Kidney Transplantation

Anatomy and Physiology

The kidneys are one of the paired retroperitoneal organs in the body. The diaphragm abuts the kidneys superiorly and posteriorly, along with the 12th rib.[3] The right kidney is bordered by the right colonic flexure, liver (hepatorenal ligament), duodenum, and head of the pancreas anteriorly. The left kidney is bordered by the colon's splenic flexure, the splenic vessels, and the pancreas anterosuperiorly. The left kidney also shares a relationship with the spleen, which is anteromedial and connected via the lienorenal ligament. Inferoposteriorly, both kidneys lie on and adjacent to the psoas muscle medially. The upper pole of both kidneys includes the adrenal glands.[3] Both kidneys are enveloped by the perinephric fascia, eponymously known as Gerota’s fascia.[4]

In the classical anatomic position, the kidney's hilar structures are organized from anterior to posterior in the following order: renal vein, renal artery, and ureter/renal pelvis.[4] The renal arteries come directly off of the aorta laterally just below the takeoff of the superior mesenteric artery to supply each kidney. The right renal artery traverses behind the inferior vena cava. The renal artery then divides into its anterior and posterior divisions. The anterior division supplies 75% of the blood to the kidney, and the posterior division supplies 25%.[3] The arterial divisions divide into segments; the anterior division divides into four segments: apical, upper, middle, and lower and the posterior division becomes the posterior segmental branch.[5] Segmental arteries are end arteries and thus do not demonstrate collateralization. Consequently, the parenchyma they supply is susceptible to ischemic injury in the event they are injured/occluded. Lastly, further branching of the segmental arteries gives rise to interlobar arteries, then arcuate arteries, and finally interlobular arteries.

The renal vein is most often found anterior to the renal artery. Similar to the arterial distribution, the venous plexus capillaries coalesce into arcuate veins, which then drain into interlobular veins, trunks, and finally the renal vein.[3] The right renal vein is often short given the ipsilateral location of the vena cava, drains directly into the cava, and has no tributaries. The left renal vein courses anterior to the aorta to reach the inferior vena cava. As such, it is 2 to 3 times longer than the right renal vein. Unlike the right renal vein, the left renal vein has many tributaries: gonadal vein, adrenal vein, inferior phrenic, lumbar, and paravertebral veins.[3] Of note, the SMA can reliably be found anterior and superior to the left renal vein as it crosses the aorta. All things being equal, the left kidney is preferred in living donation secondary to its extra length, which tends to make anastomosis technically easier to perform.

Indications

The incidence of end-stage renal disease (ESRD) is rapidly rising. The most common etiologies of renal failure are diabetes and hypertension.[6] Other causes of CKD/ESRD are grouped into prerenal (chronic or acute ischemia), intrinsic renal (glomerulonephritis, focal-segmental glomerulosclerosis), or postrenal categories (reflux nephropathy, obstruction). Patients who reach chronic kidney disease (CKD) stage 4, which correlates to a glomerular filtration rate (GFR) less than 30 mL/min/1.73 m, should be seeing a nephrologist and educated about kidney failure and treatment options, including transplantation.[7]

In the absence of contraindications for transplantation, the nephrologist will refer the patient to a transplant center, in addition to setting in motion the necessary interventions for possible initiation of dialysis. There is a clear survival benefit for kidney transplant recipients over those who remain on dialysis.[8] And the length of time on dialysis is an independent risk factor for poorer outcomes.[2]

Contraindications

Absolute contraindications for kidney transplantation are the inability to tolerate surgery due to severe cardiac or pulmonary disease, active malignancy, active infection, active drug abuse, and uncontrolled psychiatric disease.

Relative contraindications are more variable and may differ depending on the institution and geographic region: morbid obesity with a recommended body mass index (BMI) less than 40 kg/m, history of noncompliance with dialysis schedule or medication regimen, frailty, psychiatric problems, and limited life expectancy (defined as less than the anticipated waiting time for a kidney).[9]

Preparation

Patient Selection

Most ESRD patients have multiple co-morbidities and complications resulting from their kidney disease. As such, they are carefully screened for their ability to tolerate surgery and the subsequent immunosuppression which accompanies transplant surgery. Below is a summary of the evaluation of comorbid conditions:

Cardiovascular Disease: Most ESRD patients require careful cardiovascular evaluation with noninvasive testing for those at high risk or who have symptoms. For example, a dobutamine stress echocardiogram has been shown to have superior accuracy for predicting perioperative cardiac events.[10] The leading cause of death after kidney transplantation is cardiovascular disease.[11] Therefore, if noninvasive testing is positive, these patients should undergo cardiac revascularization before transplant surgery.

Cerebrovascular Disease: Any patient with a history of a cerebrovascular accident, including a transient ischemic attack, should be evaluated for carotid artery disease, if not already done.[12] Additionally, any history of polycystic kidney disease and accompanying symptoms warrants a magnetic resonance angiogram to screen for aneurysms.[13] Femoral and pedal pulses should be palpated. Further imaging (duplex US & CT) and possible referral to vascular surgery should be considered in the event of abnormalities in the peripheral pulse exam, history suggestive of PVD, and concerns regarding adequate iliac artery inflow, the intended site of implantation.  Any revascularization deemed necessary should ideally be performed before a transplant.[14]

Frailty: Several frailty tests exist to determine candidates’ fitness for transplant. The frailty test is a short physical performance battery from which an objective score is calculated. The Fried frailty criteria can also be used, and its domains include unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. These scales are particularly useful in the elderly demographic, particularly those potential recipients above years of 60.[15]

Gastrointestinal Disease: Anyone with a family or personal history of colon cancer or above the age of 50 should have a screening colonoscopy per USPSTF recommendations. Anyone with active viral hepatitis or chronic liver disease should consult with a hepatologist for possible consideration for a combined liver-kidney transplant.

Hematologic Disorder: Patients with a history of thrombosis should be evaluated for possible hypercoagulable disorders which may require treatment with anticoagulation. For those with bleeding diathesis, a full coagulation panel should be done.

Infections: As stated above, active infection is an absolute contraindication to a kidney transplant. Most centers will send a comprehensive serology panel to test for many viral infections and tuberculosis, etc. Vaccinations should also be up to date.

Malignancy: Most transplant centers will require a cancer-free period of 2 to 5 years, depending on the type of cancer, to minimize the risk of post-transplant recurrence/metastasis potentiated by immunosuppressive therapy.[16]

Pulmonary Disease: For higher-risk patients such as those who have been on dialysis for an extended period, those with heart dysfunction, known diagnosis of COPD or history of extensive tobacco use, obstructive sleep apnea, or history of pulmonary embolism should undergo pulmonary function testing and possibly an echocardiogram to rule out pulmonary hypertension.[17] For those who have severe pulmonary hypertension, preoperative treatment, and mitigation with vasodilators are recommended before transplantation surgery, in addition to pulmonology clearance. 

Donor Selection/Allocation

There are two types of kidney donors: living or deceased.

Deceased donors are broken down into those that are brain dead (DBD) and those that donate after cardiac death (DCD).  As the term would indicate, brain dead donors are those that have satisfied formal criteria for brain death testing.  DCD donors are patients who, while they do not meet the criteria for formal brain death, are deemed by neurologists as being unlikely to experience a meaningful neurologic recovery.[18] In the case of DCD donation, procurement cannot begin until the heart has stopped beating, and an independent physician pronounces the patient following terminal extubation.  Efforts by the United Network for Organ Sharing (UNOS) to further stratify deceased donors were delineated to reflect likely organ quality.  Thus, deceased donors were defined as meeting standard criteria (SCD) or otherwise fell under the umbrella of extended criteria donation (ECD). ECD kidneys are associated with shortened graft longevity secondary to donor risk factors: age over 60, or those between 50 to 59 years of age with a history of hypertension, terminal creatinine concentration above 1.5 mg/dL, or cerebrovascular cause of death.[19] 

SCD and ECD classification were ultimately replaced in 2014 by the kidney donor profile index (KDPI), a more objective graft quality measure.  KDPI is derived from the kidney donor risk index (KDRI), the percentage of donors in a reference population (as defined annually by the OPTN) that have a KDRI score less than or equal to the donor’s KDRI score.  Factors used in determining the KDPI are donor age, ethnicity, creatinine, history of HTN or DM, cause of death, height and weight, HCV status, and DCD status.  Multiple studies have shown that kidney transplant using high-KDPI kidneys is still associated with a substantial reduction in morbidity and improvement in life expectancy and remains a cost-saving treatment strategy compared with patients who remained on maintenance dialysis.

Living kidney donation offers the best graft and recipient survival, even when considering paired kidney exchange, which involves organ transport before implantation.[20] The current eligibility criteria requirements are ages 18 to 70 years, BMI less than 35 kg/m, no active malignancy, no active infection, and adequate kidney function (~ GFR > 80). Absolute contraindications to living kidney donation are BMI greater than 40 kg/m, diabetes, active malignancy, human immunodeficiency virus (HIV) positivity, GFR less than 70 mL/min/1.72m, albuminuria, hypertension requiring more than 1 medication, pelvic or horseshoe kidneys, and psychiatric disorders.

Regarding long-term consequences to living kidney donors, much research has been done; initially, it was felt that eventual development of ESRD or long-term survival was not affected by living donation.[21] In the newer National Health and Nutrition Examination Survey (NHANES III) study, however, the development of ESRD in live donors was found to be slightly higher compared to matched healthy controls but no different than in the general population.[22]

Technique or Treatment

Transplant surgery always involves two surgeries, the donor and the recipient. The approach can be performed in a minimally invasive fashion or, less commonly nowadays, via open surgery for the living donor. Implantation in the recipient is performed in an open fashion, where the kidney is placed heterotopically in the pelvis, anastomosing the vessels to the external iliac vessels and the ureter to the bladder. The iliac vessels are preferentially exposed retroperitoneally as the peritoneum is retracted medially. However, intra-peritoneal placement is also acceptable.

Laparoscopic and/or robotic surgery are both considered minimally invasive and can be used to procure either kidney. Access is gained to the intraperitoneal space for port placement. For the left kidney, the ureter and gonadal vein are identified at the pelvic brim after the left colon is freed from its peritoneal attachments and traced cephalad to identify and isolate the renal vein and artery. The adrenal gland is separated from the upper pole of the kidney, and the adrenal vein is divided. Once the kidney is fully mobilized and only attached via the artery, vein, and ureter, a slightly larger incision (often the Pfannenstiel) is made to prepare for expedient extraction. The distal ureter is divided between clips, and the hilar vessels are divided with a laparoscopic vascular-load stapler. Some differences in dissection exist depending on which kidney is procured. For the right kidney, the liver is retracted, and the right colon and duodenum are partially mobilized to access the kidney. Following extraction, the organ is then passed off of the field and prepared for implantation on the back-table.

In the open surgical technique for living donor procurement, a subcostal incision is made, and the retroperitoneal space is exposed. The ureter is followed down to the iliac vessels and ultimately divided there before extraction. The kidney is isolated on its vascular pedicle, and once the recipient team is ready, the renal artery and vein are transected, and the organ is delivered to the back-bench. The tributary stumps are then ligated or oversewn. Any residual perinephric fat is pruned as the kidney is prepared for implantation.

Organ Preservation

Once the kidneys are procured, they must be preserved before eventual implantation. During this process (and as soon as the heart stops beating in the donor and normal circulatory perfusion is halted), the kidneys experience ischemia. Cold ischemia time begins as soon as normal perfusion stops and ends when the kidney is reperfused in its recipient – the kidney should be on the ice for as much of this time as possible to diminish metabolic demand and minimize injury.  Warm ischemia time is considered more harmful to the organ. It is classically described as the “sew-in” time when the organ is removed from cold storage until it is ultimately reperfused following vascular anastomosis.  It is important to remember that there is also a period of upfront warm ischemia involved in the DCD donation process between when the patient experiences circulatory arrest and the aorta is cannulated and flushed with the preservative solution and the organs are topically cooled with ice.

During cold ischemia, the organ is stored in a static cold solution commonly used in the United States known as the University of Wisconsin Preservation Solution.

Organs can also be placed on machine perfusion for preservation. This is a newer technology, and studies suggest an improved risk of delayed graft function with the use of pulsatile machine perfusion.[23] Machine perfusion (“the kidney pump”) diagnostics may also be used to assess the organ’s vasculature patency, with particular attention paid to flow and resistance. These objective measures may aid in organ selection, particularly in the context of DCD donors (in which blood is allowed to stagnate following circulatory arrest until the flush is established) and older donors with atherosclerotic disease.

Complications

Hemorrhage – As with any vascular surgery, hemorrhage is always possible, both on-the-table and in the early postoperative period. Classical signs of bleeding may not be seen. Patients may not demonstrate classical tachycardia in response to hypovolemia as they are often on beta-blockers. Additionally, they can be hypertensive rather than hypotensive as a result of parenchymal compression. They often will complain of new-onset acute flank pain, and there may be a palpable mass or bulge near the incision. High clinical suspicion should be maintained and may warrant a return to the operating room. It’s important to remember that bleeding may be tamponaded by the kidney’s compartmentalized space in the retroperitoneum, an effect that would not be expected following intra-peritoneal placement of the allograft.

Thrombosis – Renal vein thrombosis is fortunately rare but is associated with a high risk of graft loss. This phenomenon may manifest in the early postoperative period with new-onset hematuria, sudden-onset oliguria/anuria, and/or graft dysfunction. Arterial thrombosis is rarer still but is often equally devastating and may manifest similarly in the recipient. Ultrasound is often diagnostic and should be ordered in the event of a precipitous decline in UOP in a previously functioning allograft. High suspicion for vascular complications should be maintained in the early postoperative period due to technical errors and/or clamp injury.

Infection – Infections are common as patients are placed on immunosuppression immediately postoperatively. They are most heavily immune-suppressed in the first 3-6 months post-operatively, putting them at heightened risk of infection during that window. Conventional nosocomial and bacterial infections are seen most commonly in the first month post-transplant and include UTIs and surgical site infections (SSI). High suspicion must be maintained for unconventional or opportunistic pathogens, particularly in the months that follow. Commonly tested viral pathogens include cytomegalovirus, Epstein-Barr virus, and polyomavirus (BK-type). Patients are often placed on prophylactic antivirals and antibiotics to decrease the risk of infection in the first 3-6 months – most commonly Bactrim for PCP, Valcyte for CMV, as well as some form of anti-fungal coverage.

Arterial Stenosis – This is a late complication and is often asymptomatic. Its discovery is often prompted by ultrasound examination in the setting of diminished graft function (elevated serum creatinine). Angiography is both diagnostic and therapeutic, and transluminal angioplasty may be attempted.

Lymphocele – This complication occurs due to the disruption of associated lymphatics during the exposure of the iliac vessels. Careful ligation of lymphatic tissue should thus be performed where possible during this dissection.  Patients may present with pain and bulging overlying the transplanted kidney. Alternatively, the collection can become infected or cause graft compression and diminished function. The treatment for symptomatic lymphoceles is percutaneous drainage. Drain aspirate should also be checked for fluid creatinine to rule out a urine leak.  Persistent lymphocele may be surgically treated with peritoneal window drainage.

Urinoma – Usually occurs within the first week of transplantation. Like lymphocele, patients may present with pain and swelling at the incision, compromised graft function as a result of compression, or infection. An elevated creatinine level typically confirms the diagnosis in the fluid aspirate. Many centers preemptively place a ureteral stent at the time of anastomosis to guard against this complication as well as the delayed complication of ureteral stenosis. In the event of a urine leak, bladder decompression with Foley catheter placement is typically all that is needed. However, surgical intervention and revision of the ureteroneocystostomy may be necessary.

Clinical Significance

Before transplantation was an option, patients with end-stage kidney disease didn't have excellent treatment options. Once the design of hemodialysis was established, survival was improved. Once the advent of kidney transplantation was set into gear, patients with ESRD were seen to have better long-term survival if they were placed on the waiting list and eventually underwent kidney transplantation than those who stayed on dialysis. Additionally and importantly, those who underwent transplantation experienced a better quality of life and a projected survival benefit of 10 years over those who remained on dialysis.[2]

Enhancing Healthcare Team Outcomes

Transplant is a multidisciplinary practice. Their nephrologists and hepatologists initially see the patients before referral to a transplant surgeon. Once a referral is made, and the patient is placed on a transplant list, there are many more steps before an organ is allocated. When an organ becomes available, the transplant coordinators help with matching and allocating. The patient is then admitted for surgery, which involves the surgeons, anesthesiologists, operating room technicians, and afterward, the intensive care unit doctors, nurses, pharmacists, and social workers. This large team of healthcare professionals, each specialized in their field, working together, and communicating effectively is the only way transplantation is a reality.