INDEX

Consensus Document

A. Methodological introduction

B. Definition of renal dysfunction in kidney transplant recipients: a review of the current definitions and proposed definition

C. Follow-up for kidney transplant recipient: quantification of risk based on factors associated with the donor, recipient, and transplant

D. Follow-up for kidney transplant recipients: clinical monitoring

E. Follow-up for kidney transplant recipients: histological monitoring

F. Aetiopathogenic diagnosis of renal dysfunction in kidney transplant recipients

CONSENSUS DOCUMENT

A. Methodological introduction

A group of 5 nephrologists established a scientific committee charged in 2009 with the responsibility of developing a national consensus document on renal dysfunction in kidney transplant recipients. The committee met to debate and choose the areas of greatest interest in this subject, and decided to structure the consensus document into 5 sections, primarily focused on diagnosis and follow-up: a) Definition, b) Risk-based follow-up, c) Clinical follow-up, d) Histological follow-up, and e) Aetiopathogenic diagnosis. The group deliberately decided not to broach the many different subjects of therapeutic management, leaving these topics for an eventual future consensus document with that specific focus.

In the first phase, each of the five topics was assigned to a committee member, who carried out a review of the available literature for the subject, constructing a consensus outline focused on specific issues. In a later meeting, the committee reviewed the 5 sections of the draft of the manuscript and elaborated 20 multiple- choice questions to pose to all members of the Spanish Society of Nephrology in a voluntary survey (see appendix). The results of the survey for each section were reviewed by the scientific committee, which then included the majority opinions in the body of the text.

A second version of the document was submitted for consideration by all members of the Spanish Society of Nephrology on the Society’s webpage, and after 30 days, suggestions were collected and incorporated into the final document, which was then approved by the scientific committee.

B. Definition of renal dysfunction in kidney transplant recipients: a review of the current definitions and proposed definition

In recent years, with the decreasing incidence of acute rejection and early graft loss, medical interest has been redirected towards the causes that provoke graft loss after the first year, not taking into account patient death.

The majority of late graft losses are due to a clinical/pathological entity that is still not completely defined, which, throughout the past few decades, has been referred to under many different names, including: chronic rejection, late graft dysfunction, chronic transplant nephropathy, chronic allograft nephropathy, chronic allograft dysfunction, chronic graft failure, chronic graft disease, and, more recently, terms such as “chronic graft damage and interstitial fibrosis/tubular atrophy with no evidence of specific aetiology” have been used. Initially, the term “chronic rejection” gained popularity, followed by “chronic allograft nephropathy”, both of which were subsequently rejected. None of the proposed terms has served as a completely convincing label, some for being too restrictive, others for being too ample or confusing in their applications. The controversy continues to go unresolved.

Review of terminology

Chronic rejection

Since the first years in which transplants were performed, the term “chronic rejection” has been used to describe the clinical situation characterised by a progressive decrease in glomerular filtration rate, frequently associated with proteinuria and arterial hypertension (AHT). It was first diagnosed 6-12 months following transplantation, and in contrast to the majority of episodes of acute rejection, did not respond to steroid treatment or increased immunosuppression therapy.1-3

At the histopathological level, this condition was primarily characterised by obliterating vascular lesions accompanied by interstitial fibrosis (IF), tubular atrophy (TA), and occasionally by glomerular changes.4-9

Historically, this condition was attributed to immunological factors, an idea that has been confirmed in recent years. Currently, chronic, cellular, or humoral rejection is defined according to the consensus criteria from the Banff conferences, and is generally inadequate for referencing in situations associated with late graft dysfunction not due to alloreactivity.

Late renal allograft dysfunction/chronic allograft nephropathy/chronic allograft dysfunction. Banff Project, 1991-2009

In 1991, an international, multidisciplinary project began in the city of Banff to evaluate and quantify the different histological changes associated with acute rejection, and this project was later expanded to encompass all histological types of graft lesions.

In the first meeting, the term “late renal allograft dysfunction” was proposed as a more neutral term than the more popular, although erroneous, “chronic rejection.”

In 1993, the generic term “chronic allograft nephropathy/CAN” was recommended for cases with histological findings of IF and TA with or without transplant vasculopathy that are observed in patients with (diagnostic biopsy) or without (follow-up biopsy) graft dysfunction. Later, in 1997, it was proposed to limit this term to those cases in which it was impossible to define the aetiology, reserving the term of “chronic rejection” for evidence of an immunological origin to the renal damage observed.10-15

CAN was defined as the presence of IF and TA, although on occasion, other histopathological findings can be observed such as arteriolar hyalinosis, vascular occlusive changes, glomerulosclerosis, transplant glomerulopathy, or subclinical rejection.

It was assumed that CAN was an entity with a multifactorial aetiology caused by immunological factors such as previous sensitisation, low compatibility, or episodes of acute rejection, but also by non-immunological factors, such as donor age, calcineurin inhibitor (CNI) toxicity, AHT, metabolic disorders such as diabetes, and certain infections.9,16-19

During the last decade, the clinical term “chronic allograft dysfunction” has gained widespread acceptance, as it only refers to altered renal function, regardless of the histological expression that produces it.20,21

In the 8th conference held in Edmonton in 2005, a major change occurred when the term CAN was removed from use and replaced by the term “chronic allograft injury,” a diagnosis of exclusion, which is histologically expressed as “IF and TA with no evidence of any specific aetiology” and, although vascular and glomerular damage can be observed, the grading score is established based on tubular and interstitial lesions.22

The reasoning behind this recommendation was the inadequate use of the term CAN, which came to be employed generically to refer to all causes of chronic allograft dysfunction associated with fibrosis. CAN refers to a clinical/pathological description, and should not be used as a diagnosis.

In this meeting, several chronic entities were discussed that cause IF/TA, but with specific morphological lesions that can be pathologically identified and require specific treatment: AHT lesions, CNI toxicity, obstructive uropathy, bacterial pyelonephritis, and viral infections (such as polyomavirus nephropathy).

Also at the 2005 conference, the role of chronic alloreactivity was highlighted as causing IF/TA, and morphological findings were established that lead to the diagnosis of a “true chronic rejection,” creating two new categories: “chronic active antibody-mediated rejection,” one of whose expressions is transplant glomerulopathy, and “chronic active T-cell mediated rejection.”22-26

As in all classification systems based on a multidisciplinary consensus, the recommendations from the Banff project have their advantages, but also limitations, and so these results should be considered as those of a clinical trial in progress, undergoing constant evaluation.

Despite these recommendations and the confusion surrounding the use of the term CAN (Table 1),2,27-31 this label continues to circulate around the transplant community, and its presence has been maintained in the scientific literature from recent years.32-34 In a similar manner, the term “chronic allograft dysfunction” has continued to be used colloquially.

Proposal for a definition

According to the data from the national consensus survey on chronic renal dysfunction in kidney transplant recipients, the majority of those surveyed (64%) consider the term “chronic allograft nephropathy” to be obsolete and one that should no longer be used, while 63% think that the term “chronic allograft dysfunction” is the most appropriate for referring to the progressive chronic deterioration of renal function. Although the term “chronic allograft injury” was not included among the response options, both can be used interchangeably (CAI) always keeping in mind that “dysfunction” is a functional term, and “injury” is a structural term.

• CAI is a multifactorial clinical/pathological entity characterised by a progressive decrease in glomerular filtration rate, generally associated with proteinuria and AHT. Histologically, it manifests as interstitial fibrosis and tubular atrophy, although other types of non-specific lesions can also be observed. This is a diagnosis of exclusion.

References

1. Fellström B, Larsson E, Tufveson G. Strategies in chronic rejection. Transplant Proc 1989;21:1435-9.[Pubmed]

2. Paul LC, Fellström B. Chronic vascular rejection of heart and the kidney: have rational treatment options emerged? Transplantation 1992;53:1169-79.[Pubmed]

3. Hostetter TH. Chronic transplant rejection. Kidney Int 1994;46:266.[Pubmed]

4. Hume DM, Merril JP, Millar BF, Thorn GW. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955;34:327-32.

5. Paul LC, Hayry P, Foegh M, Dennis MJ, Mihatsch MJ, Larsson E, et al. Diagnostic criteria for chronic rejection/accelerated graft atherosclerosis in heart and kidney transplants: joint proposal from the Fourth Alexis Carrel Conference on Chronic Rejection and Accelerated Arteriosclerosis in Transplanted Organs. Transplant Proc 1993;25:2022-3.[Pubmed]

6. Mihatsch MJ, Ryffel B, Gudat F. Morphological criteria of chronic rejection: differential diagnosis, including cyclosporine nephropathy. Transplant Proc 1993;25:2031-7.[Pubmed]

7. Isoniemi HM, Taskinen E, Hayry P. Histologic chronic allograft damage index accurately predicts chronic renal allograft rejection. Transplantation 1994;58:1195-8.[Pubmed]

8. Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993;44:411-22.[Pubmed]

9. Mihatsch MJ, Ryffel B, Gudat F. The differential diagnosis between rejection and cyclosporine toxicity. Kidney Int 1995;48(Suppl 52):S63-S68.

10.  Solez K. International standardization of criteria for histologic diagnosis of chronic rejection in renal allografts. Clin Transplant 1994;8:345-50.[Pubmed]

11.  Solez K, Benediktsson H, Cavallo T, Croker B, Demetris AJ, Drachenberg C, et al. Report of the Third Banff Conference on Allograft Pathology on classification and lesion scoring in renal allograft pathology. Transplant Proc 1996;28:441-4.[Pubmed]

12.  Racusen LC, Solez K, Colvin AB, Bonsib SM, Castro MC, Cavallo T, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999;55:713-23.[Pubmed]

13.  Paul LC. Chronic allograft nephropathy: a model of impaired repair from injury? Nephrol Dial Transplant 2000;15:149-51.[Pubmed]

14.  Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003;3:665-73.[Pubmed]

15.  Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, et al. Antibody-mediated rejection criteria: an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003;3:708-14.[Pubmed]

16.  Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, et al. Effect of initial slow graft function on renal allograft rejection and graft survival. Clin Transplant 1997;11:623-7.[Pubmed]

17.  Salahudeen AK, Haider N, Mau W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int 2004;65:713-8.[Pubmed]

18.  Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int 1998;53:217-22.[Pubmed]

19.  Chapman JR, Nankivell BJ. Nephrotoxicity of cyclosporine A: short-term gain, long-term pain? Nephrol Dial Transplant 2006;21:2060-3.[Pubmed]

20.  Matas AJ. Chronic Allograft Dysfunction: Clinical Definitions and Risk Factors. Graft 1998;1(Suppl II):48-51.

21.  Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16:3015-26.[Pubmed]

22.  Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, et al. Banff’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (CAN). Am J Transplant 2007;7:518-26.

23.  Joosten SA, Sijpkens YW, van Coten, Paul LC. Chronic renal allograft rejection: pathophysiologic considerations. Kidney Int 2005;68:1-13.[Pubmed]

24.  Gloor JM, Sethi S, Stegall MD, Park WD, Moore SB, DeGoey S, et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007;7:2124-32.[Pubmed]

25.  Nickeleit V, Andreoni K. The classification and treatment of antibody-mediated renal allograft injury: where do we stand? Kidney Int 2007;71:1-11.

26.  Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, et al. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant 2007;7:864-71.[Pubmed]

27.  Ponticelli C, Villa M, Cesana B, Montagnino G, Tarantino A. Risk factors for late kidney allograft failure. Kidney Int 2002;62:1848-54.[Pubmed]

28.  Hernández D, Sánchez-Fructuoso A, Serón D, Arias M, Campistol JM, Morales JM; Grupo Español para el Estudio de la Nefropatía Crónica del Trasplante. [Chronic transplant nephropathy]. Nefrología 2006;26(supl 1):1-38.

29.  Djamali A, Samaniego B, Muth B, Muehrer R, Hofmann RM, Pirsch J, et al. Medical care of kidney transplant recipients after the first posttransplant year. Clin J Am Soc Nephrol 2006;1:623-40.[Pubmed]

30.  Serón D, Arns W, Chapman JR. Chronic allograft nephropathy: clinical guidance for early detection and early intervention strategies. Nephrol Dial Transplant 2008;23:2467-73.[Pubmed]

31.  Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(Suppl 3):S1-S157.[Pubmed]

32.  Najafian B, Kasiske BL. Chronic allograft nephropathy. Curr Opin Nephrol Hypertens 2008;17:149-55.[Pubmed]

33.  Birbaun LM, Lipman M, Paraskevas S, Chaudhury P, Tchervenkov J, Baran D, et al. Management of chronic allograft nephropathy. Clin J Am Soc Nephrol 2009;4:860-5.[Pubmed]

34.  Grinyo JM, Saval N, Campistol JM. Clinical assessment and determinants of chronic allograft nephropathy in maintenance renal transplant patients. Nephrol Dial Transplant 2011;26:3750-5.

C. Follow-up for kidney transplant recipients: quantification of risk based on factors associated with the donor, recipient, and transplant

Traditionally, the risk factors for renal dysfunction have been divided into those affecting graft function that appear within a short time period following transplantation, and those that appear later.1,2 While early factors imply a greater level of risk for renal dysfunction, late factors have a lower clinical impact, but are more constant in their increase of the risk of graft dysfunction. Although this division is, to a certain point, arbitrary, since the majority of these factors are inter-related, the improvement in graft survival attained in the last 20 years is primarily associated with a better control of early post-transplant risk factors.

1) Risk factors for early renal dysfunction

In the immediate post-transplant period, several risk factors have been identified for renal dysfunction, including: delayed graft function, anti-human leukocyte antigen (anti-HLA) antibodies, the type of kidney donated, the donor’s cause of death, and the effect of the centre in which the transplant was performed, among others.

Delayed graft function. Acute tubular necrosis. Ischaemia-reperfusion

Delayed graft function (DGF) is a factor with important effects on short and long-term graft survival. In a single-centre study involving 518 patients, a multivariate analysis revealed DGF as the primary determining factor in graft survival after one year.3

Ischaemia-reperfusion injury (IR) and its histological manifestation, post-ischaemic acute tubular necrosis (ATN), is the most common cause of DGF. Frequently, the classic signs of ATN (denuded tubules with mitotic figures) are absent in early post-transplant biopsies, which suggests damage from IR that does not translate into a histological presentation indicative of patent ATN. The incidence of this complication increases in certain situations:

• When cold ischaemia exceeds 24 hours, associated with induction therapy using cyclosporine, especially at doses >10mg/kg/day.4
• The type of dialysis performed immediately before transplantation.5
• The quality of the donor, advanced age, and history of hypertension indicate the need for increased perfusion pressure.
• Additional factors that can increase the risk of ATN include preserving the graft in Euro-Collins solution, severe vascular disease in the donor or recipient, diabetic recipients,6 use of sirolimus, and possibly laparoscopic nephrectomy in the donor.7 The use of dopamine or a perfusion pump in treating the donor can reduce the incidence of renal allograft dysfunction.8,9

HLA antibodies

The results from some studies suggest that HLA antibodies are associated with an increased risk of graft loss. According to the data from an American registry of 5000 patients, HLA antibodies were observed in 21% of kidney transplant recipients.10 More than 2000 patients were prospectively studied, and the risk of graft loss after one year was significantly higher in patients with HLA antibodies (6.6% vs 3.3%) and patients that developed de novo antibodies (8.6% vs 3%).

Type of kidney

Living donor. Short-term graft survival is higher when kidneys come from living donors as compared to cadaveric donors.11,12 Graft survival in living and cadaveric donor transplants (without expanded criteria) is 98% vs 96% after three months, and 96% vs 92% after one year, respectively.12 This benefit in terms of graft survival is also observed in patients receiving a second transplant.13 This difference reflects the optimal circumstances that surround living donors as compared to the potential damaging conditions implicated in cadaveric donations.

Cadaveric donor, standard criteria. Defined by the conventional criteria for brain death. These grafts have the best short-term survival rate (approximately 91% after one year).12

Cadaveric donor, expanded criteria. These donors have a relative risk (RR) of 1.7 for graft failure during the first year following transplantation. These kidneys come from donors >60 years of age or with a history of arterial hypertension (AHT) or stroke as the cause of death. They are associated with decreased short-term graft survival, and especially among those receiving their second transplant.14

In general, graft survival is inversely correlated with the decrease in donor quality, although the exact definition of quality is unclear.15 For example, excellent survival has been described in kidneys from donors >60 years of age in a prospective cohort study, with two-year graft survival similar to kidneys from donors ≤60 years of age.16

Donation after cardiac death. Kidney donation following cardiac death is a current subject of interest, since published results have demonstrated acceptable graft survival in these situations.17 In a study involving 250 donors following cardiac death and a 30-year follow-up period, the rate of graft survival after one year was 80%.18

Effect of the hospital

In the United States, Europe, and Canada, studies have shown an important effect of the hospital in which the transplant is performed on short-term graft survival, which cannot be explained by differences in the clinical profiles of the patients analysed. This finding has been observed over the past few decades, when immunosuppression therapy has been very effective.19 It may be that the number of transplants performed at each centre and the differences in long-term patient management are underlying causes.20

Donor morbidity

Graft survival in kidneys from cadaveric donors varies based on the cause of death and specific comorbidities of the donor.11,21 For example, kidneys transplanted from donors who died of stroke have a lower one-year survival rate than kidneys from donors who died of other causes (79% vs 84%).11

2) Risk factors for late renal dysfunction

The exact mechanism responsible for the pathogenesis of chronic allograft dysfunction is still unknown, although it has been established that several factors, both dependent on and independent of alloantigens, are associated.22

Risk factors dependent on alloantigens

The risk of developing renal dysfunction, chronic rejection, and graft loss is higher in patients with a history of acute rejection, a greater degree of incompatibility, infections, and/or inadequate immunosuppression therapy. These observations are the result of the significant role played by immunological damage in chronic allograft dysfunction.23

Episodes of acute rejection

Patients with a history of episodes of acute rejection have a greater risk of suffering renal dysfunction later in life. This was demonstrated in a study involving 63 045 patients in which a history including one episode of acute rejection increased the risk of suffering chronic renal dysfunction 5.4 times.24 In a systematic literature review, the weight of the evidence indicated that acute rejection, the time of appearance, and the number of episodes were all associated with an increased risk of graft loss, but less is known regarding the severity of the rejection, which is important since many immunosuppression regimens are designed to reduce the severity of rejection.25

Level of histocompatibility

Despite the use of new immunosuppressant drugs, HLA compatibility still plays an important role in graft survival. This effect can be observed in an analysis of the data from the 2008 Organ Procurement Transplant Network/Scientific Registry of Transplant Recipient (OPTN/SRTR), where graft survival at 5 years, comparing 0 vs 6 incompatibilities, was26:

• 88% and 79% for living donor transplants, respectively.
• 75% and 66% for standard criteria cadaveric donor transplants, respectively.
• 60% and 55% for expanded criteria cadaveric donor transplants, respectively.

The beneficial effects of HLA compatibility surpass the deleterious effects of prolonged cold ischaemia,27 such that the results from an American registry indicated that the graft survival rate after 5 years in cadaveric donors with 6 compatibilities was the same with 3 hours cold ischaemia as with 36 hours cold ischaemia. However, the negative effects of prolonged cold ischaemia times are evident in recipients of incompatible grafts, with survival rates reduced by 1% to 2%, associated with >12h of cold ischaemia.

Sensitisation

Class I (A, B, or C) and class II (DR, DQ) HLA antibodies are found in patients that have been sensitised to these glycoproteins after pregnancy, blood transfusions, or previous transplants. Increased sensitisation, measured using a panel reactive antibody (PRA) test, increases the risk of graft loss. According to data from the American transplant registry in 2007, the graft survival rate after 5 years in kidneys from non-expanded criteria cadaveric donors was26:

• 71% in patients with a PRA of 0%-9%.
• 69% in patients with a PRA of 10%-79%.
• 69% in patients with a PRA>80%.

In recent years, the importance of the role of donor-specific anti-HLA antibodies (DSA) has come into focus for the adverse effects they have on graft evolution. Using high-sensitivity techniques, graft survival after 8 years was analysed in 43 patients with DSA and 194 patients without DSA, resulting in 68% vs 77% survival, respectively, while the incidence of antibody-mediated rejection was 9 times higher in patients with preformed DSA.28

Studies have also suggested that sensitisation in some cases can represent “non-HLA immunity,” and can negatively affect graft survival. The importance of non-HLA immunity was supported by a prospective study involving 2231 patients.29 After two years, graft survival was significantly higher in the 1781 patients without HLA antibodies (96% vs 85%).

Risk factors independent of alloantigens

Inadequate kidney size, damage from ischaemia-reperfusion, post-transplant hypertension, hyperlipidaemia, expanded criteria donor kidneys, recurrent or de novo glomerular disease, and nephrotoxicity inherent to anticalcineurinic drugs all contribute to the development of chronic renal dysfunction and affect graft survival.30

Graft tissue damage

Graft tissue damage plays an important role in short and long-term graft functioning, as well as in inducing rejection. This damage can be due to a variety of different factors, including brain death, time of cold ischaemia, IR, and infection.

Brain death. Brain death as a consequence of trauma or intracranial haemorrhage produces a series of adverse effects on organs before transplantation. Under these circumstances, kidney tissue becomes essential, and the activation of the recipient’s T-cells against donor alloantigens is facilitated.31 In patients with brain death, intracranial pressure increases due to cerebral oedema, compression of brain tissues, and venous congestion; this results in a massive release of catecholamines, which produces major vasoconstriction and endothelial damage, favouring the expression of HLA class II and adhesion molecules in the endothelium of the donor kidney tissue. Endothelial activation, together with cytokine release, complement activation, and a decrease in tissue plasminogen activation factor, favours a state of hypercoagulability.32

Ischaemia-reperfusion. IR damage is an important risk factor for DGF and renal dysfunction due to post-ischaemic ATN, the incidence of which increases when the time of cold ischaemia surpasses 18 hours,33 both in older34 and younger35 donors. The circumstances surrounding organ extraction, preservation, and implantation can affect the immunogenic capacity of the organ,36 and may lead to over-expression of the major histocompatibility complex antigens and the release of a cytokine cascade and adhesion molecules.

Infections. Cytomegalovirus. Seronegative recipients of seronegative grafts have a 10% higher graft survival rate than those receiving seropositive grafts. This difference may be due to the fact that infections favour cytokine activation, which can produce kidney damage.37 BK nephropathy, with different histological patterns based on the identification and extent of inflammatory infiltration and fibrosis associated with the viral infection, is responsible for 50%-100% of graft losses within 24 months, in centres where no screening programme has been established for early disease diagnosis.38

Inadequate kidney size

Transplantation of inadequately sized kidneys leads to a greater risk of renal dysfunction. Several studies have evaluated the relationship between graft function and graft survival and the ratio of graft weight to recipient weight.39 In the most relevant study involving 1189 kidney transplant recipients, the ratio of kidney/recipient weight was evaluated with respect to the risk of developing proteinuria, glomerulosclerosis, and graft failure.40 A low proportion (<2.3g/kg) was associated with an increased risk of glomerulosclerosis (17% vs 4.7%), proteinuria, and long-term graft loss (RR: 1.55; 95% confidence interval [CI]: 1.01-2.12). The risk of decreased graft survival is approximately the same as is attributed to an episode of acute rejection or DGF.

Non-compliance with treatment

A lack of adherence to immunosuppression treatment is one of the most important risk factors associated with long-term graft loss and renal dysfunction. Although the wide variability in the results and design of relevant studies impedes an analysis of the frequency of non-compliance, the true rate is believed to be currently under-estimated.41

Post-transplantation arterial hypertension

The prevalence of post-transplantation AHT, defined as the need for hypotensive treatment, is approximately 75%. AHT can favour atherosclerosis within renal vessels and glomerular hypertension, which can increase glomerular permeability and, consequentially, protein loss. No prospective studies have been carried out with the goal of determining whether strict control of blood pressure levels can prevent the development of chronic nephropathy, but since proper blood pressure control has been shown to slow the progression of renal failure, it seems reasonable to infer that these results could be extrapolated to kidney transplants.

Post-transplant AHT negatively affects long-term patient and graft survival.42 After adjusting for other important factors in a multivariate analysis,43 the relative risk of graft loss was 1.3 per 10mm Hg increase in blood pressure measured one year after transplantation.

Hyperlipidaemia and metabolic syndrome

Hypercholesterolaemia appears in 70%-80% of kidney transplant cases, and hypertriglyceridaemia appears in 30%-40%. Hyperlipidaemia is an established risk factor for the appearance of atherosclerosis and coronary disease in all patients, including heart and kidney transplant recipients, and can also increase the risk of graft loss. The importance of vascular lesions in chronic allograft nephropathy, along with several pathological similarities to atherosclerosis, has led researchers to believe that hyperlipidaemia may contribute to the pathogenesis of this entity. In a multivariate analysis involving 606 kidney transplant recipients, long-term deterioration in kidney transplant function was independently associated with hypertriglyceridaemia.44 In a similar manner, metabolic syndrome has been associated with lower kidney transplant survival.44,45

Recurrent and de novo glomerular disease

Recurrent and de novo glomerular disease negatively affect long-term graft survival.

A retrospective study evaluated the results of almost 5000 cases of kidney transplants, 167 of which had histological confirmation of de novo or recurrent glomerular disease, observing that the relative risk of graft loss was 1.9, with a higher rate of graft loss at 5 years (60% vs 32%) in patients without glomerular disease.46

In 1505 transplant recipients with terminal renal failure secondary to glomerulonephritis, 52 patients (3.5%) suffered graft loss as a consequence of recurrences of the glomerulonephritis, as confirmed by a biopsy, with an estimated incidence of graft loss from this recurring entity of 8.4%, placing it as the third-leading cause for graft loss in these patients.47

Genetic polymorphisms

Graft survival can also be affected by factors not related to alloantigens, such as different abilities to organise an effective immune response against the graft and the underlying factors that affect graft fibrosis. Several studies have focused on analysing the influence of certain genetic polymorphisms in the molecules involved in the development of chronic allograft nephropathy.48 Caveolin-1 (CAV1) appears to play an important role in the development of fibrosis in the kidneys. A retrospective study found that polymorphisms on the gene responsible for expressing CAV1 are associated with increased risk of graft loss, associated with graft fibrosis.49

A study was designed to evaluate graft survival in 1127 kidney transplant recipients who were subjected to a screening programme for carriers of a suppressed 32 base pair in the gene for the chemokine receptor 5 (CCR5). The intact molecule is a cell surface receptor for several different chemokines, as well as for the human immunodeficiency virus. Patients that were homozygous for this mutation (which results in a non-functional receptor and occurs in approximately 1% of Caucasians in the USA and Europe) had a graft survival after 20 years significantly higher than those who were not homozygous (90% vs 25%).50

Nephrotoxicity of calcineurin inhibitors

Chronic nephrotoxicity produced by calcineurin inhibitors (CNI), cyclosporine, and tacrolimus manifests in the form of chronic renal dysfunction due to vascular and glomerular injury, anomalous tubular function, and an increase in blood pressure.51

In a cohort study involving non-kidney transplant recipients in the USA, where cyclosporine was administered to 60% of patients and tacrolimus to 28%, 17% had developed chronic renal failure after 36 months of follow-up (defined as estimated glomerular filtration rate [eGFR] ≤29ml/min).52

The lack of prospective studies with proper controls impedes our ability to evaluate whether there is a safe dose of cyclosporine that would be immunologically effective and at the same time does not produce chronic renal dysfunction, although short-term studies such as the CAESAR study suggest that low maintenance doses of cyclosporine do not produce this condition.53 However, there is a strong association between chronic renal dysfunction and continued and long-term exposure to CNI. This is based on well-designed studies that have analysed CNI nephrotoxicity, including biopsies that provide more relevant information. In this manner, a prospective study involving 120 kidney/pancreas recipients with different immunosuppressant regimens (with and without CNI) and 10 years of follow-up demonstrated that, after the first year following transplantation, progressive arteriolar hyalinosis, glomerulosclerosis, and tubulo-interstitial damage were the predominant lesions observed, such that after 10 years, 60% of patients had severe allograft nephropathy, with glomerulosclerosis in almost 40% of glomeruli.54

At conventional doses, acute and chronic tacrolimus nephrotoxicity is similar to the mechanism observed with cyclosporine, but tacrolimus at lower doses can produce lower nephrotoxicity while maintaining its higher immunosuppressant value.55,56 This was reflected in the ELITE-Symphony study with 1645 kidney transplant recipients, randomised to receive different immunosuppressant regimens. After one year, the group with low doses of tacrolimus had better glomerular filtration rates (GFR), and the tacrolimus-based regimen was also associated with a lower incidence of acute rejection and increased graft survival. After 3 years, the low dose tacrolimus group continued to demonstrate better GFR values.57

Renal function and proteinuria

In the ALERT study, 2000 patients were randomised to receive fluvastatin or a placebo and were monitored for 5 years.58 In the placebo group, 137 patients suffered graft loss, with chronic allograft nephropathy being the primary cause. In a multivariate analysis, the independent risk factors for increased risk of graft loss were an increase in serum creatinine levels, proteinuria, and pulse pressure.

Deteriorated renal function 1 year after transplantation is a predictive factor for long-term renal dysfunction.59,60 In a study using data from the American patient registry, involving the analysis of 100 000 transplants, the relative risk of graft loss was 1.63 with each 1mg/dl increase in serum creatinine 1 year after the transplantation, and this value was raised to 2.26 when the ¿ creatinine value was 0.5mg/dl.

Proteinuria (even at levels <1g/day) is a predictive factor for long-term graft loss.58,61-64 In the Spanish study of chronic allograft nephropathy (CAN), persistent proteinuria ≥0.5g/day during the first year following transplantation was an independent risk factor for graft loss and mortality.62,63 Reabsorption of excessive quantities of protein by proximal tubular cells can lead to the release of inflammatory mediators in tubular cells and interstitial damage, contributing to the progression of renal failure.

References

1. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S, Cho YW, Yuge J. Risk rate and longterm kidney transplant survival. Clin Transpl. 1996:443-58.

2. Prommool S, Jhangri GS, Cockfield SM, Halloran PF. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 2000;11:565-73.[Pubmed]

3. Quiroga I, McShane P, Koo DD, Gray D, Friend PJ, Fuggle S, et al. Major effects of delayed graft function and col ischaemia tiem on renal allograft survival. Nephrol Dial Transplant 2006; 21:1689-96.[Pubmed]

4. Cravedi P, Codreanu I, Satta A, Turturro M, Sghirlanzoni M, Remuzzi G, et al. Cyclosporine prolongs delayed graft function in kidney transplantation: are rabbit anti-human thymocyte globulins the answer? Nephron Clin Pract 2005;101:c65.[Pubmed]

5. Van Biesen W, Vanholder R, Van Loo A, Van Der Vennet M, Lameire N. Peritoneal dialysis favorably influences early function after renal transplantation compared to hemodialysis. Transplantation 2000;69:508-14.[Pubmed]

6. 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(2):298-303.[Pubmed]

7. Lind MY, Zur Borg IM, Hazebroek EJ, Hop WC, Alwayn IP, Weimar W, et al. The effect of laparoscopic and open donor nephrectomy on the long-term renal function in donor and recipient: a retrospective study. Transplantation 2005;80:700-3.[Pubmed]

8. Schnuelle P, Gottmann U, Hoeger S, Boesebeck D, Lauchart W, Weiss C, et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA 2009;302:1067-75.[Pubmed]

9. Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2009;360(1):7-19.

10. Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: A prospective trial. Am J Transplant 2004;4:438-43.[Pubmed]

11. Port FK, Dykstra DM, Merion RM, Wolfe RA. Trends and results for organ donation and transplantation in the United States, 2004. Am J Transplant 2005;5:843-9.[Pubmed]

12. http://www.ustransplant.org [Accessed: February, 2010].

13. Rigden S, Mehls O, Geller R, on behalf of the scientific advisory board of the ERA-EDTA registry. Factors influencing second renal allograft survival. Nephrol Dial Transplant 1999;14:566-9.[Pubmed]

14. http://www.optn.org [Accessed: February, 2010].

15. Schold JD, Kaplan B, Baliga RS, Meier-Kriesche HU. The broad spectrum of quality in deceased donor kidneys. Am J Transplant 2005;5:757-65.[Pubmed]

16. Remuzzi G, Gravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, et al. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006;354:343-52.[Pubmed]

17. Punch JD, Hayes DH, LaPorte FB, McBride V, Seely MS. Organ donation and utilization in the United States, 1996-2005. Am J Transplant 2007;7:1327-38.[Pubmed]

18. Tojimbara T, Fuchinoue S, Iwadoh K, Koyama I, Sannomiya A, Kato Y, et al. Improved outcomes of renal transplantation form cardiac death donors: a 30-year single center experience. Am J Transplant 2007;7:609-17.[Pubmed]

19. Kim SJ, Schaubel S, Jeffery JR, Fenton SS. Centre-specific variation in renal transplant outcomes in Canada. Nephrol Dial Transplant 2004;19:1856-61.[Pubmed]

20. Ojo AO, Morales JM, Gonzalez-Molina M, Steffick D, Luan F, Merion R. Diferencia entre Estados Unidos y España en la evolución del injerto a largo plazo. I Congreso de la Sociedad Española de Trasplantes. Sevilla, 2010, Abstract book p.48.

21. Ojo AO, Leichtman AB, Punch JD, Hanson JA, Dickinson DM, Wolfe RA, et al. Impact of pre-existing donor hypertension and diabetes mellitus on cadaveric renal transplant outcomes. Am J Kidney Dis 2000;36:153-9.[Pubmed]

22. Matas AJ, Gillingham KJ, Humar A, Dunn DL, Sutherland DE, Najarian JS. Immunologic and nonimmunologic factors: different risks for cadaver and living donor transplantation. Transplantation 2000;69:54-8.[Pubmed]

23. Almond PS, Matas A, Gillingham K, Dunn DL, Payne WD, Gores P, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993;55:752-6.[Pubmed]

24. Meier-Kriesche HU, Ojo AO, Hanson JA, Cibrik DM, Punch JD, Leichtman AB, et al. Increased impact of acute rejection on chronic allograft failure in recent era. Transplantation 2000;70:1098-100.[Pubmed]

25. Wu O, Levy AR, Briggs A, Lewis G, Jardine A. Acute rejection and chronic nephropathy: A systematic rewiew of the literature. Transplantation 2009;87(9):1330-9.[Pubmed]

26. www.ustransplant.org/annual-reports [Accessed: February, 2010].

27. Opelz G, The benefit of exchanging donor kidneys among transplant centers. N Engl J Med 1988;318:1289-90.[Pubmed]

28. Lefaucheur C, Suberbielle-Bissel C, Hill GS, Nochy D, Andrade J, Antoine C, et al. Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Am J Transplant 2008;8:324-31.[Pubmed]

29. Terasaki PI, Azawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: Results of a 2 year prospective trial. Transplantation 2005;80:1194-7.[Pubmed]

30. Ponticelli C, Villa M, Cesana B, Montagnino G, Tarantino A. Risk factors for late kidney allograft failure. Kidney Int 2002;62:1848-54.[Pubmed]

31. Pratschke J, Vok HD. Brain death-associated ischemia and reperfusion injury. Curr Opin Organ Transplant 2004;9:153.

32. Van der Hoeven JA, Molema DR, Faulk WP. Relationship between duration of brain death and hemodynamic (in) stability on progresive dysfunction and increased immunologic activation of donor kidneys. Kidney Int 2003;64:1874-82.[Pubmed]

33. Opelz G, Dohler B. Multicenter analysis of kidney preservation. Transplantation 2007;83:247-53.[Pubmed]

34. Woo YM, Gill JS, Johnson N, Pereira BJ, Hariharan S. The advanced age deceased kidney donor: Current outcomes and future opportunities. Kidney Int 2005;67:2407-14.[Pubmed]

35. Hernández D, Estupiñán S, Pérez G, Rufino M, González-Posada JM, Luis D, et al. Impact of cold ischemia time on renal allograft outcome using kidneys from young donors. Transplant Int 2008;21(10):955-62.

36. Bryan CF, Luge AM, Martínez J, Muruve N, Nelson PW, Pierce GE, et al. Cold ischemia time: An independent predictor of increased HLA class I antibody production after rejection of a primary cadaveric renal allograft. Transplantation 2001;71:875-9.

37. Wadman WJ, Knight DA. Citokine-mediated induction of endothelial adhesion molecule and histocompatibility leukocyte antigen expression by cytomegalovirus-activated T cells. Am J Pathol 1996;148:105-19.[Pubmed]

38. Ramos E, Drachemberg CB, Portocarrero M, Wali R, Klassen DK, Fink JC, et al. BK virus nephropathy diagnosis and treatment: Experience at the University of Maryland Renal Transplant Program. Clin Transpl 2002:143-53.[Pubmed]

39. Kim YS, Moon JI, Kim DK, Kim SI, Park K. Ratio of donor kidney weight to recipient bodyweight as an index of graft function. Lancet 2001;357:1180-1.[Pubmed]

40. Giral M, Foucher Y, Karam G, Labrune Y, Kessler M, de Ligny BH, et al. Kidney and recipient weight incompatibility reduces long-term graft survival. J Am Soc Nephrol 2010;21:1022-9.[Pubmed]

41. Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frecuency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation 2004;77:769-76.[Pubmed]

42. Kasiske BL, Anjum S, Shah R, Skogen J, Kandaswamy C, Danielson B, et al. Hypertension after kidney transplantation. Am J Kidney Dis 2004;43:1071-81.[Pubmed]

43. Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA 2000;283:633-8.[Pubmed]

44. de Vries AP, Bakker SJ, van Son WJ, van der Heide JJ, Ploeg RJ, The HT, et al. Metabolic syndrome is associated with impaired long-term renal allograft function; nota ll component criteria contribute equally. Am J Transplant 2004;4:1675-83.[Pubmed]

45. Porrini E, Delgado P, Bigo C, Alvarez A, Cobo M, Checa MD, et al. Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis 2006;48(1):134-42.

46. Hariharan S, Adams MB, Brennan DC, Davis CL, First MR, Johnson CP, et al. Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation 1999;68:635-41.[Pubmed]

47. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonepheritis. N Engl J Med 2002;347:103-9.[Pubmed]

48. Hernández D, Sánchez-Fructuoso, Serón D, Arias M, Campistol JM, Morales JM, et al.; Grupo Español para el Estudio de la Nefropatía Crónica del Trasplante. [Chronic transplant nephropathy]. Nefrologia 2006;26(suppl 1):1-38.

49. Moore J, McKnight AJ, Simmonds MJ, Courtney AE, Hanvesakul R, Brand OJ, et al. Association of caveolin-1 gene polymosphism with kidney transplant fibrosis and allograft failure. JAMA 2010;303:1282-7.[Pubmed]

50. Fischereder M, Luckow B, Hocher B, Wüthrich RP, Rothenpieler U, Schneeberger H, et al. CC chemokine receptor 5 and renal transplant survival. Lancet 2001;357:1758-61.[Pubmed]

51. Williams D, Haragsim L. Calcineurin nephrotoxicity. Adv Chronic kidney Dis 2006;13:47-55.[Pubmed]

52. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure after transplantation of a non renal organ. N Engl J Med 2003;349:931-40.[Pubmed]

53. Ekberg H, Grinyó J, Nashan B, Vanrenterghem Y, Vincenti F, Voulgari A, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: The CAESAR study. Am J Transplant 2007;7:560-70.[Pubmed]

54. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-33.[Pubmed]

55. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al.; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75.[Pubmed]

56. Shihab FS, Waid TH, Conti DJ, Yang H, Holman MJ, Mulloy LC, et al.; CRAF Study Group. Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF study. Transplantation 2008;85:1261-9.[Pubmed]

57. Ekberg H, Bernasconi C, Tedesco-Silva H, Vítko S, Hugo C, Demirbas A, et al. Calcineurin inhibitor minimization in the symphony study: observational results 3 years after transplantation. Am J Transplant 2009;9:1876-85.[Pubmed]

58. Fellström B, Holdaas H, Jardine AG, Nyberg G, Grönhagen-Riska C, Madsen S, et al.; Assessment of Lescol in Renal Transplantation Study Investigators. Risk factors for reaching renal endpoints in the assessment of lescol in renal transplantation (ALERT) trial. Transplantation 2005;79:205-12.[Pubmed]

59. Hariharan S, McBride MA, Cherikh WS, Tolleris CB. Post-transplant renal function in the first year pedicts long-term kidney transplant survival. Kidney Int 2002;62:311-8.[Pubmed]

60. Salvadori M, Rosati A, Bock A, Chapman J, Dussol B, Fritsche L, et al. Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant. Transplantation 2006;81:202-6.[Pubmed]

61. Serón D, Arias M, Campistol JM, Morales JM; The Spanish Chronic Allograft Nephropathy Study Group. Late renal allograft failure between 1990 and 1998 in Spain: a changing scenario. Transplantation 2003;76 (11):1588-94.[Pubmed]

62. Halimi JM, Buchler M, Al-Najjar A, Laouad I, Chatelet V, Marlière JF, et al. Urinary albumin excrection ad the risk of loss and death in proteinuric and non-proteinuric renal transplant recipients. Am J Transplant 2007;7:618-25.[Pubmed]

63. Fernández-Fresnedo G, Plaza JJ, Sánchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M. Proteinuria: a new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant 2004;19 Suppl 3:III47-51.[Pubmed]

64. Hernández D, Pérez G, Marrero D, Porrini E, Rufino M, González-Posada JM, et al. Early association of low-grade albuminuria and allograft dysfunction predicts renal transplant outcomes. Transplantation 2012;93(3):297-303.

D. Follow-up for kidney transplant recipients: clinical monitoring

The definition of chronic kidney allograft dysfunction in the KDIGO guidelines1 is an estimated glomerular filtration rate (eGFR) <40ml/min and/or proteinuria >500mg/day, a definition that does not satisfy 55% of nephrologists that replied to the questionnaire from this consensus document. The prevalence of this condition one year after transplantation can surpass 20% according to unpublished data from the Spanish study of chronic transplant nephropathy.2 However, this prevalence is heavily influenced by the type of transplant and, above all, the age of the donor. For example, according to data from our centre, 60% of patients that receive kidneys from donors older than 60 years have an eGFR<40ml/min after one year. It is thus obvious that, in addition to immunological causes of chronic allograft dysfunction, several other factors can influence graft function, as mentioned in the previous section. In this section, we will focus on how to monitor patients starting 3 months after transplantation, the period in which the risk of acute injury has decreased.

Clinical monitoring of chronic renal allograft dysfunction

From a clinical standpoint, after identifying all cases of chronic allograft dysfunction, the most relevant step is to identify patients that will develop a progressive deterioration of renal function, often accompanied by proteinuria and arterial hypertension (AHT). The recommendations made in the KDIGO guidelines are based on little evidence. Recently, Kasiske et al.3 proposed a predictive model for graft survival after 5 years based on clinical data obtained prior to transplantation, after one week, or after one year. There is even a webpage where one can calculate the probability of graft loss after 5 years based on these clinical variables (http://www.txscores.org). However, these models must be approached with caution, firstly because they are based on the US population, and secondly because they have been constructed from retrospective data.

Patients are clinically monitored through periodic outpatient follow-up visits, with the objective of providing early detection of chronic allograft dysfunction in order to provide treatment and improve the prognosis.

During each visit, the nephrologist must always keep in mind the nephrological history of the patient: the cause of renal failure (possibility of recurrent pathology), immunological risk (previous kidney transplant, HLA [human leukocyte antigen] sensitisation, or history of acute rejection), and the best creatinine value reached since the current kidney transplantation.

The use of renin-angiotensin-aldosterone system inhibitors can be associated with a decrease in glomerular filtration rate in kidney transplant recipients, especially in the presence of renal dysfunction. This effect tends not to be progressive, and is usually reversible.4

Frequency of follow-up

The KDIGO guidelines recommend following up with the patient every two weeks during months 3-6 after the transplantation, a monthly visit during months 7-12, and every 2-3 months following one year after transplantation.1

Clinical variables (upon each visit) 

1. Adherence to treatment

A substantial portion of the anamnesis must be directed towards detecting a lack of compliance (both voluntary and involuntary) with pharmacological prescriptions, primarily immunosuppressants. A lack of adherence to treatment can be a significant cause of chronic allograft dysfunction. This lack of compliance may be suspected if unjustifiably varying levels of immunosuppressant drugs are detected or if appointments are missed, above all in young patients and those with psychiatric disorders or drug dependence.

Treatment protocols should be reviewed with the patient at each follow-up visit. The patient must be capable of stating the dosage and when and how to take the medication. Voluntary non-compliance is much more difficult to detect; we can indirectly measure this through questioning the patient about adverse effects (if the patient states that every time he/she takes a given product, it produces discomfort or some adverse side effect, we can suspect that he/she does not take it at some point). A lack of adherence also can be detected through patient interviews held by health personnel or by interviewing family members. The patient should also be reminded upon each visit that correct administration of the prescribed treatment is an essential component of prolonging graft survival.5

2. Physical examination and blood pressure

Transplant recipients tend to gain weight after the operation. Obesity, defined as a body mass index >30kg/m2, is a cardiovascular risk factor and can be associated with hyperfiltration, proteinuria, and progressive deterioration of renal function.6 Abrupt weight gain is associated with decreased volume of diuresis, which can be an indicator of sodium and water retention secondary to renal failure or nephrotic syndrome.

Approximately 50%-90% of transplanted patients have AHT, defined as 140/90mm Hg, which is associated with reduced graft survival.7 Seated blood pressure (BP) must be measured after at least 5 minutes, with the arm folded over the chest and a proper cuff. At least two measurements should be taken. Appropriate systolic BP is <130mm Hg, and diastolic BP<80mm Hg.1 A lack of BP control can be an indirect sign of poor compliance, progression of the nephropathy, or be associated with anticalcineurinic drug toxicity.

Patients should also be evaluated for signs of sodium and water retention and femoral murmurs or murmurs over the transplanted kidney that might suggest renal artery stenosis. Oedema can be associated with nephrotic syndrome, drug toxicity, deteriorated renal function, or heart failure.

Laboratory analyses 

1. Serum creatinine

Serum creatinine should be measured upon every visit. In particular, the best creatinine value measured since the transplantation should be kept in mind; a comparison between current and “best” post-transplant creatinine can be more informative than comparing current values with those from the previous measurement.8 Creatinine levels one year after transplantation provide a very important prognostic factor for graft survival.9,10

2. Formulas for estimating glomerular filtration rate

Glomerular filtration rate (GFR) should be estimated during each visit. As for creatinine, the concept of “best GFR since the operation” should be prioritised. Several different formulas exist for estimating glomerular filtration rate (Cockcroft-Gault, MDRD, Nankivell, CKD-EPI). We do not have sufficient evidence to suggest one formula or another,1 but the Cockcroft-Gault equation may overestimate renal function. Estimating GFR using these formulas can be useful for comparing groups of patients. However, in a single patient, it appears that they are not superior to using creatinine values for estimating renal function. The reason is that, from one visit to another, changes in estimated GFR using these formulas depend solely on creatinine values, since other variables tend to remain unchanged.

There are webpages for calculating the value of GFR using these formulas:

http://www.kidney.org/professionals/KLS/gfr_calculator.cfmhttp://www.nephron.com/mdrd/default.html

3. Proteinuria and albuminuria

Proteinuria and albuminuria, in particular, are early markers for renal damage. Transplant recipients with proteinuria tend to have worse renal function than those without it. The KDIGO guideline threshold of proteinuria >500mg/day as a sign of chronic allograft dysfunction is completely arbitrary.1 It is probable that substantially lower proteinuria values indicate established pathology in the kidney transplant that, most importantly, may potentially be reversible.11 Proteinuria can occur as a result of albuminuria or the excretion of other tubular proteins, according to the primary location of the responsible kidney damage (glomerular or tubular/interstitial). It appears that albuminuria, more than proteinuria, is a prognostic marker for graft survival.12

As regards the level of proteinuria that warrants a biopsy of the graft, 43% of nephrologists responded to this survey question with a value of 500mg/24 hours, while the other 47% responded 1000mg/day.

Proteinuria or albuminuria can be measured in 24 hour urine samples or isolated urine samples, and are expressed as values adjusted for urine creatinine. This second type of measurement is being used more and more frequently in our field, primarily since it is more comfortable and reliable since it does not depend on the volume of urine provided in the 24-hour sample.1

4. Microbiology

Urine culture

Urinary tract infections are the most common type of infection following transplantation. Practically half of all patients have at least one episode of bacteriuria or urinary tract infection.13 The primary risk factors for these infections are: female sex, diabetes, and abnormal urinary tract. Bacteriuria is a risk factor for pyelonephritis and urinary bacteraemia, even when treated with antibiotics.13 There is no clear consensus whether or not to monitor urine cultures in all patients after 3 months following transplantation or whether to treat with antibiotics. The impact of urinary tract infections on graft survival is also under debate.14

BK virus 

In kidney transplants, the prevalence of BK virus-associated nephropathy ranges from 1% to 10% based on the immunosuppressant regimen administered ad the methods used to determine the diagnosis.15 This can cause acute or chronic allograft dysfunction, whether from interstitial nephritis or urinary tract infection. The highest incidences of this type of infection are observed during the first year following transplantation. Viral loads should be measured monthly for the first 3 months, and every 3 months afterwards for the first year.1

Imaging tests

Imaging tests should be used whenever allograft dysfunction occurs. They provide very relevant information regarding vascularisation and structure of the kidneys and urinary tract.16 During follow-up, an annual or biannual kidney ultrasound is recommended in order to detect any abnormalities in the urinary tract, as well as for ruling out tumour pathologies in native kidneys. A resistance index of >0.8 3 months after receiving the transplant has also been associated with decreased graft survival.17 Finally, the use of contrast ultrasound has also been proposed for aiding in the early detection of transplant nephropathy even in the absence of altered renal function or resistance index.18

References

E. Follow-up for kidney transplant recipients: histological monitoring

Follow-up biopsies have shown that histological lesions appear before functional deterioration and/or proteinuria is observed.1,2 Interstitial fibrosis (IF) with tubular atrophy (TA) and subclinical rejection in patients with stable renal function are both associated with reduced graft survival.3,4 More recently, we have learned that it is the coexistence of IF/TA and subclinical rejection that conveys poor prognosis, and not IF/TA or subclinical rejection alone.5-7

Subclinical rejection, interstitial fibrosis/tubular atrophy, and immunosuppressant treatment

The treatment of subclinical rejection with steroid boluses in the time of cyclosporine and azathioprine, when the prevalence of subclinical rejection surpassed 50%, was associated with reduced progression of IF/TA.8 Afterwards, the introduction of tacrolimus and mycophenolate facilitated a reduction in the subclinical rejection rate from approximately 60% to 10%.9-11 This tight relationship between subclinical inflammation and immunosuppressant regimen is one of the most consistent findings in studies performed using protocol biopsies. For example, in a prospective, randomised study, the rate of subclinical rejection after 1 year and fibrosis after 5 years was lower in patients that received an anticalcineurin drug associated with an mTOR inhibitor as compared to patients receiving an anticalcineurinic with mycophenolate mofetil, suggesting yet again that the immunosuppressant treatment regimen was tightly correlated with the prevalence of early subclinical rejection and late IF/TA.12 On the other hand, in patients with a low immunological risk who receive kidneys from young donors, prescriptions without calcineurin inhibitors based on mTOR inhibitors or belatacept are associated with a reduced progression of IF/TA.13,14

In a prospective study, patients initially treated with cyclosporine, mycophenolate, and prednisone were randomised to have cyclosporine or mycophenolate removed from their prescription. In patients who were removed from treatment with cyclosporine, subclinical rejection observed in a biopsy after 3 months was associated with an increased risk of acute rejection, suggesting that subclinical rejection should serve as a contraindication for reducing immunosuppressant therapy.15

Follow-up biopsies and chronic humoral rejection

Follow-up biopsies facilitate an early diagnosis of transplant glomerulopathies,16 which have a 20% prevalence rate after 5 years; evaluating biopsies using an electron microscope provide diagnoses during very early stages of the disease, approximately two years before the appearance of abnormalities in light microscope analyses.17 C4d positivity in protocol biopsies is uncommon.18 However, in certain situations, such as ABO incompatible transplants, C4d is positive in 80% of protocol biopsies, and in patients with cross match positive transplants treated with plasmapheresis and immunoglobulins, C4d is positive in 26%. In ABO incompatible transplants, positive C4d results are not associated with histological lesions suggestive of humoral rejection, whereas cross match positive transplants with positive Cd4 results exhibit leukocyte marginalisation and progression of IF/TA.19,20

References

1. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 3003;11:349:2326-33.

2. Stegall MD, Park WD, Larson TS, Gloor JM, Cornell LD, Sethi S, et al. The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant 2010;10:1-10.[Pubmed]

3. Serón D, Moreso F. Protocol biopsies in renal transplantation: prognostic value and of structural monitoring. Kidney Int 2007;72:690-7.[Pubmed]

4. Choi BS, Shin MJ, Shin SJ, Kim YS, Choi YJ, Kim YS, et al. Clinical significance of an early protocol biopsy in living-donor renal transplantation: ten-year experience at a single center. Am J Transplant 2005;5:1354-60.

5. Shishido S, Hiroshi A, Hideo N, Mori Y, Satoh H, Kamimaki I, et al. The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy. J Am Soc Nephrol 2003;14:1046-53.[Pubmed]

6. Cosio FG, Grande JP, Larson TS, Gloor JM, Velosa JA, Textor SC, et al. Kidney allograft fibrosis and atrophy early after living donor transplantation. Am J Transplant 2005;5:1130-6.[Pubmed]

7. Moreso F, Ibernon M, Gomà M, Carrera M, Fulladosa X, Hueso M, et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant 2006;6:747-52.[Pubmed]

8. Rush D, Jeffrey J, Trpkov K, Solez K, Gough J. Beneficial effects of treatment of early subclinical rejection: a randomized study. Am Soc Nephrol 1998;9:2129-34.

9. Gloor JM, Cohen AJ, Lager DJ, Grande JP, Fidler ME, Velosa JA, et al. Subclinical rejection in tacrolimus treated renal transplant recipients. Transplantation 2002;73:1965-8.[Pubmed]

10. Moreso F, Serón D, Carrera M, Gil-Vernet S, Cruzado JM, Hueso M, et al. Baseline immunosuppression is associated with histologic findings in early protocol biopsies. Transplantation 2004;78:1064-8.[Pubmed]

11. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. Natural history, risk factors and impact of subclinical rejection in kidney transplantation. Transplantation 2004;78:242-9.[Pubmed]

12. Anil Kumar MS, Irfan Saeed M, Ranganna K, Malat G, Sustento-Reodica N, Kumar AM, et al. Comparison of four different immunosuppression protocols without long term steroid therapy in kidney recipients monitored by surveillance biopsy: five year outcomes. Transpl Immunol 2008;20:32-42.[Pubmed]

13. Mota A, Arias M, Taskinen EL, Paavonen T, Brault Y, Legendre C, et al. Sirolimus based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 2004;4:953-61.[Pubmed]

14. Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G, et al. Coestimulation blockade with belatacept in renal transplantation. N Engl J Med 2005;353:770-81.[Pubmed]

15. Hassan M, Labalette M, Copin MC, Glowacki F, Provôt F, Pruv FR, et al. Predictive factors of acute rejection after early cyclsoporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective randomized trial. J Am Soc Nephrol 2005;16:2509-16.[Pubmed]

16. Gloor JM, Sethis S, Stegall M, Park WD, Moore SB, DeGoey S, et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007;7(9):2124-33.

17. Wavamunno MD, O’Conell PJ, Vitalone M, Fung CL, Allen RD, Chapman JR, et al. Transplant glomerulopathy: ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies. Am J Transplant 2007;7:2757-68.[Pubmed]

18. Mengel M, Bogers J, Bosmans JL, Serón D, Moreso F, Carrera M, et al. Incidence of C4d stain in protocol biopsies from renal allografts: results from a multicenter trial. Am J Transplant 2005;5:1050-6.[Pubmed]

19. Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, Segev DL, et al. C4d and C3d staining in biopsies of ABO- and HLA- incompatible renal allografts: correlation with histologic findings. Am J Transplant 2006;6:1829-40.

20. Haas M, Montgomery RA, Segev DL, Rahman MH, Racusen LC, Bagnasco SM, et al. Subclinical acute antibody-mediated rejection in positive cross match renal allografts. Am J Transplant 2007;7:576-85.[Pubmed]

F. Aetiopathogenic diagnosis of renal dysfunction in kidney transplant recipients

Although we do not find it appropriate to completely ignore the clinical and syndromic concept of chronic allograft injury (CAI) and dysfunction, it is necessary to elaborate on the various aetiopathogenic origins of this similar clinical situation, which usually leads to a more or less accelerated loss of function of the kidney transplant.1 The final result of the various mechanisms implicated in each case of CAI is renal sclerosis and fibrosis, and the essential tool for characterising and diagnosing this condition is the renal biopsy.2 Using various diagnostic criteria, pathologists can and must define specific lesions that can identify the pathogenic processes affecting the allograft.3 Although some cases remain labelled as “interstitial fibrosis/tubular atrophy (IF/TA) of an unknown cause,” the majority of cases can be narrowed down to specific diagnoses.

In order to improve the diagnostic potential of renal biopsies, a pre-transplant biopsy, or “time 0” biopsy is recommended,4,5 primarily when dealing with expanded criteria donors, in order to identify pre-existing histological lesions. Even living donors are of potential interest.6 Glomerulosclerosis, atherosclerosis, arteriolar hyalinosis, and IF/TA are common. In addition to having access to baseline histological results for improving the diagnostic power of CAI and its different aetiopathogenic variations, it is very important to maintain active vigilance and arrive at the earliest and most specific possible diagnosis in order to implement the available treatment strategies with any hope of efficacy.7

Chronic allograft injury triggers progressive renal dysfunction through several mechanisms (Table 2).

The most relevant non-immunological causes of this condition are nephrotoxicity from anticalcineurinics and arterial hypertension. Chronic anticalcineurinic nephrotoxicity can be detected in standard biopsies even within the first months following transplantation. This translates into arteriolar hyalinosis and IF/TA in a band or diffuse pattern.8,9 A recent exhaustive study concluded that this nephrotoxicity is rarely the sole culprit for causing chronic damage and allograft loss.10Poorly controlled arterial hypertension produces lesions in renal grafts including thickening of the arterial fibrointima with duplication of the internal elastic lamina (fibroelastosis), arteriolar hyalinosis, glomerulosclerosis, and, of course IF/TA. Chronic urinary tract obstruction, viral nephritis (especially BK virus-associated11), and bacterial pyelonephritis are other causes of chronic allograft damage, and are very relevant components of a differential diagnosis.

In addition to the non-immunological causes of IF/TA, chronic damage can be mediated by alloantibodies or T-cells.1,2,12 In both types of damage, mixed components can be found, whether in the form of cellular infiltration that affects the graft during an episode of antibody-mediated acute rejection, or alloimmune phenomena together with T-cell mediated damage.

The development of C4d as a specific marker for the deposition of alloantibodies in the capillary endothelium and the use of specific detection techniques for these antibodies have increased the possibilities for early diagnosis and treatment of antibody-mediated chronic rejection.12,13 The typical variables mentioned in the commonly used and recently accepted criteria are C4d deposits in peritubular capillaries and a variety of chronic histological findings that are summarised in Table 2. However, more recently, the possibility of chronic rejection mediated by antibodies without C4d deposits has been described, with an underlying aetiopathogenesis of endothelial damage that is independent of complement values. According to the authors, this could explain many cases of late kidney transplant loss in patients where no peritubular C4d deposits are found.14

The histological lesions observed in transplant glomerulopathy, while having been characterised decades ago, have been incorporated from the aetiopathogenic point of view of defining antibody-mediated chronic rejection,15 and it is widely accepted that these lesions are the most characteristic histological finding of this condition, although C4d deposits are often not detected in these cases.16 The term “antibody-mediated chronic rejection” is a well-established clinical entity, and the impact of this condition on the progression and survival of both the patient and kidney transplant is progressively being elucidated. However, the requirement of C4d deposits in order to establish this diagnosis appears not to be based on current evidence and could be brought into question.14,16

Chronic active T-cell mediated rejection is diagnosed by a biopsy revealing arterial intimal fibrosis with mononuclear infiltration in areas of fibrosis and the formation of neointima.2 Standard biopsies with histological findings indicating T-cell mediated acute rejection with no apparent deterioration in renal function does not properly fit into any of the categories in the new Banff system. However, recent studies suggest that this subclinical rejection is associated with chronic allograft injury, fibrosis, and atrophy.17 The significance of subclinical C4d deposits in peritubular capillaries is unknown.

Based on the new Banff classification system from 2005, category 5 includes cases of IF/TA in which a specific aetiology cannot be established (Table 3). Quantification of these changes is based on the percentage of the renal cortex with IF/TA. Histological damage is commonly observed with no particular clinical repercussions in standard biopsies.18 However, progressive deterioration of renal function as revealed by an increase in serum creatinine or proteinuria frequently alerts the attending physician to the presence of this type of chronic renal damage. Functional deterioration is a late sign of disease that can imply severe histological damage with fibrosis and glomerulosclerosis.19

References

10.  El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM, et al. Identifying specific causes of kidney allograft loss. Am J Transplant 2009;9:527-35. [Pubmed]

11.  Nickeleit V, Mihatsch MJ. Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat. Transpl Int 2006;19(12):960.[Pubmed]

12.  Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003;3(6):708.[Pubmed]

13.  Takemoto SK, Zeevi A, Feng S, Colvin RB, Jordan S, Kobashigawa J, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4(7):1033.[Pubmed]

14.  Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant 2010;15(1):42-8.

15.  Fotheringham J, Angel CA, McKane W. Transplant glomerulopathy: morphology, associations and mechanism. Nephron Clin Pract 2009;113(1):c1-7.[Pubmed]

16.  Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, et al. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant 2009;9:2520-31.

17.  Moreso F, Ibernon M, Gomà M, Carrera M, Fulladosa X, Hueso M, et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant 2006;6(4):747-52.[Pubmed]

18.  Nankivell BJ, Chapman JR. The significance of subclinical rejection and the value of protocol biopsies. Am J Transplant 2006;6(9):2006-12.[Pubmed]

19.  Chapman JR, O'Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16(10):3015-26.[Pubmed]

Conflicts of interest

This consensus project was finance by an unrestricted research grant from Novartis Farmacéutica S.A.

Dr Julio Pascual has received economic compensation as a presenter at symposia sponsored by Novartis, and has also received financial support for research from Novartis, Amgen, Roche, Astellas, and Fresenius.

Dr Daniel Serón has received economic compensation as a presenter in symposia sponsored by Novartis, Astellas, and Bristol Myers Squibb, and has received financial support for research from Novartis, Roche, Astellas, and Pfizer.

Dr Ángel Alonso has received economic compensation as a presenter in symposia sponsored by Roche and Novartis, and has received financial support for research from Novartis, Roche, and Astellas.

Dr Dolores Burgos has received economic compensation as a presenter in symposia sponsored by Novartis, and has received financial support for research from Novartis, Roche, Astellas, and Pfizer.

Dr Josep M. Cruzado has received economic compensation as a presenter in symposia sponsored by Novartis.

ACKNOWLEDGEMENTS

The members of the scientific committee are the only writers of this article. The Novartis Pharmaceutical Company financed the meetings of the committee, but never had access to the text or opined on the content of the meetings, the elaboration of the manuscript, or the methodology.

The Scientific Committee would like to thank the executive administration of the Spanish Society of Nephrology for their assistance and motivation for developing this consensus document, and the technical support provided for the survey and data analysis.

11433_19157_31462_en_w47771258110ref.1143314651_11433_19115_28143_es_11433_anexo1_copy1_en.doc

Survey for the consensus document with the percentages corresponding to each response

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Table 1. Several definitions for chronic allograft nephropathy

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Table 2. Causes of chronic renal graft damage and morphological correlations

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Table 3. Categories of chronic damage in kidney transplant pathology (Banff ¿05 classification)