Managing end-stage of Nephropathy

Diabetes is the leading cause of end stage renal disease (ESRD) requiring renal replacement therapy accounting, for approximately 50% of patients starting dialysis in North America[1]. While dialysis rates for people with diabetes previously had been increasing by approximately 10% per year, rates may have stabilised in the last few years[1].

The increased incidence of ESRD due to diabetes is partly due to improved survival and increased life expectancy in people with diabetes, but also because of significant changes in dialysis policies. In the past, diabetes or advanced age were both viewed as contraindications to renal replacement therapy.

Although the majority of diabetic subjects with ESRD have type 2 diabetes, the risk of progressing to ESRD is estimated to be more than 10 times higher in people with type 1 diabetes. While classic diabetic nephropathy is the cause of ESRD in type 1 diabetes, the underlying pathology in type 2 diabetes is heterogeneous, including renovascular, ischaemic and hypertensive changes.

Renal Replacement Therapy

Successful renal transplantation provides normal or near-normal renal function, which is far superior to dialysis, and also provides normal synthetic function. Compared with dialysis, survival and quality of life are significantly better among renal transplant recipients [2]. Thus for people with ESRD who are eligible for transplant, dialysis would be considered a palliative or interim therapy while awaiting transplant.

Since progression to ESRD in people with diabetes is generally relatively slow and somewhat predictable, planning for renal replacement therapy is important. Access for dialysis (either Peritoneal or Haemo- Dialysis) should be in place prior to the need for dialysis. Similarly it may be possible to perform a pre-emptive renal transplant, prior to dialysis.

Choosing Between RRT Therapies

The choice of treatment for ESRD will depend on multiple factors including local resources and expertise, patient factors including co-morbidities as well as individual preference. The pros and cons of different treatment options are presented in table 1.

Table 1: Renal Replacement Therapy Options for People with Diabetes

Option Pros Cons
Supportive /symptomatic treatment Only option if dialysis and transplant are contraindicated. Avoids medicalization and adverse effects of RRT Survival will be poor. Limited availability of good palliative care
Peritoneal Dialysis Less risk of vascular instability. Independence since treatment done at home Risk of peritonitis. May not be effective long term
Hemodialysis Effective renal replacement. Regular medical supervision Time consuming with regular visits to dialysis centre
Living Donor Renal Transplant Minimal wait time. Best short and long term outcomes (high quality donor, short ischaemic time) Lack of suitable living donors. Health risks for donor
Deceased Donor Kidney Transplant Better quality of life and survival than dialysis Long wait times
Simultaneous Pancreas-Kidney (SPK) Transplant Can “cure” diabetes and ESRD. Emerging data suggests outcomes in long term (>15 years) survivors may be better than living related kidney transplant Very long wait times. Stringent inclusion criteria excludes many individuals. Higher surgical risk, with higher short term mortality
Pancreas after Kidney (PAK) Transplant Can reverse diabetes. No additional immunosuppression required Significant surgical risks with approximately 25% re-laparotomy rate. Pancreatic outcomes inferior to SPK (but much better than pancreas transplant alone)
Islet after Kidney (IAK) Transplant Has potential to reverse diabetes. Safe, minimally invasive procedure. No additional immunosuppression required Little long term experience. Few islet isolation centres. Long-term insulin independence unusual

The process for choosing between treatment options and a number of the factors which are considered when assessing the best strategy for RRT in people with diabetes is illustrated in the following Flow sheet: [Please click on the below link]

Figure 1 - Flow sheet (including footnotes) illustrating RRT options for people with diabetes who are approaching or have ESRD

Patient Work Up

Patients progressing towards ESRD should be assessed for suitability or eligibility for transplant. Much of the focus of the assessment process is directed towards identifying contraindications to transplantation. The assessment process may identify significant co-morbidities or other issues which would aversely affect the safety of the transplant procedure itself, increase risks of long term immunosuppression, or adversely affect long term function or benefits of transplant (including premature death with a functioning transplant).

Some of the typical components for pre-transplant work up are described in Table 2.

Table 2: Pre-Transplant Work-up

Assessments Rationale/Comments
History and Physical Exam
Routine Blood Tests Electrolytes, liver function tests, bone biochemistry. May need to rule out thrombophilia or bleeding tendency.
Cancer Screening This may include chest X-ray, mammogram, cervical smear, prostate examination, faecal occult blood, colonoscopy
Infection Screening Screen for TB, HIV, Hepatitis and other chronic infections
Cardiovascular Risk Factors Cardiovascular disease is a common cause of death on dialysis or transplant wait lists or after successful renal transplant
Cardiovascular Status May include ECG, echo, stress test and/or perfusion scan, angiography. Sufficient vascular reserve is required for hemodialysis and or renal transplant
Vascular Assessment Additional vascular assessment (eg arterial dopplers or angiography) may be required. Severe aortoiliac vascular disease may make renal transplant impossible
Psychological assessment Exclude significant mental health issues, including addictions, substance abuse, non-compliance
Tissue typing & anti-HLA antidody measurement (PRA*) Rare tissue types or sensitization (development of anti-HLA antibodies due to previous pregnancies, transplants or blood transfusions) may make it harder to find a compatible donor. This can help estimate wait times.

*PRA – panel reactive antibodies

RRT Options

Dialysis: Treatment of ESRD by dialysis is directed primarily towards replacing excretory functions of the diseased kidneys – removal of nitrogenous waste products of protein metabolism, maintenance of acid-base status, and fluid balance. This is achieved by diffusion of small molecules down a concentration gradient across a semi-permeable membrane between the blood and dialysis fluid. In peritoneal dialysis, the peritoneum forms the semi-permeable membrane, while for haemodialysis this function is performed by a synthetic dialysis filter.

The efficiency of dialysis is suboptimal. At best, dialysis is estimated to provide the equivalent of a glomerular filtration rate of 20 ml/min (stage 4 chronic kidney disease) [3]. Although survival rates for people with diabetes on dialysis have improved over the last 30 years, mortality rates are 60% higher than for non-diabetic subjects [4]. Furthermore, additional treatments are required to treat anaemia, and to maintain bone health and regulate vitamin D metabolism, since dialysis does not replace the synthetic functions of the kidney.

Peritoneal Dialysis: In peritoneal dialysis (PD), a catheter is inserted into the abdomen to allow the instillation (and subsequent drainage) of dialysis fluid into the peritoneal cavity. The peritoneal membrane has a rich blood supply and functions as the dialysis membrane.

Patients can manage their own dialysis at home. They do require sufficient space to store dialysis fluids (a volume equivalent to a single bed).

Advantages of PD are the avoidance of rapid fluid shifts / haemodynamic stresses and avoidance of the need for expensive equipment (except for automated PD). Glycaemic control can be difficult if dialysis fluid with higher concentrations of dextrose (“heavy bags”) is used to remove more water. In the past, administration of insulin intra-peritoneally was proposed as a means to achieve better glycaemic control. No trial data have shown clear advantages of this route and it is associated with increased risk of peritonitis, dyslipidaemia and subcapsular hepatic steatosis.

CAPD: Continuous ambulatory peritoneal dialysis (CAPD) is the classic mode for delivering peritoneal dialysis. Up to 2.5l of dialysate is instilled under aseptic technique by the patient through a catheter placed in the anterior abdominal wall. After 4-6 hours in situ the used dialysate is drained from the abdomen under gravity and “exchanged” for fresh dialysate. Usually four exchanges are made each day.

IPD: Intermittent peritoneal dialysis (IPD) is broadly similar to CAPD. In the past IPD referred to patients who would come to hospital three times per week for peritoneal dialysis. This approach is generally obsolete. For patients with residual renal function starting peritoneal dialysis, IPD generally means dialysing at home overnight but spending the day with no dialysate in the peritoneal cavity, avoiding the discomfort experienced by some of carrying a large volume of intraperitoneal fluid.

Automated: The process of instilling and draining dialysate is time consuming for the patient. Automated peritoneal dialysis uses a machine to perform this process automatically while the patient is sleeping. While this approach may be preferred by some patients it is more expensive and there is no clear evidence for superiority versus CAPD [5].

Complications of PD: One of the most important complications of PD is bacterial peritonitis, which may present with abdominal discomfort or fever or with non-specific symptoms such as malaise or fatigue. The presence of cloudy dialysate can be an early sign. The diagnosis can be confirmed by sending dialysate for cell count, culture and sensitivity. Antibiotic treatment is usually effective. In some cases, temporary haemodialysis may be required until peritonitis has resolved.

Recurrent peritonitis can be a significant challenge in some cases and may lead to a progressive decline in the efficiency of dialysis across the peritoneum.

Haemodialysis

Haemodialysis relies upon the extracorporeal circulation of blood through a dialysis machine. High volumes of blood are circulated through a dialysis filter while on the other side of the semi-permeable membrane there is counter-current flow of dialysis fluid. This is an efficient process, but requires access to a large, high flow blood vessel and sufficient cardiovascular reserve to maintain the required increase in cardiac output (200 - 400 ml/min).

Although dialysis can be performed through a dialysis catheter placed in a large central vein, this is only suitable when dialysis is required acutely, or for a short period of time, because of risk of infection. For chronic dialysis it is preferred if a permanent means for vascular access is established. Most commonly an arteriovenous fistula is fashioned in the non-dominant arm. The venous limb must mature for some time before it can be used for frequent venepuncture.

Most patients will attend a specialized dialysis unit three times per week, spending approximately four - six hours dialysing. The use of home hemodialysis is growing and appears to be associated with better health outcomes. This is partly due to more efficient dialysis because home hemodialysis is performed daily (often overnight). However, selection bias likely accounts for the majority of the apparent benefit. Younger, healthier individuals and those who are able to perform their own venipuncture will be selected for home hemodialysis.

Transplantation

Figure 2: Reasons for people leaving the renal transplant waiting list in the US in 2012
Figure 2: Reasons for people leaving the renal transplant waiting list in the US in 2012
Renal transplantation is the treatment of choice for ESRD but is severely limited by the shortage of organ donors. In the US, the wait list is growing by approximately 5% per year with only 20% receiving transplants each year. After 3 years on the wait list, 40% will be transplanted, 45% will still be waiting, with the remainder dying or becoming too sick to transplant [6].

The median wait time for renal transplant in the US is around 4 years. Diabetic individuals are at highest risk for death on the waiting list (mainly due to cardiovascular disease) with mortality rates of 7% per year – which, though improving, is still double the rate in patients with ESRD due to glomerulonephritis or polycystic kidney disease [see KI 1.14 in ref 6].

While an effective treatment for ESRD, renal transplantation will not address their diabetes, which in many cases caused ESRD. Indeed, of renal transplant recipients will require lifelong immunosuppression, many of which (steroids, calcineurin inhibtors and mTOR inhibitors) have adverse effects for glucose metabolism. Recurrent diabetic nephropathy in the transplanted kidney has been observed with poor glycemic control and can be an important cause of graft loss in the longer term. Whether the risk of recurrent diabetic nephropathy is more closely correlated with the recipient’s underlying risk or in fact of the donor is not clearly established, but tight glycemic control and blood pressure management is recommended for all. Beta cell replacement for people with type 1 diabetes (eg whole pancreas or islet transplantation, either simultaneously with kidney transplant (same donor), or subsequently (different donor)) provides a potential solution to both ESRD and diabetes.

Renal Transplantation

Deceased Donor: Most renal transplants are performed from deceased donors. Donation rates in most countries are stable or falling, not least because of improvements in road safety and legislation requiring seat belts and motorbike helmets. To address diminishing organ supply at a time of increasing demand, extended criteria are being employed to select donors, including more marginal donors. In addition, organs from non-heart beating donors are being used, with improving outcomes. Several factors predictive of worse graft outcome have been identified. These include long cold ischaemia time (time between harvesting and transplant), HLA mismatch, and older donor age.

Live Donor: An alternate source of organs is from living donors. The number of live donor transplants is approaching the number of deceased donors [7]. Although mostly donors are related to the recipient, altruistic donation to strangers does take place.

Outcomes of living donor renal transplants are superior to cadaveric donors. Cold ischaemia is minimal, HLA matching may be closer and donors may be younger and healthier. In addition, brain death appears to be associated with risk for organ damage, including ischaemia-reperfusion injury, which is clearly not a factor in living donation.

Simultaneous Pancreas Kidney

While the gold-standard for type 1 diabetic individuals with ESRD, simultaneous pancreas kidney (SPK) transplants are conducted less frequently than kidney alone in people with diabetes. Donor criteria for whole pancreas transplant are very stringent, and pancreata are very susceptible to injury if trauma was the cause of death. Because of the exceedingly constrained supply of donor organs, recipient criteria are similarly strict. Many programs will only accept recipients younger than 45 years who are free from significant cardiovascular disease. Since waiting times for SPK are substantial and survival after renal transplant is superior to remaining on the wait list, many diabetic subjects waitlisted for SPK will opt for kidney-alone transplant, particularly if they have a living donor.

From a technical perspective, SPK is significantly more challenging. As well as the vascular and ureteric anastomoses required for the renal transplant, the pancreas graft requires arterial and venous anastomoses, but also requires drainage of exocrine secretions. In the past, the most common technique had systemic vascular drainage with exocrine drainage to the bladder. Subsequently portal venous with enteric drainage has become the technique of choice. The presence of atherosclerotic and/or calcified vessels, which are common in this population, is a significant challenge for the surgeon.

There is a finite mortality associated with SPK and repeat laparotomy is not uncommon to deal with leaking anastomoses, pancreatitis, abscesses or even to remove the pancreas graft in cases of thrombosis.

In contrast to earlier data suggesting best outcomes for live related kidney transplant [8], with improving techniques, outcomes after SPK now appear to be superior to live related renal transplant, which in turn is superior to deceased donor renal transplant [9].

Pancreas or Islet after Kidney Transplant

In general the highest quality donor pancreata are reserved for transplantation in combination with a kidney (SPK). Some high quality pancreata will be available for pancreas after kidney (PAK) or pancreas transplant alone (PTA). Pancreata from older and obese donors are generally discarded, but may be suitable for processing for islet transplantation.

The major objection to transplantation as a therapy for type 1 diabetes is based on the risks associated with the requirement for lifelong immunosuppression. However following renal transplantation, the risks are predominantly associated with an additional transplant procedure. Islet transplantation is a minimally invasive procedure requiring transhepatic puncture and cannulation of the portal vein with no reported mortality. PAK involves major abdominal surgery, with similar risks as for SPK.

The ability to achieve and maintain insulin independence following islet after kidney (IAK) is well established, but reliable estimates of metabolic outcomes of PAK are scant. Nevertheless, even in the absence of insulin independence, functioning islets are associated with improved renal, cardiovascular and microvascular outcomes. Emerging data support a major contribution of islet transplantation to prevent hypoglycaemia, which might identify a sub-group for whom islet transplant should be considered [10].

Renal Transplant Outcomes in People with Diabetes

Acute rejection has been a leading cause of graft loss. With improving immunosuppression, a major emerging challenge is death with a functioning graft. The majority of these deaths are due to cardiovascular disease, followed by infectious causes. People with diabetes are already at increased cardiovascular risk so it is not surprising that they have increased mortality compared with non-diabetic subjects.

Registry data would suggest that survival rates for people with diabetes on dialysis are far inferior to those receiving transplants. Time on dialysis is a negative prognostic factor. In many series, outcomes for living donor renal transplant recipients are superior to those of SPK recipients. This apparent paradox may be partly due to closer HLA matching, but is more likely due to the difference in time spent on dialysis. More recent data suggests that among survivors, the longer term outcomes for SPK may be superior, but this advantage may not be apparent for more than 10 or 15 years.

Renal Transplant Outcomes

Figure 3: Kaplan Meier Graft survival of renal transplants from deceased or living donors by primary cause of renal disease[6]
Figure 3: Kaplan Meier Graft survival of renal transplants from deceased or living donors by primary cause of renal disease[6]
Outcomes after renal transplantation from US registry data are illustrated in Figure 3. Graft survival is superior after living donor kidney transplant compared with deceased donors, with five year survival rates of 82% versus 72%, respectively in diabetic recipients [6].

Pancreas graft survival is better when performed in association with a renal transplant, with the best outcomes seen in SPK, with 74% of SPK recipients maintaining pancreas graft function at 5 years, compared with 65% of PAK recipients [11]. Without a renal transplant, pancreas transplantation (PTA) outcomes are less favourable, with only 53% maintaining graft function at 5 years [11].

The optimal transplant option for individuals will depend on multiple factors, including age and co-morbidity – and particularly the availability of a living donor, but will also include local waiting lists and organ allocation policies. These will have to be weighed by the individual and their physicians particularly in the light of their blood and tissue type and the presence of any anti-HLA antibodies which will influence the waiting time for a suitable donor.

References

  1. ^ USRDS Annual Data Report vol 2 Ch1 Incidence, prevalence, patient characteristics, and treatment modalities. In: usrds.org. http://www.usrds.org/2013/view/v2_01.aspx. Accessed 14 Nov 2013

  2. ^ Tonelli M, Wiebe N, Knoll G, et al. (2011) Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant 11:2093–2109. doi: 10.1111/j.1600-6143.2011.03686.x

  3. ^ Mallick NP, Gokal R (1999) Haemodialysis. Lancet 353:737–742.

  4. ^ van Walraven C, Manuel DG, Knoll G (2013) Survival Trends in ESRD Patients Compared With the General Population in the United States. American Journal of Kidney Diseases. doi: 10.1053/j.ajkd.2013.09.011

  5. ^ Rabindranath KS, Adams J, Ali TZ, et al. (1996) Continuous ambulatory peritoneal dialysis versus automated peritoneal dialysis for end-stage renal disease. doi: 10.1002/14651858.CD006515

  6. ^ Matas, A. J., Smith, J. M., Skeans, M. A., Thompson, B., Gustafson, S. K., Schintzler, M. A., et al. (2014). OPTN/SRTR 2012 Annual Data Report: Kidney. American Journal of Transplantation, 14(S1), 11–44. doi:10.1111/ajt.12580

  7. ^ Organ Procurement and Transplant Network. In: optn.transplant.hrsa.gov. http://optn.transplant.hrsa.gov/latestData/rptData.asp. Accessed 14 Nov 2013

  8. ^ Knoll GA, Nichol G (2003) Dialysis, kidney transplantation, or pancreas transplantation for patients with diabetes mellitus and renal failure: a decision analysis of treatment options. J Am Soc Nephrol 14:500–515.

  9. ^ Lindahl JP, Hartmann A, Horneland R, et al. (2013) Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease. Diabetologia 1–8.

  10. ^ Barton FB, Rickels MR, Alejandro R, et al. (2012) Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 35:1436–1445. doi: 10.2337/dc12-0063

  11. ^ Israni, A. K., Skeans, M. A., Gustafson, S. K., Schnitzler, M. A., Wainright, J. L., Carrico, R. J., et al. (2014). OPTN/SRTR 2012 Annual Data Report: Pancreas. American Journal of Transplantation, 14(s1), 45–68.

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