Kidney transplantation

Already in 1902 the 1st experimental kidney transplantation in a dog was performed (Keller 2010). The first human kidney transplantation was performed by U. Voronoy in 1936 in Kiev. However, it failed because the kidney did not take up its function. In 1954 J. H. Harrison, J. E. Murray and J. P. Merril in Boston performed the first successful kidney transplantation in identical twins (Pfitzmann 2001). In Germany, the first homologous kidney transplantation was performed in 1963 in Berlin by the urologists W. Brosing and R. Nagel. However, the patient died after 6 days due to a rupture of the transplant. In 1965 the urologist Winfried Vahlensieck (1929 - 2008) in Bonn performed the first successful kidney transplant in Germany (Halling 2015).

With regard to the rejection of the transplant, the development of immunosuppressive drugs was of decisive importance. In 1958, the drug azithromycin was launched on the market and in 1981 Ciclosporin A (Keller 2010).

Kidney transplantation (NTX) is the implantation of a functional kidney into the body of a recipient (Ullrich 2005).

In a kidney transplant, a differentiation is made between

• Living donation
• Donation of corpses (Ullrich 2015)

The number of kidney transplants in Germany is between 2,000 - 2,500 cases per year. The proportion of living donations rose to 19 % by 2006 (Jocham 2007). Preemptive transplantations (transplantation before initiation of dialysis treatment) are rare in Germany with < 2%, although they are associated with an increase in transplant survival and a better survival of the patient (Kasper 2015). There are currently about 11,000 patients on the waiting list for a kidney transplant (Herold 2020).

In the case of rejection, nephrotoxicity may also be present by differential diagnosis. The diametrically opposed therapy causes problems. For this reason, the KDIGO guidelines recommend diagnostic kidney puncture before the start of any rejection therapy to confirm the diagnosis (Kasper 2015).

Postoperative complications such as:

• Acute renal failure of the transplanted kidney (in about 50% of cadaveric kidney transplants, renal function is delayed, so that dialysis is required in the first 7 days)
• Bleeding
• Thrombosis in the area of the renal vessels
• Ureteral leakage
• lymphocytes and others
• Consequences of immunosuppression; The lifelong required immunosuppression leads:
  • - to an accumulation of specific infections
  • - increases the tumour risk by a factor of 4 (Kuhlmann 2015)
• Myocardial infarction: Transplanted patients with a risk profile such as diabetes mellitus or cardiovascular heart disease have an approximately 30% increased risk of myocardial infarction in the first 5 years after transplantation (Kuhlmann 2015).
• Cerebrovascular diseases: The risk of suffering from cerebrovascular diseases within the next 15 years after transplantation is increased by approx. 15% (Kuhlmann 2015).
• Rejection (rejection reaction): Rejection represents a histologically detectable change in the graft kidney (Mühlfeld 2015), which can be divided into the following categories with the help of the Banff Working Classification of Renal Allograft Pathology(BANFF):
  • Category 1: normal
  • Category 2: antibody-mediated rejection (type I-III)
  • Category 3: Borderline rejection (cellular)
  • Category 4: T-cell mediated rejection (type IA/B, IIA/B, III), cTCMR (grade IA, IB, II)
  • Category 5: Tubular atrophy and interstitial fibrosis (grades I-III)
  • Category 6: Non-rejection-related changes:(Gäckler 2018)

Symptoms of rejection can be:

• fever
• Feeling of tension in the area of the transplant organ
• Swelling (Kasper 2017)
• Renal dysfunction
• However, sometimes only:
  • in the first p. o. days a delayed drop in serum creatinine (this should be clarified by puncture on the 7th day at the latest)
  • Increase in serum creatinine
  • Decrease of the urine quantity (Kasper 2017)

If rejection is suspected, two adequate puncture cylinders with at least ten glomeruli and two small arteries should be obtained (Mühlfeld 2015).

to category 2: antibody-mediated rejection

Antibody-mediated rejection may occur within a few days after transplantation. Approximately 20 % occur within the first 3 months after transplantation (Kuhlmann 2015). The chronically active form of antibody-mediated rejection is the most important cause of later transplant failure.

In antibody-mediated rejection, donor-specific antibodies (DSA) directed against the donor's HLA antigen can be detected in the patient's serum. However, preformed antibodies are already present in about 30% of all transplant patients preoperatively and de novo between 20% - 30% of patients develop DSAs.

Histologically, DSAs are detectable in these patients:

• Disruption of the microcirculation
• Endothelial damage
• immunohistochemical detection: C4d- positive (marker for graft rejection [Frei 2001]) (Herold 2020)

to category 3: Borderline alterations: The borderline alteration represents a pathological entity whose clinical significance is not yet clearly defined. Probably it is a T-cell-mediated rejection in which

• one arteriitis missing
• a focally existing inflammation of 10 % - 25 % in the interstitium area and
• a tubulitis is present (Gäckler 2018)

to category 4: T-cell-mediated rejection. T-cell-mediated rejection typically involves histologically typical endotheliitis and often non-specific changes such as:

• interstitial inflammation
• Tubulitis (Gäckler 2018 / Mühlfeld 2015)

to category 5: Tubular atrophy and interstitial fibrosis (grades I-III): Previously category 5 was called "chronic allograft nephropathy (CAN)" (Herold 2020).

Kidney transplantation is clearly superior to all other forms of renal replacement therapy in terms of quality of life (Kuhlmann 2015).

The German Transplantation Act regulates the donation, removal, procurement and transfer of organs and the Federal Medical Association has the guideline authority for organ transplantation itself. In the Benelux countries, Germany, Croatia, Austria, Slovenia and Hungary, Eurotransplant (ET), based in Leiden, has been mediating the procurement of donor organs since 1967 (MacFee 2012) (Herold 2020).

• Indications for NTX:
  • Terminal chronic kidney disease (Herold 2020).

• Timing for NTX: A patient's fitness for transplantation should be evaluated from a GFR of < 15 ml / min / 173m2 KOF and the patient prepared accordingly (Kuhlmann 2015). Preparations for transplantation should be initiated in parallel with preparations for dialysis. The patient should also be made aware of the possibility of pre-emptive transplantation (transplantation before dialysis treatment is initiated).

Preparations include:

• patients should be presented to a transplant centre as soon as it is foreseeable that they will be permanently in need of dialysis within a year

• patients already requiring dialysis should be presented to the transplant center after medical stabilization (Kuhlmann 2015)

• Contraindication to transplantation:
  • metastatic malignancy
  • Active systemic infection, as experience has shown that these worsen under immunosuppression
  • life expectancy less than 2 years
  • lack of compliance
  • advanced arteriosclerosis (Herold 2020)
  • serious diseases of other organs
  • foreseeable serious surgical-technical problems (Bundesärztekammer 2013)
  • Drug addiction
  • reversibility of renal failure
  • severe psychiatric illnesses (Kuhlmann 2015)

• Vaccinations: Preoperatively, patients should have adequate vaccination protection and have it refreshed regularly, such as:
  • Polio
  • Diphtheria
  • Tetanus
  • hepatitis B
  • Pneumococcus
  • Influenza
• Postoperatively, no vaccinations should be given for the first 6 months (except for influenza vaccination) and thereafter only vaccinations with inactive inactivated vaccines (live vaccines are contraindicated because of lifelong immunosuppression) (Herold 2020).

• Acceptable Mismatch- Program (AM- Program): Ideally, donor and recipient should have the same blood group. However, a high number of dialyzed patients are highly immunized and have HLA- AK. Therefore, while patients are on the transplant waiting list, their blood should be tested regularly every 3 months for HLA- AK by the so-called panel reactivity determination (Herold 2020). Patients with HLA-AK would have a much poorer chance of being allocated a transplant, which is why a so-called AM programme has been developed, for which the probability of the HLA characteristics of donor and recipient matching to a large extent can be calculated with the aid of mismatch probatility = MMP (Bundesärztekammer 2013). Therefore, the following blood group rules apply to highly immunised patients who have been accepted into the AM programme:
  • Donor 0 Recipient 0, A, B, AB
  • Donor A Recipient A, AB
  • Donor B Recipient B, AB
  • Donor AB Recipient AB (Herold 2020)

Infection prophylaxis: Postoperatively the patient should receive immediately:

• Cotrimoxazole 480 mg or 960 mg every 2nd - 3rd day for at least 3 months against Pneumocystis jirovecii
• if you are intolerant to cotrimoxazole, you can switch to a pentamidine inhalation of 300 mg 1 - 2 x monthly
• Valganciclovir over 3 - 4 months, if the recipient is negative and the donor is positive for cytomegalovirus (CMV / HCMV). The dosage must be adjusted to the respective kidney function. (Herold 2020)

In addition, patients should be treated prophylactically against thrush and ulcer diseases as part of immunosuppressive treatment (Suwelack 2018). Therapy recommendation: e.g. Ampho Moronal 4 x 2 ml and Cimetidine 200- 400 mg / d (Aktories 2017)

immunosuppression:

Circulating antibodies: It is possible to eliminate circulating antibodies by plasmapheresis (Manski 2020). Plasmapheresis can be used pre- and post-operatively for both cadaver donation and living donation (Morath 2013). Transplanted patients require post-operative lifelong immunosuppression (Herold 2020) with the exception of genetically identical twins (Kasper 2015). Immunosuppression is differentiated between induction therapy and maintenance therapy (Kasper 2015).

1. induction therapy: Induction therapy is intended to prevent early acute rejection (rejection of the transplant) and at the same time to reduce the side effects of steroids and calcineurin inhibitors (basic therapy of immunosuppressive drugs) (Kasper 2015). Induction therapy starts already at the time of transplantation on day 0, approx. 30 - 60 min. before opening of the anastomoses and is usually continued for 3 months (Manski 2020) (Suwelack 2018). Alternatively, a combination therapy with an mTOR inhibitor such as sirolimus or everolimus, which prevent the T-cells from dividing, can be used. Studies have shown a serious reduction of the risk of malignoma by up to 40 % and for non-melanocytic skin tumours by 56 %. However, the mortality risk is increased exclusively for recipients of a cadaver donation due to infections or cardiovascular diseases (Manski 2020 / Knoll 2014 / Siegmund- Schultze 2015). The following therapy modalities are common:

• Calcineurin inhibitors (CNI): As a standard, the patients receive the drug tacrolimus. Ciclosporin A can also be given in case of good HLA- concordance, diabetes mellitus, first NTX and BMI > 30.
• Steroids
• IL- 2- receptor antibodies such as Basiliximab or the polyclonal antibody (Melloh 2010) e.g. thymoglobulin (Suwelack 2018)
• 1. a. Standard therapy: The standard therapy is given to > 60% of patients (Kasper 2015). These are IL- 2 receptor antibodies, which are able to inactivate or eliminate T- cells. Basiliximab, for example, belongs to this group of drugs. Basiliximab also reduces mortality in the 1st year after transplantation by 25 %, the risk of CVM disease by 19 %, the number of rejections by 28 % (Kasper 2015)
• 1. b. Immunological high-risk patients: Patients with an immunologically high risk such as second transplantation, post-rejection, unacceptable HLA antigens (NAHA [Altermann 2019]) or PRA% (Panel reactive Antibody: This indicates the percentage of cells that reacted with the patient serum [Gschwendtner 2018]) receive the polyclonal antibody thymoglobulin (Suwelack 2018) instead.

2nd maintenance therapy: The maintenance therapy phase is also carried out as triple therapy, but the immunosuppressive drugs are reduced. The following are used for example

• Calcineurin inhibitors such as Tacrolimus or Ciclosporin A (Suwelack 2018)
• Immunosuppressive drugs such as nitroimidazole, azathioprine or mycophenolate mofetil (MMF) or CellCept (Suwelack 2018)
• Steroids

Note: If rejections occur, they are treated with high-dose steroids or with antibodies against immune cells such as rituximab (Manski 2020). Belatacept, a relatively new immunosuppressive agent, is contraindicated in Epstein-Barr Virus (EBV) seronegative patients, as these patients have a 9 times higher risk of post-transplant lymphoproliferative disease (PTLD) when treated with Belatacept (Herold 2020 / Ippoliti 2012).

Cadaveric donation: Patients eligible for cadaveric donation must be registered with Eurotransplant Leiden (The Netherlands) to be placed on a waiting list with different levels of urgency.

Allocation is done by the Euro Transplant Kidney Allocation System (ETKAS), which was introduced in 1996. Points are allocated depending on:

• Blood group compatibility
• Mismatch probability (see above "Therapy")
• HLA match
• Waiting time
• Ischemia time

Additional points are awarded for

• High urgency
• Children, adolescents, adolescents (Bundesärztekammer 2013).

The waiting time for a cadaveric donation is currently 5 - 6 years on average (Herold 2020).

Living donation: The Transplantation Act specifies exactly who is eligible for living organ donation (Kuhlmann 2015). Currently, living kidney donation is about 30% of all kidney transplants. Donors are close relatives or people from the person's immediate family who have a close personal relationship with the recipient (Herold 2020). Donors commit to lifelong follow-up (Kuhlmann 2015).

Relative contraindications for the donor are:

• Obesity
• impaired glucose tolerance
• increased risk of developing type 2 diabetes mellitus (Kuhlmann 2015).

In living donation, there is a possibility of AB0 incompatible transplantation after pre-treatment with Rituximab and immunosuppressants (Herold 2020).

• Ischemia time: Important for a successful transplantation is the time period from organ removal to reperfusion. A distinction is made between warm and cold ischemia time (Kuhlmann 2015).
• warm ischemia time:
  • The 1st warm ischemia time comprises the period lasting only a few minutes between the cessation of blood flow and cooling of the graft to approx. 4 degrees Celsius.
  • The 2nd warm ischemia time comprises the time span between the beginning of anastomosis and the release of blood flow.
• cold ischemia time: cold ischemia time is the period between cooling of the graft to the start of anastomosis, which can last up to 36 h (Herold 2020).

A warm ischemia time of 30 min causes greater tissue damage to the organ and also delayed organ function than a cold ischemia time of > 24 h (Wüthrich 2013).

Surgery:

• Cross-match test.

The last and decisive immunological test before transplantation is the so-called cross-match test, with which any preformed antibodies of the recipient against donor HLA antigens can be detected(Herold 2020).

The donor kidney is usually transplanted into the extraperitoneal left or right iliac fossa (Herold 2020).

Postoperatively, about 50 % of cadaveric kidney transplants result in a delayed onset of renal function, which requires a further dialysis of about 7 days (Herold 2020). The life expectancy in years depending on age is

dialysed patients: transplanted patients:

• 18 - 34 years: 27,22 41,5
• 35 - 49 years: 6,71 18,03
• 50 - 59 years: 5,12 11,18
• 60 - 64 years: 4,32 7,84
• 65 years and older: 3,69 7,6 (Kuhlmann 2015)

The prognosis after NTX is better in patients with living donation than in patients with cadaver donation because of the short ischemia time and the possibly more motivated postoperative compliance (Herold 2020).

Decisive for the prognosis of renal function are:

• an optimal blood pressure setting of ≤ 140 / 90 mmHg or in case of proteinuria of ≤ 130 / 80 mmHg
• Treatment of possible hyperlipidemia with statins (do not use in children < 10 years of age) Target areas:
  • LDL cholesterol ≤ 130 mg/dl (preferably ≤ 100 mg/dl)
  • Triglycerides < 500 mg/dl
  • Total cholesterol < 250 mg/dl
  • Non-HDL cholesterol < 160 mg/dl (Tönshoff 2013)
• Treatment of a possible proteinuria (e.g. with an ACE inhibitor depending on the amount of proteinuria [Eknoyan 2012])
• Abstinence from nicotine
• Normalization of body weight (Herold 2020)

Mortality: Following kidney transplantation, the 5-year survival rate is 77% for cadaveric donations and 85% for living donors (Herold 2020), with the best long-term results in preemptive transplantation (transplantation before initiation of dialysis treatment) (Kuhlmann 2015). Although lifelong immunosuppression according to NTX leads to an accumulation of specific infections and the tumor risk is 4 times higher under immunosuppression (Kuhlmann 2015), cardiovascular diseases are the main cause of death in dialysed patients with about 50% (Herold 2020). In 2nd and 3rd place among the causes of death in kidney transplanted patients are infections caused by hyperimmune suppression with approx. 20 % (Herold 2020) and tumors with approx. 6 % [Herold 2020]). (Kasper 2015)

• Donor mortality: In the case of a live kidney donation, there is also a risk of mortality for the donor. In the first 90 days postoperatively, the mortality rate is 3.1 cases per 10,000 operations. However, long-term mortality is not increased compared to a collective of the same age (Kuhlmann 2015).

The risk of developing terminal kidney disease later in life is generally not increased in donors. However, in one study, renal failure occurred in 1% of donors, with African Americans showing a significantly increased risk (Herold 2020).

Aftercare: Regular follow-up is crucial for the success of the transplantation. Follow-up should be carried out at predetermined intervals:

• in the 1st month 1 - 2 x a week in the transplant centre
• in the first 3 months 1 x weekly, alternating with resident nephrologists
• at least once a month until the 6th month at the resident nephrologist and every 2 months at the transplant centre
• up to the 12th month every 4 - 8 weeks at the resident nephrologist and every 3 months at the transplant centre
• after the 1st year, every 4 - 8 weeks at the resident nephrologist and every 6 - 12 months at the transplant centre (Suwelack 2018)

The small routine includes - besides the physical examination - the following laboratory chemical values:

• Serum chemistry (creatinine / eGFR, urea, Na, K, Ca, P, Cl, LDH, GOT, GPT, GGT, AP, bilirubin, glucose, CrP, Ges-Ew)
• Blood count
• Differential blood count
• Determination of the level of immunosuppressive drugs
• Examination of spontaneous urine for proteinuria / albuminuria
• Urine sediment
• if necessary blood gas analysis (Suwelack 2018)

In addition to the physical examination, the following laboratory chemical values are part of the routine:

• Serum chemistry (creatinine / eGFR, urea, Na, K, Ca, P, Cl, LDH, GOT, GPT, GGT, AP, bilirubin, glucose, CrP, Ges-Ew)
• Blood count
• Differential blood count
• Coagulation
• Iron status
• HbA1c
• PSA
• TSH
• parathyroid hormone (PTH)
• BNP
• Lipid status
• Determination of the level of immunosuppressive drugs
• Examination of spontaneous urine for proteinuria / albuminuria
• Urine sediment
• if necessary blood gas analysis (Suwelack 2018)

Decoy cells

In 4 % - 8 % (Doer 2010) of kidney transplant patients, so-called decoy cells can occur in urine in the course of a polyoma viral disease caused by BK or JC viruses (Hahn 2009).

Patients with polyoma virus nephropathy lose the transplant in up to 80% of cases (Herold 2020).

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