplantation	Both strategies had comparable patient survival, graft survival, allograft function and percentage of successful withdrawal	5
			ESW was associated with less wound healing complications (4% vs 21%, P = 0.02). On the other hand, LSW was associated with a lower incidence of acute rejection at 12 mo (30% vs 48%, P < 0.04), and at 48 mo (33% vs 53%, P < 0.03)
Delgado et al[52], 2009	37 patients with follow up for five years	Evaluating ESW (7 d post-transplant) effect on the development of de novo donor-specific anti HLA antibodies (DSA)	ESW was not associated with increased risk of development of de novo DSA compared with conventional steroid maintenance protocol	5
Sandrini et al[53], 2009	148 patients were followed for the first 15 d	To measure the impact of ESW on wound healing in comparison to maintenance steroids in patients receiving sirolimus therapy	ESW was associated with a significantly lower rate of wound healing complications (18.8% vs 45.6%, P < 0.0004)	3
Woodle et al[11], 2008	386 patients with follow up for five years	To compare the outcome of ESW (7 d post-transplant) with low dose chronic corticosteroid therapy	ESW was associated with increased risk of BPAR mostly corticosteroid-sensitive Banff class 1A rejections. However, the five-year allograft survival and function were similar in both groups	8
			Steroid withdrawal was associated with better metabolic and cardiovascular risk profiles
Vincenti et al[54], 2008	337 patients with follow up for 12 mo	Comparing the safety and efficacy of total SA (n = 112), ESW (n = 115) and standard maintenance steroid regimen (n = 109) in first kidney allograft recipients	The median eGFR by the end of the first year was comparable between all groups	6
			The incidence of BPAR was significantly higher with both steroid-free and early withdrawal groups compared to patients maintained on steroids
			Lipid profile, weight gain, and glycaemic control were better in steroid-free groups
Pelletier et al[55], 2006	120 recipients with follow up of minimum 1 yr after randomisation	To assess the impact of LSW compared to maintenance steroids	Patient and allograft survival, acute rejection rates and allograft function were similar in both groups	5
			Steroid withdrawal was associated with a significant improvement in bone density and total cholesterol levels
Rostaing et al[56], 2005	538 patients with follow up for six months	Short term outcome with a steroid-free protocol using Dac, Tac and MMF versus Tac, MMF, and corticosteroids regimen	Steroid free protocol was associated with a significant reduction in the incidence of NODAT (5.4% vs 0.4%, P = 0.003), in addition to improvement of serum total cholesterol levels	6
			No clinically significant difference detected between the two groups in the term of acute rejection or serum creatinine levels at the end of the study
Laftavi et al[57], 2005	60 patients were followed up by protocol biopsies at 1, 6, and 12 mo	Short term outcome of ESW (7 d after transplantation)	ESW was associated with significant and accelerated allograft fibrosis as proved by protocol biopsy findings. However, this did not affect the renal functions measured by eGFR	6
Vítko et al[58], 2005	451 low-risk recipients of first kidney allograft were followed up for 6 mo	Short term outcome of a steroid-free protocol using tacrolimus monotherapy after basiliximab induction (Bas/Tac) (n = 153), tacrolimus + MMF (Tac/MMF) (n = 151) or triple therapy of tacrolimus + MMF + steroids (n = 147)	Short term patient and graft survival at 6 mo post-transplantation were similar in all groups. However, the incidence of BPAR was higher in steroid-free groups [26.1% in (Bas/Tac) group, 30.5% in (Tac/MMF) group, and 8.2% in triple therapy group (P < 0.001)]	6
			The average creatinine clearance was higher in triple therapy group (65.3 ml/min), compared to Bas/Tac group (55.1 ml/min) and Tac/MMF group (59.4 ml/min) (P = 0.007)
Kumar et al[59], 2005	77 patients with follow up for 2 yr	Evaluating the impact of ESW (days 2-7) in comparison to low dose maintenance steroids	There were no statistically significant differences between both groups in all aspects (patient and allograft survival, acute rejection, metabolic profiles, and protocol biopsy findings)	5
Vanrenterghem et al[60], 2005	833 recipients with follow up for 6 mo	Estimating the short-term outcome of either steroid or MMF withdrawal after 3 mo of transplantation in comparison to standard triple therapy	The next 3 mo after randomisation showed a similar incidence of BPAR	5
			Steroid withdrawal group had a better lipid profile (P < 0.001)
			MMF withdrawal group had lower frequency of serious CMV infection (P = 0.024) and leukopenia (P = 0.0082)
Vincenti et al[61], 2003	83 recipients with follow up for 12 mo	Evaluating the impact of ESW (day 4 post-transplantation) in comparison to standard steroid therapy	Patient and allograft survival, the incidence of BPAR, graft function and rate of infections were similar in both groups	5
Boots et al[62], 2002	62 patients with a median follow up for 2.7 yr	To compare the outcome of ESW (7 d post-transplant) versus LSW (3-6 mo post-transplant)	Both groups had a similar patient and graft survival with similar acute rejection episodes. However, the incidence of NODAT was significantly lower in early withdrawal group	6
Sola et al[63], 2002	92 patients with follow up for 2 yr	Comparing the effect of LSW and maintenance steroids	There were no statistically significant differences between both groups in all aspects (patient and allograft survival, acute rejection, and metabolic profiles)	2
Boletis et al[64], 2001	66 patients with follow up for 12 mo	Short term outcome of LSW (6 mo post-transplant)	Serum creatinine levels were comparable in both groups, and none of them has rejection episode during the follow-up period	4
			Serum triglycerides, cholesterol and mean arterial blood pressure levels were also similar in both groups
Vanrenterghem et al[65], 2000	248 patients with follow up for 12 mo	Evaluating the short-term outcome of steroid withdrawal (3 mo post-transplant) in comparison to maintenance steroids.	Despite the increased incidence of BPAR in steroid withdrawal group (23% versus 14%; P = 0.008), yet the mean serum creatinine levels were comparable in both groups by the end of 12 mo follow up	6
			Steroid withdrawal was associated with a better lipid profile, blood pressure measurements and bone densitometry measurements at 12 mo
Matl et al[66], 2000	88 patients with follow up for 12 months.	To estimate the safety of LSW compared to continuation on triple therapy.	The allograft function, acute rejection rate and biopsy findings were similar in both groups	2
			LSW was associated with a significantly lower serum cholesterol level. However, no significant changes were observed in serum triglycerides or blood pressure measurements
Ahsan et al[67], 1999	266 patients were followed up for one year	The effect of LSW vs continuation on low dose steroid (all patients were receiving cyclosporine and MMF)	LSW was associated with better control of hypertension and lower serum cholesterol level	7
			There is an increased risk of Acute rejection among steroid withdrawal group 30.8% vs 9.8% only within maintenance steroid group
			The risk of rejection or treatment failure within the first-year post-transplantation was 39.6% in blacks versus 16% in nonblack (P < 0.001)
Steroid free immune suppression in paediatrics
Höcker et al[68], 2019	42 paediatric patients (aged 11.2 ± 3.8 yr) were followed for 15 mo	The effect of steroid withdrawal on the recipient’s blood pressure measured via ABPM	After 15 mo of follow up, there were no significant differences between both study groups in terms of allograft functions	6
			Steroid withdrawal was associated with better blood pressure readings as well as restoration of circadian blood pressure rhythm in 71.4% of cases versus 14.3% at baseline (P = 0.002)
Tönshoff et al[69], 2019	106 paediatric recipients with follow up for 12 mo	To estimate the short-term outcome of initiating everolimus with steroid elimination 5 mo post transplantation in comparison to conventional triple therapy	Patient and graft survival were 100% in both groups	6
			No statistically significant differences in the incidence of BPAR, proteinuria, and longitudinal growth
Webb et al[70], 2015	196 subjects with follow up for up to 2 yr	Evaluating the impact of ESW (at day 4 post-transplant) on the longitudinal growth	There was a significant and sustained growth improvement with ESW documented through the two years of follow up, especially in prepubertal children	5
			Patient and graft survival, the incidence of rejection and eGFR were comparable in both groups
Mericq et al[71], 2013	30 paediatric recipients were followed for 12 mo post-transplantation	Evaluating the effect of ESW on the longitudinal growth, body composition, and insulin sensitivity	Steroid withdrawal group showed better longitudinal growth, had lower trunk fat and improved lipid profile parameters compared to the control group	6
Sarwal et al[72], 2012	130 paediatric cases with follow up for 3 yr	Evaluating the safety and efficacy of total SA in comparison to low dose maintenance steroids	Complete SA was associated with improved cholesterol levels (P = 0.034) and lower systolic blood pressure readings (P = 0.017)	5
			Recipients below the age of 5 years showed a significant linear growth catch up with the steroid-free protocol, while other age groups did not show a significant growth difference over the 3 years of follow up
			Non-significant lower incidence of NODAT was recorded in steroid free group (1.7% versus 5.7%; P = 0.373)
			Incident of BPAR, patient survival and graft outcome were comparable between both groups
Benfield et al[73], 2010	132 paediatric cases with data collected for up to 3 yr	Evaluating the outcome of LSW (6 mo post-transplantation) in comparison to low dose maintenance steroids	LSW resulted in a significant improvement of the Cushingoid facies compared to the control group	6
			The standardised height velocity was higher in the withdrawal group (P = 0.033)
			The allograft survival rate at 3 yr was higher in the withdrawal group (98.6% vs 84.5%; P = 0.002)
			Lipid profile, systolic and diastolic blood pressures showed no statistical differences between both groups
			The study was terminated prematurely due to high incidence of PTLD
Grenda et al[74], 2010	196 paediatric recipients follow up data of the first 6 mo post-transplantation	Evaluating the short-term outcome of ESW (at day 4 post-transplant)	ESW significantly improved the growth, especially in prepubertal recipients	6
			Parameters of lipid and glucose metabolism were significantly better in the withdrawal group. However, they suffered a higher incidence of infection and anaemia (P < 0.05 for all mentioned comparisons)
			Incident of BPAR, allograft function, patient and graft survival were similar for both groups
Höcker et al[75], 2010	42 paediatric patients with follow up for 2 yr after the withdrawal of steroids	Evaluating the effect of LSW (1 yr post-transplant) in comparison to maintenance steroids	LSW was associated with superior longitudinal growth (P < 0.001)	6
			Steroid withdrawal was associated with a significant decrease in the prevalence of metabolic syndrome, better control of blood pressure, and improved lipid and carbohydrate metabolism
			Patient survival, graft function and graft survival were not affected by steroid withdrawal

IL-2: Interleukin-2; Dac: Daclizumab; Tac: Tacrolimus; MMF: Mycophenolate mofetil; ABPM: Ambulatory blood pressure monitoring; PTLD: Post-transplant lymphoproliferative disorder; ESW: Early steroid withdrawal; eGFR: Epidermal growth factor receptor; LSW: Late steroid withdrawal; NODAT: New-onset diabetes after transplantation; CMV: Cytomegalovirus; DSA: Donor-specific antibody; HLA: Human leukocyte antigens; BPAR: Biopsy-proven acute rejection.