Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single‐center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non‐steroidal anti‐inflammatory drugs is a safe and non‐invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.


| INTRODUC TI ON
Nephrotic syndrome is a glomerular disorder that is defined by massive proteinuria, hypoalbuminemia, and general edema. Children with nephrotic syndrome mostly respond well to steroids and have a favorable prognosis. In contrast, therapy-resistant nephrotic syndrome generally results in ESRD within a few years. 1,2 Kidney transplantation in patients with active nephrotic syndrome poses 2 major risks. First of all, hypoalbuminemia leads to an unfavorable circulatory status and an increased risk of thromboembolic events, both resulting in major risks for the renal transplant. 3,4 In fact, optimal hydration is the most important perioperative intervention to ensure graft function. 5 Second, nephrotic syndrome may relapse after transplantation. Early detection of proteinuria after transplantation is vital to start treatment for such relapses in order to improve prognosis. "Contamination" of the urine with proteinuria from the native kidneys may hinder such early detection. Furthermore, proteinuria may also indicate rejection of the transplant kidney, for which prompt diagnosis and treatment are also necessary. 6 Ponticelli et al have shown that renal survival rates of patients with proteinuria are worse in comparison with non-proteinuric patients. 7 In fact, the quantity of proteinuria is a reliable predictor of the allograft outcome. 7 In order to improve the circulatory status during and after renal transplantation and allow for early detection of proteinuria of the transplant kidney, treatment to stop the native proteinuria is often needed. Currently, the treatment of choice in such patients is surgical nephrectomy. 2,8 This leads to at least one additional operation in these patients, which is known to have high rates of morbidity and even mortality (up to 2.0%). 9,10 A less invasive but successful therapy is bilateral renal artery embolization, which may have severe side effects, such as severe flank pain and fever, and requires specific interventional skills that may not be readily available. [11][12][13] ACE inhibitors and NSAIDs have antiproteinuric effects and are used as such in patients with (congenital) nephrotic syndrome. [14][15][16] Case reports show that non-invasive nephrectomy by using NSAID and/or ACE inhibitors may have an immediate effect on urine output and proteinuria, resulting in a sharp rise of serum protein levels. 14,17,18 Unfortunately, little effect was seen in some other reports. 13,19 In our center, we have used medical nephrectomy as a first-line option in children with therapy-resistant nephrotic syndrome on dialysis during the workup for renal transplantation. Our retrospective case study investigated the feasibility and safety of the use of ACE inhibitors and/or NSAIDs instead of surgical nephrectomy or renal artery embolization in order to achieve medical nephrectomy in a safe non-invasive way in patients with persistent severe proteinuria in the workup toward renal transplantation.

| PATIENTS AND ME THODS
In this single-center retrospective case study, we did a data search of all pediatric renal transplant candidates with ESRD due to nephrotic syndrome in the period 2013-2018. This period was chosen for reasons of data availability in the digital hospital data system. Of these patients, we identified those who were treated with medication in order to induce a medical nephrectomy prior to renal transplantation.
Such patients received an ACE inhibitor and/or NSAID after starting dialysis. The dosage of the medication was based on body weight and blood pressure, and adjusted based on the anti-diuretic effect, blood pressure, and side effects such as liver function tests. In all cases, the medication was stopped at least 1 day before kidney transplantation.
Patient characteristics extracted from electronic patient records were date of birth and diagnosis, gender, weight, date of medical nephrectomy, date of dosage changes of ACE inhibitor and/or NSAIDs, and date of kidney transplantation. Furthermore, we extracted clinical and genetic diagnosis, medication type and dosages pre-and post-surgery, and complications like thrombosis. Clinical and laboratory results extracted were blood pressure, urine output, amount of proteinuria if measured, and serum albumin levels before and after the start of the medical nephrectomy.

| Statistical analysis
Descriptive analyses were performed using SPSS, version 22.0 (IBM). Results are expressed as median with range and counts with percentages.

| Demographics
Eleven pediatric patients with nephrotic syndrome who were prepared for renal transplantation were identified in this study. Three patients were not started on ACE inhibitors for medical nephrectomy, because of severe illness (N = 1, surgical nephrectomy was performed to stabilize the patient due to extensive fluid overload) and therapy-resistant malignant hypertension (N = 2). Eight patients did receive medication to induce a medical nephrectomy prior to renal transplantation ( Figure 1 and Table 1). The diagnosis leading to ESRD was CNS due to a mutation in the NPHS1 gene (n = 2) or NPHS2 gene (n = 3), and FSGS without a proven genetic basis (n = 3).
All patients were on dialysis prior to the kidney transplantation, whereof 4 patients on hemodialysis and 4 on peritoneal dialysis. Table 1 shows the demographics, preoperative characteristics, and post-operative outcome of these patients. The median age at  In both patients, medical nephrectomy with indomethacin had to be stopped due to elevated transaminases after 1 and 6 months, respectively. In 1 patient, diclofenac was added to enalapril because of persistent proteinuria and significant urine output despite an acceptable serum albumin level of 34 g/L. It was started at a dose of 50 mg 3 times a week after the hemodialysis session and increased to 100 mg 3 times a week.

| Medical nephrectomy
Albumin levels increased or stayed in within normal range in all patients ( Table 2). After starting enalapril albumin levels increased from a median of 18 (range 11-28) g/L to a median of 31 (range 21-36) g/L. With indomethacin albumin levels increased from a median of 25 (range 21-29) g/L to a median of 29 (27-31) g/L. The patient who received diclofenac in addition to enalapril showed no change in serum albumin levels, as the albumin level before start was already 34 g/L.
In all patients, the medication for medical nephrectomy was stopped at least 1 day before kidney transplantation.
In 6 patients, medical nephrectomy prior to renal transplantation was successful. In two patients, treatment was unsuccessful and surgical bilateral nephrectomy was performed as preparation for renal transplantation. Both these patients were diagnosed with NPHS1 mutations. In 1 patient, medical nephrectomy failed because of side effects (enalapril because of hypotension and indomethacin because of elevated transaminases). The other patient had no relevant change in urine output and proteinuria despite enalapril and indomethacin, and medication dose could not be increased because of a low blood pressure and a slight increase in liver function tests.

| Side effects
The only side effect of enalapril seen was hypotension. In 3 cases, ceasing other anti-hypertensive drugs was enough to normalize blood pressure, in 1 case a reduction in dosage was sufficient and in 2 cases enalapril needed to be stopped. In both patients that were started on indomethacin, liver function tests were elevated as a side effect, leading to cessation of treatment and subsequent surgical bilateral nephrectomy. In contrast, there were no side effects seen in the patient that was treated with diclofenac in combination with enalapril. After transplantation, no thrombosis, delayed graft function, hypotension, or need of diuretics was noted.

| D ISCUSS I ON
Our case series showed that controlled medical nephrectomy in children with ESRD due to nephrotic syndrome is a feasible and safe non-invasive treatment in the preparation of renal transplantation.
ACE inhibitors seem to be the drug of first choice because of the high success rate and mild side effects in a dosage up to 0.30 mg/kg per day. In contrast, indomethacin has a low success rate and considerable side effects, that is, hepatic impairment, which makes its use questionable for medical nephrectomy, even in low doses, in our experience. No conclusion can be drawn with regard to diclofenac since it was only given to one patient in our institution.
Previous case reports evaluating medical nephrectomy observed variable results (for an overview, see Table 3). [12][13][14]17,19 In all reports, ACE inhibitors, indomethacin, or another NSAID were used to achieve an acceptable circulatory state before transplantation. Dosages used in these case reports are 2 mg/kg/day to 14 mg/kg/day of indomethacin, a maximum of 5 mg/kg/day of captopril, and a dose of 1 mg/kg/ day of quinapril. A possible reason for the difference in outcome between some of the previous case reports and our experience could be the difference in type of nephrotic syndrome. Another reason could be the fact that in our center all patients were on dialysis, which we used as an effective method to achieve intravascular volume depletion in addition to the medical nephrectomy. The differences in dosage are not likely the cause, as we used lower dosages in our study compared to the above-mentioned case reports.
Of the 11 patients identified, 5 underwent surgical nephrectomy.
The complication rate in these patients was favorable, with no mortality and only minor morbidity, mainly related to the surgery. As described, 2 patients were already treated with anti-hypertensive agents, including ACE inhibitors, and had a surgical nephrectomy for uncontrolled blood pressure. In addition, in 1 patient surgical nephrectomy was performed to stabilize the patient due to extensive fluid overload, in whom it was deemed impossible to perform a medical nephrectomy. These cases illustrate that surgical nephrectomy may be a preferred option, and an individualized consideration of the treatment options should be made.
Another option to shut down the kidneys is by bilateral renal artery embolization. The reported success rate is higher than in medical nephrectomy, but side effects can be severe. [11][12]19 Side effects that have been previously described are fever and challenging flank pain, requiring narcotic analgesics in combination with epidural TA B L E 1 Demographics and clinical characteristics of individual patients with ESRD due to nephrotic syndrome who underwent medical nephrectomy  infusion of local anesthetic. [11][12]19 This method seems to be more invasive, especially in children, frequently needing general anesthesia. In addition, an experienced physician is needed to perform this treatment and there is a risk of injuring the femoral artery, which may hamper arterial anastomosis during kidney transplantation.
Despite the small patient group and the retrospective charac-