Fig. 15.1
Natural history of renal disease
To determine the timing, i.e., when to proceed to transplantation, a distinction must be made between theory and practice. In theory, transplant should be entertained when residual kidney function is around 10–15 %, irrespective of the start of regular dialysis treatment. However, this “early” optimal timing is only feasible if a living donor is available. In practice, almost all patients undergo kidney transplant when they have reached the terminal stage of uremia, the start of regular dialysis treatment (RDT), and placement on the renal transplant waiting list. The length of time spent on the waiting list will depend on organ availability and the number of patients awaiting transplantation.
In the United States, the number of people on the transplant waiting list has risen every year in the last decade, whereas the number of transplants has remained unchanged. During the same period, the average time on the waiting list before transplantation rose to 2.7–4.2 years [1]. In Italy, the number of patients on the waiting list remained relatively stable in the same period (from 6,816 to 6,707) along with the number of transplants (from 1,487 to 1,501), with a high but stable average waiting time of 3.1 years [2].
The indications and timing for potential kidney transplant recipients include an assessment of transplantation suitability, any contraindications, and monitoring while on the waiting list. In addition to those related to surgery and immunology, many different aspects need to be addressed, not only those purely nephrological, but also those referring to other organs and systems.
From a nephrological standpoint, transplant candidates must have advanced chronic kidney disease (from stage 4) [3] or already be on dialysis treatment, as occurs in most cases. Tests should be carried out to identify the underlying kidney disease to determine any risks that may be particularly high in conditions like focal segmental glomerulosclerosis, uremic hemolytic syndrome, and primary oxalosis [4]. In addition, the type of dialysis treatment (hemodialysis or peritoneal dialysis) must be considered together with its depurative efficacy, paying special attention to the patient’s nutritional status.
Age is an important parameter: recent decades have seen a marked increase in the number of elderly patients on the waiting list for transplantation. While patients aged over 65 years accounted for 36 % of those on the transplant waiting list in the United States in the 1980s, this percentage had risen to 48 % in 2009; 36 % of new patients with end-stage renal disease are currently aged over 70 years [5–7]. Age itself is not a contraindication to kidney transplant. Although elderly patients have a more than twofold risk of dying in the perioperative period [8] and a high risk of cancer, cardiovascular events, and infections, they have a survival advantage of 61 % with respect to remaining on the transplant waiting list, with an increased life expectancy of around 4 years [9] compared with continued RDT.
Many urological indications must be addressed before transplantation. Any abnormalities or diseases can be treated before transplant, carefully weighing the risks and benefits in each individual case [10, 11].
In particular, the progressive contraction of diuresis common in many patients after years of dialysis may lead to reduced bladder capacity and hypertrophy of the detrusor muscle. Possible removal of the native kidneys must also be entertained especially in patients with polycystic disease (increased abdominal burden, hemorrhage, lithiasis, or infection) or infected lithiasis [11, 12].
In establishing the indications for kidney transplant, assessment of the cardiovascular apparatus is essential as it is the prime cause of death after transplantation in both the short and long term [5, 13]. In-depth history taking should be followed by tests including cardiac examination, basal ECG, and chest x-ray. An echocardiogram is also useful to determine left ventricular hypertrophy, dilatation, and valve disorders. The latest guidelines of the American College of Cardiology/American Heart Association [14] suggest using noninvasive stress tests in patients without active heart problems but with at least three of the following risk factors: age over 60 years, more than 1 year of dialysis, diabetes mellitus, previous cardiovascular disease, hypertension, dyslipidemia, and smoking. The European guidelines [11] recommend pharmacological stress testing by ultrasound scan or scintigraphy in patients with a positive or inconclusive stress test. Coronarography is indicated in patients presenting features of inducible ischemia.
Any signs or symptoms of cerebrovascular or peripheral vascular disease must also be evaluated. If stenosis of the large vessels is suspected, angiography may be indicated possibly followed by endoscopic treatment, especially in patients with clinical symptoms [15].
Uremic patients have a higher incidence of cancer than the general population [16, 17]. There is a general consensus on the need to investigate patients on entry onto the transplant waiting list, even though shared screening protocols are currently lacking. The latest European guidelines suggest patients undergo the same screening tests indicated for the general population, mainly to search for any renal tumors, especially in patients on dialysis for many years. Hepatocellular carcinoma should be ruled out in patients with HCV and HBV infection [11, 18]. The American guidelines emphasize the use of the PAP test and a gynecological examination at least every 3 years in women after the age of 20 years, an annual breast examination and mammogram after the age of 40 years, thyroid gland assessment, a search for fecal occult blood after the age of 50 years, and rectal exploration with PSA measurement in men over 50 years [12]. A cancer screening protocol was recently published in Italy for patients on the waiting list for kidney transplantation [16].
Patients with a history of cancer need to be assessed on a case-by-case basis for entry onto the transplant waiting list, with a multidisciplinary approach also involving the cancer specialist.
A series of indications and recommendations have been published on the length of the waiting period following diagnosis and treatment of cancer, designed to harmonize decision-making in different transplant centers [19].
Active infection may require eradication or prophylactic interventions before transplant or the inclusion of these patients in special transplantation programs.
The indications for kidney transplant also include serologic tests for HIV infection, hepatitis B and C, herpes simplex, HHV-8, varicella zoster, rubella, EBV, CMV, Toxoplasma gondii, and syphilis and the Mantoux test. If a second transplant is envisaged, the BK virus should also be investigated.
Currently, around 1 % of patients on dialysis in the United States present HIV infection [20]. This condition initially represented an absolute contraindication to transplant as these patients had a limited life expectancy and a high incidence of opportunistic infections. Nowadays, indications can be put in place for transplantation in patients compliant with specific treatment, a CD4+ cell count above 200/μL and a viral load undetectable for at least 3–6 months, with no opportunistic infection in the past 6 months and no signs of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphomas. Posttransplant antiretroviral therapy must be defined in the light of its possible competitive effects with immunosuppressants [11, 21].
Patients with hepatitis B and C virus have a better survival rate with kidney transplant than dialysis. However, their postoperative course can be complicated by an increased incidence of HCV-related renal disease, new-onset diabetes mellitus, and shorter graft/patient survival rates. Patients with decompensated liver disease can be assessed for the combined liver-kidney transplant program [22, 23].
CMV and EBV serology are crucial for posttransplant decision-making. CMV infection is a risk factor for graft failure, infection, the onset of lymphoproliferative disease, cardiovascular events, diabetes mellitus, and acute graft rejection [24].
Patients positive for EBV are considered at high risk for the development of lymphoproliferative disease: the indications for transplant include a very cautious management of immunosuppressive therapy, with serological monitoring before transplant possibly including antiviral prophylaxis [12]. Vaccination is recommended before transplant in patients negative for herpes-varicella zoster virus [25] and in rubella-negative women of fertile age given the likelihood of future pregnancy [26].
The increase in the immigrant population has led to a resurgence of tuberculosis. The Mantoux test must be administered in all kidney transplant candidates together with chest x-ray. Prophylaxis is advisable in the case of latent tuberculosis while active forms of tuberculosis require appropriate specific treatment before any indication for kidney transplantation.
Many centers also undertake a dental assessment prior to transplant to treat any infection of the teeth or gums [12].
Diabetes mellitus is currently the most common cause of chronic kidney failure in the United States and increasingly one of the most common in Europe and Italy. Diabetic patients merit special attention in establishing an indication for kidney transplant due to the high incidence of associated comorbidities: cardiovascular and dysmetabolic abnormalities, risk of infection, neurological impairment, peripheral vascular disease, etc. A combined kidney-pancreas transplant is the best option in insulin-dependent diabetes patients to normalize glucose metabolism [27, 28].