There are as such no randomized control trials to assess risks and benefits of screening for specific health issues.

Medical Management of the Kidney Transplant Recipient 73

vi. Meningococcal (conjugated or polysaccharide): Recommended before and after transplant for adults with asplenia, terminal complement deficiencies, first-year college

vii. Pneumococcal (conjugated or polysaccharide); Recommended before and after

viii. Tetanus, Diphtheria, Acellular Pertussis (Td/Tdap): Recommended before and after

*Department of Medicine, Division of Nephrology, NewYork-Presbyterian Hospital/Weill Cornell*

[1] Danovitch, G. Handbook of Kidney Transplantation. 5th edition. Philadelphia:

[3] Fuge WW, Hogg BM. The Insensible Losses In Surgical Patients. Ann. Surg. 1938; 108:1-

[4] Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: A systematic review and

[5] Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Posttransplant renal function in the first year predicts long-term kidney transplant survival.

[6] United Network of Organ Sharing Database. https://www.unos.org. (Accessed July 21,

[7] Siedlecki A, Irish W, Brennan DC. Delayed Graft Function in Kidney Transplant. Am.J.

[8] Pretagostini R, Lai Q, Poli L, Levi Sandri GB, Travaglia D, Rossi M. Predicitive Characteristics of Delayed Graft Function After Expanded And Standard Criteria Donor

[9] Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed Graft function: Risk factors and implications for renal allograft survival. Transplantation 1997; 63: 968–974. [10] Koning OH, Ploeg RJ, van Bockel JH, Groenewegen M, van der Woude FJ, Persijn GG, et al. Risk factors for delayed graft function in cadaveric kidney transplantation: A prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study

students living in dormitories and other patients identified to be at-risk

ix. Varicella: Recommended only before, but not after transplant x. Zoster: Recommended only before, but not after transplant

[2] Uptodate, Inc. https://www.uptodate.com. (Accessed July 20, 2012)

meta-analysis. Nephrol Dial Transplant 2009; 24: 1039–1047.

Kidney Transplantations. Transplant Proc. 2009; 41:1149-51

Group. Transplantation 1997; 63: 1620–1628.

transplant

transplant

**Author details**

**6. References**

14.

2012).

Dhaval Patel and Jun Lee

*Medical College, New York, NY, USA*

Lippincott Williams & Wilkins. 2009.

Kidney Int 2002; 62: 311–318.

Transplant. 2011; 11: 2279-2296

The following recommendations for cancer screening are based on American Transplantation Society and European Best Practices Guidelines for renal transplantation (82-86):

For oral health, again, there are no specific recommendations, but certain general management strategies have been agreed upon by dentists.

Transplant patients should not be given a live vaccine. The following vaccines are recommended for transplant patients (1):

#### **Author details**

72 Current Concepts in Kidney Transplantation

There are as such no randomized control trials to assess risks and benefits of screening for

The following recommendations for cancer screening are based on American Transplantation Society and European Best Practices Guidelines for renal transplantation

A. Breast: Annual or biennial mammography for all women older than 50 yr. Women between 40 and 49 could still undergo screening, but no evidence for or against

C. Colorectal: Annual FOBT or 5-year flexible sigmoidoscopy for patients older than 50

D. Prostate: Annual Digital Rectal Exam and PSA levels in all male transplant recipients

E. Hepatocellular: No firm guidelines, but alpha-fetoprotein and ultrasound can be

G. Renal: No firm recommendation. Some physicians choose to do ultrasound of native

H. PTLD: Patients should be screened for EBV antibodies prior to or at the time of

For oral health, again, there are no specific recommendations, but certain general

 Routine dental exam should be avoided until 6 months after transplant. For emergency dental exams, it may be preferred to manage these patients in a hospital setting. Annual or biennial dental exam with a dentist should be pursued for long-term dental care. All routine dental procedures will need antibiotic prophylaxis and the choice of antibiotics should be made after consuting with patient's transplant physician. The most common *oral manifestations* in transplant patients are: viral, bacterial and fungal infections, gingival hyperplasia due to cyclosporine and higher risk in developing oral malignancy, and patients should be screened for them on routine

Transplant patients should not be given a live vaccine. The following vaccines are

v. Measles, mumps and rubella (MMR): Recommended only before, but not after

i. Haemophilus Influenza b: Recommended before and after transplant

iii. Human Papillomavirus: Recommended before and after transplant iv. Influenza, injected: Recommended before and after transplant

ii. Hepatitis B: Recommended before and after transplant

B. Cervical: Annual pap smear and pelvic exam once sexually active

F. Skin: Monthly-self exam and annual or biennial exam by dermatologists

performed every 6 months in patients at high risk

management strategies have been agreed upon by dentists.

**5.12. Screening**

(82-86):

years

older than 50

transplantation

dental exams (87).

transplant

recommended for transplant patients (1):

specific health issues.

screening at this age

kidneys on a regular basis.

Dhaval Patel and Jun Lee

*Department of Medicine, Division of Nephrology, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York, NY, USA*

#### **6. References**

	- [11] Shoskes DA, Cecka JM. Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 1998; 66: 1697– 1701.

Medical Management of the Kidney Transplant Recipient 75

[28] Midtvedt K, Hartmann A, Foss A, Fauchald P, Nordal KP, Rootwelt K et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation 2001;

[29] Dunn BL, Teusink AC, Taber DJ, Hemstreet BA, Uber LA, Weimert NA. Management of Hypertension in Renal Transplant Patients: A Comprehensive Review of Nonpharmacologic and Pharmacologic Treatment Strategies. Ann Pharmacother

[30] K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. http://www.kidney.org. (Accessed on July 31, 2012). [31] Bruno S, Remuzzi G, Ruggenenti P. Transplant Renal Artery Stenosis. J.Am.Soc.Neph,

[34] Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes Mellitus After Kidney

[35] Davidson J. Diabetes after transplantation: revised guidelines; target early treatment.

[36] Davidson J, Wilkinson A, Dantal J, Dotta F, Haller H, Hernández D et al. New-onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003.

[37] Kasiske B, Cosio FG, Beto J, Bolton K, Chavers BM, Grimm R Jr et al. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 2004;

[38] Potluri K, Hou S. Obesity in kidney transplant recipients and candidates. AJKD July

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[28] Midtvedt K, Hartmann A, Foss A, Fauchald P, Nordal KP, Rootwelt K et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation 2001; 72:1787-1792

74 Current Concepts in Kidney Transplantation

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[11] Shoskes DA, Cecka JM. Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 1998; 66: 1697–

[12] Shoskes DA, Cecka JM. Effect of delayed graft function on short and long-term kidney

[13] McLaren AJ, Jassem W, Gray DW, Fuggle SV, Welsh KI, Morris PJ. Delayed graft function: Risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation. Clin Transplant 1999; 13: 266–272. [14] Giral M, Bertola JP, Foucher Y, Villers D, Bironneau E, Blanloeil Y, et al. Effect of braindead donor resuscitation on delayed graft function: Results of a monocentric analysis.

[15] Doshi MD, Garg N, Reese PP, Parikh CR. Recipient risk factors associated with delayed

[16] Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: A significant independent risk factor for graft failure and patient

[17] Parekh J, Bostrom A, Feng S. Diabetes mellitus: A risk factor for delayed graft function after deceased donor kidney transplantation. Am J Transplant 2010; 10: 298–303. [18] Johnston O, O'kelly P, Spencer S, Donohoe J, Walshe JJ, Little DM, et al. Reduced graft function (with or without dialysis) vs immediate graft function—a comparison of long-

[20] Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant 2001;

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[65] Akbari F, Alavi M, Esteghamati A, Mehrsai A, Djaladat H, Zohrevand R et al. Effect of renal transplantation on sperm quality and sex hormone levels. BJU Int. 2003 Aug; 92 :

[66] Tondolo V, Citterio F, Panocchia N, Nanni G, Favi E, Brescia A, et al. Gonadal function and immunosuppressive therapy after renal transplantation. Transplant Proc. 2005

[67] Kaczmarek I, Groetzner J, Adamidis I, Landwehr P, Mueller M, Vogeser M. Sirolimus impairs gonadal function in heart transplant recipients. Am J Transplant. 2004

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[44] Counseling to prevent tobacco use and tobacco-caused disease. In, Rockville,MD, US Preventive Services Task Force. Agency for Healthcare Research and Quality. 2003; 1–5 [45] Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM.. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a

[46] Winkelmayer WC, Kramar R, Curhan GC, Chandraker A, Endler G, Födinger M et al. Fasting plasma total homocysteine levels and mortality and allograft loss in kidney

[48] World Health Organization. Nutritional anemias: Report of a WHO Scientific Group.

[49] Chadban SJ, Baines L, Polkinghorne K, Jefferys A, Dogra S, Kanganas C, *et al.* Anemia after kidney transplantation is not completely explained by reduced kidney function.

[50] Mix TCH, Kazmi W, Khan S, Ruthazer R, Rohrer R, Pereira BJG. *et al.* Anemia: a continuing problem following kidney transplantation. Am J Transplant 2003; 3: 1426-

[51] Winkelmayer WC, Chnadraker A, Brookhart MA, Kramar R,Sunder-Plassmann Gl. A prospective study of anemia and long-term outcomes in kidney transplant recipients.

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[53] Moore LW, Smith SO, Winsett RP, Acchiardo SR, Gaber AO. Factors affecting erythropoietin production and correction of anemia in kidney transplant recipients.

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[55] Gaston RS, Julian BA, Curtis JJ. Post-transplant erythrocytosis: an enigma revisited. Am

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[58] Kiberd BA. Post-transplant erythrocytosis: a disappearing phenomenon? Clin

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**Chapter 4**

© 2012 Kim et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Technical variations exist for kidney transplant, such as in the retroperitoneal exposure or implantation of the ureter, but the basic surgical procedure will be described in this section. The right iliac fossa has traditionally been described as the initial choice for implantation, but previous operations, quality of vessels, or other recipient factors may make the left side

and reproduction in any medium, provided the original work is properly cited.

**Surgical Management**

Sandip Kapur and Jim Kim

http://dx.doi.org/10.5772/54145

**1. Introduction**

transplant patient.

**2. Surgical procedure**

**of the Kidney Transplant Recipient**

Cheguevara Afaneh, Meredith J. Aull, Anthony Watkins,

The early postoperative course and management can have a significant impact on the longterm success of a kidney transplant recipient. Several factors affect long-term outcomes including the occurrence of delayed graft function (DGF), episodes of acute rejection (AR), surgical complications, and overwhelming infections, especially sepsis [1-3]. Certain medications, including calcineurin inhibitors (CNI), also have potential for nephrotoxic effects, which can later lead to transplant glomerulopathy [4]. Furthermore, recipient characteristics, such as sensitization status, and donor characteristics, such as donation after cardiac death (DCD) donors and expanded criteria donors (ECD) can all affect long-term outcomes [5]. Although basic postoperative surgical principles are applied, there are certain parameters that need to be closely monitored, especially as it pertains to fluid management, blood pressure control, and immunologic status. Early detection of graft dysfunction is paramount in determining reversibility from both medical and surgical complications. Recognizing the technical limitations during surgery can also help prevent potentially devastating mechanical complications. Thus, appropriate initial management and mitigation of various risk factors is extremely important in the long-term success of the kidney

Additional information is available at the end of the chapter

## **Chapter 4**

## **Surgical Management of the Kidney Transplant Recipient**

Cheguevara Afaneh, Meredith J. Aull, Anthony Watkins, Sandip Kapur and Jim Kim

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54145

## **1. Introduction**

78 Current Concepts in Kidney Transplantation

Aug;36:1138-61.

4]:31– 33, 35–36

Transplantation. 2004 Mar 15;77:769-76

transplant recipients. Drugs 2007;67:1463-81.

[75] Fine RN, Becker Y, De Geest S, Eisen H, Ettenger R, Evans R et al. Nonadherence

[76] Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: A systematic review.

[77] Morrissey PE, Flynn ML, Lin S. Medication noncompliance and its implications in

[78] Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve

[79] Roter DL, Hall JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. Effectiveness of interventions to improve patient compliance: A meta-analysis. Med Care 1998

[80] Claxton AJ, Cramer J, Pierce C. A systematic review of the association between dose

[81] Chisholm MA, Mulloy LL, Jagadeesan M and DiPiro, JT. Impact of clinical pharmacy services on renal transplant patients' compliance with immunosuppressive

[82] EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): Prevention and treatment. Nephrol Dial Transplant 2002. 17[Suppl

[83] EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 6.3. Cancer risk after renal transplantation. Solid organ cancers: Prevention and

[84] EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 6.2. Cancer risk after renal transplantation. Skin cancers: Prevention and treatment.

[85] Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, et al.: Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000 11[Suppl 15]:S1– S86. [86] Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is

Carlos FL, Gavaldá EC, Sarrión PMG. Dental management in transplant patients. J Clin Exp. Dent. 2011;3(1):e43-52. http://www.medicinaoral.com/odo/volumenes/v3i1/

consensus conference summary report. Am J Transplant. 2009 Jan;9:35-41.

medication adherence. Am J Health Syst Pharm 2003 Apr 1;60:657-65.

regimens and medication compliance. Clin Ther 2001 Aug;23:1296-310.

medications. Clinical Transplantation. 2001; 15: 330–336.

treatment. Nephrol Dial Transplant. 2002 17[Suppl 4]:32,34– 36,

the evidence? Clin J Am Soc Nephrol. 2008 Mar;3 Suppl 2:S87-S100.

Nephrol Dial Transplant 2002 17[Suppl 4]:31– 36.

jcedv3i1p43.pdf (Accessed September 28, 2012).

The early postoperative course and management can have a significant impact on the longterm success of a kidney transplant recipient. Several factors affect long-term outcomes including the occurrence of delayed graft function (DGF), episodes of acute rejection (AR), surgical complications, and overwhelming infections, especially sepsis [1-3]. Certain medications, including calcineurin inhibitors (CNI), also have potential for nephrotoxic effects, which can later lead to transplant glomerulopathy [4]. Furthermore, recipient characteristics, such as sensitization status, and donor characteristics, such as donation after cardiac death (DCD) donors and expanded criteria donors (ECD) can all affect long-term outcomes [5]. Although basic postoperative surgical principles are applied, there are certain parameters that need to be closely monitored, especially as it pertains to fluid management, blood pressure control, and immunologic status. Early detection of graft dysfunction is paramount in determining reversibility from both medical and surgical complications. Recognizing the technical limitations during surgery can also help prevent potentially devastating mechanical complications. Thus, appropriate initial management and mitigation of various risk factors is extremely important in the long-term success of the kidney transplant patient.

## **2. Surgical procedure**

Technical variations exist for kidney transplant, such as in the retroperitoneal exposure or implantation of the ureter, but the basic surgical procedure will be described in this section. The right iliac fossa has traditionally been described as the initial choice for implantation, but previous operations, quality of vessels, or other recipient factors may make the left side

© 2012 Kim et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

more approachable. In the case of polycystic kidney disease, where the native kidneys need to be removed, a midline incision is made.

Surgical Management of the Kidney Transplant Recipient 81

The initial management of the kidney transplant recipient involves proper fluid management, focusing on volume status and electrolyte balance. Assessing volume status is multifaceted and includes monitoring urine output, central venous pressure, heart rate, and blood pressure. Attention to daily weights and total input-output tabulations can help dictate fluid management, especially regarding the use of diuretics postoperatively. A decrease in urine volume can result from hypovolemia, obstruction, acute tubular necrosis

Recipients of living donor kidney transplants have brisk urine output immediately or within minutes of implantation. Fluids may need to be replaced adequately to avoid a negative fluid balance within the first 24 hours. This can potentially compromise blood flow to the new kidney. Deceased donor allografts, in comparison, not make significant urine amounts initially. Fluid and furosemide challenges should be considered; however, if there has been little to no response after several attempts, then fluids should be administered judiciously in consideration of overall volume status from a respiratory, cardiovascular, and renal standpoint. The goal of fluid resuscitation in the early postoperative period focuses on

Changes in urine output should be assessed in an objective and systematic manner. First, the foley should be assessed for patency and flushed, as patients may have mild hematuria leading to clot formation. If hypovolemia is suspected, then a fluid challenge with crystalloid or albumin should be administered [6]. Failure to respond to a fluid challenge and increases in serum creatinine should prompt assessment of the graft with Duplex ultrasonography (DUS), which can be used to assess perfusion to the allograft, rule out hydronephrosis and evaluate perinephric fluid collections. Significant, but less dramatic decreases in urine output should raise clinical suspicion for renal artery or vein thrombosis, which would warrant surgical re-exploration if caught in a timely fashion. Patients with little to no response to fluid challenges should also be administered a furosemide challenge. Patients who fail to respond to fluid or furosemide without any structural or vascular

Assessment and maintenance of adequate blood pressure control is imperative to the success of the kidney transplant. Because the transplanted kidney is an end-organ, it is susceptible to injury during episodes of hypotension, which can lead to ATN. Careful attention to the choice of induction therapy being administered, such as rabbit antithymocyte globulin (rATG), is important as the side effect profile includes fever, dyspnea, respiratory distress, and hypotension [7]. If other causes of respiratory distress or hypotension have been excluded, the rate of rATG administration may need to be slowed or even stopped temporarily or permanently. Basiliximab, an interleukin-2 receptor antagonist

abnormalities on DUS may have ATN, which can be confirmed with a biopsy.

(ATN), urinary leak, or in the most severe case, vascular thrombosis.

maintaining good perfusion to the transplanted allograft.

**3.2. Cardiovascular and pulmonary assessment**

**3. Early postoperative course**

**3.1. Renal and fluid management**

#### **2.1. Backtable kidney preparation**

The kidney is kept cold in an ice slush bath during the preparation, which involves dissecting the renal artery and vein from the surrounding tissue. The ureter is identified and retracted away so as to avoid injury when removing extraneous fat and tissue from the kidney and hilum. Attention must be directed to protecting the blood supply to the ureter by avoiding the so-called "golden triangle" at the inferior pole of the kidney. Multiple renal arteries may also require repair and a Carrel patch may or may not be preserved depending on the degree of aortic plaque seen. In the case of a right kidney, the renal vein may require lengthening, which can be accomplished by utilizing the attached IVC.

#### **2.2. Surgical exposure**

An oblique curvilinear incision is made in the right or left lower quadrant of the abdomen, extending from near the pubic symphysis to above the anterior superior iliac spine of the iliac crest. Muscle layers can be directly divided, lateral to the rectus sheath, or split along the fibers of the external and internal obliques and transversalis. The peritoneum is identified and retracted superiorly and medially to expose the retroperitoneum. Selfretaining retractors can be placed to facilitate subsequent exposure of the psoas and iliac vessels.

### **2.3. Operative procedure**

The common or external iliac artery and vein are identified and dissected. Lymphatics that course along the length of the vessels need to be meticulously tied or cauterized to prevent occurrence of lymphoceles. Vascular flow is controlled proximally and distally with vascular clamps and the kidney is brought into the surgical field. A venotomy is first made in the recipient iliac vein and an end-to-side anastomosis with the renal vein is created with 5-0 or 6-0 monofilament non-absorbable suture. Similarly, an arteriotomy is then made and the arterial anastomosis is completed in an end-to-side fashion. The clamps are released sequentially, with the vein before the artery, and the kidney is perfused. Once hemostasis is attained, the urinary tract is reconstructed. The bladder, which should be irrigated with antibiotic solution prior to start of the procedure, can be filled by way of a three-way Foley catheter or instilled with the antibiotic solution at the start of the operation. The kidney is positioned in the retroperitoneum and an area on the bladder is identified for implantation of the ureter. The layers of the bladder are carefully dissected and a cystostomy is created. The transplant ureter is cut to length and the anastomosis is done with or without a stent using monofilament absorbable suture. One technique described for ureteroneocystostomy is the Lich-Gregoir technique, which involves an anastomosis between the ureteral and bladder mucosa with a myotomy closure over the ureter. The abdominal wall is then reapproximated and closed in layers.

## **3. Early postoperative course**

80 Current Concepts in Kidney Transplantation

to be removed, a midline incision is made.

**2.1. Backtable kidney preparation**

**2.2. Surgical exposure**

**2.3. Operative procedure**

reapproximated and closed in layers.

vessels.

more approachable. In the case of polycystic kidney disease, where the native kidneys need

The kidney is kept cold in an ice slush bath during the preparation, which involves dissecting the renal artery and vein from the surrounding tissue. The ureter is identified and retracted away so as to avoid injury when removing extraneous fat and tissue from the kidney and hilum. Attention must be directed to protecting the blood supply to the ureter by avoiding the so-called "golden triangle" at the inferior pole of the kidney. Multiple renal arteries may also require repair and a Carrel patch may or may not be preserved depending on the degree of aortic plaque seen. In the case of a right kidney, the renal vein may require

An oblique curvilinear incision is made in the right or left lower quadrant of the abdomen, extending from near the pubic symphysis to above the anterior superior iliac spine of the iliac crest. Muscle layers can be directly divided, lateral to the rectus sheath, or split along the fibers of the external and internal obliques and transversalis. The peritoneum is identified and retracted superiorly and medially to expose the retroperitoneum. Selfretaining retractors can be placed to facilitate subsequent exposure of the psoas and iliac

The common or external iliac artery and vein are identified and dissected. Lymphatics that course along the length of the vessels need to be meticulously tied or cauterized to prevent occurrence of lymphoceles. Vascular flow is controlled proximally and distally with vascular clamps and the kidney is brought into the surgical field. A venotomy is first made in the recipient iliac vein and an end-to-side anastomosis with the renal vein is created with 5-0 or 6-0 monofilament non-absorbable suture. Similarly, an arteriotomy is then made and the arterial anastomosis is completed in an end-to-side fashion. The clamps are released sequentially, with the vein before the artery, and the kidney is perfused. Once hemostasis is attained, the urinary tract is reconstructed. The bladder, which should be irrigated with antibiotic solution prior to start of the procedure, can be filled by way of a three-way Foley catheter or instilled with the antibiotic solution at the start of the operation. The kidney is positioned in the retroperitoneum and an area on the bladder is identified for implantation of the ureter. The layers of the bladder are carefully dissected and a cystostomy is created. The transplant ureter is cut to length and the anastomosis is done with or without a stent using monofilament absorbable suture. One technique described for ureteroneocystostomy is the Lich-Gregoir technique, which involves an anastomosis between the ureteral and bladder mucosa with a myotomy closure over the ureter. The abdominal wall is then

lengthening, which can be accomplished by utilizing the attached IVC.

#### **3.1. Renal and fluid management**

The initial management of the kidney transplant recipient involves proper fluid management, focusing on volume status and electrolyte balance. Assessing volume status is multifaceted and includes monitoring urine output, central venous pressure, heart rate, and blood pressure. Attention to daily weights and total input-output tabulations can help dictate fluid management, especially regarding the use of diuretics postoperatively. A decrease in urine volume can result from hypovolemia, obstruction, acute tubular necrosis (ATN), urinary leak, or in the most severe case, vascular thrombosis.

Recipients of living donor kidney transplants have brisk urine output immediately or within minutes of implantation. Fluids may need to be replaced adequately to avoid a negative fluid balance within the first 24 hours. This can potentially compromise blood flow to the new kidney. Deceased donor allografts, in comparison, not make significant urine amounts initially. Fluid and furosemide challenges should be considered; however, if there has been little to no response after several attempts, then fluids should be administered judiciously in consideration of overall volume status from a respiratory, cardiovascular, and renal standpoint. The goal of fluid resuscitation in the early postoperative period focuses on maintaining good perfusion to the transplanted allograft.

Changes in urine output should be assessed in an objective and systematic manner. First, the foley should be assessed for patency and flushed, as patients may have mild hematuria leading to clot formation. If hypovolemia is suspected, then a fluid challenge with crystalloid or albumin should be administered [6]. Failure to respond to a fluid challenge and increases in serum creatinine should prompt assessment of the graft with Duplex ultrasonography (DUS), which can be used to assess perfusion to the allograft, rule out hydronephrosis and evaluate perinephric fluid collections. Significant, but less dramatic decreases in urine output should raise clinical suspicion for renal artery or vein thrombosis, which would warrant surgical re-exploration if caught in a timely fashion. Patients with little to no response to fluid challenges should also be administered a furosemide challenge. Patients who fail to respond to fluid or furosemide without any structural or vascular abnormalities on DUS may have ATN, which can be confirmed with a biopsy.

#### **3.2. Cardiovascular and pulmonary assessment**

Assessment and maintenance of adequate blood pressure control is imperative to the success of the kidney transplant. Because the transplanted kidney is an end-organ, it is susceptible to injury during episodes of hypotension, which can lead to ATN. Careful attention to the choice of induction therapy being administered, such as rabbit antithymocyte globulin (rATG), is important as the side effect profile includes fever, dyspnea, respiratory distress, and hypotension [7]. If other causes of respiratory distress or hypotension have been excluded, the rate of rATG administration may need to be slowed or even stopped temporarily or permanently. Basiliximab, an interleukin-2 receptor antagonist

(IL2RA), has fewer side effects and can be administered as an alternative under different immunosuppression protocols.

Surgical Management of the Kidney Transplant Recipient 83

or equal to 80 mm Hg approximately 3 months before kidney transplantation is a risk factor for PNF [18]. Certain donor factors, such as prolonged cold ischemia time, have also been associated with PNF [20]. Patients with PNF have poorer overall patient survival, compared to patients with immediate graft function, probably as a result of returning to renal

> **Common Causes of Early Graft Dysfunction Medical Surgical** Delayed graft function Hemorrhage

Hypovolemia Urinary obstruction Acute rejection Vascular thrombosis

Infection Arterial stenosis Disease recurrence Extrinsic obstruction

Hyperacute rejection occurs in the setting of ABO incompatible transplants or in the setting of a positive lymphocytotoxic crossmatch, where the incidence is approximately 85%. Some antibodies may have lower binding affinity to receptors or fail to bind any complement. Once this process has occurred, treatment involves immediate removal of the allograft. Some protocols utilizing plasmapheresis have been used with modest results [21], but graft survival remains poor. The emergence of kidney-paired donation and chains has circumvented the need for transplantation across ABO blood groups [22]. Renal scan typically demonstrates no perfusion and pathology reveals microvascular thrombosis, thus necessitating a transplant nephrectomy. With the advent of modern immunologic testing

Accelerated vascular rejection is an early aggressive form of acute rejection that may occur in sensitized recipients with a high panel-reactive antibody or patients with a previous transplant, despite a negative T cell crossmatch. This type of rejection occurs as early as postoperative day 2 or can be as late as postoperative day 5. Anti-rejection treatment modalities generally fail to be effective in these patients. Histology reveals fibrin deposition and endothelitis. These patients are typically treated similar to antibody-mediated rejection episodes with plasmapheresis, intravenous immunoglobulin, and/or antibody-depleting

Drug-induced nephrotoxicity Hematuria

**Table 1.** Common causes of early graft dysfunction stratified by medical or surgical causes.

prior to transplant, hyperacute rejection remains a rare occurrence.

replacement therapy at an earlier time.

**4.3. Immunologic events**

*4.3.1. Hyperacute rejection*

*4.3.2. Accelerated vascular rejection*

agents [23].

The use of calcium channel blockers has been shown to be beneficial in kidney transplantation. Intra-arterial administration of calcium channel blockers, such as verapamil, improves renal blood flow as well as augments immunosuppression [8]. Postoperative administration of oral calcium channel blockers has also been implemented, as there is evidence that the incidence of DGF is decreased [9]. In a large systematic review and metaanalysis of randomized controlled trials, the use of calcium channel blockers has been shown to decrease the risk of graft loss and improved post-transplant glomerular filtration rates (GFR) [10]. Furthermore, in the early transplant period, the use of calcium channel blockers have been shown to be superior to angiotensin-converting enzyme inhibitors with regards to avoiding nephrotoxicity, improving GFR, improving hemoglobin levels, minimizing the incidence of hyperkalemia, and minimizing proteinuria post-transplant [10].

Respiratory complications can lead to poor outcomes. As previously stated, the use of rATG may lead to respiratory distress as capillary leak can occur. Acute respiratory failure posttransplant can compromise allograft outcomes [11,12]. The leading cause of respiratory failure is typically bacterial pneumonia [12]. Patients with prolonged intensive care hospitalizations are at risk of invasive fungal and opportunistic infections, especially in the setting of intense perioperative immunosuppression. These infections have been linked to increased mortality [13]. Appropriate chemoprophylaxis with trimethoprimsulfamethoxazole for *Pneumocystis jiroveci* pneumonia may be beneficial and potentially mitigate the infectious risks [14].

## **4. Assessment of graft function**

## **4.1. Early graft dysfunction**

Early complications leading to graft dysfunction can be separated into two categories: medical or surgical. Marginal donors, including ECD and DCD allografts, have the highest rate of medical and surgical complications [15,16]. Various medical and surgical complications resulting in early graft dysfunction are listed in Table 1. The following sections will discuss the most common culprits in each category. Hypovolemia has been discussed in a previous section.

## **4.2. Primary non-function**

Primary non-function (PNF), defined as the lack of adequate allograft function by the third month post transplant, has a reported incidence between 1-8% [17-19]. Typically, patients at risk of PNF include highly sensitized patients and those on renal replacement therapy for a prolonged duration of time prior to transplantation. Acute rejection and surgical complications are the most common causes of PNF [19]. The use of histidine-tryptophanketoglutarate (HTK) solution has also been implicated as a cause of PNF in deceased donor renal transplants [17]. A recent study suggests that a mean arterial blood pressure less than or equal to 80 mm Hg approximately 3 months before kidney transplantation is a risk factor for PNF [18]. Certain donor factors, such as prolonged cold ischemia time, have also been associated with PNF [20]. Patients with PNF have poorer overall patient survival, compared to patients with immediate graft function, probably as a result of returning to renal replacement therapy at an earlier time.

**Table 1.** Common causes of early graft dysfunction stratified by medical or surgical causes.

#### **4.3. Immunologic events**

82 Current Concepts in Kidney Transplantation

immunosuppression protocols.

mitigate the infectious risks [14].

**4.1. Early graft dysfunction**

discussed in a previous section.

**4.2. Primary non-function**

**4. Assessment of graft function**

(IL2RA), has fewer side effects and can be administered as an alternative under different

The use of calcium channel blockers has been shown to be beneficial in kidney transplantation. Intra-arterial administration of calcium channel blockers, such as verapamil, improves renal blood flow as well as augments immunosuppression [8]. Postoperative administration of oral calcium channel blockers has also been implemented, as there is evidence that the incidence of DGF is decreased [9]. In a large systematic review and metaanalysis of randomized controlled trials, the use of calcium channel blockers has been shown to decrease the risk of graft loss and improved post-transplant glomerular filtration rates (GFR) [10]. Furthermore, in the early transplant period, the use of calcium channel blockers have been shown to be superior to angiotensin-converting enzyme inhibitors with regards to avoiding nephrotoxicity, improving GFR, improving hemoglobin levels, minimizing the incidence of hyperkalemia, and minimizing proteinuria post-transplant [10]. Respiratory complications can lead to poor outcomes. As previously stated, the use of rATG may lead to respiratory distress as capillary leak can occur. Acute respiratory failure posttransplant can compromise allograft outcomes [11,12]. The leading cause of respiratory failure is typically bacterial pneumonia [12]. Patients with prolonged intensive care hospitalizations are at risk of invasive fungal and opportunistic infections, especially in the setting of intense perioperative immunosuppression. These infections have been linked to increased mortality [13]. Appropriate chemoprophylaxis with trimethoprimsulfamethoxazole for *Pneumocystis jiroveci* pneumonia may be beneficial and potentially

Early complications leading to graft dysfunction can be separated into two categories: medical or surgical. Marginal donors, including ECD and DCD allografts, have the highest rate of medical and surgical complications [15,16]. Various medical and surgical complications resulting in early graft dysfunction are listed in Table 1. The following sections will discuss the most common culprits in each category. Hypovolemia has been

Primary non-function (PNF), defined as the lack of adequate allograft function by the third month post transplant, has a reported incidence between 1-8% [17-19]. Typically, patients at risk of PNF include highly sensitized patients and those on renal replacement therapy for a prolonged duration of time prior to transplantation. Acute rejection and surgical complications are the most common causes of PNF [19]. The use of histidine-tryptophanketoglutarate (HTK) solution has also been implicated as a cause of PNF in deceased donor renal transplants [17]. A recent study suggests that a mean arterial blood pressure less than

#### *4.3.1. Hyperacute rejection*

Hyperacute rejection occurs in the setting of ABO incompatible transplants or in the setting of a positive lymphocytotoxic crossmatch, where the incidence is approximately 85%. Some antibodies may have lower binding affinity to receptors or fail to bind any complement. Once this process has occurred, treatment involves immediate removal of the allograft. Some protocols utilizing plasmapheresis have been used with modest results [21], but graft survival remains poor. The emergence of kidney-paired donation and chains has circumvented the need for transplantation across ABO blood groups [22]. Renal scan typically demonstrates no perfusion and pathology reveals microvascular thrombosis, thus necessitating a transplant nephrectomy. With the advent of modern immunologic testing prior to transplant, hyperacute rejection remains a rare occurrence.

#### *4.3.2. Accelerated vascular rejection*

Accelerated vascular rejection is an early aggressive form of acute rejection that may occur in sensitized recipients with a high panel-reactive antibody or patients with a previous transplant, despite a negative T cell crossmatch. This type of rejection occurs as early as postoperative day 2 or can be as late as postoperative day 5. Anti-rejection treatment modalities generally fail to be effective in these patients. Histology reveals fibrin deposition and endothelitis. These patients are typically treated similar to antibody-mediated rejection episodes with plasmapheresis, intravenous immunoglobulin, and/or antibody-depleting agents [23].

#### *4.3.3. Acute rejection*

Acute rejection can occur at any time in the early post-transplant period. The most common time point, however, is 5 to 7 days post-transplant. Acute cellular rejection remains the most common type of rejection episode. The incidence of acute rejection is highest in the first 6 months post-transplant, with overall acute rejection rates between 10-20%. The immunologic profiles of the donor and recipient as well as the use of different immunosuppression protocols are important in stratifying acute rejection risk. Signs and symptoms of acute rejection include fever, elevated serum creatinine, increasing weight, and graft tenderness. Transplant biopsy remains the gold standard for diagnosis. Histological changes in acute rejection include tubulitis and interstitial infiltrates, with or without arteritis [24].

Surgical Management of the Kidney Transplant Recipient 85

nephrostomy tube placement for complete urinary decompression as well as percutaneous

**Figure 1.** Doppler ultrasound demonstrates global hypoperfusion of the transplanted kidney consistent

Renal vein thrombosis is also an uncommon, but potentially devastating, complication. The usual causes include injuries to the donor renal vein that was narrowed after repair of an injury or twisting of the vein on the renal pedicle. Previously, the use of right-sided living donor renal allografts was associated with an increased risk of renal vein thrombosis due to the short length. However, we have not seen this in our large series of right-sided donors, even with modern procurement techniques, such as laparoendoscopic single-site surgery [31,32]. Patients present with gross hematuria, decreased urine output and engorgement of the graft due to venous outflow obstruction. DUS will show parvus tardus and reversal of diastolic flow in the renal artery. Immediate repair is necessary if there is to be any chance of

Most postoperative hematomas are small and insignificant. They are usually incidentally found on a post-transplant DUS. Larger and more clinically significant hematomas may occur in the setting of antiplatelet therapy or anticoagulation for patients with risk factors for venothromboembolic events (Figure 2). Patients with clinically significant hematomas will present with swelling from the incision, pain over the graft, and an acute drop in hemoglobin values. The hematoma will continue to increase in size until it ultimately impinges on the vascular pedicle of the allograft, which can lead to thrombosis or

drain placement in the event of urinoma development.

with renal artery thrombosis on postoperative day 1.

*5.1.2. Renal vein thrombosis*

salvaging the allograft.

*5.1.3. Hemorrhage and hematoma*

Treatment of acute cellular rejection depends on the severity. First-line therapy includes a steroid pulse. In more severe cases of acute rejection, an antibody-depleting agent, such as rATG should be administered in addition to a steroid pulse. CNI levels should be monitored closely in the setting of acute rejection, as nephrotoxicity is more common. Moreover, in the setting of antibody-depleting therapy, patients should be monitored closely for infectious complications [25]. Graft survival is negatively impacted by episodes of acute rejection [26].

## **5. Technical complications**

#### **5.1. Vascular**

#### *5.1.1. Renal artery thrombosis*

Renal artery thrombosis is a rare event. Technical issues, such as arterial kinking or intimal dissection, are the usual culprits. The majority of these events occur in the first few days following transplantation. Sudden cessation of urine production should raise the suspicion for vascular compromise. Risk factors for this devastating condition include the use of pediatric donors less than or equal to 15 kg without an aortic patch as well as kidneys from donors less than 5 years of age [27,28]. However, use of pediatric donors less than 10 kg has also been successfully reported without an increased rate of arterial thrombosis [29]. The diagnosis must be made promptly, as the allograft can only tolerate 30-60 minutes of warm ischemia before the allograft has irreversible injury. Even in ideal situations, recovery from ischemic injury may still be impossible. A high-index of suspicion is necessary to ensure prompt and adequate treatment of this condition with emergent re-operation. In cases where the recipient had previously made urine at baseline, the diagnosis becomes even more difficult. The diagnosis is made with DUS, which demonstrate lack of color flow (Figure 1).

When multiple renal arteries are present on the donor allograft, reconstruction may be necessary during implantation. Most authors have reported no difference in vascular complications or graft survival [30]. However, thrombosis of some minor branches supplying superior or inferior poles can lead to partial infarction of the renal allograft. Patients may present with elevated serum creatinine or hypertension. Subsequent angiogram will demonstrate a wedge perfusion defect of the allograft. Patients may then present with urine leak if caliceal infarction is present. In such circumstances, the patient may benefit from nephrostomy tube placement for complete urinary decompression as well as percutaneous drain placement in the event of urinoma development.

**Figure 1.** Doppler ultrasound demonstrates global hypoperfusion of the transplanted kidney consistent with renal artery thrombosis on postoperative day 1.

#### *5.1.2. Renal vein thrombosis*

84 Current Concepts in Kidney Transplantation

**5. Technical complications**

*5.1.1. Renal artery thrombosis*

**5.1. Vascular**

Acute rejection can occur at any time in the early post-transplant period. The most common time point, however, is 5 to 7 days post-transplant. Acute cellular rejection remains the most common type of rejection episode. The incidence of acute rejection is highest in the first 6 months post-transplant, with overall acute rejection rates between 10-20%. The immunologic profiles of the donor and recipient as well as the use of different immunosuppression protocols are important in stratifying acute rejection risk. Signs and symptoms of acute rejection include fever, elevated serum creatinine, increasing weight, and graft tenderness. Transplant biopsy remains the gold standard for diagnosis. Histological changes in acute

Treatment of acute cellular rejection depends on the severity. First-line therapy includes a steroid pulse. In more severe cases of acute rejection, an antibody-depleting agent, such as rATG should be administered in addition to a steroid pulse. CNI levels should be monitored closely in the setting of acute rejection, as nephrotoxicity is more common. Moreover, in the setting of antibody-depleting therapy, patients should be monitored closely for infectious complications [25]. Graft survival is negatively impacted by episodes of acute rejection [26].

Renal artery thrombosis is a rare event. Technical issues, such as arterial kinking or intimal dissection, are the usual culprits. The majority of these events occur in the first few days following transplantation. Sudden cessation of urine production should raise the suspicion for vascular compromise. Risk factors for this devastating condition include the use of pediatric donors less than or equal to 15 kg without an aortic patch as well as kidneys from donors less than 5 years of age [27,28]. However, use of pediatric donors less than 10 kg has also been successfully reported without an increased rate of arterial thrombosis [29]. The diagnosis must be made promptly, as the allograft can only tolerate 30-60 minutes of warm ischemia before the allograft has irreversible injury. Even in ideal situations, recovery from ischemic injury may still be impossible. A high-index of suspicion is necessary to ensure prompt and adequate treatment of this condition with emergent re-operation. In cases where the recipient had previously made urine at baseline, the diagnosis becomes even more difficult. The diagnosis is made with DUS, which demonstrate lack of color flow (Figure 1).

When multiple renal arteries are present on the donor allograft, reconstruction may be necessary during implantation. Most authors have reported no difference in vascular complications or graft survival [30]. However, thrombosis of some minor branches supplying superior or inferior poles can lead to partial infarction of the renal allograft. Patients may present with elevated serum creatinine or hypertension. Subsequent angiogram will demonstrate a wedge perfusion defect of the allograft. Patients may then present with urine leak if caliceal infarction is present. In such circumstances, the patient may benefit from

rejection include tubulitis and interstitial infiltrates, with or without arteritis [24].

*4.3.3. Acute rejection*

Renal vein thrombosis is also an uncommon, but potentially devastating, complication. The usual causes include injuries to the donor renal vein that was narrowed after repair of an injury or twisting of the vein on the renal pedicle. Previously, the use of right-sided living donor renal allografts was associated with an increased risk of renal vein thrombosis due to the short length. However, we have not seen this in our large series of right-sided donors, even with modern procurement techniques, such as laparoendoscopic single-site surgery [31,32]. Patients present with gross hematuria, decreased urine output and engorgement of the graft due to venous outflow obstruction. DUS will show parvus tardus and reversal of diastolic flow in the renal artery. Immediate repair is necessary if there is to be any chance of salvaging the allograft.

#### *5.1.3. Hemorrhage and hematoma*

Most postoperative hematomas are small and insignificant. They are usually incidentally found on a post-transplant DUS. Larger and more clinically significant hematomas may occur in the setting of antiplatelet therapy or anticoagulation for patients with risk factors for venothromboembolic events (Figure 2). Patients with clinically significant hematomas will present with swelling from the incision, pain over the graft, and an acute drop in hemoglobin values. The hematoma will continue to increase in size until it ultimately impinges on the vascular pedicle of the allograft, which can lead to thrombosis or hydronephrosis. Postoperatively, patients may show signs of bruising in dependent regions of the wound, flank and groin.

Surgical Management of the Kidney Transplant Recipient 87

Transplant renal artery stenosis is a late complication of kidney transplantation. The diagnosis is usually made with DUS, which demonstrates parvus tardus waveforms as well as elevated resistive indices. An MRA is necessary to confirm the diagnosis. Treatment includes interventional procedures involving balloon angioplasty and potentially stenting or surgical repair with cadaveric graft. This topic is discussed in detail in another chapter of this textbook.

Pelvicaliceal dilation seen on DUS implies obstruction in the urinary flow. Placement of a foley catheter and examination of its patency can provide relief if the cause is from an enlarged prostate or dysfunctional bladder. Failure of the foley catheter to relieve obstruction necessitates immediate decompression via placement of a percutaneous nephrostomy tube. An antegrade pyelogram can be performed to visualize where the obstruction occurs (Figure 3). A decrease in the serum creatinine following decompression confirms the diagnosis. After 1-2 days of allowing the postoperative edema to subside, a nephrogram is performed to evaluate whether ureteral obstruction or stenosis remains. Early strictures usually require surgical repair, where as late strictures are more amenable to

**Figure 3.** An antegrade pyelogram is shown demonstrating complete obstruction (red arrow) at the

ureteroneocystostomy anastomosis of the transplanted kidney in the right lower quadrant.

less invasive procedures, such as stent placement and angioplasty.

*5.1.4. Renal artery stenosis*

*5.2.1. Ureteral obstruction*

**5.2. Urinary**

**Figure 2.** Panel A demonstrates an early postoperative hematoma (as outlined by plus signs) above the fascia in a transplant patient on systemic anticoagulation. Panel B illustrates a perinephric hematoma (as outlined by plus signs) in the same patient.

Patients requiring postoperative anticoagulation for prophylaxis of a vascular thrombotic event are at greatest risk of developing a hematoma [33,34]. The reported risk of a postoperative bleed on heparin requiring surgical exploration has been reported as high as 60% in patients on anticoagulation. Moreover, patients with a history of lupus and lupus anticoagulant are especially sensitive to heparin anticoagulation, leading to an increased risk of postoperative hemorrhage [35]. Percutaneous drainage of large hematomas is insufficient and operative exploration and evacuation should be undertaken to avoid vascular thrombosis and to remove clot as a potential nidus of infection.

#### *5.1.4. Renal artery stenosis*

Transplant renal artery stenosis is a late complication of kidney transplantation. The diagnosis is usually made with DUS, which demonstrates parvus tardus waveforms as well as elevated resistive indices. An MRA is necessary to confirm the diagnosis. Treatment includes interventional procedures involving balloon angioplasty and potentially stenting or surgical repair with cadaveric graft. This topic is discussed in detail in another chapter of this textbook.

### **5.2. Urinary**

86 Current Concepts in Kidney Transplantation

of the wound, flank and groin.

(as outlined by plus signs) in the same patient.

hydronephrosis. Postoperatively, patients may show signs of bruising in dependent regions

**Figure 2.** Panel A demonstrates an early postoperative hematoma (as outlined by plus signs) above the fascia in a transplant patient on systemic anticoagulation. Panel B illustrates a perinephric hematoma

Patients requiring postoperative anticoagulation for prophylaxis of a vascular thrombotic event are at greatest risk of developing a hematoma [33,34]. The reported risk of a postoperative bleed on heparin requiring surgical exploration has been reported as high as 60% in patients on anticoagulation. Moreover, patients with a history of lupus and lupus anticoagulant are especially sensitive to heparin anticoagulation, leading to an increased risk of postoperative hemorrhage [35]. Percutaneous drainage of large hematomas is insufficient and operative exploration and evacuation should be undertaken to avoid

vascular thrombosis and to remove clot as a potential nidus of infection.

#### *5.2.1. Ureteral obstruction*

Pelvicaliceal dilation seen on DUS implies obstruction in the urinary flow. Placement of a foley catheter and examination of its patency can provide relief if the cause is from an enlarged prostate or dysfunctional bladder. Failure of the foley catheter to relieve obstruction necessitates immediate decompression via placement of a percutaneous nephrostomy tube. An antegrade pyelogram can be performed to visualize where the obstruction occurs (Figure 3). A decrease in the serum creatinine following decompression confirms the diagnosis. After 1-2 days of allowing the postoperative edema to subside, a nephrogram is performed to evaluate whether ureteral obstruction or stenosis remains. Early strictures usually require surgical repair, where as late strictures are more amenable to less invasive procedures, such as stent placement and angioplasty.

**Figure 3.** An antegrade pyelogram is shown demonstrating complete obstruction (red arrow) at the ureteroneocystostomy anastomosis of the transplanted kidney in the right lower quadrant.

Ureteral strictures in the early postoperative period are related to technical issues. Patients with ureteral stents will not present with obstruction in the early postoperative period. Rather they may present with this problem several weeks after stent removal. This complication is usually the result of a twist in the ureter or narrowing at the anastomosis due to distal ureteral ischemia [36]. Short segment strictures (< 2 cm) are usually amenable to percutaneous dilatation whereas longer strictures (>2 cm) and those involving the proximal or mid-ureter typically require surgical revision. The treatment options include excising the stricture and creating a new ureteroneocystostomy, if sufficient length is available on the transplant ureter. A psoas hitch or Boari flap can be performed to bring the bladder closer to the kidney to assist in this approach. Otherwise, a ureteroureterostomy using the ipsilateral native ureter or ureteropyelostomy may be required. A 6 French double-J stent can be left in place for 4 to 6 weeks. In cases where the ipsilateral native ureter is unavailable, the contralateral ureter can also be used. Graft survival is not significantly affected in patients undergoing correction or revision of urologic complications in the first year post-transplant [37].

Surgical Management of the Kidney Transplant Recipient 89

Causes of urine leak include technical issues related to creation of the ureteroneocystostomy or ischemic necrosis of the distal ureter. Urgent surgical management of this condition is mandatory to decrease the risk of wound infection and improve potential for recovery of the

A lymphocele is a collection of lymphatic fluid that develops in the postoperative field in a nonepithelialized cavity. These collections typically form around the divided lymphatics surrounding the recipient iliac vasculature. Most lymphoceles are asymptomatic and do not require any intervention; however, lymphoceles can cause compressive symptoms from mass effect on surrounding tissue and structures, or can become infected. Most lymphoceles occur between 2 weeks and 6 months post-transplant [38]. The peak incidence is about 6 weeks post-transplant. The source of the lymphocele is from disrupted lymphatic channels surrounding the iliac vasculature during implantation. Lymphocele formation can be prevented by meticulous dissection and ligation of all lymphatic trunks with a nonabsorbable suture. Some have even suggested that lymphocele formation can be avoided by anastomosing to the common iliac vasculature were less lymphatic tissue is present [39]. The use of mTOR inhibitors has been strongly and positively correlated with the

**Figure 5.** A lymphocele (white arrow) can be seen on CT scan compressing the right lower quadrant

development of lymphoceles in kidney transplantation [40].

transplanted kidney (red arrow) causing hydronephrosis.

allograft.

**5.3. Lymphocele**

#### *5.2.2. Urine leak*

Urine leak usually occurs in the first month after transplant and is due to a disruption in the ureteral-bladder anastomosis. Caliceal infarction from a partial thrombosis of the renal allograft can also present as a urine leak. The presenting symptoms include abdominal pain, increasing serum creatinine level and a decrease in urine output. Typically, a DUS or renal scan shows a fluid collection in the retroperitoneal space (Figure 4). Sampling of the fluid and analysis for creatinine can confirm the diagnosis of a urinoma.

**Figure 4.** Urinoma (yellow arrow) located at the inferior pole of the transplanted kidney as a result of a urine leak.

Causes of urine leak include technical issues related to creation of the ureteroneocystostomy or ischemic necrosis of the distal ureter. Urgent surgical management of this condition is mandatory to decrease the risk of wound infection and improve potential for recovery of the allograft.

#### **5.3. Lymphocele**

88 Current Concepts in Kidney Transplantation

*5.2.2. Urine leak*

urine leak.

Ureteral strictures in the early postoperative period are related to technical issues. Patients with ureteral stents will not present with obstruction in the early postoperative period. Rather they may present with this problem several weeks after stent removal. This complication is usually the result of a twist in the ureter or narrowing at the anastomosis due to distal ureteral ischemia [36]. Short segment strictures (< 2 cm) are usually amenable to percutaneous dilatation whereas longer strictures (>2 cm) and those involving the proximal or mid-ureter typically require surgical revision. The treatment options include excising the stricture and creating a new ureteroneocystostomy, if sufficient length is available on the transplant ureter. A psoas hitch or Boari flap can be performed to bring the bladder closer to the kidney to assist in this approach. Otherwise, a ureteroureterostomy using the ipsilateral native ureter or ureteropyelostomy may be required. A 6 French double-J stent can be left in place for 4 to 6 weeks. In cases where the ipsilateral native ureter is unavailable, the contralateral ureter can also be used. Graft survival is not significantly affected in patients undergoing correction or

Urine leak usually occurs in the first month after transplant and is due to a disruption in the ureteral-bladder anastomosis. Caliceal infarction from a partial thrombosis of the renal allograft can also present as a urine leak. The presenting symptoms include abdominal pain, increasing serum creatinine level and a decrease in urine output. Typically, a DUS or renal scan shows a fluid collection in the retroperitoneal space (Figure 4). Sampling of the fluid

**Figure 4.** Urinoma (yellow arrow) located at the inferior pole of the transplanted kidney as a result of a

revision of urologic complications in the first year post-transplant [37].

and analysis for creatinine can confirm the diagnosis of a urinoma.

A lymphocele is a collection of lymphatic fluid that develops in the postoperative field in a nonepithelialized cavity. These collections typically form around the divided lymphatics surrounding the recipient iliac vasculature. Most lymphoceles are asymptomatic and do not require any intervention; however, lymphoceles can cause compressive symptoms from mass effect on surrounding tissue and structures, or can become infected. Most lymphoceles occur between 2 weeks and 6 months post-transplant [38]. The peak incidence is about 6 weeks post-transplant. The source of the lymphocele is from disrupted lymphatic channels surrounding the iliac vasculature during implantation. Lymphocele formation can be prevented by meticulous dissection and ligation of all lymphatic trunks with a nonabsorbable suture. Some have even suggested that lymphocele formation can be avoided by anastomosing to the common iliac vasculature were less lymphatic tissue is present [39]. The use of mTOR inhibitors has been strongly and positively correlated with the development of lymphoceles in kidney transplantation [40].

**Figure 5.** A lymphocele (white arrow) can be seen on CT scan compressing the right lower quadrant transplanted kidney (red arrow) causing hydronephrosis.

Lymphoceles are suggested by DUS or CT scan findings demonstrating a large fluid periallograft collection (Figure 5). The most common location is adjacent to the bladder and multiple collections may be present. Sending aspirated fluid for cytological and biochemical analysis for lymphocytes can confirm the diagnosis. Small, asymptomatic collections should be left alone, as spontaneous resolution is common. Larger collections and those that are causing obstructive symptoms can be initially managed by placement of a percutaneous drain. Recurrence is common and several aspirations may be necessary. Each aspiration carries a theoretical risk of infection. Sclerotherapy with povidone-iodine can be effective [41]. A possible complication of povidone-iodine is acute renal failure and this should be monitored during and after treatment [42]. Operative drainage of lymphoceles provides definitive therapy. The goal for drainage is to allow communication with the peritoneal cavity where it can be reabsorbed. This can be done via an open or the preferred laparoscopic approach [38]. The lymphocele is unroofed or fenestrated with a 5 cm opening to allow direct drainage into the peritoneal cavity.

Surgical Management of the Kidney Transplant Recipient 91

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppression regimens. Early administration post-transplant has helped mitigate the risk of acute rejection in kidney transplantation. Most institutions have implemented the use of polyclonal antibody-depleting or monoclonal antibody induction therapy in conjunction with introduction of CNIs as early as postoperative day 1 or 2, as we do in our institution. CNIs can have a nephrotoxic effect on the allograft by decreasing renal blood flow in the afferent arteriole, leading to tubular injury [48]. Variable oral absorption of CNIs, especially cyclosporine, in the early postoperative period can lead to either overdosing or

Differentiating calcineurin inhibitor toxicity from other causes of graft dysfunction is difficult based on clinical context. Percutaneous transplant biopsy can be used to diagnose other causes of graft dysfunction. Histologic findings are non-specific with tubular injury and tubular vacuolization being the most common early findings. Hyaline deposition and fibrosis can be found with chronic injury. Obtaining daily calcineurin inhibitor levels can prevent supratherapeutic dosing, predisposing patients to the nephrotoxic effects. Avoiding nephrotoxicity is important, as chronic nephrotoxicity has been shown to correlate with

chronic transplant nephropathy, ultimately affecting long-term allograft survival [49].

Infectious complications in the early postoperative period are typically related to the operation. The most common postoperative infections include surgical site infections, urinary tract infections, bacteremia from central venous catheters, and pneumonia [50]. Careful and meticulous surgical technique and attention to detail can help prevent most early infectious complications, such as surgical site infections, central venous catheter sepsis, and urinary tract infections from foley catheter placement. Encouraging early ambulation and the use of incentive spirometry decreases the incidence of atelectasis and the risk of postoperative pneumonia. Removing foley catheters and stents once they no longer serve an appreciable purpose can help prevent and eliminate urinary tract infections. Central venous catheters should be removed as early as possible to decrease the incidence of line sepsis.

Typically, opportunistic infections are relatively uncommon in the early postoperative period (<30 days). Cytomegalovirus (CMV) infection occurs, especially in seronegative recipients receiving allografts from seropositive donors. Institution of CMV prophylaxis with oral valganciclovir or high-dose oral acyclovir for a minimum of 3 months has significantly reduced the incidence and severity of CMV infection [51]. Once antiviral prophylaxis has been halted, CMV infection may still occur. Appropriate prophylaxis with trimethoprim/sulfamethoxazole has almost entirely eliminated early *Pneumocystis carinii* pneumonia. Prophylactic antifungal agents, such as nystatin or clotrimazole troches, have also been instituted to decrease the risk of oral *Candida* infections in the early postoperative period.

underdosing, causing either nephrotoxicity or acute rejection, respectively.

**6.2. Drug-induced nephrotoxicity**

**6.3. Infectious complications**

## **6. Medical complications**

## **6.1. Delayed graft function**

Delayed graft function (DGF) is the most common cause of early graft dysfunction and is defined as the need for dialysis within the first week after transplant. DGF has been reported to affect approximately 20-25% of all deceased donor transplant recipients [43]. Recipients of marginal donors, including ECD and DCD, have rates of DGF as high as 70% in some studies [15, 44]. The use of pulsatile hypothermic machine perfusion has been shown in studies to reduce that risk, though the overall rate still remains higher than SCD allografts [44]. Various donor risk factors for DGF include age, cause of death, and ischemia reperfusion injury [45].

DGF is a well-documented risk factor for poor graft survival. In a 2011 study analyzing 40 years of deceased donor renal transplant recipients, the occurrence of DGF and acute rejection were the most significant predictors of renal allograft survival rates [26]. As previously discussed, marginal donors have the highest rates of DGF, while the rate of DGF in living donors is relatively uncommon. Additionally, patients undergoing retransplantation have higher rates of DGF than first time recipients of renal allografts. ECD allograft recipients may have a higher rate of acute rejection, which may be related to the higher rate of DGF in these allografts [46]. Prolonged cold ischemia has been a welldocumented cause of DGF; however, recent data suggests that cold ischemia-induced DGF may play a limited role in long-term outcomes [47].

The use of DUS and biopsy can differentiate DGF from other causes of early graft dysfunction, such as acute rejection or surgical complications. A transplant biopsy is usually necessary to differentiate between other causal factors, such as acute rejection or recurrent disease. Radiographic studies in the proper clinical context can also aid in the diagnosis of DGF. Typically, transplants with DGF will demonstrate good renal perfusion and good parenchymal uptake of radionucleotide tracer with little or no renal excretion. Primary nonfunction should be considered in the differential at this time point.

### **6.2. Drug-induced nephrotoxicity**

90 Current Concepts in Kidney Transplantation

to allow direct drainage into the peritoneal cavity.

may play a limited role in long-term outcomes [47].

function should be considered in the differential at this time point.

**6. Medical complications**

**6.1. Delayed graft function**

reperfusion injury [45].

Lymphoceles are suggested by DUS or CT scan findings demonstrating a large fluid periallograft collection (Figure 5). The most common location is adjacent to the bladder and multiple collections may be present. Sending aspirated fluid for cytological and biochemical analysis for lymphocytes can confirm the diagnosis. Small, asymptomatic collections should be left alone, as spontaneous resolution is common. Larger collections and those that are causing obstructive symptoms can be initially managed by placement of a percutaneous drain. Recurrence is common and several aspirations may be necessary. Each aspiration carries a theoretical risk of infection. Sclerotherapy with povidone-iodine can be effective [41]. A possible complication of povidone-iodine is acute renal failure and this should be monitored during and after treatment [42]. Operative drainage of lymphoceles provides definitive therapy. The goal for drainage is to allow communication with the peritoneal cavity where it can be reabsorbed. This can be done via an open or the preferred laparoscopic approach [38]. The lymphocele is unroofed or fenestrated with a 5 cm opening

Delayed graft function (DGF) is the most common cause of early graft dysfunction and is defined as the need for dialysis within the first week after transplant. DGF has been reported to affect approximately 20-25% of all deceased donor transplant recipients [43]. Recipients of marginal donors, including ECD and DCD, have rates of DGF as high as 70% in some studies [15, 44]. The use of pulsatile hypothermic machine perfusion has been shown in studies to reduce that risk, though the overall rate still remains higher than SCD allografts [44]. Various donor risk factors for DGF include age, cause of death, and ischemia

DGF is a well-documented risk factor for poor graft survival. In a 2011 study analyzing 40 years of deceased donor renal transplant recipients, the occurrence of DGF and acute rejection were the most significant predictors of renal allograft survival rates [26]. As previously discussed, marginal donors have the highest rates of DGF, while the rate of DGF in living donors is relatively uncommon. Additionally, patients undergoing retransplantation have higher rates of DGF than first time recipients of renal allografts. ECD allograft recipients may have a higher rate of acute rejection, which may be related to the higher rate of DGF in these allografts [46]. Prolonged cold ischemia has been a welldocumented cause of DGF; however, recent data suggests that cold ischemia-induced DGF

The use of DUS and biopsy can differentiate DGF from other causes of early graft dysfunction, such as acute rejection or surgical complications. A transplant biopsy is usually necessary to differentiate between other causal factors, such as acute rejection or recurrent disease. Radiographic studies in the proper clinical context can also aid in the diagnosis of DGF. Typically, transplants with DGF will demonstrate good renal perfusion and good parenchymal uptake of radionucleotide tracer with little or no renal excretion. Primary nonCalcineurin inhibitors (CNIs) have become the cornerstone of immunosuppression regimens. Early administration post-transplant has helped mitigate the risk of acute rejection in kidney transplantation. Most institutions have implemented the use of polyclonal antibody-depleting or monoclonal antibody induction therapy in conjunction with introduction of CNIs as early as postoperative day 1 or 2, as we do in our institution. CNIs can have a nephrotoxic effect on the allograft by decreasing renal blood flow in the afferent arteriole, leading to tubular injury [48]. Variable oral absorption of CNIs, especially cyclosporine, in the early postoperative period can lead to either overdosing or underdosing, causing either nephrotoxicity or acute rejection, respectively.

Differentiating calcineurin inhibitor toxicity from other causes of graft dysfunction is difficult based on clinical context. Percutaneous transplant biopsy can be used to diagnose other causes of graft dysfunction. Histologic findings are non-specific with tubular injury and tubular vacuolization being the most common early findings. Hyaline deposition and fibrosis can be found with chronic injury. Obtaining daily calcineurin inhibitor levels can prevent supratherapeutic dosing, predisposing patients to the nephrotoxic effects. Avoiding nephrotoxicity is important, as chronic nephrotoxicity has been shown to correlate with chronic transplant nephropathy, ultimately affecting long-term allograft survival [49].

#### **6.3. Infectious complications**

Infectious complications in the early postoperative period are typically related to the operation. The most common postoperative infections include surgical site infections, urinary tract infections, bacteremia from central venous catheters, and pneumonia [50]. Careful and meticulous surgical technique and attention to detail can help prevent most early infectious complications, such as surgical site infections, central venous catheter sepsis, and urinary tract infections from foley catheter placement. Encouraging early ambulation and the use of incentive spirometry decreases the incidence of atelectasis and the risk of postoperative pneumonia. Removing foley catheters and stents once they no longer serve an appreciable purpose can help prevent and eliminate urinary tract infections. Central venous catheters should be removed as early as possible to decrease the incidence of line sepsis.

Typically, opportunistic infections are relatively uncommon in the early postoperative period (<30 days). Cytomegalovirus (CMV) infection occurs, especially in seronegative recipients receiving allografts from seropositive donors. Institution of CMV prophylaxis with oral valganciclovir or high-dose oral acyclovir for a minimum of 3 months has significantly reduced the incidence and severity of CMV infection [51]. Once antiviral prophylaxis has been halted, CMV infection may still occur. Appropriate prophylaxis with trimethoprim/sulfamethoxazole has almost entirely eliminated early *Pneumocystis carinii* pneumonia. Prophylactic antifungal agents, such as nystatin or clotrimazole troches, have also been instituted to decrease the risk of oral *Candida* infections in the early postoperative period.

Prompt diagnosis and treatment of infectious complications leads to better outcomes. Aggressive treatment with intravenous antibacterial, antiviral or antifungal agents for severe infections improve outcomes. Infected intra-abdominal collections should be drained. Minimizing external instrumentation should be part of the fundamental strategy in preventing infectious complications.

Surgical Management of the Kidney Transplant Recipient 93

Cheguevara Afaneh, Meredith J. Aull, Anthony Watkins, Sandip Kapur and Jim Kim *Department of Surgery, Division of Transplant Surgery, New York-Presbyterian Hospital- Weill*

[1] Almond, P.S.; Matas, A.; Gillingham, K., et al. (1993). Risk factors for chronic rejection in renal allograft recipients. *Transplantation*, Vol.55, No.4, (April 1993), pp. 752-6, ISSN

[2] Aultman, D.F.; Sawaya, D.E.; Zibari, G.B., et al. (1999). Are all successful renal transplants really successful? *Am J Kidney Dis*, Vol.34, No.1, (July 1999), pp. 61-4, ISSN 0272-6386. [3] Troppmann, C.; Gillingham, K.J.; Benedetti, E., et al. (1995). Delayed graft function, acute rejection, and outcome after cadaver renal transplantation: a multivariate analysis.

[4] Nankivell, B.J.; Borrows, R.J.; Fung, C.L., et al. (2003). The natural history of chronic allograft nephropathy. *N Engl J Med*, Vol.349, No.24, (December 2003), pp. 2326-33,

[5] Matsuoka, L.; Shah, T.; Aswad, S., et al. (2006). Pulsatile perfusion reduces the incidence of delayed graft function in expanded criteria donor kidney transplantation. *Am J*

[6] Dawidson, I.J.; Sandor, Z.F.; Coorpender, L., et al. (1992). Intraoperative albumin administration affects the outcome of cadaver renal transplantation. *Transplantation*,

[7] Buchler, M.; Hurault de Ligny, B.; Madec, C., et al. (2003). Induction therapy by antithymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. *Clin Transplant*, Vol.17, No.6, (December 2003), pp. 539-45, ISSN 0902-0063. [8] Dawidson, I.; Rooth, P.; Fry, W.R., et al. (1989). Prevention of acute cyclosporineinduced renal blood flow inhibition and improved immunosuppression with verapamil. *Transplantation*, Vol.48, No.4, (October 1989), pp. 575-80, ISSN 0041-1337. [9] Dawidson, I.; Rooth, P.; Alway, C., et al. (1990). Verapamil prevents posttransplant delayed function and cyclosporine A nephrotoxicity. *Transplant Proc*, Vol.22, No.4,

[10] Cross, N.B.; Webster, A.C.; Masson, P.; O'connell, P.J.; Craig, J.C. (2009). Antihypertensives for kidney transplant recipients: systematic review and meta-analysis of randomized

[12] Canet, E.; Osman, D.; Lambert, J., et al. (2011). Acute respiratory failure in kidney transplant recipients: a multicenter study. *Crit Care*, Vol.15, No.2, (March 2011), R91, ISSN 1364-8535. [13] Sharifipour, F.; Resaeetalab, F.; Naghibi, M. (2009). Pulmonary fungal infection in kidney transplant recipients: an 8-year study. *Transplant Proc*, Vol.41, No.5, (June 2009),

controlled trials. *Transplantation*, Vol.88, No.1, (July 2009), pp. 7-18, ISSN 0041-1337. [11] Candan, S.; Pirat, A.; Varol, G.; Torgay, A.; Zeynelgolu, P.; Arslan, G. (2006). Respiratory problems in renal transplant recipients admitted to intensive care during long-term follow-

up. *Transplant Proc*, Vol.38, No.5, (June 2006), pp. 1354-6, ISSN 0041-1345.

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*Transplant*, Vol.6, No.6, (June 2006), pp. 1473-8, ISSN 1600-6135.

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(August 1990), pp. 1379-80, ISSN 0041-1345.

pp. 1654-6, ISSN 0041-1345.

**Author details**

**8. References**

0041-1337.

ISSN 0028-4793.

*Cornell Medical College, New York, NY, USA*

#### **6.4. Disease recurrence**

The majority of causes of end-stage renal disease (ESRD) do not recur early in the posttransplant period. Disease processes such as diabetes mellitus and hypertension can cause recurrence of ESRD if poorly controlled over a long period of time. Two causes of ESRD, however, can recur immediately post-transplant: focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA).

FSGS is a form of glomerulonephritis that can recur immediately post-transplant. Although the exact mechanism is unclear, a serum factor causes glomerular injury and early massive proteinuria [52,53]. The development of nephrotic range proteinuria can be suggestive of disease recurrence in a patient with a pretransplant diagnosis of FSGS. The diagnosis can be verified with electron microscopy demonstrating effacement of foot processes. Current treatment strategies include increasing calcineurin inhibitor dosing, steroids, and plasmapheresis, with the latter modality being the most effective [52]. If patients fail to respond over several weeks, then further treatments are not likely to be effective.

Thrombotic microangiopathy can also recur relatively quickly post-transplant. Causes of TMA include recurrent disease, endothelial damage from calcineurin inhibitor use, hypercoagulable disorders, or antibody-mediated rejection episodes [54]. Clinical manifestations include hemolysis and decreases in hemoglobin, platelet count, and haptoglobin. Additionally, microangiopathy will be present on peripheral blood smears. Patients will have increases in lactate dehydrogenase and serum creatinine, signifying allograft dysfunction. Transplant biopsy will show fibrin clot in arterioles. Treatment includes removing inciting factors, such as calcineurin inhibitors, as well as plasmapheresis [55]. Eculizumab, a humanized monoclonal antibody to complement component 5 (C5) to mediate complement-mediated injury, has emerged as a possible treatment option for TMA [56]. Blocking complement activation, especially the last step of the complement cascade, has important implications in TMA. Treatment of TMA posttransplant has been successfully reported [57], but still carries a poor prognosis.

### **7. Summary**

Early management of the kidney transplant recipient is crucial for optimizing outcomes and avoiding early graft loss, or even death. Given the surgical and medical complexity of these patients, attention to detail and prompt diagnosis of complications is critical to achieving excellent outcomes. Clinical scenarios need to be recognized where early operative intervention is necessary to save the graft. However, whenever possible, prevention of complications provides the best outcomes.

## **Author details**

92 Current Concepts in Kidney Transplantation

preventing infectious complications.

and thrombotic microangiopathy (TMA).

reported [57], but still carries a poor prognosis.

complications provides the best outcomes.

**7. Summary**

**6.4. Disease recurrence**

Prompt diagnosis and treatment of infectious complications leads to better outcomes. Aggressive treatment with intravenous antibacterial, antiviral or antifungal agents for severe infections improve outcomes. Infected intra-abdominal collections should be drained. Minimizing external instrumentation should be part of the fundamental strategy in

The majority of causes of end-stage renal disease (ESRD) do not recur early in the posttransplant period. Disease processes such as diabetes mellitus and hypertension can cause recurrence of ESRD if poorly controlled over a long period of time. Two causes of ESRD, however, can recur immediately post-transplant: focal segmental glomerulosclerosis (FSGS)

FSGS is a form of glomerulonephritis that can recur immediately post-transplant. Although the exact mechanism is unclear, a serum factor causes glomerular injury and early massive proteinuria [52,53]. The development of nephrotic range proteinuria can be suggestive of disease recurrence in a patient with a pretransplant diagnosis of FSGS. The diagnosis can be verified with electron microscopy demonstrating effacement of foot processes. Current treatment strategies include increasing calcineurin inhibitor dosing, steroids, and plasmapheresis, with the latter modality being the most effective [52]. If patients fail to

Thrombotic microangiopathy can also recur relatively quickly post-transplant. Causes of TMA include recurrent disease, endothelial damage from calcineurin inhibitor use, hypercoagulable disorders, or antibody-mediated rejection episodes [54]. Clinical manifestations include hemolysis and decreases in hemoglobin, platelet count, and haptoglobin. Additionally, microangiopathy will be present on peripheral blood smears. Patients will have increases in lactate dehydrogenase and serum creatinine, signifying allograft dysfunction. Transplant biopsy will show fibrin clot in arterioles. Treatment includes removing inciting factors, such as calcineurin inhibitors, as well as plasmapheresis [55]. Eculizumab, a humanized monoclonal antibody to complement component 5 (C5) to mediate complement-mediated injury, has emerged as a possible treatment option for TMA [56]. Blocking complement activation, especially the last step of the complement cascade, has important implications in TMA. Treatment of TMA posttransplant has been successfully

Early management of the kidney transplant recipient is crucial for optimizing outcomes and avoiding early graft loss, or even death. Given the surgical and medical complexity of these patients, attention to detail and prompt diagnosis of complications is critical to achieving excellent outcomes. Clinical scenarios need to be recognized where early operative intervention is necessary to save the graft. However, whenever possible, prevention of

respond over several weeks, then further treatments are not likely to be effective.

Cheguevara Afaneh, Meredith J. Aull, Anthony Watkins, Sandip Kapur and Jim Kim *Department of Surgery, Division of Transplant Surgery, New York-Presbyterian Hospital- Weill Cornell Medical College, New York, NY, USA*

## **8. References**

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later. *Exp Clin Transplant*, Vol.2, No.1, (June 2004), pp. 208-13, ISSN 1304-0855. [22] Leeser, D.B.; Aull, M.J.; Afaneh, C., et al. (2012). Living donor kidney paired donation transplantation: experience as a founding member center of the National Kidney Registry. *Clin Transplant*, Vol.26, No.3, (May/June 2012), pp. E213-22, ISSN 0902-0063. [23] Jordan, S.C.; Vo, A.A.; Tyan, D.; Nast, C.C.; Toyoda, M. (2005). Current approaches to treatment of antibody-mediated rejection. *Pediatr Transplant*, Vol.9, No.3, (June 2005),

solution. *Am J Transplant*, Vol.9, No.5, (May 2009), pp. 1055-62, ISSN 1600-6135. [18] Webber, A.; Hambleton, J.; Chami, A., et al. (2012). Mean arterial blood pressure while awaiting kidney transplantation is associated with the risk of primary nonfunction.

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[43] Cecka, J.M. (2003). The UNOS Renal Transplant Registry. In Cecka JM. Terasaki PI (eds): Clinical Transplants 2002. Los Angeles, UCLA Immunogenetics Center, 2003, pp. 1-20, ISSN 0890-9016.

**Section 2**

**Immunologic Considerations in**

**Kidney Transplantation**

**Immunologic Considerations in Kidney Transplantation**

96 Current Concepts in Kidney Transplantation

1-20, ISSN 0890-9016.

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[43] Cecka, J.M. (2003). The UNOS Renal Transplant Registry. In Cecka JM. Terasaki PI (eds): Clinical Transplants 2002. Los Angeles, UCLA Immunogenetics Center, 2003, pp.

[44] Jochmans, I.; Moers, C.; Smits, J.M., et al. (2010). Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter, randomized, controlled trial. *Ann Surg*, Vol.252, No.5, (November 2010), pp. 756-64, ISSN 1528-1140. [45] Land, W. (1998). Postischemic reperfusion injury and kidney transplantation. *Transplant*

[46] Cecka, J.M. (2005). The UNOS Renal Transplant Registry. In Cecka JM. Terasaki PI (eds): Clinical Transplants 2004. Los Angeles, UCLA Immunogenetics Center, 2003, pp.

[47] Kayler, L.K.; Srinivas, T.R.; Schold, J.D. (2011). Influence of CIT-induced DGF on kidney transplant outcomes. *Am J Transplant*, Vol.11, No.12, (December 2011), pp. 2657-64, ISSN

[48] Perico, N.; Ruggenenti, P.; Gaspari, F., et al. (1992). Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation. *Transplantation*, Vol.54, No.1,

[49] Solez, K., Vincenti, F.; Filo, R.S. (1998). Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. *Transplantation*,

[50] Rubin, R.H. Infectious diseases in transplantation/pre- and post-transplantation. In Norman DJ, Suki, WN (eds): Primer on Transplantation. Thorofare, NJ, American

[51] Paya, C.; Humar, A.; Dominguez, E., et al. (2004). Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant

[54] Chiurchiu, C.; Ruggenenti, P.; Remuzzi, G. (2002). Thrombotic microangiopathy in renal transplantation. *Ann Transplant*, Vol.7, No.1, (2002), pp. 28-33, ISSN 1425-9524. [55] Kaplan, A.A. (2001). Therapeutic apheresis for renal disease. *Ther Apher*, Vol.5, No.2,

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recipients. *Am J Transplant*, Vol.4, No.4, (April 2004), pp. 611-20, ISSN 1600-6135. [52] Artero, M.L.; Sharma, R.; Savin, V.J.; Vincentin, F. (1994). Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. *Am J Kidney Dis*, Vol.23, No.4, (April 1994), pp. 574-81, ISSN 0272-6386. [53] Savin, V.J.; Sharma, R.; Sharma, M., et al. (1996). Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. *N Engl*

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**Chapter 5**

© 2012 Lee and Muthukumar, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Immunologic Concepts**

**in Kidney Transplantation**

John R. Lee and Thangamani Muthukumar

Additional information is available at the end of the chapter

On December 23, 1954, the first successful kidney transplantation was performed at the Peter Bent Brigham Hospital in Boston with the donor being an identical twin of the recipient [1]. This sentinel event marked one of the first in the history of modern medicine that a perfectly healthy individual underwent an invasive surgical procedure for the benefit of another. It also revealed that kidney donation and kidney transplantation were feasible and thus ushered the era of renal transplantation. Crossing immunological barriers between donor and recipient became the next major hurdle in the field. Over the past decades, advances in immunosuppression and crossmatch techniques have significantly improved the survival of renal transplants. Allograft survival has improved from 10% in the 1960's to

This chapter will introduce the basics of transplantation immunology with an emphasis on the HLA system and mechanisms for HLA typing. It will also provide an overview of different crossmatch techniques and also expound upon methods to determine sensitization to the donor. Lastly, it will introduce the basis for acute rejection, the diagnostic criteria that

The Human Leukocyte Antigen (HLA) is composed of proteins expressed on all nucleated cells encoded by a gene cluster called the major histocompatibility complex (MHC) and is the cornerstone of how mammals can differentiate between self and non-self. The work on MHC originated from Peter Gorer in the 1930's where he identified a set of four bloodgroup antigens [4]. Since these important findings, much research has been performed in investigating the MHC system and the equivalent H-2 system in mice. Understanding the

and reproduction in any medium, provided the original work is properly cited.

is currently employed, and noninvasive methods to diagnose acute rejection.

http://dx.doi.org/10.5772/53798

over 90% in the modern era [2,3].

**1. Introduction**

**2. HLA system**

**Chapter 5**

## **Immunologic Concepts in Kidney Transplantation**

John R. Lee and Thangamani Muthukumar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53798

## **1. Introduction**

On December 23, 1954, the first successful kidney transplantation was performed at the Peter Bent Brigham Hospital in Boston with the donor being an identical twin of the recipient [1]. This sentinel event marked one of the first in the history of modern medicine that a perfectly healthy individual underwent an invasive surgical procedure for the benefit of another. It also revealed that kidney donation and kidney transplantation were feasible and thus ushered the era of renal transplantation. Crossing immunological barriers between donor and recipient became the next major hurdle in the field. Over the past decades, advances in immunosuppression and crossmatch techniques have significantly improved the survival of renal transplants. Allograft survival has improved from 10% in the 1960's to over 90% in the modern era [2,3].

This chapter will introduce the basics of transplantation immunology with an emphasis on the HLA system and mechanisms for HLA typing. It will also provide an overview of different crossmatch techniques and also expound upon methods to determine sensitization to the donor. Lastly, it will introduce the basis for acute rejection, the diagnostic criteria that is currently employed, and noninvasive methods to diagnose acute rejection.

## **2. HLA system**

The Human Leukocyte Antigen (HLA) is composed of proteins expressed on all nucleated cells encoded by a gene cluster called the major histocompatibility complex (MHC) and is the cornerstone of how mammals can differentiate between self and non-self. The work on MHC originated from Peter Gorer in the 1930's where he identified a set of four bloodgroup antigens [4]. Since these important findings, much research has been performed in investigating the MHC system and the equivalent H-2 system in mice. Understanding the

© 2012 Lee and Muthukumar, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HLA system is critical to transplantation because differences in HLA between donor and recipient allow the immune system of a recipient to reject a donor's kidney. The HLA system is divided into two major classes of molecules: class I and class II.

Immunologic Concepts in Kidney Transplantation 101

are 3 major alleles of the HLA class II genes: HLA-DP, HLA-DQ, and HLA-DR. The function of the HLA class II molecule is to present extracellular foreign antigens to the immune system.

The structure of the HLA class II molecule can be divided into the following regions: a cytoplasmic tail, a transmembrane segment, and an extracellular alpha component that has two external domains. Unlike the HLA class I molecule, the HLA class II molecule is composed of a dimer. Once a dimer is formed, the extracellular units of the dimer create a groove like structure that can bind peptides for presentation. This peptide binding groove is

To understand the process of presentation in the HLA class II system, we will use an example of extracellular bacteria. A macrophage, which is one of the cell types that express HLA class II molecules, can endocytose an extracellular bacteria. The endocytosed bacteria fuse with lysosomes, which contain enzymes that will degrade peptides of the bacteria. Peptides from this degradation event are loaded onto the HLA class II molecules which are brought to the surface for display to the immune system. The HLA class II molecules present the peptides to the host lymphocytes resulting in various immune responses that

For transplantation, the immune response can be summarized in a similar way. Specialized recipient cells that express the HLA class II molecule routinely endocytose contents of their environment. As such, these specialized cells can endocytose the contents of donor cells which may include donor HLA class I or class II molecules. These peptides are subsequently loaded onto the HLA class II molecule and can now be presented to the recipient's

A major functional difference between the two classes of HLA is that the class I molecules present peptides derived from intracellular proteins to cytotoxic CD8 T cells, whereas class II molecules present peptides derived from extracellular proteins to CD4 T cells. After a kidney transplant, donor antigen presenting cells migrate to the draining lymph nodes of the recipient. The recipient CD4+T cells respond to donor class II HLA-peptide complex and the recipient CD8+T cells respond to donor class I HLA-peptide complex. This is called the direct pathway and is fundamentally different from the way the immune system responds to a foreign antigen. Contrary to MHC-restriction by which the T cells that respond to foreign peptides do so only when the foreign peptides are presented by antigen presenting cells expressing the same MHC as the responding T cells, T lymphocytes of the recipient respond and proliferative to donor derived non-self HLA molecules. In the indirect pathway, the sequence of events is similar to the host response towards an extracellular pathogen; recipient's antigen presenting cells internalize donor derived peptides and

present as recipient HLA-donor peptide complex to the recipient lymphocyte [6].

Determining the HLA make up of an individual is called HLA typing. The HLA system is extremely diverse with hundreds of known alleles for each HLA class molecule. We have two alleles, one derived from each parent, for each HLA molecule. Alleles derived from each

the place where foreign antigens can be presented to lymphocytes.

culminate in the killing of the bacteria.

circulating lymphocytes.

**2.3. HLA typing**

#### **2.1. HLA class I system**

There are three major alleles of the HLA class I genes: HLA-A, HLA-B, and HLA-C. The HLA class I molecule is a membrane-bound glycoprotein that is expressed on the surface of all nucleated cells and presents peptides for recognition by the host immune cells. The structure of the HLA class I molecule can be divided into the following regions: a cytoplasmic tail, a transmembrane segment, and an extracellular alpha component that has three external domains: a1, a2, and a3. In order to be able to present antigen to lymphocytes for recognition, the HLA class I molecule must associate with B2-microglobulin. Between the a1 and a2 domains is a groove like structure that can bind peptides of 8 to 10 amino acids.

To understand the process of presentation in the HLA class I system, we will use an example of an intracellular bacteria that has invaded a nucleated cell of the host. Presentation of antigen by an HLA class I molecule requires an important step called loading of the antigen on the HLA class I molecule. Inside each cell is a protein-degrading machinery called the proteasome which constantly degrades proteins into amino acids. Following bacterial invasion, some of the bacterial proteins will be degraded by the cell's proteasome. The short peptide segments of the bacterial proteins are loaded onto the groove of the host HLA class I molecule. The HLA class I molecule is then brought to the surface of the cell and can now present the peptide to the host's circulating lymphocytes. If a lymphocyte recognizes the bacterial antigen in the groove of the host HLA class I molecule, it can become activated and can initiate a cascade of intracellular changes, resulting in the proliferation of lymphocytes that can specifically attack the infected cell. It is through the host HLA class I antigen processing and presentation that the immune system can eliminate cells infected with intracellular bacteria. If presented without the host HLA class I molecule, naked bacterial proteins are not recognized by the host immune system [4,5].

For transplantation, this process can be summarized in a similar way. Just as the proteasome processes proteins associated with intracellular bacteria, it also degrades all proteins in a foreign cell including the HLA class I molecules. As such, donor leukocytes that travel along the kidney at the time of transplantation undergo the fate of an intracellular bacteria. They present peptides of the donor HLA class I molecule to circulating host lymphocytes. Lymphocytes recognize the donor peptides and mount a response against the foreign HLA class I molecule.

#### **2.2. HLA class II system**

An important difference between HLA class I molecules and HLA class II molecules is that the HLA class II molecules are expressed in a limited number of cell lines such as dendritic cells, macrophages, and B lymphocytes. Certain other cells like vascular endothelial cells and various epithelial and mesenchymal cells can be induced to express class II molecules. There are 3 major alleles of the HLA class II genes: HLA-DP, HLA-DQ, and HLA-DR. The function of the HLA class II molecule is to present extracellular foreign antigens to the immune system.

The structure of the HLA class II molecule can be divided into the following regions: a cytoplasmic tail, a transmembrane segment, and an extracellular alpha component that has two external domains. Unlike the HLA class I molecule, the HLA class II molecule is composed of a dimer. Once a dimer is formed, the extracellular units of the dimer create a groove like structure that can bind peptides for presentation. This peptide binding groove is the place where foreign antigens can be presented to lymphocytes.

To understand the process of presentation in the HLA class II system, we will use an example of extracellular bacteria. A macrophage, which is one of the cell types that express HLA class II molecules, can endocytose an extracellular bacteria. The endocytosed bacteria fuse with lysosomes, which contain enzymes that will degrade peptides of the bacteria. Peptides from this degradation event are loaded onto the HLA class II molecules which are brought to the surface for display to the immune system. The HLA class II molecules present the peptides to the host lymphocytes resulting in various immune responses that culminate in the killing of the bacteria.

For transplantation, the immune response can be summarized in a similar way. Specialized recipient cells that express the HLA class II molecule routinely endocytose contents of their environment. As such, these specialized cells can endocytose the contents of donor cells which may include donor HLA class I or class II molecules. These peptides are subsequently loaded onto the HLA class II molecule and can now be presented to the recipient's circulating lymphocytes.

A major functional difference between the two classes of HLA is that the class I molecules present peptides derived from intracellular proteins to cytotoxic CD8 T cells, whereas class II molecules present peptides derived from extracellular proteins to CD4 T cells. After a kidney transplant, donor antigen presenting cells migrate to the draining lymph nodes of the recipient. The recipient CD4+T cells respond to donor class II HLA-peptide complex and the recipient CD8+T cells respond to donor class I HLA-peptide complex. This is called the direct pathway and is fundamentally different from the way the immune system responds to a foreign antigen. Contrary to MHC-restriction by which the T cells that respond to foreign peptides do so only when the foreign peptides are presented by antigen presenting cells expressing the same MHC as the responding T cells, T lymphocytes of the recipient respond and proliferative to donor derived non-self HLA molecules. In the indirect pathway, the sequence of events is similar to the host response towards an extracellular pathogen; recipient's antigen presenting cells internalize donor derived peptides and present as recipient HLA-donor peptide complex to the recipient lymphocyte [6].

#### **2.3. HLA typing**

100 Current Concepts in Kidney Transplantation

**2.1. HLA class I system**

class I molecule.

**2.2. HLA class II system**

HLA system is critical to transplantation because differences in HLA between donor and recipient allow the immune system of a recipient to reject a donor's kidney. The HLA

There are three major alleles of the HLA class I genes: HLA-A, HLA-B, and HLA-C. The HLA class I molecule is a membrane-bound glycoprotein that is expressed on the surface of all nucleated cells and presents peptides for recognition by the host immune cells. The structure of the HLA class I molecule can be divided into the following regions: a cytoplasmic tail, a transmembrane segment, and an extracellular alpha component that has three external domains: a1, a2, and a3. In order to be able to present antigen to lymphocytes for recognition, the HLA class I molecule must associate with B2-microglobulin. Between the a1

and a2 domains is a groove like structure that can bind peptides of 8 to 10 amino acids.

naked bacterial proteins are not recognized by the host immune system [4,5].

For transplantation, this process can be summarized in a similar way. Just as the proteasome processes proteins associated with intracellular bacteria, it also degrades all proteins in a foreign cell including the HLA class I molecules. As such, donor leukocytes that travel along the kidney at the time of transplantation undergo the fate of an intracellular bacteria. They present peptides of the donor HLA class I molecule to circulating host lymphocytes. Lymphocytes recognize the donor peptides and mount a response against the foreign HLA

An important difference between HLA class I molecules and HLA class II molecules is that the HLA class II molecules are expressed in a limited number of cell lines such as dendritic cells, macrophages, and B lymphocytes. Certain other cells like vascular endothelial cells and various epithelial and mesenchymal cells can be induced to express class II molecules. There

To understand the process of presentation in the HLA class I system, we will use an example of an intracellular bacteria that has invaded a nucleated cell of the host. Presentation of antigen by an HLA class I molecule requires an important step called loading of the antigen on the HLA class I molecule. Inside each cell is a protein-degrading machinery called the proteasome which constantly degrades proteins into amino acids. Following bacterial invasion, some of the bacterial proteins will be degraded by the cell's proteasome. The short peptide segments of the bacterial proteins are loaded onto the groove of the host HLA class I molecule. The HLA class I molecule is then brought to the surface of the cell and can now present the peptide to the host's circulating lymphocytes. If a lymphocyte recognizes the bacterial antigen in the groove of the host HLA class I molecule, it can become activated and can initiate a cascade of intracellular changes, resulting in the proliferation of lymphocytes that can specifically attack the infected cell. It is through the host HLA class I antigen processing and presentation that the immune system can eliminate cells infected with intracellular bacteria. If presented without the host HLA class I molecule,

system is divided into two major classes of molecules: class I and class II.

Determining the HLA make up of an individual is called HLA typing. The HLA system is extremely diverse with hundreds of known alleles for each HLA class molecule. We have two alleles, one derived from each parent, for each HLA molecule. Alleles derived from each

parent that are transmitted together is called a haplotype. Matching or mismatching between donor and receipient is reported based on haplotypes for living related transplants and on individual antigens for deceased donor transplants. Typically, there are three major HLA alleles that are routinely assessed: 2 alleles of HLA-A, 2 alleles of HLA-B, and 2 alleles of HLA-DR. It is important to remember that, immunologically, a 6-antigen matched deceased donation is not the same as a 2-haploidentical living-related donation. Similarly, due to differences in minor histocompatibility antigens, donation between 2-haploidentical siblings is not the same as donation between identical twins. In the following sections, we will review the methods for determining the composition of the HLA antigen system of an individual.

Immunologic Concepts in Kidney Transplantation 103