Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define chronic kidney disease (CKD) as abnormalities of kidney structure or function present for more than 3 months with implications for overall health . Although transplantation is clearly the treatment of choice for most patients with end stage renal disease (ESRD), virtually all recipients have dealt with medical complications related to CKD before transplantation, and a compromised glomerular filtration rate (GFR) afterward may contribute to ongoing or additional morbidity . Accordingly, the management of CKD in transplant recipients is in many ways similar to that in other patients, with preventive measures to control hypertension, hyperlipidemia, hyperglycemia, proteinuria, anemia, and other comorbidities. In the transplant recipient, there is added complexity related to immunosuppression and preservation of GFR. Finally, if the CKD progresses, the failing allograft presents new challenges related to return to dialysis, immunosuppression and preparing suitable candidates for retransplantation.
IMMUNOSUPPRESSION AND PRESERVATION OF GLOMERULAR FILTRATION RATE
Preservation of GFR after transplantation is critically important in ensuring long-term success of an allograft, and it is increasingly clear that adequacy of immunosuppression is a key variable. A decade ago, nephrotoxicity related to calcineurin inhibitor (CNIs) use was thought to be the major determinant of a declining GFR posttransplant . Consistent with observations first made 20 years ago numerous studies now indicate that preventing immunologic injury is substantially more important than nephrotoxicity in ensuring the long-term preservation of GFR . In SYMPHONY [a large randomized, controlled trial (RCT) of CNI minimization and avoidance] the best-preserved GFR after 3 years occurred in patients on tacrolimus, mycophenolate mofetil and prednisone, who also had the fewest episodes of acute rejection . A series of studies from several groups, including surveillance biopsy, found the greatest histologic evidence of chronic allograft injury in patients with lower, not greater, exposure to tacrolimus, with transplant glomerulopathy and chronic allograft vasculopathy linked to nonadherence and development of donor specific antibody (DSA) [6▪▪,7]. Data from both single and multicenter studies indicate that the greatest risk of graft failure and compromised eGFR is associated with evidence of immunologic injury, including inflammation and antibody-mediated injury, with histologic lesions (arterial hyalinosis and arteriosclerosis) previously attributed to CNI toxicity now clearly attributable to allo-immune injury [8▪,9,10].
These observations are supported by evidence derived from clinical trials of CNI minimization and withdrawal. Thus far, these trials, specifically replacing CNIs with mTOR inhibitors, have demonstrated more rejection and de-novo DSA formation in the withdrawal groups, with little or no benefit in GFR or allograft survival [11,12]. Most recently, long-term results from the BENEFIT trials (substituting belatacept for cyclosporine in de-novo recipients) appear to counter these trends, with better preservation of GFR in those patients not on CNI-based therapy despite more early episodes of acute rejection . However, the greater impact of co-stimulation blockade relative to CNIs in reducing alloantibody formation and enhanced adherence associated with monthly injections of belatacept, offers a mechanistic basis for an alternative interpretation supportive of enhanced long-term immunosuppressive efficacy.
These findings raise the issue of the difficulty in defining adequacy of immunosuppression while avoiding over-immunosuppression. In the CTOT-09 trial, patients with a pristine clinical course during the first 6 months after transplant (defined by the absence of rejection episodes as well as normal GFR, surveillance biopsy, and biomarker profiles) were randomized to staged discontinuation of, or maintenance, tacrolimus [14▪▪]. The study was halted by its data monitoring committee after only 21 patients were randomized because of excessive rejection and DSA formation in the withdrawal group. Going forward, better approaches to define and monitor immunosuppressant adequacy are essential to promote preservation of renal allograft function, with recent advances in pharmacogenomics and molecular diagnostics displaying promise in this regard [15▪,16▪]
As in CKD, and despite the reduction in risk with transplantation relative to dialysis, cardiovascular disease remains the most common cause of death in renal transplant recipients [17,18]. Although conventional risk factors such as smoking, hyperlipidemia, hypertension (particularly systolic), and diabetes play a role, studies indicate that preexisting cardiovascular disease, duration of dialysis prior to transplant, compromised GFR, and obesity are also strong risk factors [19–22]. To promote the greatest benefit, a multifaceted approach to reduce cardiovascular morbidity and mortality must begin prior to transplantation . Although randomized clinical trials of cardioprotective medications in kidney transplant recipients are few, general consensus and clinical practice guidelines support the use of statins, aspirin, renin–angiotensin blockade, and beta blockers as indicated in the general population . Implementation of these practices, however, remains quite variable, at least in part because of marginal support from randomized clinical trials. Both the PORT study database (an international survey of 14 236 kidney transplant patients from 10 centers worldwide) and a more limited survey of several centers in the United States and Canada, indicated that the use of potential cardio-protectants was suboptimal although longitudinal data indicate an improvement in recent years [20,25].
Since the mixed results of the ALERT trial [a reduction in LDL cholesterol with fluvastatin that did not reduce major adverse cardiac events but demonstrated some lowering of cardiac death and nonfatal MI (myocardial infarction)], there have not been large RCTs investigating lipid lowering therapy in the renal transplant population [26,27]. Guidelines support the use of statins or other agents as derived from the general CKD population .
KDIGO guidelines suggest a target blood pressure of below 130/80 mmHg based on research in other high risk populations . A higher systolic blood pressure as a risk factor has been supported by recent evidence from a post-hoc analysis of the FAVORIT trial, with every 20 mmHg increase in systolic blood pressure strongly and independently associated with increased risk of cardiovascular disease and all-cause mortality [28▪▪]. Additionally, every 10 mmHg decrease in diastolic blood pressure below 70 mmHg was also associated with increased cardiovascular risk.
The choice of antihypertensive medication should be individualized on the basis of patient tolerability, side-effects, potential drug interactions (especially through the cytochrome p450 system), and medical comorbidity. Calcium channel blockers are favored in renal transplant patients because of their potential ability to counteract the vaso-constrictive effects of CNIs . A Cochrane review pooling data from small trials concluded that calcium channel blockers have salutary effects on graft survival and GFR . The effect of angiotensin converting enzyme inhibitors (ACEi) on these outcomes was inconclusive. However, ACEi as well as angiotensin receptor blockers (ARB) have been shown to reduce proteinuria and reduce disease progression in the general CKD population  and are endorsed by KDIGO in transplant recipients with proteinuria of over 1 g/day .
Building on earlier data indicating that ACEi limited biopsy-proven expansion of the interstitium (a histologic precursor of fibrosis) in diabetic patients treated with perindopril , a recent small RCT randomized 153 patients to either losartan or placebo . The trial intervention of losartan 100 mg daily did not, however, lead to significant reduction in a composite endpoint of interstitial expansion or ESRD with interstitial fibrosis/tubular atrophy in kidney transplant recipients. In a large retrospective study, ACEi and ARB were found to benefit patient and graft survival  and a large Canadian ACEi RCT studying the effect of ramipril versus placebo on renal and patient outcomes is currently underway .
METABOLIC BONE DISEASE
Renal transplantation does not cure renal osteodystrophy. Bone mineral density (BMD) decreases in the early posttransplant period, in part as a consequence of glucocorticoid use, with persistence demonstrable over time posttransplant . A very recent study of transplant patients in Ontario, Canada, however, indicates that although fracture risk in transplant recipients is higher than in the general population and the nondialysis CKD population, the overall risk was substantially lower than previously thought [37▪▪].
KDIGO guidelines recommend the monitoring of calcium and phosphorus at least weekly in the early posttransplant period . Subsequent monitoring, as well as testing for intact parathyroid hormone level and 25(OH) vitamin D (calcidiol) levels, should vary according to CKD stage. Monitoring BMD with dual-energy x-ray absorptiometry (DEXA) scanning is controversial as BMD does not correlate well with fracture risk, and fractures may occur even at normal and low-normal BMD . KDIGO guidelines suggest that in the first year posttransplant, checking BMD may be of value if the eGFR exceeds 30 ml/min. A low BMD may be treated with vitamin D, calcitriol/alfacalcidol, or bisphosphonates.
Regrettably, pharmacologic treatment for metabolic bone disease after transplantation is not well defined. A Cochrane review concluded that individually, bisphosphonates, vitamin D sterols, and calcitonin were not associated with a reduction in fracture risk compared with placebo but when results for all active interventions were compared against placebo any treatment of bone disease was associated with a reduction in the relative risk of fracture . A small RCT (129 kidney recipients) by Smerud and colleagues compared treatment with i.v. ibandronate 3 mg or placebo every 3 months for 12 months. Both groups received oral calcitriol 0.25 mcg/day and calcium 500 mg twice daily. Patients in both treatment arms showed stable BMD at various skeletal sites after 12 months, with no significant difference between ibandronate and placebo . There may also be a negative effect to bisphosphonate therapy with the potential to cause adynamic bone disease. A randomized trial by Coco and colleagues compared pamidronate against placebo; whereas pamidronate preserved vertebral BMD, it was associated with universal development of adynamic bone histology on bone biopsy . Evidence is more limited for treatment with cinacalcet, parathyroidectomy, and teriparatide (recombinant parathyroid hormone) .
Anemia (defined as a hemoglobin concentration below 13 mg/dl for men and 12 mg/dl for women) is common after transplantation. Anemia peaks in incidence and severity shortly after transplant with blood loss from surgery as well as cessation of erythropoietin supplementation. Over time, anemia incidence varies. As described by Mix and colleagues, the proportion of patients with a hematocrit less than 36% was 76% at transplantation and 21% and 36%, 1 year and 4 years after transplantation, respectively . A UK report from three London hospitals documented anemia in 45.6% of recipients (44% of males and 48% of females) . Posttransplant anemia is likely to be multifactorial, although at times reflective of simple causes such as iron deficiency, and related to allograft GFR. Other contributing factors, however, include immunosuppressive agents (particularly azathioprine, mycophenolate mofetil, and sirolimus), other drugs (such as ganciclovir, valganciclovir, dapsone, trimethoprim-sulfamethoxazole, ACE inhibitors, and ARBs), and, viruses [including parvovirus B19, hepatitis B, hepatitis C, herpetoviruses, cytomegalovirus, Epstein–Barr virus (EBV), HIV, and, rarely, BK virus] . Just as in CKD, identification and treatment of a specific cause of anemia is desirable whenever possible.
The benefit of using erythropoiesis stimulating agents and the optimum target hemoglobin remain uncertain in transplant patients . In a small randomized controlled trial, Choukroun and colleagues administered epoetin-beta to normalize hemoglobin values (13.0–15.0 g/dl) versus a lower target of 10.5–11.5 g/dl in patients with anemia (hemoglobin below 11.5 g/dl) and CKD (eGFR below 50 ml/min) . After 2 years of follow-up, the higher hemoglobin target was associated with slower decline in eGFR, (2.4 ml/min per 1.73 m2 vs. 5.9 ml/min per 1.73 m2), a lower rate of progression to ESRD, and better cumulative death-censored graft survival of 95% versus 80%. Moreover, complete correction was associated with a significant improvement in quality of life. The number of cardiovascular events was low and similar between groups. These findings are supported by novel observations of Cravedi and colleagues demonstrating that human CD4(+) and CD8(+) T cells express erythropoietin receptors, whose stimulation downregulates Th1 responses and is favorable to Treg proliferation, and, potentially, better graft survival [47▪].
The Specific Management of Anemia and Hypertension in Renal Transplant recipients study examined the effect of telmisartan 80 mg versus placebo, and hemoglobin management with darbepoetin alpha [48▪]. Originally planned for a recruitment of 2000 patients, the study was stopped prematurely because of a low event rate. Of the 125 patients recruited with a mean follow-up of 15 months, the use of telmisartan was not associated with an increased risk of adverse events such as worsening anemia or hyperkalemia. Likewise, the correction of hemoglobin with darbepoetin was not associated with any increase in thrombotic events.
Posttransplant erythrocytosis (PTE) is defined as a persistently elevated hematocrit (>51%) and occurs most commonly during the first 2 years posttransplant in hypertensive men with excellent allograft function and may increase the risk of thromboembolic events. PTE incidence may be declining in recent years because of an increased prevalence in the use of ACEi, ARB, and antiproliferative immunosuppressive therapy . Both ACEi and ARB have been used successfully to treat PTE with phlebotomy reserved for refractory PTE when hematocrit is persistently above 55%.
CARE FOR THE PATIENT WITH THE FAILING ALLOGRAFT
Although death with function accounts for about half of late graft failure, and preventing it by the management of CKD-related morbidity is essential, the other half reflects a loss of GFR, requiring reinstitution of renal replacement therapy (RRT). Fortunately, rates of death-censored graft failure at 10 years posttransplant have declined by 20–30% over the last decade . Unfortunately, evidence exists that mortality within the first year of return to dialysis is very high, and CKD disease burden in transplant recipients resuming RRT may exceed that for other CKD patients [50,51]. Additional issues that must be addressed in the patient with a declining GFR include dialysis access and modality, timing of dialysis institution, allograft nephrectomy, and weaning of immunosuppression [52▪▪].
In the patient with a failing allograft, the rate of decline in GFR is less predictable and may be slower than in native CKD, and both clinician and patient at times are reluctant to anticipate graft failure . Dawoud and colleagues found this to result in substantially fewer predialysis access operations than with native CKD, despite a higher eGFR 3 months prior to RRT, a factor that may contribute to early dialysis morbidity . Although some data indicate greater mortality with higher eGFR at dialysis initiation, it seems likely in this population that confounding factors reflecting comorbidities make the observation uncertain . At the very least, there seems no benefit from the early initiation of dialysis, and no significant advantage or disadvantage to choosing either hemo or peritoneal dialysis .
In a kidney recipient, the cost and adverse effects related to immunosuppression are offset most visibly by the benefits of a functional allograft; with return to dialysis, the consequences of ongoing immunosuppression were traditionally thought to be even greater, with little benefit, and drugs would be tapered and discontinued over 3–6 months. A relatively early posttransplant (<1 year) patient was presumed to be at greater risk of becoming ill from the retained allograft and would often undergo preemptive transplant nephrectomy . Later, graft failure would result in gradual discontinuation of immunosuppression but not elective nephrectomy. Cessation of immunosuppression increases the risk of subsequent fever, hematuria, or graft tenderness (graft intolerance syndrome) ultimately resulting in graft nephrectomy, but reduces the risk of infection [58▪▪]. To our knowledge, there are no evidence-based guidelines for this process. The British Transplant Society suggests immediate cessation of antiproliferative agents (azathioprine, mycophenolate), followed by a gradual reduction by 25% per week of the CNI or mTOR inhibitor, with steroids withdrawn as a slow taper no faster than 1 mg per month once the dose is below 5 mg daily [59▪▪].
Over the last decade, clinical practice is changing. As suggested earlier, the maintenance of even low-dose immunosuppression may prevent graft intolerance syndrome, avoiding pain, fever, potential erythropoietin resistance, along with hospitalization and an operation [60,61]. Maintenance of low-dose immunosuppression may also be beneficial in preserving residual renal function, of particular benefit in patients who opt for peritoneal dialysis . More importantly, it is now clear that withdrawal of immunosuppression increases the risk of sensitization, whether in response to the graft itself or blood transfusions [63,64]. In patients for whom a living donor is available or, if retransplantation is anticipated within a relatively predictable period following allograft failure, it is now considered most prudent to continue maintenance immunosuppression, although some may not choose to maintain target therapeutic drug levels. Immunosuppression, however requires the commitment of additional cost to patient care and more importantly comes with a tradeoff for increased metabolic, cardiovascular, infection, and malignancy complications that may all contribute to poorer patient survival [65–67].
Although some have used transplant nephrectomy to avoid ongoing maintenance immunosuppression after return to dialysis, others now view it as a sensitizing event to be avoided. Data are inconclusive. In an analysis of USRDS data, Ayus and colleagues found transplant nephrectomy associated with a 32% lower adjusted relative risk for all-cause death . Tittelbach-Helmrich and colleagues compared 245 patients at two centers in Germany who received a nephrectomy prior to retransplant with 60 patients who did not undergo graft nephrectomy [69▪▪]. Although panel reactive antibodies (PRA) were transiently increased after nephrectomy, PRA levels leading up to a second transplant did not differ between the two groups and second graft survival was similar. In the nephrectomy group, age-adjusted patient survival was improved at 1 and 5 years.
Our interpretation of these data has resulted in a much less aggressive approach to nephrectomy and tapering of immunosuppression in recent years. Nephrectomy is performed preemptively only in patients losing their grafts within the first 6–12 months posttransplant, and only in the patient not considered a candidate for early retransplantation. In retransplant candidates, especially those with identified living donors, even relatively early graft failure may not require nephrectomy, with immunosuppression maintained until the repeat transplant is performed. In patients with later graft failure, immunosuppression is tapered and discontinued in a fashion consistent with British Transplant Society guidelines.
In the long-term management of kidney recipients, transplant physicians often labor under two misconceptions. The first is that ‘time zero’ for the patient is the date of transplant surgery, although in reality many clinical management issues originate long before the transplant. The second is a failure to recognize the impact of CKD-related issues over time. Appropriate management of both preexisting and evolving morbidity offers the promise of greater longevity for allograft and patient alike.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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