Post-transplant Kidney Function Research Articles

Long-term evolution, secular trends, and risk factors of renal dysfunction following cardiac transplantation

Recent reports suggest that individuals who underwent heart transplantation in the last decade have improved post-transplant kidney function. The objectives of this retrospective study were to describe the incidence and to identify fixed and time-dependent predictors of renal dysfunction in cardiac recipients transplanted over a 25-year period (1983-2008). To illustrate temporal trends, patients (n=306) were divided into five groups based on year of transplantation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at year 1. Secondary endpoints were time to moderate (eGFR <60ml/min/1.73m(2) ) and severe renal dysfunction (eGFR <30ml/min/1.73m(2) ). Risk factor analyses relied on multivariable regression models. Kidney function was mildly impaired before transplant (median eGFR=61.0ml/min/1.73m(2) ), improved at discharge (eGFR=72.3 ml/min/1.73m(2) ; P<0.001), decreased considerably in the first year (eGFR=54.7 ml/min/1.73m(2) ; P<0.001), and deteriorated less rapidly thereafter. At year 1, 2004-2008 recipients exhibited a higher eGFR compared with all other patients (P<0.001). Factors independently associated with eGFR at year 1 and with moderate and severe renal dysfunction included age, gender, pretransplant eGFR, blood pressure, glycemia, and use of prednisone (P<0.05). In summary, kidney function worsens constantly up to two decades after cardiac transplantation, with the greatest decline occurring in the first year. Corticosteroid minimization and treatment of modifiable risk factors (hypertension, diabetes) may minimize renal deterioration.

Gene expression profile in delay graft function: inflammatory markers are associated with recipient and donor risk factors.

Background. Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found. Methods. Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors. Results. From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P = 0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-β showed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia. Conclusions. Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.

Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function

Renal injury induced by brain death is characterized by ischemia and inflammation and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 hours of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 hours of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain dead rats showed significant improvement in function over the first 2 to 4 days post transplantation compared to untreated brain dead animals. Gene microarray analysis after 2 hours of brain death without or with nitrite therapy showed the latter significantly altered the expression of about 400 genes. Ingenuity Pathway analysis indicated multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription and genes related to humoral immune responses. Thus, nitrite-therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

Polycystic liver and kidney disease: post-transplant kidney function in patients receiving pre-emptive kidney transplantation

The aim of the study is to evaluate the changes in kidney function after pre-emptive kidney transplantation in patients with polycystic liver and kidney disease (PLKD) and to establish whether pre-emptive kidney transplantation is warranted. Between 1998 and 2006, five patients with severe anatomical changes in both native kidneys but only mild alteration of the clearance function received combined liver and kidney transplantation. Preoperatively, Technetium-99m mercaptoacetyltriglycine (Tc99m MAG3) scintigraphy was used to evaluate separately the function of each native kidney. This examination was repeated six months after transplantation, additionally measuring the function of the transplanted kidney. Pretransplant creatinine levels were 77-115 mumol/l and Tc99m MAG3 clearance was 141-163 ml/min/1.73 sqm (74 +/- 8% of minimum-for-age values). Six months after transplant, creatinine values were not significantly different. Minimum-for-age clearance decreased by 12.5 +/- 11.5% in four patients, and increased by 26% in one patient. In four patients, the transplanted and the native kidneys assumed each about one third of total tracer clearance. In one patient, the transplanted kidney assumed 92% of the clearance function. Kidney function decreases despite pre-emptive kidney transplantation. Native kidneys are not functionally excluded and the clearance seems to be divided between native and transplanted organs. Kidney transplantation in nonuremic PLKD patients does not improve the overall kidney function and should be performed only in exceptional cases.

Early Experience of a Living Donor Kidney Transplant Program

ObjectivesLaparoscopic nephrectomy has been shown to reduce the morbidity of live donor nephrectomy, but post-transplant kidney function and safety issues with the procedure are still of some concern. The review of our early experience could detect errors that should be avoided in the refining of the technique. MethodsOur first sixty consecutive laparoscopic donor nephrectomies were analyzed retrospectively. ResultsThere were conversions to open surgery (5%), all three in the first 18 cases. All donors were alive at 1 year with a glomerular filtration rate of 85±21ml/min (78% of the basal). Patient and graft survival at 1 year was 100% and 95%, respectively. Creatinine nadir was achieved on post-transplant day 3 (creatinine, 176±122μmol/l). Late renal function proved a continuous improvement until the 2-year follow-up (creatinine, 135±29μmol/l). Renal function recovery was better in both recipient and donor when the donor was ≤50 years old, compared with older patients. Transplant complications that required reintervention included one ureteral fistula, one ureteral stenosis and one case of low renal flow that was re-vascularised. ConclusionsTechnical surgical aspects such the use of Haemoloc® clips in the clipping of the artery, the hand-assisted extraction of the kidney, a refined surgical technique during the transplant and avoidance of prolonged warm and cold ischemia, taken together with an adequate intraoperative hemodynamic management of the donor aid in avoiding life-threatening complications and achieving a good post-transplant renal function recovery.

Kidney dysfunction in the recipients of liver transplants

1. Pretransplant kidney function is an important predictor of posttransplant kidney function. 2. Chronic kidney disease is present in 20% of liver transplant recipients by 5 years. 3. Kidney function is impacted by pretransplant management of the consequences of the hepatorenal syndrome. 4. The use of calcineurin inhibitor (CNI)-based immunosuppression is an important factor in the development of chronic kidney disease, and the use of mycophenolic acid- or sirolimus-based immunosuppression with reduced-dose CNI may be of benefit.

Initial experience using histidine‐tryptophan‐ketoglutarate solution in clinical pancreas transplantation*

The colloid-based University of Wisconsin (UW) preservation solution has been used extensively in clinical pancreas transplantation. Experimental studies support the use of the crystalloid-based histidine-tryptophan-ketoglutarate (HTK) preservation solution for this purpose. We report our initial experience with HTK for pancreas allograft preservation and compare this to a contemporary experience with UW solution in conventional multiorgan deceased donors (<50 yr). Retrospectively collected information on 33 pancreas transplants between September 2001 and October 2002 were analyzed for early graft function and complications up to 30 d after procurement and storage in either HTK or UW solutions. During multi-organ recovery, either UW solution (4-5 L) or HTK solution (8-10 L) was used for aortic perfusion and subsequent back-table flush and storage. Exocrine drainage of 31 pancreas allografts was enteric, while the bladder was used for drainage in two cases. Patient outcomes were analyzed according to the preservation solution used. Sixteen pancreata were used in combination with a kidney allograft (SPK), seven were used in patients after prior kidney transplantation (PAK), while 10 were used in patients who were not in renal failure (PTA). The UW group consisted of 17 patients (10 SPK, three PAK, four PTA) with a mean donor age of 29.5 +/- 10.7, and a mean cold ischemia time of 15.1 +/- 2.1 h. The mean post-transplant pancreas and kidney function on days 1 and 10 were amylase (315 and 99 IU/L), lipase (1727 and 346 IU/L), glucose (121 and 100 mg/dL) and creatinine (5.01 and 1.77 mg/dL). Patient and graft survival was 100% at 1-month post transplant. In the HTK group there were 16 patients (six SPK, four PAK, six PTA) with a mean donor age 21.9 +/- 5.7 and a mean cold ischemia time 14.0 +/- 1.3 h. The mean post-transplant pancreas and kidney function on days 1 and 10 were amylase (588 and 126 IU/L), lipase (4711 and 441 IU/L), glucose (97 and 109 mg/dL) and creatinine (5.28 and 2.42 mg/dL). Patient survival was 100% while graft survival was 94% at 1-month post-transplant. Early graft function and complications are comparable with HTK and UW solutions for pancreas allograft preservation.

Re-186 HEDP Conditioning Therapy in Patients With Advanced Acute Lymphoblastic Leukemia Before Allogeneic Bone Marrow Transplantation

The authors present their experience with dose calculation of Retin1,1-hydroxyethylidene-186-diphosphonate (Re-186 HEDP) therapy used as part of an intensified conditioning regimen before allogeneic stem cell transplantation in 2 patients with advanced acute lymphoblastic leukemia during the second partial or third complete remission. Kidneys were shielded during total-body irradiation (TBI) to limit the TBI-mediated renal radiation dose to 7 Gy. The aim of this dose calculation of Re-186 HEDP therapy was to deliver additional radiotherapy to the red bone marrow without exposing more than an additional 5 Gy to the kidneys in addition to the TBI standard dose of 12.6 Gy. Pretherapeutic kidney scintigraphy (Tc-99m mercaptoacetyltriglycine) showed normal results. Thus, dynamic Tc-99m methylene diphosphonate bone scintigraphy was used to calculate the expected bone marrow and kidney doses. A total amount of 8.8 GBq (238 mCi) Re-186 HEDP was given to patient no. 1 and 14.3 GBq (387 mCi) Re-186 HEDP was given to patient no. 2. Re-186 HEDP activity was monitored based on its gamma radiation measurement daily for 5 days in patient no. 1 and 7 days in patient no. 2. Therapeutic Re-186 isotope distribution and biologic half-life correlated well with the prediction by a pretherapeutic Tc-99m methylene diphosphonate scan. The calculated effective Re-186 bone marrow dose was 3.3 Gy for patient no. 1 and 5.6 Gy for patient no. 2. Effective kidney doses were 1.6 Gy and 2.1 Gy respectively. No unexpected complications occurred after completing conditioning and allogeneic stem cell transplantation. Posttransplant kidney function remained normal. Patient no. 1 remains in a second complete remission of his advanced acute lymphoblastic leukemia 18 months after HEDP therapy. Patient no. 2 relapsed 5 months after transplantation and eventually died as a result of progressive disease. The authors conclude that Re-186 HEDP will be able to increase the total additional bone marrow dose. In patients in whom the kidney dose is limited to 5 Gy in addition to TBI, doses near 10 Gy can be achieved on the bone marrow.

HYDROGEN IONS EQUILIBRIUM DURING HYPOTHERMIC PULSATILE PERFUSION AND POSTTRANSPLANT KIDNEY FUNCTION.

451 There are many factors that affect post-transplant kidney function and very few of them can be influenced by transplant teams. Hydrogen ions equilibrium within preservation solution during organ machine perfusion definitely belongs to the latter group. Injury to the organ caused by profound acidosis is well known and carefully avoided. However, there is much less concern on alkalinity. While analysing pH of solution during hypothermic perfusion of kidneys, which later underwent acute tubular necrosis (ATN), we surprisingly observed its bimodal distribution. In organs with good immediate function after revascularisation pH values distribution was always normal or close to normal. To analyse this observation, we reviewed 122 perfusion procedures. Material. Organs were preserved with Waters Instr. (MN) MOX 100 machine perfusion system in UW-gluconate solution. Temperature of solution was stabilised at + 6°C and perfusion was begun with 50-mmHg initial systolic pressure at 1 Hz pulse rate. Samples of preservation fluid for hydrogen ions concentration were taken hourly for the first 4 hours and than 4-hourly till the end of perfusion. Abnormalities were corrected with 8,4% NaHCO3, 5M KOH infusions or CO2 insuflation when necessary. Ninety-eight kidneys transplanted after pulsatile preservation functioned immediately. Forty-four had ATN defined as requirement of at least 1 hemodialysis within the first week. Four kidneys never functioned, 2 patients died in short postoperative period and 6 kidneys were discarded due to perfusion parameters, organ trauma, hipoplasia or infection. Results. Mean pH values in established time-points have been calculated for kidneys with immediate function: (Table) As distribution of the values was normal, the range, which covered 95,46% of the area (mean ±2SD), was calculated. None of the preservation solutions from organs with delayed function (DF) exceeded calculated range until 8th hour of perfusion. From 8th hour alkalosis of two solutions was observed (pH=7.52 and 7.58). Only one solution from DF group became too acidic in 24th hour (pH=6,95).TableConclusions. In 3 above mentioned cases improper preservation could be a reason, or at least add to organ damage and posttransplant ATN. Alkalosis of preservation solution can be as harmful to the organ as profound acidosis. Frequent pH measures (1-hourly) urge perfusionist's reaction and prevent accidental long-lasting disturbances of hydrogen equilibrium. One should control pH of the solution to keep it between 6,99-7,35 during perfusion.

Deferoxamine confers striking protection against cold storage injury to isolated mouse proximal tubules

Byproducts of oxidant tissue stress, most notably malondialdehyde (MDA) and Schiff bases, have been documented in renal tissues following cold storage (CS) and subsequent transplantation (such as [1—3]). While the exact nature and the source(s) of the responsible free radicals remain unclear, it is widely assumed that they are generated during the early reperfusion period [4, 5]. CS may help set the stage for this early reperfusion oxidant attack. As examples: (1) ATP breakdown to hypoxanthine during CS may fuel xanthine oxidase-mediated reperfusion oxidant stress [6]; (2) CS associated changes in plasma membrane phospholipids and arachidonate availability could predispose to subsequent lipid peroxidative damage [3, 5]; and (3) since tissue injury can liberate iron from intracellular binding sites [7, 8], iron catalyzed oxidant injury during reperfusion could result. Free iron can amplify diverse forms of tissue damage, suggesting that this could be a particularly important injury pathway [9]. These considerations have prompted past explorations of whether iron chelation therapy (such as with deferoxamine), administered at the time of tissue harvesting and re-implantation, improves post-transplant kidney function. While it is clear that such therapy can decrease lipid peroxidation [1—5], no clear evidence for improved tubular cell integrity has been provided [1, 3, 10, 11]. This may be due to the fact that these studies have primarily assessed protection by direct or indirect assessments of GFR, performed in small numbers of animals. Since a panoply of factors can impact on GFR in addition to structural tubular integrity (such as glomerular hemodynamics), a cytoprotective effect expressed directly at the proximal tubule could easily have been missed. Therefore, the present study has sought to clarify whether iron chelation can specifically protect proximal tubular cells from CS injury. To achieve this end, proximal tubular segments (PTS) were harvested from mouse kidneys, and they were subjected to 22 hours of CS in the presence or absence of an iron chelator, deferoxamine (DFO). Cellular integrity was determined immediately after CS and during a subsequent two-hour 37°C re-oxygenation period. Male CD-i mice (—25 g; Charles River Laboratories, Wilmington, MA, USA), housed under standard vivarium conditions, were anesthetized with pentobarbital (—2 mg i.p.), the kidneys were