Predictors and Risk Factors for Recurrent Scleroderma Renal Crisis in the Kidney Allograft: Case Report and Review of the Literature

Authors


*Corresponding author: Phuong-Thu T. Pham, PPham@mednet.ucla.edu

Abstract

Scleroderma renal crisis (SRC) can lead to end-stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1–2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987–July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5-year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new-onset anemia and cardiac complications.

Introduction

Scleroderma renal crisis (SRC) occurs in approximately 10% of patients with scleroderma and is more common in patients with diffuse scleroderma compared to those with limited skin disease 1,2. For those who develop end-stage renal disease (ESRD), treatment options include peritoneal dialysis, hemodialysis, and/or renal transplantation. Currently, our understanding of SRC recurrence in the allograft kidney is limited. We herein report the outcomes of two patients who underwent renal transplantation due to ESRD secondary to scleroderma, review reported transplantation outcomes for patients with scleroderma, discuss potential predictors and risk factors for allograft recurrence and present UNOS data on patient and graft survivals.

Case Reports

Patient one is a 46-year-old woman with diffuse scleroderma diagnosed following a 2-month history of bilateral hand puffiness, progressive hand contractures and diffuse joint pain. Medical therapy included hydroxychloroquine for 6–8 months, followed by prednisone 5 mg daily. Two weeks after starting prednisone, she developed SRC manifested by accelerated hypertension and rapidly progressive renal failure, necessitating hemodialysis within 1 week. Despite good blood pressure control with lisinopril and extended-release nifedipine, her renal function failed to recover.

After approximately 2 years on dialysis, the patient underwent a living unrelated donor renal transplant from her husband. She was given basiliximab induction therapy followed by tacrolimus, sirolimus and prednisone maintenance immunosuppression. She was also started on lisinopril 5 mg daily in the early post-transplant period. Corticosteroid therapy included intraoperative methylprednisolone 500 mg intravenously followed by steroid taper: prednisone 15 mg daily by postoperative week 4, and 7.5 mg daily by month 8. The patient did well and had noticed skin softening and slowly improving dexterity over the next 3 months. However, at 8 months post-transplant, she noted increasing skin tightening and developed new-onset severe anemia with hemoglobin (Hb) and hematocrit (Hct) drop to 7 g/dL and 24–25% from a baseline of 10 g/dL and low 30 %, respectively. Upper endoscopy revealed gastric vascular ectasia with active bleeding. She received multiple packed red blood cell (PRBC) transfusions with stabilization of her Hb/Hct to the 10 g/dL and 30s% range, respectively. One week later, she had a rise in serum creatinine to 1.4 mg/dL from a baseline of 0.7–0.9 mg/dl and again a fall in Hb/Hct to 8.3 g/dL and 26.3%, respectively. On physical exam, her vital signs were: blood pressure: 170/100 mm Hg, pulse rate: 100, and respiratory rate: 20. She had diffuse proximal and truncal skin thickening and sclerodactyly. Rectal exam revealed strongly positive Hemoccult stool, prompting hospital admission. A repeat upper endoscopy revealed antral arteriovenous malformation and an actively oozing vascular ectasia, which was promptly cauterized. A transplant kidney biopsy performed on hospital day 4 revealed mild acute cellular rejection, tubulointerstitial type, and changes compatible with SRC (Figure 1 & 2). C4d staining was negative. The patient's blood pressure was in the 160–170/90–100 mm Hg range and she was treated with lisinopril 40 mg twice a day, clonidine No. 2 patch, metoprolol 50 mg twice a day, and amlodipine 10 mg twice a day. Despite the mild acute cellular rejection, we elected to treat the patient with thymoglobulin, a rabbit anti-human thymocyte globulin, (Thymoglobulin; Sangstat, Menlo Park,CA) 1.5 mg/kg/day for 8 days instead of methylprednisolone pulse to avoid the possibility of high dose steroid induced and/or exacerbation of SRC. Her serum creatinine peaked at 2.1 mg/dL and gradually stabilized at 1.7 mg/dL. An echocardiogram and pulmonary function tests performed to rule out extrarenal manifestations of scleroderma revealed a large pericardial effusion without echocardiographic or clinical evidence of cardiac tamponade and a restrictive lung pattern with total lung capacity at 67% predicted and diffusing capacity of carbon monoxide (DLCO) at 34% predicted, respectively. Owing to the persistently high serum creatinine, the patient underwent a repeat biopsy which revealed treated acute cellular rejection, tubulointerstitial type, and further changes compatible with SRC (Fig. 3). The patient was discharged on hospital day 19 with a serum creatinine of 1.7 mg/dL and blood pressure 110–130/60–80 mm Hg. She returned to her primary nephrologist for further care and was lost to our follow-up. She reportedly developed progressive allograft dysfunction and returned to hemodialysis 14 months following her transplant.

Figure 1.

Arteriole involved by intraluminal fibrin thrombus and glomerulus with swollen endothelial cells and basement membrane double-contours (Jones' methenamine silver stain, original magnification ×200).

Figure 2.

Tubulointerstitial edema and mononuclear cell infiltration with tubular injury and lymphocytic tubulitis (hematoxylin & eosin stain, original magnification ×400).

Figure 3.

Artery with prominent mucoid intimal hyperplasia (arrow) and glomerulus with ischemic changes (Masson's trichrome stain, original magnification ×200).

Patient 2 is a 46-year-old female diagnosed with scleroderma when she began to notice tight hands, swollen extremities and Raynaud's phenomenon. Shortly after the diagnosis, she was placed on a research protocol using low-dose cyclosporine with some resultant improvement in the flexibility of her extremities. Four years later, she developed SRC manifested by accelerated hypertension and acute renal insufficiency. Despite angiotensin converting enzyme inhibitor (ACEI) therapy and discontinuation of cyclosporine, her renal function deteriorated over the following 4 years and she was placed on peritoneal dialysis. Over the same period, she also developed disabling bilateral hand contractures, diffuse skin thickening and board-like skin tightness over her abdomen.

After being on peritoneal dialysis for 6 years, she underwent a living-related donor renal transplant from her daughter. She was given intravenous (i.v.) basiliximab induction therapy followed by tacrolimus, sirolimus and prednisone maintenance immunosuppression. She was also started on enalapril 2.5 mg daily in the early postoperative period and titrated up as tolerated. Her corticosteroid therapy included intraoperative methylprednisolone 500 mg intravenously followed by prednisone taper: 15 mg daily by postoperative week 5, and 5 mg daily by month 8. Her postoperative course was unremarkable and she was discharged on postoperative day 5 with a serum creatinine of 0.6 mg/dL. She did well and has maintained a serum creatinine of 0.6 mg/dL at the 32-month follow-up. In addition, her physical exam was notable for significantly softened abdominal skin in association with a decline in the modified Rodnan skin score by more than 70%.

Literature search based on PubMed database

There were a total of 11 reports of renal transplantation involving scleroderma patients (3–13). Detailed information and long-term follow-up were not provided in all cases which limited our analysis to only nine patients from the literature and two of our own. Five patients, including our present case had recurrent SRC in the allograft (Table 1) and six patients had no disease recurrence (Table 2) at at least 2-year follow-up. The characteristics of patients with and without disease recurrence were studied for identification of potential predictors and/or risk factors for disease recurrence. Of the five cases with recurrent SRC, all five developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1–2 years after the onset of SCR had disease recurrence. Although data were incomplete in some cases, anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others.

Table 1.  Characteristics of patients with disease recurrence

Patient
Time from
SRC to ESRD

Time on dialysis

Transplant source
Time to allograft
SRC/graft loss

References
  1. NX: nephrectomy.

1.2 weeks3 months (native NX)Deceased donor2 month/3 monthsMerino
2.Within 2 weeks2 months (native NX)Mother1 month/2 monthWoodhall
3.At onset of SRC18 monthsIdentical twin sister2 yearsCaplin
4.1 week12 monthsHLA-identical twin sister7 monthsChang
5.At onset of SRC2 yearsSpouse8 months/14 monthsPresent report
Table 2.  Characteristics of patients without disease recurrence with at least 2-year follow-up

Patient1
Time from
SRC to ESRD

Time on dialysis

Transplant source
Time at latest
follow-up/SCr

References
  1. 1With the exception of patient 4, all patients were females.

  2. 2Time from the diagnosis of scleroderma to transplantation (time from SRC to ESRD unknown).

  3. 3CR = chronic rejection on biopsy (graft functioned well for 2 years).

1.17 months>4 yearsDeceased donor6 1/2 years/SCr 2.1 mg/dLChang
2.3 years1 monthMother3 years/SCr 1.3 mg/dlMerino
3.2 years2Native NXLiving-related donor3 years/CR3Merino
4.At onset of SRCDeceased Donor7 months (native NX)4 1/2 years/SCr 1.2 mg/dLPaul
5.2 months13 monthsDeceased donor4 years/SCr 0.7 mg/dlJavier
6.4 years6 yearsDaughter>2 1/2 years/SCr 0.6 mg/dLPresent report

Patient and graft survivals based on UNOS database:

The United Network for Organ Sharing (UNOS) database revealed that between October 1987 and July 2004, two hundred sixty transplants were performed for the renal diagnosis of scleroderma or progressive systemic sclerosis (14) with a total reported graft loss of 75 (28.8%). Of all graft loss cases, five (6.7%) were reported to be due to disease recurrence, with time to graft loss at 70, 117, 131, 645 and 802 days. Other causes of graft loss included infection (2.7%), graft thrombosis (4%), primary failure (8%), acute rejection (16%), chronic rejection (30.7%) and other unreported causes (32%). Kaplan–Meier patient survival rates at 12, 24, 36, 48, 60 and 120 months were 89.79%, 83.94%, 81.09%, 78.95%, 72.69% and 53.66%, respectively. Corresponding graft survival rates were 78.70%, 73.30%, 68.59%, 64.88%, 56.70% and 26.67% (Figure 4).

Figure 4.

United Network for Organ Sharing Kidney Transplants between 10/1987 – 12/2003: Survival Over Time. Primary Diagnosis: Scleroderma or Progressive Systemic Sclerosis.

Discussion

The risk of recurrent SRC after transplantation has been reported to range from 20% to 50% in various case reports (3–13). In our present report, one patient had recurrent SRC at 8 months and subsequent graft loss at 14 months post-transplant, while the other had a well-functioning graft at 32-month follow-up. In contrast to the high documented recurrence rates from various reports, the UNOS database revealed a smaller recurrence rate of 1.9% (5 out of 260 patients). We suspect that published case series may overreport the recurrence rate because of a bias in publications of more difficult cases with worse outcomes while UNOS may underreport the actual recurrence rate because the causes of graft loss were not known in up to 32% of the cases and not all graft-loss and non-graft-loss recurrence were reported to UNOS.

Predictors and risk factors for recurrent SRC in the kidney allograft have not been studied. In the non-transplant settings, the suggested predictors for SRC include rapid progression of skin thickening, new-onset anemia, new-onset pericardial effusion or congestive heart failure, antecedent use of high dose steroids, defined as the use of more than 15 mg to 40 mg of prednisone a day, and disease duration of less than 3–4 years (1,2,15,16).

Interestingly, progression of skin thickening, pericardial effusion and anemia preceded the development of recurrent SRC in our first patient. Our literature review also revealed that skin tightening and anemia preceded the development of recurrent SRC in two cases 11,12. Although scleroderma is a chronic systemic disease, anemia is an uncommon manifestation. The presence of anemia is often ominous and has been suggested to be predictive of SRC 1,2 as its etiologies may include microangiopathic hemolytic anemia or gastrointestinal (GI) bleed from underlying sclerodermal gastrointestinal lining changes.

It is not known whether the use of high-dose steroids may precipitate SRC in renal transplant recipients. Data on steroid dosage in our collected case reports from PubMed were lacking. Both of our patients received a similar initial intraoperative i.v. methylprednisolone pulse dose. However, by month 8, patient 1 had received a higher cumulative dose of prednisone compared to patient 2. Whether this might have precipitated SRC in patient 1 is not known.

In the non-transplant setting, there have been contradictory reports on the incidence of SCR in males versus females. Nonetheless, in a large retrospective study involving nearly 1000 patients with diffuse cutaneous scleroderma, no gender difference in terms of occurrence of SRC in the native kidneys was detected (1). Currently, there has been no report documenting any gender difference in allograft disease recurrence or outcomes. Our data obtained from the UNOS database from October 1987 and December 2004 revealed no gender difference in recurrent disease that had led to graft loss, 1 out of 74 males (1.4%) versus 4 out of 202 females (2.0%) (chi-square p = 0.73) (17).

For those with recurrent SRC, the time of onset following transplantation is not known. Review of the cases reported in the literature revealed that recurrence usually occurred within the first few months to the first 1–2 years after transplantation. Of the five well-described cases of disease recurrence after transplantation, those who developed ESRD within a year of SRC had disease recurrence (Table 1) whereas none of those who developed ESRD more than 1–2 years after the onset of SCR had disease recurrence at 2–6 1/2 years of follow-up (Table 2). Although never systematically studied, we suspect that the risk for disease recurrence in the allograft kidney may be predicted from an aggressive course of SRC in the native kidneys, reflecting intrinsically worse immunologic dysfunction, pro-inflammatory and pro-fibrotic states, and abnormal endothelial cell function. It should be noted, however, that while an aggressive course of SRC leading to early ESRD appears to be a risk factor for allograft SRC, rapid onset to ESRD does not necessarily result in disease recurrence (Table 2). Finally, for those with SRC who developed advanced renal failure, early transplantation should be avoided due to the potential for recovery of renal function at up to 3–18 months follow-up.

In summary, our current knowledge regarding SRC recurrence in the allograft kidney is limited. On the basis of the data obtained from UNOS, 5-year patient and graft survival rates were approximately 73% and 57%, respectively. In contrast to the high incidence of disease recurrence reported in the literature, the current UNOS data only revealed a minimal incidence. Although it is difficult to draw any conclusions from anecdotal case reports because of the high probability of bias in favor of publications of difficult cases, our analysis suggests that SRC behaves similarly in the allograft as in native kidneys. To our knowledge, this is the first report to present data suggesting that recurrent SRC in the allograft may be heralded by multiple events known to be predictive of SRC in the native kidneys including progression of diffuse skin thickening, new-onset anemia, and cardiac complications. The role and dose of steroid-induced SRC in the allograft kidney are unclear. Rapid progression to ESRD from the onset of SRC in the native kidneys appears to increase the risk for recurrent disease following transplantation. Literature review and UNOS data suggest that most recurrences occur within a few months and usually by the first 1–2 years after transplantation. Close monitoring for evidence of recurrence within the first 2 years after transplantation is warranted.

Acknowledgments

We are indebted to Ms. Katarina Anderson for providing us UNOS data on the number of renal transplants performed during October, 1987 to July, 2004 for the primary diagnosis of Scleroderma or Progressive Systemic Sclerosis. We would also like to thank Elisabeth Hands, R.N. and Angela Henderson, R.N. for their excellent care of our patients.

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