Available studies have serious limitations and report conflicting results. Several observational studies have also shown that MPA AUC early after transplantation correlates with acute rejection 91 - Most studies showed little correlation between MPA pharmacokinetic parameters and adverse effects 89 - In addition, there is an important intrapatient variability of MPA pharmacokinetics and an increasing number of different drug combinations, which may affect MPA bioavailability.
In general, MPA C 0 1. The pharmacokinetics of mTORi sirolimus and everolimus differ substantially In general, C 0 correlates well with AUC 0—12 95 , Therefore, C 0 is probably adequate for monitoring mTORi levels. There are limited observational data suggesting that mTORi C 0 correlate with adverse effects We recommend corticosteroids for the initial treatment of acute cellular rejection.
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We suggest adding or restoring maintenance prednisone in patients not on steroids who have a rejection episode. For patients who have a rejection episode, we suggest adding mycophenolate if the patient is not receiving mycophenolate or azathioprine, or switching azathioprine to mycophenolate. An acute rejection episode is the consequence of an immune response of the host to destroy the graft.
An acute rejection is clinically suspected in patients experiencing an increase in serum creatinine, after the exclusion of other causes of graft dysfunction generally with biopsy. We know from the early days of transplantation, before there were effective antirejection treatments, that untreated acute rejection inevitably results in graft destruction.
Subclinical acute rejection is defined by the presence of histological changes specific for acute rejection on screening or protocol biopsy, in the absence of clinical symptoms or signs. A rejection episode is said to be unresponsive to treatment when graft function does not return to baseline after the last dose of treatment. Treatment of decreased kidney allograft function that is not caused by acute rejection with additional immunosuppressive medication may be harmful.
Increasing the amount of immunosuppressive medication after an acute cellular rejection may help prevent further rejection. Although there are no RCTs to establish that obtaining a biopsy improves outcomes of suspected acute rejection, there are alternative diagnoses that might mimic an acute rejection episode.
BK polyomavirus BKV nephropathy would generally be treated differently than acute rejection, for example with a reduction in immunosuppressive medication. Therefore, logic dictates that, whenever possible, biopsy confirmation should be obtained to avoid inappropriate treatment. Some centers use protocol biopsies to detect and treat subclinical acute rejection. Uncontrolled data suggest that, when the incidence of clinical acute rejection is low, the number of patients with subclinical acute rejection may be too small to warrant the inconvenience and cost of protocol biopsies Although most patients respond to corticosteroids, the dose and duration of treatment has not been well defined by RCTs.
Treatment starting with intravenous solumedrol — mg daily for 3 days is a common practice. The systematic review concluded that treatment with an antibody is associated with more adverse effects, but whether the overall benefits of antibody treatment vs. It is also possible that the addition of MMF to the postrejection maintenance immunosuppressive medication regimen, or replacement of azathioprine with MMF, will help to prevent subsequent acute rejection.
Patients receiving MMF had fewer subsequent rejections, and among the who completed the trial, at 3 years graft survival was better in the MMF group Whether or not to treat borderline acute rejection is controversial. There are no RCTs addressing whether treatment of borderline acute rejection prolongs graft survival, and whether overall benefits outweigh harm. If function does not return to baseline, or if there is a new decline in function after successful treatment of an acute rejection, a biopsy should be considered to rule out additional rejection, BKV nephropathy and other causes of graft dysfunction.
In such circumstances, benefits generally outweigh harm. However, the optimal protocol to treat acute humoral rejection remains to be determined. Indeed, there are no RCTs with adequate statistical power to compare the safety and efficacy of these different therapeutic strategies. Clearly, additional studies to define the optimal treatment of acute humoral rejection are needed.
However, of those who return to dialysis or require retransplantation, the most common cause is CAI, followed by acute rejection and recurrent primary kidney disease , CAI is a diagnosis of exclusion characterized by the progressive reduction in graft function not due to recurrence of disease or other recognized causes. Other features may include subclinical rejection, transplant glomerulopathy or transplant vasculopathy. Graft function 6—12 months after kidney transplantation is an outcome reported in most RCTs of immunosuppressive medications. These are described in the relevant sections of these guidelines.
Some causes of CAI may be reversible. Patients found to have acute rejection, BKV nephropathy or recurrent kidney disease, for example, may respond to appropriate treatments. Therefore, it is important that patients suspected of having CAI undergo biopsy, if possible. In other words, the diagnosis of CAI is a diagnosis of exclusion. The treatment of CAI has been controversial There were no differences in mortality, graft loss, acute rejection, infection or blood pressure between the two groups.
There was no difference in death, graft loss, acute rejection, treatment discontinuations, NODAT, hypertension, infections or cancer between the two arms. However, incident cardiac events favored tacrolimus.
However, the patients in this trial were not selected to have CAI per se , and it is possible that patients with CAI, preserved kidney function and low levels of proteinuria may still benefit from conversion. Additional study is needed. We suggest including a kidney allograft ultrasound examination as part of the assessment of kidney allograft dysfunction. Some tests need to be performed routinely to detect abnormalities that may lead to treatment or prevention of complications that are common in KTRs Table 4. The frequency of screening is based on the incidence of the complication being screened, because there are no other data to determine the best interval for screening.
Serum creatinine is easily measured and readily available in most laboratories. Urine output that is inappropriately low, or inappropriately high, is an indication of possible graft dysfunction. Serum creatinine and urine protein measurements are readily available and are useful for detecting acute and chronic allograft dysfunction. Ultrasound is relatively inexpensive and reasonably accurate for diagnosing treatable causes of kidney allograft dysfunction.
The recovery of kidney function, measured as a decrease in serum creatinine and blood urea nitrogen, is generally preceded by an increase in urine volume Rarely, excessive urine volume may indicate the presence of a saline diuresis or a water diuresis caused by tubular damage. In addition to its role in assessing early allograft dysfunction, measuring the urine volume is an important part of overall fluid and electrolyte management.
Proteinuria is an early and sensitive marker of kidney damage in CKD Many causes of proteinuria are potentially reversible with appropriate treatment Table 5 , and detection of proteinuria can therefore improve graft outcomes , - Patients with proteinuria generally have lower kidney function compared to patients without proteinuria , Proteinuria includes albuminuria as well as other proteins.
The urinary excretion rate for albumin and total protein can be estimated from the ratio of albumin or total protein to creatinine concentration in a casual urine specimen - Creatinine excretion is higher in men than in women. Causes of kidney allograft dysfunction that require rapid intervention for treatment to be effective include acute rejection, obstruction, urine leak, vascular compromise and some recurrent diseases, for example focal segmental glomerulosclerosis FSGS.
These causes are more common in the first few days to weeks after kidney transplantation than in subsequent months to years.
Therefore, it is important to closely monitor kidney function early after transplantation. Measurement of the serum creatinine concentration is a simple, inexpensive and universally available method for estimating GFR, and it is reliable for detecting acute changes of kidney function , The level of serum creatinine at year 1 after transplantation is a risk factor for subsequent outcomes, and may help guide care, for example the frequency of visits , A gradual increase in serum creatinine after the first year may be due to acute rejection, but more often is caused by CAI, recurrence of the original kidney disease, or de novo kidney disease.
Unfortunately, serum creatinine is less reliable for detecting chronic changes over months to years in kidney function. As is true in the general population, measurement of GFR with inulin, iothalamate, iohexol or other suitable markers of GFR, either with urinary or plasma clearance techniques, provides the most accurate measure of allograft function in KTRs.
Although these tests are appropriate for clinical use, the Work Group did not recommend their use in routine clinical practice due to cost, low patient acceptance, and lack of availability outside of academic medical centers.
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Measurement of cystatin C has also been used to monitor kidney function. The advantage of cystatin C is its independence from body weight. Formulas to estimate GFR have been tested in KTRs, but no formula has been consistently shown to be superior to any other formula - It is unlikely that these formulas will improve the ability of serum creatinine to estimate acute changes in kidney function since, in most formulas, the only component of the formula that changes significantly is serum creatinine.
It is similarly unclear whether formulas improve the ability of serum creatinine to measure chronic changes in kidney transplant function, especially when serum creatinine may change due to changes in muscle mass due to an improved nutritional status after kidney transplantation - Many of the most common causes of allograft dysfunction, other than rejection, can be diagnosed by ultrasound.
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These include arterial occlusion, venous thrombosis, urinary obstruction, a urine leak large fluid collection , compressing perinephric hematoma and arteriovenous fistula from a kidney biopsy - Ultrasound is also useful in guiding a kidney allograft biopsy, so it is often obtained at the time of biopsy.
In the kidney allograft, mild to moderate calyceal distension can be normal, so a baseline ultrasound examination when kidney function is normal may be useful to compare to subsequent ultrasound examinations for allograft dysfunction. We suggest kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection. We suggest kidney allograft biopsy if expected kidney function is not achieved within the first 1—2 months after transplantation. Kidney allograft biopsies are performed for specific clinical indications, or as part of a surveillance program or protocol.
In both cases, the biopsy is obtained to find histological changes prompting treatment to improve outcomes. DGF is graft function low enough to require dialysis in the first week after kidney transplantation, or lack of improvement in pretransplant kidney function.