Kidney Disease in Non-kidney Solid Organ Transplantation

Abstract 

Kidney disease after non-kidney solid organ transplantation (NKSOT) is a common post-transplant complication associated with deleterious outcomes. Kidney disease, both acute kidney injury and chronic kidney disease (CKD) alike, emanates from multifactorial, summative pre-, peri- and post-transplant events. Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types. The aim of this review is to summarize the current literature describing kidney disease in NKSOT. We conducted a narrative review of pertinent studies on the subject, limiting our search to full-text studies in the English language. Kidney disease after NKSOT is prevalent, particularly in intestinal and lung transplantation. Management strategies in the peri-operative and post-transplant periods including proteinuria management, calcineurin-inhibitor minimization/ sparing approaches, and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation. Kidney disease after NKSOT is an important consideration in organ allocation practices and ethics of transplantation. Kidney disease after SOT is an incipient condition demanding further inquiry. While some truths have been revealed about this chronic disease, as we have aimed to describe in this review, continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival. 

Key Words: Acute kidney injury; Chronic kidney disease; Solid organ transplant; Native kidneys; Calcineurin inhibitor toxicity; Renal replacement therapy; Kidney after solid organ transplant

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Core Tip: Kidney disease in the non-kidney solid organ transplant population occurs at a significantly higher rate than the general population. Pre-transplant morbidity as well as peri-/post-transplant events contribute to this prevalence. Management strategies throughout the journey of non-renal solid organ transplantation are being studied, including transplantation after native kidney failure to help offset the morbidity/mortality of chronic kidney disease and maximize the benefit of non-kidney solid organ transplantation. 

INTRODUCTION 

Chronic kidney disease (CKD), most commonly defined as decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 or markers of kidney damage persistent at least 90 d per Kidney Disease Improving Global Outcomes (KDIGO) criteria, is a frequently observed post-transplant complication for non-kidney solid organ transplantation (NKSOT) recipients and is associated with adverse outcomes[1- 3]. While quantifying the prevalence of CKD in any population is daunting, several studies have noted an incidence of CKD in NKSOT ranging between 6%-21%[2,3]. Notably, this is derived via CKD definition as GFR < 30 mL/min/1.73 m2. In one study of liver transplant recipients, approximately 57% had a GFR between 30-59 mL/min/1.73 m2 [2,3]. This is compared to the estimated CKD rate of 15% in the general population[1]. 

Intuitively, end-organ disease compelling transplantation often leads to impaired kidney function, stemming from recurrent acute kidney injury (AKI) and subsequent CKD. Furthermore, the post-transplant milieu portends CKD through injurious transient and persistent insults, leading to the well-described disproportionately high burden of kidney disease in SOT recipients[2-4]. The goal of this review is to condense the current literature in this field to: (1) Illustrate the scope of the problem; (2) Examine mechanisms leading to CKD in this population; and (3) Identify potentially modifiable risk factors and discuss management/treatment of CKD after NKSOT. In the following sections, we will discuss common factors driving AKI and CKD and then describe kidney disease after NKSOT in the following distinct contexts: Pancreas, liver, heart, lung, and intestinal transplantation. 

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KEY DEFINITIONS AKI

While several definitions exist, we will use those endorsed by the KDIGO workgroup whereby AKI is defined as at least a 0.3 mg/dL increase in creatinine within 48 h or at least 1.5-1.9 times baseline increase in creatinine within 1 wk or decrease in urine output of at least 0.5 mL/kg/h for at least 6 h[1]. 

CKD As in AKI, KDIGO has defined CKD, which is identified by markers of kidney damage, estimated GFR (eGFR) < 60 mL/min/1.73 m2 , and degree of albuminuria given the well-described relationship between proteinuric kidney disease and CKD progression[1]. Unless otherwise stated, we will use these criteria to define CKD

SCOPE OF CKD AFTER NKSOT

How common is CKD after NKSOT? This is an important question many have sought to answer given the well-documented deleterious impact CKD has on cardiovascular and survival outcomes[2]. As described by Bloom et al[3] in their landmark review, historically varied CKD definitions as well as the reliance of estimating equations based on serum creatinine (SCr), of which their distinct strengths/weaknesses/limitations has made the assessment of CKD prevalence enigmatic at best. An oft-cited key study by Ojo et al[2] notes the following rates of 5-year post-transplant CKD: 21.3% among intestinal transplant (IT) recipients, 18.1% among liver transplant recipients, 15.8% among lung transplant recipients, 10.9% among heart transplant recipients, and 6.9% among heart-lung transplant recipients. Whereas this study offers a reference point, they utilized a stringent definition of CKD [GFR < 30 mL/min per 1.73 m2 , via four-variable Modification of Diet in Renal Disease Study (MDRD).

equation]. While such conservative criteria lead to underestimation of CKD prevalence (as most patients with CKD fall in the eGFR 30-60 mL/min/1.73 m2 range), shared patient characteristics of low muscle mass/malnutrition accentuate the already flawed estimating creatinine-based equations. Moreover, the paucity of proteinuria measurements performed clinically and/or analyzed in studies is a major contributor to the underestimation of CKD in NKSOT recipients. 

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Several studies have helped improve our understanding of CKD prevalence in NKSOT recipients which will be highlighted below. In their recent study, Shaffi et al[5] compared 26 eGFR equations in NKSOT recipients [n = 3622, including recipients of kidney (53%), liver (35%), and other or multiple organs (12%)] to measured GFR (mGFR) either via urinary iothalamate clearance or plasma iohexol clearance. They found that the proportion of absolute percent error < 30% (P30) and mean absolute error for the CKD Epidemiology Collaboration equation (CKD-EPI) and the MDRD Study equations were 78.9% [99.6%, 95% confidence interval (CI): 76.9%-80.8%] for both and 10.6 (99.6%, 95%CI: 10.1-11.1) vs 11.0 (99.6%, 95%CI: 10.5-11.5) mL/min/1.73 m2 . Compared to the other 24 estimating eGFR equations the authors examined, the CKD-EPI and MDRD equations were significantly more accurate (P < 0.001). In their study examining 1135 pancreas transplant alone (PTA) recipients in Scientific Registry of Transplant Recipients (SRTR), Kim et al[6] observed that about 25% of the cohort had an eGFR below 61.3 mL/min/1.73 m2 . Gonwa et al[7] via a prospective study serially measuring iothalamate clearance in 1447 liver transplant recipients observed the following: At 3 mo, 1 year, and 5 years post-transplant, the mean mGFR was 59.5 ± 27.1 mL/min, 62.7 ± 27.8 mL/min, and 55.3 ± 26.1 mL/min. Interestingly, the mean mGFR at the time of initial evaluation was 90.7 ± 40.5 mL/min. In their analysis of risk factors for CKD after heart transplantation, Hamour et al[8] observed that CKD post-heart transplant is common, noting probabilities of eGFR < 45 mL/min/1.73 m2 were the following: 45% at year 1, 71% at year 5 and 83% at year 10. In their review which included 186 lung transplant recipients, Ishani et al[9] showed that CKD was commonly observed at 1 year post-transplant and progressed henceforth: From a mean pre-transplant SCr of 0.88 ± 0.19 mg/dL to 1.22 ± 0.82 mg/dL at one month 1.67 ± 0.88 mg/dL at 12 mo and to 1.98 ± 1.1 mg/dL at three years post-transplant. Kidney disease after NSKOT appears to be common, and progressive and is likely substantially underestimated due to patient factors as well as understated albuminuria.

MECHANISMS LEADING TO CKD IN NON-KIDNEY SOT 

Across NSKOT, both shared and organ-specific factors give rise to CKD onset and progression. Comorbidities directly related to primary end-organ failure e.g., diabetes mellitus, liver failure, heart failure, lung failure in addition to common baseline demographic characteristics (advancing age, female gender, diabetes mellitus, hypertension, hepatitis C virus infection, drug-induced nephrotoxicity) as well as transplant specific factors, namely perioperative AKI, as well as calcineurin inhibitor (CNI) use, all contribute to the development of CKD[2-4].

The perioperative setting is a crucial shared risk factor impacting kidney function both short and long-term. Hypotension, hypoperfusion, fluid shifts, nephrotoxic agents, sepsis in the perioperative period all spur AKI[3,10]. In a fashion similar to pre-transplant organ dysfunction leading to kidney impairment, marginal allograft function begets renal decompensation and vice versa[3,10]. CNI use and its impact on renal function after NKSOT is a controversial topic. While CNI use is an oft-implicated cited reason for post-SOT kidney disease, it does not tell the entire story[10]. In a recent study, Ojo et al[10] noted that CNI use constitutes the majority of histologic lesions observed on kidney biopsy, ranging from between 46%-60% of cases. Non-CNI-related pathology, as illustrated in their description of orthotopic heart and liver transplant recipients in their cited figures, is also an important player and has been observed in 27%-40% of kidney biopsies. Importantly, histologic findings must be interpreted cautiously as these biopsies were subject to having multiple concurrent histologic patterns. 

Kubal et al[11] expounded on this, conducting their own histologic study of 62 nonrenal SOT recipients with kidney biopsies, where they showed that only 35.5% (n = 22) of those biopsied had predominant features consistent with chronic CNI toxicity. Hypertensive nephropathy [43.5% (n = 27)], not without its own disputes, was the most common diagnosis. Nearly 20% (n = 12) of the cohort had biopsies showing alternative pathology including acute tubular necrosis (n = 5), mesangioproliferative glomerulonephritis (n = 2), diabetic nephropathy (n = 1), post-infectious glomerulonephritis (n = 1), and membranous nephropathy (n = 1)[11]. 

In a recent review, Wiseman[12], as adapted from Schwarz et al[13], describes the clinical characteristics and histology of biopsy-proven kidney disease after liver, lung, and heart transplantation. Of note, primary glomerulonephritis was 26% in liver transplant recipients and acute tubular injury was the most commonly observed histologic pattern in lung and heart recipients. In addition to shared mechanisms leading to CKD, distinct factors inherent to the various subtypes of organ transplant exist. These have been suitably defined in the literature and will be discussed in the following sections[10]. Though SOT recipients may recover from these early post-transplant kidney perturbations, often AKI, irrespective of renal replacement therapy (RRT) need, in addition to a “pro-nephrotoxic” environment with ongoing insults (post-transplant diabetes, hypertension, hyperlipidemia, CNI use, transplant organ 

KIDNEY DISEASE AFTER PANCREAS TRANSPLANTATION

PTA is a novel transplant option for non-uremic diabetic patients. Interestingly, there is evidence that PTA may be renoprotective via proteinuria reduction and reversal of diabetic kidney lesions[16,17]. Despite this, kidney disease often progresses for PTA recipients. The following studies detail some of the contributing factors leading to kidney disease. 

Kim et al[6], in their study examining 1135 adult PTA recipients, showed that kidney function prior to transplantation is a strong predictor of end-stage kidney disease (ESKD): PTA recipients with pre-transplant eGFR < 60 and 60-89.9 mL/min/1.73 m2 were 7.74 (95%CI: 4.37-13.74) and 3.25 (95%CI: 1.77- 5.97) times more likely to develop ESKD than patients with eGFR ≥ 90 mL/min/1.73 m2 . Smail et al[18] also found that a pre-transplant eGFR < 60mL/min/1.73 m2 was associated with an end-stage renal disease (ESRD) incidence at 1, 3, 5 years of 0%, 28.6% and 61.9% compared to those with an eGFR > 60 mL/min/1.73 m2 (P = 0.006). Younger age, female sex, and duration of diabetes predicted the development of ESRD (all P < 0.05). However, there was no difference in patient survival based on pre-transplant eGFR (P = 0.73). Gruessner et al[19] examined 513 PTAs transplanted from 1966 to 2006. They observed a 5 year post-transplant ESKD rate of 13% and found that SCr > 1.5 mg/dL at time of transplant and age < 30 predicted kidney failure. Odorico et al[20] performed a retrospective analysis comparing PTA recipients (n = 27) and pancreas after kidney transplant (PSK) recipients (n = 61) to assess changes in kidney function. They observed that pre-transplant eGFR < 60 mL/min/1.73 m2 was associated with CKD progression. Fascinatingly, 67% PTA patients showed an increase (> 10%) in their SCr from baseline vs 34% PAK patients (P = 0.035). PTA transplant was considered mildly protective in terms of progression of CKD, though this finding was not significant [hazard ratio (HR) = 0.29, 95%CI: 0.04-2.37, P = 0.182). Chatzizacharias et al[21] in their risk analysis of progression to kidney failure after pancreas transplant found that tacrolimus levels > 12 mg/dL at 6 mo post-transplant were associated with declining kidney function (HR = 14.3, 95%CI: 1.3-161, P = 0.03). Surprisingly, pre-transplant proteinuria (urine protein creatinine ratio > 100 mg/mmol) and low eGFR, which they defined as ≤ 45 and ≤ 40 mL/min/1.73 m2 , were not significantly associated with worsening CKD. Marchetti et al[22] in their inquiry of 28 PTA recipients observed stable native kidney function comparing pre-transplant to post-transplant (0.95 ± 0.2 vs 0.96 ± 0.22, P > 0.05). However, this follow-up was only at 3 mo posttransplant. Cappelli et al[17] showed that at 1 year follow-up, 32 PTA recipients did not have significantly different creatinine pre-and post-transplant (0.95 ± 0.25 mg/dL vs 1.00 ± 0.19 mg/dL, P > 0.05). They observed improvement in lipid levels, blood pressure as well as albuminuria. Genzini et al [23] in their single center retrospective review followed 45 PTA recipients. After stratifying by 24 h creatinine clearance (CrCl) post-PTA [group 1 = CrCl ≤ 70 mL/min; (n = 20); group 2 = CrCl > 70; (n = 25)], they observed significant decreases in native kidney function at 1 year in both groups (group 1 CrCl pre- vs post-transplantation = 57.3 ± 9 vs 34.8 ± 32 mL/min, P = 0.003); (group 2 CrCl pre- vs post-transplantation = 107.1 ± 25 vs 81.0 ± 23 mL/min, P = 0.008). In group 1, 10/20 patients (50%) ended up with a CrCl < 30 mL/min, 5/20 (25%) initiated on hemodialysis, and 3/20 (15%) underwent kidney after pancreas transplantation. No patients in group 2 ended up with significantly decreased kidney function. Scalea et al[24] looked at PTA recipients over 14 years retrospectively and saw that 88% of patients had eGFR decrease with a mean decrement of 32.1 mg/min/1.73 m2 . Mean eGFR pre-transplantation was 88.9 vs 55.6 post-transplantation (P < 0.0001) with mean follow-up of 3.68 years. Donor demographics, immunosuppression, human leukocyte antigen mismatch were not significantly associated with progressive CKD in their analysis. 

Studies on kidney function after PTA are limited in terms of sample size and duration of follow up. However, it would appear that the presence of pre-transplant CKD with eGFR < 60 mL/min/1.73 m2 tends to be associated with cumulative CKD. While more robust studies are needed to better characterize kidney function in this population, it would appear that pre-transplant native kidney function is an important predictor of progressive CKD for pancreas transplant recipients and ought to inform organ allocation practices as well as evaluation for kidney after pancreas transplantation. These results are summarized in Table 1.