Recurrent glomerulonephritis (GN) was first reported by Hume et al in 1955 (2). In their series of nine allografts, one patient developed GN and irreversible graft failure. In 1968, Glassock et al (5) reported that recurrent and de novo diseases are more frequent in patients receiving isografts. Among 19 recipients with GN who received isografts, 11 developed recurrent GN. In 1970, Hume et al (4) also found recurrent GN in 10% of transplant recipients in long-term follow-up (5). An additional four cases suspected to have recurrent GN (the original kidney disease was unknown) resulted in the conclusion that the overall prevalence of recurrent GN was as high as 20%. In various single- and multicenter series, the recorded prevalence of recurrent disease varied between 1.8% and 6.5% (6, 7, 8). In a pooled analysis from the Renal Allograft Disease Registry (RADR), the incidence of recurrent disease was found to be 4.1% (9). Briganti et al (10) reported a prevalence
of 8.4% from the Australia and New Zealand (ANZ) Transplant Registry.

The true prevalence of recurrent and de novo diseases has not been well studied. Approximately 20% of ESRD patients undergo a native kidney biopsy prior to ESRD to define the cause of renal disease (11). Many patients often present with advanced renal failure with bilateral contracted kidneys and are not candidates for renal biopsy. African American patients with ESRD who are not subjected to biopsy are often characterized as having hypertensive nephrosclerosis but may in fact have glomerulonephritis (11).

Posttransplant evaluation in many centers is based on renal function using serum creatinine concentrations only. Urinalysis and 24-hour urine for protein are tests not routinely performed, therefore missing potential cases of recurrent and de novo diseases. Identifying the recurrence of primary renal diseases is dependent on adequate biopsy material. Furthermore, transplant biopsy specimens are not routinely analyzed with immunofluorescence and electron microscopic examination. Lack of routine donor (cadaver) biopsies at the time of implantation makes the diagnostic interpretation of posttransplant biopsy specimens difficult. Chronic allograft nephropathy (CAN) and membranoproliferative GN (MPGN) are misdiagnosed for each other, making it more difficult to evaluate the true prevalence of recurrent disease (11). However, MPGN can be distinguished by the presence of immune deposits in capillary walls. Large databases such as U.S. Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) do not define the cause of ESRD for each individual case. In addition, recurrent disease in these databases is identified only when the graft fails, underscoring the true prevalence of this disease.

Recurrent glomerular diseases are most often diagnosed during evaluation of proteinuria, hematuria, or elevated serum creatinine (12,13). Because of this, routine evaluation of qualitative proteinuria and hematuria is an appropriate part of long-term follow-up of the transplant patient. While low levels of proteinuria may be seen in many transplant patients, proteinuria in excess of 2 grams per 24 hours has been reported in about 10% of patients and has been associated with recurrent or de novo disease and CAN (12). An occasional patient may present with significant posttransplant acute renal failure due to recurrent oxalosis. Protocol renal biopsies may also single out cases of immunoglobulin A nephritis. In the recent past there has been an increasing prevalence of thrombotic microangiopathic disease in renal graft due to nephrotoxicity from immunosuppressive agents.

The recurrence time to diagnosis varies widely. Multiple studies have revealed that focal segmental glomerulosclerosis (FSGS) recurs usually early after transplantation and in many cases within the first week after transplantation. However, late recurrence is not unusual. MPGN also recurs within the first year. Diseases such as immunoglobulin A nephritis and diabetes can recur many years after transplantation.

Recurrent and de novo diseases can be classified for clinical purposes as follows: true recurrence (same disease recurring in the graft and both confirmed by histology), de novo (appearance of a new disease in the graft), and clinical recurrence (development of new disease in allograft when native kidney disease is unknown). The classification of recurrent and de novo diseases shown in Table 13.1 is according to primary, systemic, and de novo disease. Primary diseases are those that develop idiopathic glomerulonephritis, systemic diseases are those metabolic/inherited disorders, and de novo diseases are those that have new disease in the renal graft.

The prevalence of recurrent disease is dependent on criteria for the diagnosis of recurrence and the duration of posttransplant follow-up. Many, if not most, observational studies report
a crude grid of recurrence rather than actuarial rates, which are dependent on other causes of graft failure such as death acute and chronic rejection. In some studies, the rate of histologic recurrence was reported; while in others, patients with clinical presentation suggestive of recurrence was defined as recurrence. The rate of recurrence is not only dependent on the definition of recurrence but also on the follow-up after transplantation. Large databases such as USRDS and UNOS report only recipients who lose their graft due to recurrence, underscoring the true prevalence of recurrence. Prevalence of recurrent disease is also dependent on the ESRD population. For instance, prior to 1980s only nondiabetic patients were accepted for renal transplantation in most centers, thus the prevalence was higher with predominant GN recipients undergoing transplantation. However, in recent years nearly 50% of recipients have diabetes as the cause of ESRD, and smaller proportion of patients with GN are undergoing transplantation. Due to a very low incidence of most recurrence disease, many studies lack statistical power to directly assess the incidence and risk factors for recurrence. All these factors make it difficult to estimate the true incidence of recurrent diseases after renal transplantation, and in the end only very crude estimates can be provided.

With notable exception (such as Alport syndrome, polycystic kidney disease, chronic pyelonephritis, and chronic interstitial nephritis), virtually all diseases affecting the native kidney can recur in the transplant kidney. The risk of recurrence is generally small. For example, in an analysis of all transplants performed between 1980 and 1991 in the European Renal Association-European Dialysis and Transplant Association Registry, only 3% of the graft loss was attributable to recurrent disease (14). Similar rate of graft failure has been reported from the Organ Procurement and Transplantation Network (OPTN) registry.

Recurrent GN occurred in one out of nine (11%) renal transplants reported in 1955. Hume et al in 1970 recorded an incidence of 10% recurrence in their series (2). Glassock et al (5) reported a high incidence of recurrence in 58% of recipients receiving isografts. Various single- and multicenter studies have reported prevalence anywhere from 1.8% to 6.5%. A report from RADR in 1999 recorded the prevalence of recurrent and de novo disease as 3.4% of renal transplants. In a recent prospective study through RADR, true recurrence, clinical recurrence and de novo disease were seen in 3.8 %, 1.4 %, and 1.6 %, respectively. The overall recurrence rate was 2.6% after a mean follow-up period of less than 2 years. An analysis from the ANZ registry recorded a recurrence of glomerulonephritis rate as 8.4% (10).

The risk of recurrence is divided into risk for developing recurrent disease (Table 13.2) and risk for graft failure.

Patients with recurrent disease may progress to renal insufficiency and graft failure. Thus, informing potential renal transplant candidates and their living donors of the risk of recurrence and graft failure is an important part of the pretransplant evaluation. The reported risk for graft failure varies in all published studies. A comprehensive analysis from the RADR reported a graft failure of 55% in patients with recurrent disease compared to 25% of other recipients (Fig. 13.1A). This translated to a relative risk of 1.9 (1.57 to 2.4) after correcting for key variables in a study of 4,913 transplants (15). The relative risk for graft failure related to individual recurrent and de novo diseases were as follows: MPGN (2.37), FSGS (2.25), and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) (5.36). These were recipients transplanted during the cyclosporine A era from 1987 to December 1996. A similar risk profile of 8.4% for graft failure was reported from the ANZ registry (10). In a recent prospective study on 3,214 transplant recipients from 1998, recurrent and de novo disease was seen in 85, with a significant lower graft survival within 1-year posttransplant (Fig. 13.1B). Thus the negative impact on graft survival due to recurrent disease is seen both for short- and long-term graft survival. This is secondary to diminishing short-term graft failure rates due to acute rejection episodes.

Risk factors for individual diseases will be discussed in individual disease types. Recurrent disease in the transplanted kidney can be characterized into primary renal diseases, systemic diseases and de novo diseases.