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Percutaneous Nephrolithotomy and Chronic Kidney Disease: Results from the CROES PCNL Global Study
Urolithiasis/Endourology
Percutaneous Nephrolithotomy and Chronic Kidney Disease: Results from the CROES PCNL Global Study Krish Sairam, Cesare M. Scoffone, Peter Alken, Burak Turna, Hiren S. Sodha, Jorge Rioja, J. Stuart Wolf, Jr. and Jean J.M.C.H. de la Rosette*,† on behalf of the CROES PCNL Study Group From the Department of Urology, Global Hospitals and Health City (KS), Chennai, Tamil Nadu and RG Stone Urology and Laparoscopy Hospital (HSS), Mumbai, India, and Departments of Urology, Cottolengo Hospital (CMS), Torino, Italy, University Hospital Mannheim (PA), Mannheim, Germany, Ege University School of Medicine (BT), Izmir, Turkey, Hospital Miguel Servet (JR), Zaragoza, Spain, University of Michigan (JSW), Ann Arbor, Michigan, and Academic Medical Center University Hospital (JJMCHdlR), Amsterdam, The Netherlands
Purpose: We compared the characteristics and outcomes of patients treated with percutaneous nephrolithotomy in the CROES (Clinical Research Office of the Endourological Society) Global Study according to preoperative renal function. Materials and Methods: Prospective data on consecutive patients treated with percutaneous nephrolithotomy in a 1-year period were collected from 96 participating centers. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula based on preoperative serum creatinine measurement. Patients were divided into 3 groups by glomerular filtration rate, including chronic kidney disease stages 0/I/II— greater than 60, stage III—30 to 59 and stages IV/V—less than 30 ml/minute/1.73 m2. Patient characteristics, operative characteristics, outcomes and morbidity were assessed. Results: Estimated glomerular filtration rate data were available on 5,644 patients, including 4,436 with chronic kidney disease stages 0/I/II, 994 with stage III and 214 with stages IV/V. A clinically significant minority of patients with nephrolithiasis presented with severe chronic kidney disease. A greater number of patients with stages IV/V previously underwent percutaneous nephrolithotomy, ureteroscopy or nephrostomy and had positive urine cultures than less severely affected patients, consistent with the higher incidence of staghorn stones in these patients. Patients with chronic kidney disease stages IV/V had statistically significantly worse postoperative outcomes than those in the other chronic kidney disease groups. Conclusions: Poor renal function negatively impacts the post-percutaneous nephrolithotomy outcome. By more aggressive removal of kidney stones, particularly staghorn stones, at first presentation and more vigilantly attempting to prevent recurrence through infection control, pharmacological or other interventions, the progression of chronic kidney disease due to nephrolithiasis may be mitigated.
Abbreviations and Acronyms CKD ⫽ chronic kidney disease eGFR ⫽ estimated GFR GFR ⫽ glomerular filtration rate PCNL ⫽ percutaneous nephrolithotomy URS ⫽ ureteroscopy Submitted for publication February 17, 2012. Supported by an unrestricted educational grant from Olympus. Supplementary material for this article can be obtained at http://www.croesoffice.org. * Correspondence: Department of Urology, AMC University Hospital, Meibergdreef 9, 1105 AZ Amsterdam Z-O, The Netherlands (telephone: ⫹31-20-5666030; FAX: ⫹31-20-5669585; e-mail: [email protected]). † Financial interest and/or other relationship with Boston Scientific.
Key Words: kidney; renal insufficiency; nephrostomy, percutaneous; nephrolithiasis; glomerular filtration rate THE detrimental effects of nephrolithiasis on renal function is well known but it was not until recently that the
risk of renal insufficiency was considered during the clinical metabolic evaluation of patients with renal stones.1 It
0022-5347/12/1884-1195/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.027 Vol. 188, 1195-1200, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
www.jurology.com
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PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
is now widely recognized that while renal failure due directly to renal stones is infrequent, certain types of kidney stones, eg struvite stones, have a greater detrimental effect on kidney function than others.1,2 Nephrolithiasis duration, the stone recurrence rate, urinary tract infection and obstruction, gravel size and the number of stone procedures are other factors that influence renal function.1,3 In certain circumstances even small stones, when left untreated, might lead to renal insufficiency and potentially cause renal failure.4,5 The true prevalence of obstructive nephropathy associated with nephrolithiasis is unknown.5 Jungers et al suggested that the overall proportion of nephrolithiasis related end stage renal disease in patients on maintenance dialysis was 3.2%,6 while others estimated the prevalence of urinary stone disease to be between 1.9% and 7.7% in patients with CKD.7,8 Historically, serum creatinine measurements have been used to assess renal function but currently eGFR is considered a more accurate tool and the method of choice for evaluating overall renal function. The Modification of Diet in Renal Disease formula for GFR estimation is recommended for routine use.9 Renal insufficiency is a recognized risk factor for increased intraoperative and postoperative complications, and managing urinary stones in patients with CKD is often difficult.10,11 After renal insufficiency is present at any level, it is important that any further renal nephropathy likely to be caused through invasive procedures to remove stones effectively is balanced against further loss of kidney function due to the detrimental effects caused by the presence of stones. Clearly, a stone removal procedure that is effective, minimizes recurrence and decreases renal damage is highly desirable for kidney stone management. In this context, the technique of PCNL is currently considered an attractive option with minimal associated morbidity and mortality in patients with CKD. Several reports highlight that the PCNL procedure does not provoke any clinically significant nephron damage and, indeed, renal function outcomes were noted to improve after surgery.5,12–14 To generate a global database on the usefulness of PCNL, principally by assessing morbidity and factors that influence outcomes, CROES performed the PCNL Global Study.15 In this CROES analysis, postoperative PCNL outcomes were compared in patients presenting with varying levels of preoperative renal function.
MATERIALS AND METHODS CROES centrally collected prospective data on patients treated with PCNL for the primary or secondary management of kidney stones. At 96 participating centers data
were collected on consecutive patients for a full year. Details of the study organization and methods, including the imaging techniques used, were previously published.16 Local guidelines and PCNL practices were followed. There were no study exclusion criteria. The procedure was considered complete when all removable stones had been extracted and patients were stone free for 30 days. Patients who had preoperative serum creatinine level measured were included in this substudy. GFR was estimated using the Modification of Diet in Renal Disease formula based on preoperative serum creatinine measurement. Race was not included in GFR estimates since these data were not collected in the CROES PCNL Global Study. Patients were subsequently divided into 3 groups based on CKD class, including CKD stages 0/I/II—GFR greater than 60, stage III—30 to 59 and stages IV/V—less than 30 ml/minute/1.73 m2. Patient and operative characteristics, outcome and morbidity were assessed. Complications were assessed according to the Clavien score. Bleeding severity was recorded by the treating physician and blood transfusions were given according to local guidelines.
Statistical Analyses SPSS®, version 16.0 was used to analyze the collected data. All data are descriptive and based on frequencies. Comparisons were made of the demographic and postoperative outcomes among the 3 groups of patients classified based on renal function. Statistical tests of significance of the outcome variables were the repeated chi-square test to compare the outcome among each of the 3 categories and the Tukey HSD tests to compare continuous outcome variables.
RESULTS Of the 5,803 patients enrolled in the CROES PCNL study, eGFR data were available on 5,644, including 4,436 with CKD stages 0/I/II, 994 with stage III and 214 with stages IV/V. Table 1 shows a comparison of patient characteristics. The rate of comorbid conditions, eg diabetes mellitus and cardiovascular disease, staghorn stones and the mean stone burden, was lower in patients with CKD stages 0/I/II than in those with more advanced stages. Similarly, those with more advanced CKD tended to have undergone a greater proportion of previous procedures, particularly previous PCNL. Patients with more advanced CKD had a greater incidence of positive urine cultures and had undergone a greater degree of preoperative urinary drainage through placement of percutaneous nephrostomy tubes than patients with CKD stages 0/I/II. The presence of renal anomalies was similar across the 3 groups. Table 2 shows a comparison of outcomes based on renal function. Operative time was significantly longer in patients with CKD stages IV/V than in those with the other levels of renal impairment (III vs 0/I/II p ⫽ 0.003 and IV/V vs 0/I/II p ⫽ 0.001). The
PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
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Table 1. Patient characteristics by CKD stage p Value
No. pts Mean ⫾ SD age No. gender (%): M F Mean ⫾ SD preop creatinine (gm/dl) No. diabetes mellitus (%) No. cardiovascular disease (%) Mean ⫾ SD stone burden (mm2) No. staghorn (%) No. prior PCNL (%) No. prior URS (%) No. prior extracorporeal shock wave lithotripsy (%) No. pos urine culture (%) No. prior nephrostomy (%) No. renal anomaly (%): Ectopic Horseshoe Malrotation
0/I/II
III
IV/V
0/I/II vs III
0/I/II vs IV/V
4,436 47.0 ⫾ 15.2
994 57.8 ⫾ 13.8
214 56.2 ⫾ 13.8
⬍0.001
⬍0.001
0.131
2,609 (58.8) 1,827 (41.2) 0.9 ⫾ 0.2 460 (10.4) 843 (19.1) 357.5 ⫾ 309.5 25.3 581 (13.2) 403.0 (9.1) 979.0 (22.2) 577 (13.4) 258 (5.9)
469 (47.2) 525 (52.8) 1.4 ⫾ 0.3 253 (25.6) 383 (38.8) 358.3 ⫾ 328.8 32.0 166 (16.9) 113.0 (11.5) 187.0 (18.9) 209 (21.9) 106 (10.9)
112 (52.3) 102 (47.7) 3.9 ⫾ 2.2 44 (20.6) 66 (31.0) 357.0 ⫾ 368.0 42.6 51 (23.9) 25.0 (11.9) 25.0 (11.9) 74 (36.3) 63 (29.9)
⬍0.001
0.060
0.171
⬍0.001 ⬍0.001 ⬍0.001 0.311 ⬍0.001 0.002 0.020 0.023 ⬍0.001 ⬍0.001
⬍0.001 ⬍0.001 ⬍0.001 0.780 ⬍0.001 ⬍0.001 0.176 ⬍0.001 ⬍0.001 ⬍0.001
⬍0.001 0.122 0.032 0.859 0.004 0.015 0.881 0.015 ⬍0.001 ⬍0.001
0.003
0.706
0.829
23.0 (0.5) 91.0 (2.1) 50.0 (1.2)
2.0 (0.2) 7.0 (0.7) 19.0 (2.0)
difference in operative time between stages III and IV/V was not statistically significant (p ⫽ 0.214). The stone-free rate decreased with increasing severity of kidney function impairment and it achieved statistical significance when stages 0/I/II were compared with stages III (p ⫽ 0.006) and IV/V (p ⫽ 0.042). No statistical significance was noted in
1.0 (0.5) 2.0 (1.0) 3.0 (1.5)
III vs IV/V
the stone-free rate between CKD stages III and IV/V (p ⫽ 0.565). Hospital stay increased as kidney function decreased and all statistical comparisons between patient groups were significantly different (stage III vs 0/I/II p ⫽ 0.012, IV/V vs 0/I/II p ⫽ 0.001 and III vs IV/V p ⫽ 0.001).
Table 2. Outcome comparison by renal function according to CKD stage p Value
No. pts % Postop nephrostomy % Postop stent Mean ⫾ SD operative time (mins) % Stone free Mean ⫾ SD hospital stay (days) % Fever % Blood transfusion % Pole puncture site: Upper Middle Lower Multiple % Stone re-treatment: URS PCNL Extracorporeal shock wave lithotripsy % Clavien score: I II IIIA IIIB IVA IVB V % Total complication rate
0/I/II
III
IV/V
0/I/II vs III
0/I/II vs IV/V
III vs IV/V
4436 91.0 42.1 83.3 ⫾ 46.9 76.9 4.1 ⫾ 3.2 9.7 4.9
994 91.8 42.4 88.8 ⫾ 50.1 73.2 4.5 ⫾ 3.6 11.7 6.1
214 94.9 47.2 94.9 ⫾ 59.1 71.2 5.8 ⫾ 4.5 18.3 18.4
0.415 0.881 0.003 0.006 0.012 0.061 0.121
0.049 0.141 0.001 0.042 0.001 ⬍0.001 ⬍0.001
0.123 0.195 0.214 0.565 0.001 0.008 ⬍0.001
9.6 16.1 67.3 7.0
10.4 15.6 64.1 9.8
13.6 16.0 51.6 18.8
0.015
⬍0.001
1.4 5.9 6.4
1.7 7.9 5.8
0.9 12.3 3.3
0.155
0.002
0.160
9.5 4.9 2.3 1.3 0.3 0.2 0.0 18.5
16.4 6.1 2.9 1.3 0.6 0.2 0.1 27.6
21.1 6.6 4.2 0.0 1.4 0.5 0.0 33.8
0.001
⬍0.001
0.042
0.001
⬍0.001
0.023
0.0003
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PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
Although it was not significant when CKD stages 0/I/II and III were compared (p ⫽ 0.121), the blood transfusion rate among the groups significantly increased with decreasing kidney function when stages 0/I/II and III were compared with stages IV/V (IV/V vs 0/I/II 4.9%, p ⫽ 0.001 and III vs IV/V p ⫽ 0.001). The fever rate increased with the severity of kidney function impairment. It achieved statistical significance when the rate in patients with CKD stages IV/V was compared with the rate in those with stages 0/I/II (p ⫽ 0.001) and III (p ⫽ 0.008). However, it was not statistically significant when the rate of the moderately severe group was compared with that of the mildly affected group (stage III vs 0/I/II p ⫽ 0.06). As assessed by Clavien scores, the overall complication rate significantly increased as kidney function decreased (stages 0/I/II vs III p ⬍0.001, 0/I/II vs IV/V p ⬍0.001 and III vs IV/V p ⫽ 0.042).
DISCUSSION As part of an ongoing series of CROES PCNL Global Study analyses, outcomes in patients undergoing PCNL were assessed by renal function. In this study 4,436 of 5,644 patients (78.6%) were classified as having CKD stages 0/I/II, which is essentially no or mild disease, 994 (17.6%) had CKD stage III and 214 (3.8%) had CKD stages IV/V, the most severe form of the disease. Therefore, it would appear that kidney stones are essentially a benign condition in terms of the effect on renal function in most kidney stone cases. However, a clinically significant minority of patients with nephrolithiasis presented with more severe CKD, suggesting that kidney stones may contribute to the worsening of renal function. However, the extent of this contribution is unclear. An increase in mean age was noted in patients as kidney function deterioration progressed from stages 0/I/II to stages III, IV and V. This probably reflects the generally reported increase in the prevalence of CKD as the population ages, which is even more marked in stone formers.17 A similar trend in renal function deterioration is also noted in patients with other comorbid conditions, which suggests that a proportion of renal function loss may be due to a comorbidity. Nevertheless, kidney stones clearly have a part in worsening renal function, particularly in patients with staghorn stones. Staghorn stones typically fill a large proportion of the renal pelvis and extend into the calyces.18 –20 Rapidly growing staghorn stones are associated with renal infection and, if untreated, prolonged infection promotes nephropathy and compromises renal function.21 Residual staghorn fragments seed rapid recurrent stone formation, making aggressive clearance of these stones
imperative if multiple nephrolithotripsy procedures are to be avoided.20,21 The study revealed that patients with CKD stages IV/V previously underwent PCNL, URS or nephrostomy and had positive urine cultures to a greater extent than less severely affected patients, consistent with the greater incidence of staghorn stones in these patients. However, increased infection rates may not be due only to staghorn stones. Patients with CKD are immunosuppressed, which may contribute to the increased rate of infection before surgery.5 Preoperative nephrostomy to decompress the pelvicalyceal system and preserve renal function is a potential source of pre-PCNL urinary infection in patients with previously culture negative urine. Clearly, a complex interaction among stone disease, interventions, chronic infection and poor drainage impacts renal function. Regardless of the significantly increased operative time, the stone-free rate in patients with CKD stages IV/V was significantly less than in those with stages 0/I/II. Hospital stay was also significantly greater and the incidence of pyrexia in patients with CKD stages IV/V was approximately twice that in those with stages 0/I/II. This higher sepsis rate observed in more severely affected patients with CKD is most likely related to the increase in preoperative risks factors for infection noted in this patient group, such as higher preoperative positive cultures, and staghorn stone and preoperative nephrostomy rates. The greater rate of staghorn stones in patients with CKD stages IV/V may also contribute to the poorer stone-free rate in these patients compared with the rate in those with stages 0/I/II. However, the increase in operative time could also be attributable in part to the greater need for blood transfusion in patients with CKD stages IV/V, reflecting a greater hemolytic tendency during PCNL. Renal nephrosis and the associated thinning of the renal parenchyma associated within CKD result in poor hemostasis by tamponade which, compounded by the tendency of patients with CKD toward anemia, may also contribute to the need for transfusion.5 Patients with CKD are frequently immunocompromised and susceptible to chronic recurrent infections, which may promote further nephritic damage and fibrosis. Therefore, combined with the inadvertent nephritic damage to the kidney due to percutaneous procedures, the tendency to bleed further increases during repeat PCNL cycles to remove recurrent stones.1 The CROES PCNL Global Study analysis reported sought to assess the effect of PCNL on postoperative outcomes by renal function. While the majority of patients treated with PCNL do not have CKD to any great extent, a clinically significant minority have severely restricted renal function and
PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
in this group of patients post-PCNL outcomes are worse. A major contributory factor to worsening renal function is staghorn stones. Also known as struvite or infection stones, they are universally considered the most frequent cause of urolithiasis associated with end stage renal disease.1,22,23 Of the 3.2% of patients requiring renal replacement therapy due to nephrolithiasis, this was attributable to struvite stones in 42.2%, while calcium and uric acid stones contributed 26.7% and 17.8%, respectively.6 Struvite stones in particular are difficult to eradicate and are associated with persistent disease/infection, high recurrence levels and the need for multiple procedures, which negatively impact renal function.3 Furthermore, small stones or fragments that move and obstruct the urinary tract also accelerate the course of renal disease.1 Several reports document that early, aggressive intervention with PCNL, aiming at complete stone clearance and prevention of urinary stone infection, improves or stabilizes renal function in many such patients.4,8,10,12,24 –26 While patients with compromised renal function may benefit from stone removal and, therefore, an improvement in renal function, this must be balanced by the detrimental effects of the procedures. However, many studies claiming renal improvement following PCNL used serum creatinine as a measure of success. More recent studies sought to show improvements in eGFR.7,11 The outcome in 1
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study suggested that an improvement in eGFR was greater in patients with mild to moderate renal failure than in those with severe CKD.7 It would be reasonable to assume that those patients with severe renal failure would be less likely to gain benefit, principally because the damage already done to the kidney was severe and irreversible. However, in the second study, patients with late stage CKD, although a small number, achieved significant improvement, while unexpected deterioration was seen in some patients with less severe CKD.11 Urinary tract infection appeared to be the underlying cause of the observation in the latter study, emphasizing the need for constant vigilance against infection in all PCNL cases regardless of CKD status. However, the 2 studies agree that through ever more aggressive stone removal and more effective prevention of infection, renal replacement therapy can still be deferred in most patients with renal stone disease.7,11
CONCLUSIONS Poor renal function negatively impacts the postPCNL outcome. Although other factors almost certainly contribute to CKD, by more aggressively removing these stones, particularly staghorn stones, at first presentation and more vigilantly attempting to prevent recurrence through infection control, pharmacological or other interventions, the progression of CKD due to nephrolithiasis may be halted.
REFERENCES 1. Gambaro G, Favaro S and D’Angelo A: Risk of renal failure in nephrolithiasis. Am J Kidney Dis 2001; 37: 233. 2. Worcester EM, Parks JH, Evan AP et al: Renal function in patients with nephrolithiasis. J Urol 2006; 176: 600. 3. Marangella M, Bruno M, Cosseddu D et al: Prevalence of chronic renal insufficiency in the course of idiopathic recurrent calcium stone disease: risk factors and patterns of progression. Nephron 1990; 54: 302. 4. Yaycioglu O, Egilmez T, Gul U et al: Percutaneous nephrolithotomy in patients with normal versus impaired renal function. Urol Res 2007; 35: 101. 5. Gopalakrishnan G and Prasad GS: Management of urolithiasis with chronic renal failure. Curr Opin Urol 2007; 17: 132. 6. Jungers P, Joly D, Barbey F et al: ESRD caused by nephrolithiasis: prevalence, mechanisms and prevention. Am J Kidney Dis 2004; 44: 799. 7. Kurien A, Baishya R, Mishra S et al: The impact of percutaneous nephrolithotomy in patients with
chronic kidney disease. J Endourol 2009; 23: 14031. 8. Kukreja R, Desai M, Patel SH et al: Nephrolithiasis associated with renal insufficiency: factors predicting outcome. J Endourol 2003; 17: 875. 9. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis, suppl., 2002; 39: S1. 10. Chandhoke PS, Albala DM and Clayman RV: Long-term comparison of renal function in patients with solitary kidneys and/or moderate renal insufficiency undergoing extracorporeal shock wave lithotripsy or percutaneous nephrolithotomy. J Urol 1992; 147: 1226.
13. Jones DJ, Kellett MJ and Wickham JEA: Percutaneous nephrolithotomy and the solitary kidney. J Urol 1991; 145: 477. 14. Vupputuri S, Soucie JM, McClellan W et al: History of kidney stones as a possible risk factor for chronic kidney disease. Ann Epidemiol 2004; 14: 222. 15. Clinical Research Office of the Endourological Society (CROES). Available at http://www.croesoffice. org/ONGOINGPROJECTS/PCNLstudy/tabid/63/ Default.aspx. Accessed February 17, 2012. 16. de la Rosette J, Assimos D, Desai M et al: The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: indications, complications and outcomes in 5803 patients. J Endourol 2011; 25: 11.
11. Bilen CY, Inci K, Kocak B et al: Impact of percutaneous nephrolithotomy on estimated glomerular filtration rate in patients with chronic renal disease. J Endourol 2008; 22: 895.
17. Worcester E, Parks JH, Josephson MA et al: Causes and consequences of kidney loss in patients with nephrolithiasis. Kidney Int 2003; 64: 2204.
12. Goel MC, Ahlawat R, Kumar M et al: Chronic renal failure and nephrolithiasis in a solitary kidney: role of intervention. J Urol 1997; 157: 1574.
18. Preminger GM, Assimos DG, Lingeman JE et al: Chapter 1. AUA guideline on management of staghorn calculi: diagnosis and treatment recommenda-
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tions. AUA Nephrolithiasis Guideline Panel. J Urol 2005; 173: 1991. 19. Ganpule AP and Desai M: Management of the staghorn calculus: multiple-tract versus single-tract percutaneous nephrolithotomy. Curr Opin Urol 2008; 18: 220. 20. Meng M, Stoller ML and Minor T: Struvite and staghorn calculi. Emedicine, November 24, 2009. Available at http://emedicine.medscape.com/ article/439127. Accessed February 17, 2012.
21. Koga S, Arakaki Y, Matsuoka M et al: Staghorn calculi—long-term results of management. Br J Urol 1991; 68: 122. 22. Streem SB: Long-term incidence and risk factors for recurrent stones following percutaneous nephrolithotomy or percutaneous nephrolithotomy/extracorporeal shock wave lithotripsy for infection related calculi. J Urol 1995; 153: 584. 23. Teichman JM, Long RD and Hulbert JC: Longterm renal fate and prognosis after staghorn calculus management. J Urol 1995; 153: 1403.
24. Gupta M, Bolton DM, Gupta PN et al: Improved renal function following aggressive treatment of urolithiasis and concurrent mild to moderate renal insufficiency. J Urol 1994; 152: 1086. 25. Agrawal MS, Aron M and Asopa HS: Endourological renal salvage in patients with calculus nephropathy and advances uraemia. BJU Int 1999; 84: 252. 26. Kuzgunbay B, Gul U, Turunc T et al: Long-term renal function and stone recurrence after percutaneous nephrolithotomy in patients with renal insufficiency. J Endourol 2010; 24: 305.
Percutaneous Nephrolithotomy and Chronic Kidney Disease: Results from the CROES PCNL Global Study Krish Sairam, Cesare M. Scoffone, Peter Alken, Burak Turna, Hiren S. Sodha, Jorge Rioja, J. Stuart Wolf, Jr. and Jean J.M.C.H. de la Rosette*,† on behalf of the CROES PCNL Study Group From the Department of Urology, Global Hospitals and Health City (KS), Chennai, Tamil Nadu and RG Stone Urology and Laparoscopy Hospital (HSS), Mumbai, India, and Departments of Urology, Cottolengo Hospital (CMS), Torino, Italy, University Hospital Mannheim (PA), Mannheim, Germany, Ege University School of Medicine (BT), Izmir, Turkey, Hospital Miguel Servet (JR), Zaragoza, Spain, University of Michigan (JSW), Ann Arbor, Michigan, and Academic Medical Center University Hospital (JJMCHdlR), Amsterdam, The Netherlands
Purpose: We compared the characteristics and outcomes of patients treated with percutaneous nephrolithotomy in the CROES (Clinical Research Office of the Endourological Society) Global Study according to preoperative renal function. Materials and Methods: Prospective data on consecutive patients treated with percutaneous nephrolithotomy in a 1-year period were collected from 96 participating centers. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula based on preoperative serum creatinine measurement. Patients were divided into 3 groups by glomerular filtration rate, including chronic kidney disease stages 0/I/II— greater than 60, stage III—30 to 59 and stages IV/V—less than 30 ml/minute/1.73 m2. Patient characteristics, operative characteristics, outcomes and morbidity were assessed. Results: Estimated glomerular filtration rate data were available on 5,644 patients, including 4,436 with chronic kidney disease stages 0/I/II, 994 with stage III and 214 with stages IV/V. A clinically significant minority of patients with nephrolithiasis presented with severe chronic kidney disease. A greater number of patients with stages IV/V previously underwent percutaneous nephrolithotomy, ureteroscopy or nephrostomy and had positive urine cultures than less severely affected patients, consistent with the higher incidence of staghorn stones in these patients. Patients with chronic kidney disease stages IV/V had statistically significantly worse postoperative outcomes than those in the other chronic kidney disease groups. Conclusions: Poor renal function negatively impacts the post-percutaneous nephrolithotomy outcome. By more aggressive removal of kidney stones, particularly staghorn stones, at first presentation and more vigilantly attempting to prevent recurrence through infection control, pharmacological or other interventions, the progression of chronic kidney disease due to nephrolithiasis may be mitigated.
Abbreviations and Acronyms CKD ⫽ chronic kidney disease eGFR ⫽ estimated GFR GFR ⫽ glomerular filtration rate PCNL ⫽ percutaneous nephrolithotomy URS ⫽ ureteroscopy Submitted for publication February 17, 2012. Supported by an unrestricted educational grant from Olympus. Supplementary material for this article can be obtained at http://www.croesoffice.org. * Correspondence: Department of Urology, AMC University Hospital, Meibergdreef 9, 1105 AZ Amsterdam Z-O, The Netherlands (telephone: ⫹31-20-5666030; FAX: ⫹31-20-5669585; e-mail: [email protected]). † Financial interest and/or other relationship with Boston Scientific.
Key Words: kidney; renal insufficiency; nephrostomy, percutaneous; nephrolithiasis; glomerular filtration rate THE detrimental effects of nephrolithiasis on renal function is well known but it was not until recently that the
risk of renal insufficiency was considered during the clinical metabolic evaluation of patients with renal stones.1 It
0022-5347/12/1884-1195/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.06.027 Vol. 188, 1195-1200, October 2012 RESEARCH, INC. Printed in U.S.A.
AND
www.jurology.com
1195
1196
PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
is now widely recognized that while renal failure due directly to renal stones is infrequent, certain types of kidney stones, eg struvite stones, have a greater detrimental effect on kidney function than others.1,2 Nephrolithiasis duration, the stone recurrence rate, urinary tract infection and obstruction, gravel size and the number of stone procedures are other factors that influence renal function.1,3 In certain circumstances even small stones, when left untreated, might lead to renal insufficiency and potentially cause renal failure.4,5 The true prevalence of obstructive nephropathy associated with nephrolithiasis is unknown.5 Jungers et al suggested that the overall proportion of nephrolithiasis related end stage renal disease in patients on maintenance dialysis was 3.2%,6 while others estimated the prevalence of urinary stone disease to be between 1.9% and 7.7% in patients with CKD.7,8 Historically, serum creatinine measurements have been used to assess renal function but currently eGFR is considered a more accurate tool and the method of choice for evaluating overall renal function. The Modification of Diet in Renal Disease formula for GFR estimation is recommended for routine use.9 Renal insufficiency is a recognized risk factor for increased intraoperative and postoperative complications, and managing urinary stones in patients with CKD is often difficult.10,11 After renal insufficiency is present at any level, it is important that any further renal nephropathy likely to be caused through invasive procedures to remove stones effectively is balanced against further loss of kidney function due to the detrimental effects caused by the presence of stones. Clearly, a stone removal procedure that is effective, minimizes recurrence and decreases renal damage is highly desirable for kidney stone management. In this context, the technique of PCNL is currently considered an attractive option with minimal associated morbidity and mortality in patients with CKD. Several reports highlight that the PCNL procedure does not provoke any clinically significant nephron damage and, indeed, renal function outcomes were noted to improve after surgery.5,12–14 To generate a global database on the usefulness of PCNL, principally by assessing morbidity and factors that influence outcomes, CROES performed the PCNL Global Study.15 In this CROES analysis, postoperative PCNL outcomes were compared in patients presenting with varying levels of preoperative renal function.
MATERIALS AND METHODS CROES centrally collected prospective data on patients treated with PCNL for the primary or secondary management of kidney stones. At 96 participating centers data
were collected on consecutive patients for a full year. Details of the study organization and methods, including the imaging techniques used, were previously published.16 Local guidelines and PCNL practices were followed. There were no study exclusion criteria. The procedure was considered complete when all removable stones had been extracted and patients were stone free for 30 days. Patients who had preoperative serum creatinine level measured were included in this substudy. GFR was estimated using the Modification of Diet in Renal Disease formula based on preoperative serum creatinine measurement. Race was not included in GFR estimates since these data were not collected in the CROES PCNL Global Study. Patients were subsequently divided into 3 groups based on CKD class, including CKD stages 0/I/II—GFR greater than 60, stage III—30 to 59 and stages IV/V—less than 30 ml/minute/1.73 m2. Patient and operative characteristics, outcome and morbidity were assessed. Complications were assessed according to the Clavien score. Bleeding severity was recorded by the treating physician and blood transfusions were given according to local guidelines.
Statistical Analyses SPSS®, version 16.0 was used to analyze the collected data. All data are descriptive and based on frequencies. Comparisons were made of the demographic and postoperative outcomes among the 3 groups of patients classified based on renal function. Statistical tests of significance of the outcome variables were the repeated chi-square test to compare the outcome among each of the 3 categories and the Tukey HSD tests to compare continuous outcome variables.
RESULTS Of the 5,803 patients enrolled in the CROES PCNL study, eGFR data were available on 5,644, including 4,436 with CKD stages 0/I/II, 994 with stage III and 214 with stages IV/V. Table 1 shows a comparison of patient characteristics. The rate of comorbid conditions, eg diabetes mellitus and cardiovascular disease, staghorn stones and the mean stone burden, was lower in patients with CKD stages 0/I/II than in those with more advanced stages. Similarly, those with more advanced CKD tended to have undergone a greater proportion of previous procedures, particularly previous PCNL. Patients with more advanced CKD had a greater incidence of positive urine cultures and had undergone a greater degree of preoperative urinary drainage through placement of percutaneous nephrostomy tubes than patients with CKD stages 0/I/II. The presence of renal anomalies was similar across the 3 groups. Table 2 shows a comparison of outcomes based on renal function. Operative time was significantly longer in patients with CKD stages IV/V than in those with the other levels of renal impairment (III vs 0/I/II p ⫽ 0.003 and IV/V vs 0/I/II p ⫽ 0.001). The
PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
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Table 1. Patient characteristics by CKD stage p Value
No. pts Mean ⫾ SD age No. gender (%): M F Mean ⫾ SD preop creatinine (gm/dl) No. diabetes mellitus (%) No. cardiovascular disease (%) Mean ⫾ SD stone burden (mm2) No. staghorn (%) No. prior PCNL (%) No. prior URS (%) No. prior extracorporeal shock wave lithotripsy (%) No. pos urine culture (%) No. prior nephrostomy (%) No. renal anomaly (%): Ectopic Horseshoe Malrotation
0/I/II
III
IV/V
0/I/II vs III
0/I/II vs IV/V
4,436 47.0 ⫾ 15.2
994 57.8 ⫾ 13.8
214 56.2 ⫾ 13.8
⬍0.001
⬍0.001
0.131
2,609 (58.8) 1,827 (41.2) 0.9 ⫾ 0.2 460 (10.4) 843 (19.1) 357.5 ⫾ 309.5 25.3 581 (13.2) 403.0 (9.1) 979.0 (22.2) 577 (13.4) 258 (5.9)
469 (47.2) 525 (52.8) 1.4 ⫾ 0.3 253 (25.6) 383 (38.8) 358.3 ⫾ 328.8 32.0 166 (16.9) 113.0 (11.5) 187.0 (18.9) 209 (21.9) 106 (10.9)
112 (52.3) 102 (47.7) 3.9 ⫾ 2.2 44 (20.6) 66 (31.0) 357.0 ⫾ 368.0 42.6 51 (23.9) 25.0 (11.9) 25.0 (11.9) 74 (36.3) 63 (29.9)
⬍0.001
0.060
0.171
⬍0.001 ⬍0.001 ⬍0.001 0.311 ⬍0.001 0.002 0.020 0.023 ⬍0.001 ⬍0.001
⬍0.001 ⬍0.001 ⬍0.001 0.780 ⬍0.001 ⬍0.001 0.176 ⬍0.001 ⬍0.001 ⬍0.001
⬍0.001 0.122 0.032 0.859 0.004 0.015 0.881 0.015 ⬍0.001 ⬍0.001
0.003
0.706
0.829
23.0 (0.5) 91.0 (2.1) 50.0 (1.2)
2.0 (0.2) 7.0 (0.7) 19.0 (2.0)
difference in operative time between stages III and IV/V was not statistically significant (p ⫽ 0.214). The stone-free rate decreased with increasing severity of kidney function impairment and it achieved statistical significance when stages 0/I/II were compared with stages III (p ⫽ 0.006) and IV/V (p ⫽ 0.042). No statistical significance was noted in
1.0 (0.5) 2.0 (1.0) 3.0 (1.5)
III vs IV/V
the stone-free rate between CKD stages III and IV/V (p ⫽ 0.565). Hospital stay increased as kidney function decreased and all statistical comparisons between patient groups were significantly different (stage III vs 0/I/II p ⫽ 0.012, IV/V vs 0/I/II p ⫽ 0.001 and III vs IV/V p ⫽ 0.001).
Table 2. Outcome comparison by renal function according to CKD stage p Value
No. pts % Postop nephrostomy % Postop stent Mean ⫾ SD operative time (mins) % Stone free Mean ⫾ SD hospital stay (days) % Fever % Blood transfusion % Pole puncture site: Upper Middle Lower Multiple % Stone re-treatment: URS PCNL Extracorporeal shock wave lithotripsy % Clavien score: I II IIIA IIIB IVA IVB V % Total complication rate
0/I/II
III
IV/V
0/I/II vs III
0/I/II vs IV/V
III vs IV/V
4436 91.0 42.1 83.3 ⫾ 46.9 76.9 4.1 ⫾ 3.2 9.7 4.9
994 91.8 42.4 88.8 ⫾ 50.1 73.2 4.5 ⫾ 3.6 11.7 6.1
214 94.9 47.2 94.9 ⫾ 59.1 71.2 5.8 ⫾ 4.5 18.3 18.4
0.415 0.881 0.003 0.006 0.012 0.061 0.121
0.049 0.141 0.001 0.042 0.001 ⬍0.001 ⬍0.001
0.123 0.195 0.214 0.565 0.001 0.008 ⬍0.001
9.6 16.1 67.3 7.0
10.4 15.6 64.1 9.8
13.6 16.0 51.6 18.8
0.015
⬍0.001
1.4 5.9 6.4
1.7 7.9 5.8
0.9 12.3 3.3
0.155
0.002
0.160
9.5 4.9 2.3 1.3 0.3 0.2 0.0 18.5
16.4 6.1 2.9 1.3 0.6 0.2 0.1 27.6
21.1 6.6 4.2 0.0 1.4 0.5 0.0 33.8
0.001
⬍0.001
0.042
0.001
⬍0.001
0.023
0.0003
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Although it was not significant when CKD stages 0/I/II and III were compared (p ⫽ 0.121), the blood transfusion rate among the groups significantly increased with decreasing kidney function when stages 0/I/II and III were compared with stages IV/V (IV/V vs 0/I/II 4.9%, p ⫽ 0.001 and III vs IV/V p ⫽ 0.001). The fever rate increased with the severity of kidney function impairment. It achieved statistical significance when the rate in patients with CKD stages IV/V was compared with the rate in those with stages 0/I/II (p ⫽ 0.001) and III (p ⫽ 0.008). However, it was not statistically significant when the rate of the moderately severe group was compared with that of the mildly affected group (stage III vs 0/I/II p ⫽ 0.06). As assessed by Clavien scores, the overall complication rate significantly increased as kidney function decreased (stages 0/I/II vs III p ⬍0.001, 0/I/II vs IV/V p ⬍0.001 and III vs IV/V p ⫽ 0.042).
DISCUSSION As part of an ongoing series of CROES PCNL Global Study analyses, outcomes in patients undergoing PCNL were assessed by renal function. In this study 4,436 of 5,644 patients (78.6%) were classified as having CKD stages 0/I/II, which is essentially no or mild disease, 994 (17.6%) had CKD stage III and 214 (3.8%) had CKD stages IV/V, the most severe form of the disease. Therefore, it would appear that kidney stones are essentially a benign condition in terms of the effect on renal function in most kidney stone cases. However, a clinically significant minority of patients with nephrolithiasis presented with more severe CKD, suggesting that kidney stones may contribute to the worsening of renal function. However, the extent of this contribution is unclear. An increase in mean age was noted in patients as kidney function deterioration progressed from stages 0/I/II to stages III, IV and V. This probably reflects the generally reported increase in the prevalence of CKD as the population ages, which is even more marked in stone formers.17 A similar trend in renal function deterioration is also noted in patients with other comorbid conditions, which suggests that a proportion of renal function loss may be due to a comorbidity. Nevertheless, kidney stones clearly have a part in worsening renal function, particularly in patients with staghorn stones. Staghorn stones typically fill a large proportion of the renal pelvis and extend into the calyces.18 –20 Rapidly growing staghorn stones are associated with renal infection and, if untreated, prolonged infection promotes nephropathy and compromises renal function.21 Residual staghorn fragments seed rapid recurrent stone formation, making aggressive clearance of these stones
imperative if multiple nephrolithotripsy procedures are to be avoided.20,21 The study revealed that patients with CKD stages IV/V previously underwent PCNL, URS or nephrostomy and had positive urine cultures to a greater extent than less severely affected patients, consistent with the greater incidence of staghorn stones in these patients. However, increased infection rates may not be due only to staghorn stones. Patients with CKD are immunosuppressed, which may contribute to the increased rate of infection before surgery.5 Preoperative nephrostomy to decompress the pelvicalyceal system and preserve renal function is a potential source of pre-PCNL urinary infection in patients with previously culture negative urine. Clearly, a complex interaction among stone disease, interventions, chronic infection and poor drainage impacts renal function. Regardless of the significantly increased operative time, the stone-free rate in patients with CKD stages IV/V was significantly less than in those with stages 0/I/II. Hospital stay was also significantly greater and the incidence of pyrexia in patients with CKD stages IV/V was approximately twice that in those with stages 0/I/II. This higher sepsis rate observed in more severely affected patients with CKD is most likely related to the increase in preoperative risks factors for infection noted in this patient group, such as higher preoperative positive cultures, and staghorn stone and preoperative nephrostomy rates. The greater rate of staghorn stones in patients with CKD stages IV/V may also contribute to the poorer stone-free rate in these patients compared with the rate in those with stages 0/I/II. However, the increase in operative time could also be attributable in part to the greater need for blood transfusion in patients with CKD stages IV/V, reflecting a greater hemolytic tendency during PCNL. Renal nephrosis and the associated thinning of the renal parenchyma associated within CKD result in poor hemostasis by tamponade which, compounded by the tendency of patients with CKD toward anemia, may also contribute to the need for transfusion.5 Patients with CKD are frequently immunocompromised and susceptible to chronic recurrent infections, which may promote further nephritic damage and fibrosis. Therefore, combined with the inadvertent nephritic damage to the kidney due to percutaneous procedures, the tendency to bleed further increases during repeat PCNL cycles to remove recurrent stones.1 The CROES PCNL Global Study analysis reported sought to assess the effect of PCNL on postoperative outcomes by renal function. While the majority of patients treated with PCNL do not have CKD to any great extent, a clinically significant minority have severely restricted renal function and
PERCUTANEOUS NEPHROLITHOTOMY AND CHRONIC KIDNEY DISEASE
in this group of patients post-PCNL outcomes are worse. A major contributory factor to worsening renal function is staghorn stones. Also known as struvite or infection stones, they are universally considered the most frequent cause of urolithiasis associated with end stage renal disease.1,22,23 Of the 3.2% of patients requiring renal replacement therapy due to nephrolithiasis, this was attributable to struvite stones in 42.2%, while calcium and uric acid stones contributed 26.7% and 17.8%, respectively.6 Struvite stones in particular are difficult to eradicate and are associated with persistent disease/infection, high recurrence levels and the need for multiple procedures, which negatively impact renal function.3 Furthermore, small stones or fragments that move and obstruct the urinary tract also accelerate the course of renal disease.1 Several reports document that early, aggressive intervention with PCNL, aiming at complete stone clearance and prevention of urinary stone infection, improves or stabilizes renal function in many such patients.4,8,10,12,24 –26 While patients with compromised renal function may benefit from stone removal and, therefore, an improvement in renal function, this must be balanced by the detrimental effects of the procedures. However, many studies claiming renal improvement following PCNL used serum creatinine as a measure of success. More recent studies sought to show improvements in eGFR.7,11 The outcome in 1
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study suggested that an improvement in eGFR was greater in patients with mild to moderate renal failure than in those with severe CKD.7 It would be reasonable to assume that those patients with severe renal failure would be less likely to gain benefit, principally because the damage already done to the kidney was severe and irreversible. However, in the second study, patients with late stage CKD, although a small number, achieved significant improvement, while unexpected deterioration was seen in some patients with less severe CKD.11 Urinary tract infection appeared to be the underlying cause of the observation in the latter study, emphasizing the need for constant vigilance against infection in all PCNL cases regardless of CKD status. However, the 2 studies agree that through ever more aggressive stone removal and more effective prevention of infection, renal replacement therapy can still be deferred in most patients with renal stone disease.7,11
CONCLUSIONS Poor renal function negatively impacts the postPCNL outcome. Although other factors almost certainly contribute to CKD, by more aggressively removing these stones, particularly staghorn stones, at first presentation and more vigilantly attempting to prevent recurrence through infection control, pharmacological or other interventions, the progression of CKD due to nephrolithiasis may be halted.
REFERENCES 1. Gambaro G, Favaro S and D’Angelo A: Risk of renal failure in nephrolithiasis. Am J Kidney Dis 2001; 37: 233. 2. Worcester EM, Parks JH, Evan AP et al: Renal function in patients with nephrolithiasis. J Urol 2006; 176: 600. 3. Marangella M, Bruno M, Cosseddu D et al: Prevalence of chronic renal insufficiency in the course of idiopathic recurrent calcium stone disease: risk factors and patterns of progression. Nephron 1990; 54: 302. 4. Yaycioglu O, Egilmez T, Gul U et al: Percutaneous nephrolithotomy in patients with normal versus impaired renal function. Urol Res 2007; 35: 101. 5. Gopalakrishnan G and Prasad GS: Management of urolithiasis with chronic renal failure. Curr Opin Urol 2007; 17: 132. 6. Jungers P, Joly D, Barbey F et al: ESRD caused by nephrolithiasis: prevalence, mechanisms and prevention. Am J Kidney Dis 2004; 44: 799. 7. Kurien A, Baishya R, Mishra S et al: The impact of percutaneous nephrolithotomy in patients with
chronic kidney disease. J Endourol 2009; 23: 14031. 8. Kukreja R, Desai M, Patel SH et al: Nephrolithiasis associated with renal insufficiency: factors predicting outcome. J Endourol 2003; 17: 875. 9. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis, suppl., 2002; 39: S1. 10. Chandhoke PS, Albala DM and Clayman RV: Long-term comparison of renal function in patients with solitary kidneys and/or moderate renal insufficiency undergoing extracorporeal shock wave lithotripsy or percutaneous nephrolithotomy. J Urol 1992; 147: 1226.
13. Jones DJ, Kellett MJ and Wickham JEA: Percutaneous nephrolithotomy and the solitary kidney. J Urol 1991; 145: 477. 14. Vupputuri S, Soucie JM, McClellan W et al: History of kidney stones as a possible risk factor for chronic kidney disease. Ann Epidemiol 2004; 14: 222. 15. Clinical Research Office of the Endourological Society (CROES). Available at http://www.croesoffice. org/ONGOINGPROJECTS/PCNLstudy/tabid/63/ Default.aspx. Accessed February 17, 2012. 16. de la Rosette J, Assimos D, Desai M et al: The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: indications, complications and outcomes in 5803 patients. J Endourol 2011; 25: 11.
11. Bilen CY, Inci K, Kocak B et al: Impact of percutaneous nephrolithotomy on estimated glomerular filtration rate in patients with chronic renal disease. J Endourol 2008; 22: 895.
17. Worcester E, Parks JH, Josephson MA et al: Causes and consequences of kidney loss in patients with nephrolithiasis. Kidney Int 2003; 64: 2204.
12. Goel MC, Ahlawat R, Kumar M et al: Chronic renal failure and nephrolithiasis in a solitary kidney: role of intervention. J Urol 1997; 157: 1574.
18. Preminger GM, Assimos DG, Lingeman JE et al: Chapter 1. AUA guideline on management of staghorn calculi: diagnosis and treatment recommenda-
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tions. AUA Nephrolithiasis Guideline Panel. J Urol 2005; 173: 1991. 19. Ganpule AP and Desai M: Management of the staghorn calculus: multiple-tract versus single-tract percutaneous nephrolithotomy. Curr Opin Urol 2008; 18: 220. 20. Meng M, Stoller ML and Minor T: Struvite and staghorn calculi. Emedicine, November 24, 2009. Available at http://emedicine.medscape.com/ article/439127. Accessed February 17, 2012.
21. Koga S, Arakaki Y, Matsuoka M et al: Staghorn calculi—long-term results of management. Br J Urol 1991; 68: 122. 22. Streem SB: Long-term incidence and risk factors for recurrent stones following percutaneous nephrolithotomy or percutaneous nephrolithotomy/extracorporeal shock wave lithotripsy for infection related calculi. J Urol 1995; 153: 584. 23. Teichman JM, Long RD and Hulbert JC: Longterm renal fate and prognosis after staghorn calculus management. J Urol 1995; 153: 1403.
24. Gupta M, Bolton DM, Gupta PN et al: Improved renal function following aggressive treatment of urolithiasis and concurrent mild to moderate renal insufficiency. J Urol 1994; 152: 1086. 25. Agrawal MS, Aron M and Asopa HS: Endourological renal salvage in patients with calculus nephropathy and advances uraemia. BJU Int 1999; 84: 252. 26. Kuzgunbay B, Gul U, Turunc T et al: Long-term renal function and stone recurrence after percutaneous nephrolithotomy in patients with renal insufficiency. J Endourol 2010; 24: 305.