Jing Gan,Xin Guan,Sheng-Qiang Yu,Yi-Yi Ma,Jian-Dong Gao*

1Department of Nephrology,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; TCM institute of kidney disease,Shanghai University of Traditional Chinese Medicine; Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine),Ministry of Education; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (14DZ2273200),Shanghai,China.2Department of Nephrology,Shanghai Changzheng Hospital affiliated to second military medical University,Shanghai,China.

Abstract

Keywords:LCD,OCD,ADPKD,Meta-analysis

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal cystic disease associated with continuous cyst growth leading to deterioration of kidney function,which is representing the fourth cause of end-stage renal disease (ESRD),for which dialysis or kidney transplantation is needed [1].ESRD occurs between the fourth and seventh decade of life in the majority of affected patients [2].The main clinical symptoms include bilateral renal enlargement,renal pain,gross hematuria and mild albuminuria.There are approximately 1.5 million patients with ADPKD in China [3].ADPKD is a heterogeneous disorder with 2 genes identified:PKD1 and PKD2 [4].The clinical symptoms of PKD1 and PKD2 are similar.The difference between them is that the onset age of PKD2 is relatively late,and the average age of developing into ESRD is l0-20 years later [5].A study [6] on genetic differences in Chinese Han population showed that patients with PKD1 were more than ten years earlier occurrence of hypertension and entered ESRD than PKD2.Therefore,the prognosis of patients with PKD1 is worse than PKD2 [7].

There is no effective drug to control the disease progress.Current therapies are directed towards limiting morbidity and mortality from complications of ADPKD,but not specifically targeting the inhibition of cyst formation [8].In addition to the conservative treatment,surgery method is another choice especially for cysts with diameters of more than 4 cm which are more obvious in the compression of renal parenchyma.At present,though cyst decortication surgery does not appear to significantly retard or arrest progressive renal insufficiency and there is no clinical guide or expert consensus on the cyst decortication surgery in the treatment of ADPKD [9],on the other hand,widespread fears that cyst decompression might hasten renal failure are clearly unfounded.In patients with symptomatic ADPKD who have failed medical management,surgical intervention is a reasonable option since cyst decompression can provide longterm pain relief in the majority of patients [9].In recent years,LCD has been widely used in mainland China for ADPKD with the rapid development of laparoscopic technique.Cyst decompression methods include traditional open cyst decortication (OCD),transabdominal laparoscopic cyst decortication (TLCD) and retroperitoneal laparoscopic cyst decortication (RLCD).With unremitting efforts from surgeons,more safe and effective innovative surgical treatment for ADPKD has been explored in China.Studies about laparoscopic decompression of cysts combined with endodecortication of cyst by flexible ureterscope with holium laser [10],laparoscopic cyst decompression combined with renal capsule decortication surgery [11],and flexible ureteroscope incision drainage unite imaging-guided percutaneous catheterization drainage [12] have been reported in treating ADPKD.These research data showed that LCD combined with flexible ureterscope can achieve better clinical outcome.Although more and more clinical studies have confirmed that LCD can reduce patients' pain and shorten the length of hospital stay,due to the uneven quality of these studies and large differences in research results,their efficacy is not supported by evidence-based medical evidence.Therefore,this study adopted the systematic evaluation method to conduct a comprehensive analysis of the published control studies of LCD and OCD,so as to evaluate the safety,feasibility and other potential advantages of LCD.

1 Methods

We reported the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist [13].The PRISMA checklist was provided (supplement Figure1).

1.1 Search Strategy

Electronic databases were searched using EMBASE (1947 to March 2019),Medline (1989 to March 2019),Cochrane Library (1993 to March 2019),the China National Knowledge Infrastructure (1979 to March 2019),the Wanfang database (1982 to March 2019) and the Chinese Biomedical Literature (1990 to March 2019).The search terms used individually or in combination were "cyst decortication or cyst decompression" and "laparoscopic,laparoscopicassisted,or laparoscopy" and "open or laparotomy" and "autosomal dominant polycystic kidney disease or polycystic kidney disease."The last search was performed on March 16,2019.Furthermore,we also performed a manual search of references of articles and reviews for additional relevant studies.

1.2 Inclusion and exclusion criteria

The included criteria were:(1) Methods:randomized controlled trials (RCTs),prospective cohort studies,retrospective cohort studies,case-control studies.(2) Interventions:LCD and OCD.(3) Population:patients diagnosed with PKD.(4) Locations:mainland China.The excluded criteria were:(1) Studies lacking complete literature data.(2) Non-comparable.(3) Duplications; (4) Review articles,conference reports,and case reports.(5) Studies with a sample size of less than 30.

1.3 Data abstraction

Detailed data abstracted from the included trials were:the name of first author,study design,year of publication,study sample included in the laparoscopic and open surgeries,sex and age of subjects,cyst diameter,operative time,postoperative hospital stay,time to postoperative ambulation,time to first flatus,intraoperative blood loss,analgesic dosage,Scr,Bun,systolic and diastolic blood pressure.

1.4 Data analysis and quality assessment

The statistical analysis was conducted with Revman 5.3 software provided by Cochrane Collaboration for all statistical calculations [14].For continuous variables (operative time,postoperative hospital stay,time to postoperative ambulation,time to first flatus,intraoperative blood loss,analgesic dosage,Scr,Bun,systolic and diastolic blood pressure),mean difference (MD) with 95% confidence interval (CI) was calculated.

The heterogeneity was assessed usingI2test.The value ofI2was used to determine the presence of heterogeneity.IfP＜ 0.01 orI2＞ 50%,heterogeneity was considered statistically significant,randomeffect model was used; Otherwise,it was determined that there be no heterogeneity,fixed-effect model was used.A subgroup analysis was conducted when the heterogeneity was high.The Z test was used to compare the overall effects of treatment group and control group,and differences were considered to be statistically significant atP＜ 0.05.

Risk of bias of RCTs was performed by the Cochrane risk of bias method [15].The quality of nonrandomized controlled studies (nRCTs) was assessed using the Newcastle-Ottawa scale (NOS) [16].This scale rates the quality of the included studies on eight parameters,categorised into three topics:selection of the study population,comparability of the groups under study and number of outcomes reported.The maximum score of this scale is 9,and we considered high quality to a study awarded 6 or more score.

2 Results

Finally,a total of 9 studies enrolling 761 patients were identified as appropriate for inclusion in this analysis (Figure1),which contained 5 RCTs [21-25] and 4 nRCTs [17-20],of these enrolling patients,362 (48%) and 399 (52%) patients underwent LCD and OCD,respectively.Characteristics of all the included studies were summarized (Table1).Risk of bias for RCTs were assessed,all these studies presented low risks (Figure2).The quality of nRCTs assessed by the NOS is presented (Table2).Most of them had a score of 6-8,and 1 study had a score of 9.All these studies considered high quality.

Figure1.PRISMA flow diagram of the meta-analysis

Table1:Characteristics of 9 included trials

Figure2.Risk of bias for 5 RCTs

Table2.Newcastle-Ottawa scale assessment of 4 nRCTs

2.1 Meta-analysis

Operative time

A total of 5 studies included data on operative time.The LCD had an obvious advantage of a shorter operative time (MD = -36.24,95%CI:-44.20 ～ -28.28,P＜ 0.00001).This result showed a significant heterogeneity among these studies (I2= 72%,P= 0.006) (Figure3).

Postoperative hospital stay

Six articles presented this outcome.The length of postoperative hospital stay in the LCD group was shorter than that of the OCD group (MD = -4.04,95%CI:-5.13 ～ -2.95,P＜ 0.00001).This result also showed a significant heterogeneity among these studies (I2= 90%,P＜ 0.00001) (Figure4).

Time to postoperative ambulation

We identified only 3 trials with relevant data.The time to postoperative ambulation in the LCD group was earlier than that of the OCD group (MD = -14.90,95%CI:-16.33 ～ -13.48,P＜ 0.00001).This result showed no heterogeneity (I2= 0%,P=0.78) (Figure5).

Time to first flatus

Six trials reported this outcome.The time to first flatus in the LCD group was earlier than that of the OCD group [(MD = -1.52 days,95% CI:-1.65 ～ -1.40,P＜ 0.00001) (Figure6a); (MD = -10.76 hours,95% CI:-12.71 ～ -8.81,P＜ 0.00001) (Figure6b)].This result showed no heterogeneity measured by days (I2= 0%,P= 0.80) (Figure6a) or by hours (I2= 0%,P= 0.67) (Figure6b).

Intraoperative blood loss

We identified 6 trials with relevant data.The intraoperative blood loss in the LCD group was lower than that of the OCD group (MD = -159.81,95%CI:-243.32 ～ -76.31,P= 0.0002).This result also showed a significant heterogeneity among these studies (I2= 100%,P＜ 0.00001) (Figure7).

Analgesic dosage

Three trials presented this outcome.The analgesic dosage in the LCD group was lower than that of the OCD group (MD= -56.62,95%CI:-84.16 ～ -29.08,P＜ 0.0001).This result also showed a significant heterogeneity among these studies (I2= 97%,P＜ 0.00001) (Figure8).

Figure3.Forest plot of operative time

Figure4.Forest plot of postoperative hospital stay

Figure5.Forest plot of time to postoperative ambulation

Figure6.Forest plot of time to first flatus

Figure7.Forest plot of intraoperative blood loss

Figure8.Forest plot of analgesic dosage

Scr and Bun

Three literatures reported the changes of renal function (Scr and Bun) after one month follow-up.For the subgroup analysis based on different surgical approaches,we divided the studies into two subgroups:retroperitoneal approach or transabdominal approach.There was no significant difference of these two subgroups in Scr (MD = -30.27,95%CI:-41.42 ～ -193,P= 0.38),this result showed no heterogeneity (I2= 0%,P= 0.66) (Figure9a).There was no significant difference of these two subgroups in Bun (MD = -2.31,95%CI:-2.87 ～ -1.75,P= 0.14),this result also showed no heterogeneity (I2= 19%,P= 0.29) (Figure9b).Four studies reported the changes of Scr and three studies mentioned the changes of Bun after three months follow-up.Meta-analysis showed no statistical significance between the groups in Scr (MD = -12.65,95%CI:-26.82 ～ 1.52,P= 0.08),this result showed a high heterogeneity (I2= 76%,P= 0.005) (Figure9c).Meta-analysis showed no statistical significance between the groups in Bun (MD = -1.69,95%CI:-4.03 ～ 0.65,P= 0.16),this result also showed a significant heterogeneity among these studies (I2= 96%,P＜ 0.00001) (Figure9d).

Systolic and diastolic blood pressure

We identified four trials reported systolic blood pressure,three trials with retroperitoneal approach and only one trial with transabdominal approach.Considering the different surgical approaches,we divided the studies into two subgroups:retroperitoneal approach or transabdominal approach.There was no significant difference of these two subgroups (MD = -1.02,95%CI:-5.79 ～ 3.74,P= 0.18),this result showed a moderate heterogeneity (I2= 55%,P= 0.08) (Figure10a).The diastolic blood pressure was recorded in only two trials.Meta-analysis showed no statistical significance between the groups (MD = -0.90,95%CI:-4.79 ～ 2.99,P= 0.65),this result also showed a moderate heterogeneity (I2= 55%,P= 0.14) (Figure10b).

2.2 Sensitivity analysis and subgroup analysis

The sensitivity analysis of heterogeneity in metaanalysis includes changing inclusion criteria,excluding low-quality research,using different statistical methods or models to analyze the same data.Since there is no significant controversy about inclusion criteria,no obvious low-quality research,we used different models to analyze heterogeneity.Fixed and random effects models were used to test the indicators with higher sensitivity.Moreover,we divided the studies into two subgroups:retroperitoneal approach or transabdominal approach.It was found that there was no significant change in the results of the two models,which indicated that the sensitivity was low and the results were more reliable.The underlying reasons of heterogeneity may be differences in the surgical experience of different operators and most articles in this meta-analysis were retrospective studies.

Figure9.Forest plot of Scr and Bun

Figure10.Forest plot of Systolic and diastolic blood pressure

3 Discussion

Currently,there is no effective method to prevent the progress of ADPKD or induce cyst degeneration.Symptomatic treatment is the only one available so far,which including controlling blood pressure and delaying the progress of chronic renal failure (CRF) [26].Many studies have shown that renal volume is an important indicator to evaluate the development degree of ADPKD and reflect the degree of impaired renal function.There exists a significant negative correlation between renal volume and renal function [27,28].The compression of cysts especially cysts over 4cm in diameter is more obvious to renal parenchyma.Cysts located in the hilum of the kidney will compress the renal artery,which can easily induce the increase of plasma renin leading to hypertension and other symptoms such as secondary infection caused by calyx obstruction [29].This suggests that the purpose of surgery for ADPKD is to remove cysts as far as possible,especially the larger cysts that have obvious compression on the kidney,reduce the volume of the kidney and relieve the internal pressure of the kidney to protect most of the remaining renal units from squeezing and further damage.So as to partly improve the condition of renal ischemia and restore renal function units to delay disease progression of ESRD.At present,there is no standard surgical treatment for ADPKD [30].The surgical methods used to treat ADPKD mainly include renal cyst puncture,OCD,LCD and kidney transplantation [9].Renal cyst decompression as a method of treating ADPKD is still being carried out in China.A retrospective study [31] reported 450 patients with ADPKD who were treated with cyst decompression achieving substantial longterm effects.The follow-up data showed that cyst decompression as a domestically prevalent method for polycystic kidney cysts may affect the natural process of renal function decline in patients with ADPKD and delay the progression of these patients into renal failure stage.Patients with ADPKD may benefit from cyst decompression for survival.The author also found that PKD2 compared to PKD1 may be a protective factor for the kidney failure.Hematuria and hypertention,as common complications in patients with ADPKD,may be risk factors.

With the popularization of laparoscopic technology and the growth of patient needs,most medical institutions are currently using LCD for the treatment of ADPKD.Laparoscopy can magnify and display more fine structures such as blood vessels,nerves and fascia,which is conducive to the delicate anatomical operation.According to the different surgical approaches,laparoscopic surgery can be divided into transperitoneal and retroperitoneal approaches.It needs to go through more abdominal organs through the abdominal approach for the characteristics of anatomical structure,so the operation time is longer,the recovery of patients is slower,and there are many serious complications such as vascular or organ injury [32].Retroperitoneal approach is a better choice.One of the most important advantages of retroperitoneal approach is that it can directly reach to the affected area with isolating and damaging less tissue.There is no risk of contaminating of the abdominal cavity since it does not interfere with the abdominal viscera.Which means it can greatly reduce the occurrence of complications such as gastrointestinal reactions,abdominal infection and adhesion [33].As can be seen from Table1,there are 9 trails about RLCD while only 2 trails about TLCD included in our study.Retroperitoneal approach is more commonly used in clinical practice for its advantages.

This study included 5 RCTs and 4 retrospective casecontrol studies.Through analysis and comparison,it can be seen that LCD is more safe and feasible compared with OCD in the treatment of ADPKD.Meta-analysis shows that LCD can not only shorten the operation time,hospital stay,time to postoperative ambulation,and time to first flatus,but also reduce the intraoperative blood loss,postoperative pain and the use of painkillers.Cyst decortication is highly effective in the management of disease-related chronic pain for the majority of patients with ADPKD,providing durable pain relief in this patient population [34].As a minimally invasive operation,LCD not only can alleviate the compression of cysts on renal parenchyma but also can protect most the remaining renal units from squeezing and further damage,thus better solve hypertension,improve the status of renal ischemia and delay the development of CRF [20].LCD has the advantages of small incision,low trauma,short operation time,less bleeding and pain relief,which can enable patients to get out of bed as soon as possible (P ＜ 0.00001 ).That is conducive to the recovery of the patient's body and brings better short-term curative effect to the patient [35].Compared with the traditional open surgery,the effect is equally ideal.However,OCD with greater trauma is generally not used clinically.It can be combined with LCD when dealing with other kidney diseases.The key to successful surgical treatment is to perform operation as early as possible.Cyst decompression must be thorough,the decompression of small deep cysts should not be abandoned [36].

Although LCD has many advantages,it also has some limitations.The operation and hospitalization time was significantly shortened,which could not show the performance of surgeons.In clinical practice and other literatures,it is common to see that some patients still fail to achieve the expected results of surgery.The author [11] thinks that LCD can only remove the surface and superficial cysts of the kidney,some of them are large cysts in the deep part of the kidney or in the sinus of the kidney,which are far away from the capsule of the kidney,it is difficult to find these missing deep cysts in laparoscopic surgery,the compression of the kidney is greater than that located on the surface of the kidney.Failure to clear the facial and superficial cysts leads to unsatisfactory decompression,which may be one of the controversial reasons for this surgery.In order to solve this problem,some researchers [10,12] tried flexible ureteroscopic cyst incision and internal drainage combined with LCD in many cases.Compared with laparoscopic surgery,flexible ureteroscopic cyst incision has the advantages of easy operation,mild trauma,little stimulation and injury to the kidney [37].The disadvantage is that it can only drain the cysts which protrude into the pelvis inside the kidney,but can not deal with the cysts on the surface and superficial cysts of the kidney.Combined with the advantages and disadvantages of the two metod of operations,the authors [10,12] found that the advantages and disadvantages of the two methods can be complementary.Laparoscopic surgery can remove the surface and superficial cysts of the kidney [38].The application of ureteroscopic endoscopic incision can remove those deep cysts that cannot be touched by laparoscope.From the results of these study,it can be seen that flexible ureteroscopic cyst incision combined with LCD is more effective in removing cysts more than 4 cm in diameter,reducing the size of the kidney to a greater extent and improving renal function,thus achieving better clinical results.This study explored the clinical effects and potential advantages of LCD in the treatment of ADPKD from the perspective of evidence-based medicine.LCD can be used as a choice for minimally invasive surgery of ADPKD.

3.1 Limitation

Some limitations of this meta-analysis need to be noted.Provost [39] argued that the best evidence came from meta-analysis based on homogeneous randomized controlled studies,followed by prospective cohort studies,and then retrospective cohort studies,case-control studies.As can be seen from table 1,six of the eleven literatures included in this study were retrospective trials,the results of this study still need to be further verified by large sample and randomized controlled trials.In addition,the short follow-up time and lack of postoperative follow-up criteria in some cases may affect the accuracy of meta-analysis results.For example,only four articles reported the changes of blood pressure and renal function after operation.Whether the renal metabolic indexes of patients with ADPKD have been improved or the renal physiological function has been restored postoperative need further study.It is suggested that patients should be reexamined by CT or B-mode ultrasonography one week to three months after operation to clarify the improvement of kidney shape,so as to compare with preoperative kidney volume.Therefore,the above conclusions still need to be further validated by rigorously designed large sample control experiments.What's more,differences in indications and technical approaches of LCD by different operators may lead to sample bias or selection bias.Finally,we did not discuss the long-term prognosis and recurrence rate of LCD and OCD.

3.2 Conclusion

In conclusion,LCD in adult patients with ADPKD has obtained equivalent clinical effect to OCD,has smaller trauma,and is beneficial to postoperative recovery.Which has a certain guiding significance for the clinical use and treatment of ADPKD.