De novo idiopathic nodular glomerulosclerosis in a kidney transplant patient

Chronic Kidney Disease is a condition characterized by a progressive and irreversible decrease in kidney function that can be caused by different etiologies, among which are primary or secondary glomerular diseases (1). Within renal replacement therapies; Transplantation is the modality that provides the greatest benefit in terms of quality of life and mortality. Renal graft survival can be affected not only by rejection and infections but also by relapse in the graft of a glomerular disease that affected the native kidney or otherwise, a de novo onset (2)(3). A study of 1505 transplant patients between 1988-1997 with a diagnosis of confirmed glomerular disease documented that recurrence was the third most common cause of allograft loss at 10 years, after chronic rejection and death with a functioning allograft (4). It should be noted that live transplantation has better HLA compatibility and therefore greater graft survival, however increased rates of primary glomerulonephritis recurrence have been noted in this group of patients (5).

Nodular glomerulonephritis is a histological lesion pattern characterized by the presence of hyaline deposits in the mesangial matrix with a nodule-like distribution; It also shows glomerular vascular involvement, and its usual clinical manifestation may be complete nephrotic syndrome or significant proteinuria. This type of injury is closely related mainly in patients with Diabetes Mellitus and smokers with a high rate of smoking activity. The de novo appearance of this type of lesion in the post-transplant period would constitute a primary form, whose presentation would be infrequent, corresponding to only 0.45% in the series published to date (6).

Clinical case:

A 24-year-old male patient from Soledad (Atlántico, Col) presented renal disease at the age of 16 with subnephrotic proteinuria with clear renal failure, in addition to being congenital monorenal without prior knowledge and since then with renal replacement therapy, so the etiology of CKD was unknown. He denied a history of smoking, or metabolic pathologies, with a normal weight and BMI. Subsequently, there was the appearance of hypertension, for which pharmacological management was initiated with beta-blocker, central alpha agonist, ARB II. He entered the transplant protocol in September 2018 and was transplanted in April 2024, his donor was cadaverous, with cold ischemia time of 17 hours and hot ischemia of 50 minutes. Induction treatment was performed with rabbit antithymocyte immunoglobulin plus methylprednisolone pulses and subsequently initiation of maintenance with mycophenolate, prednisolone and tacrolimus. Early on, he began to present elevation of azotes without an apparent cause, for which a first renal biopsy was performed with an official report given by BANFF category 3: suspected (borderline) of cell rejection, in the same way a change of therapeutic scheme was carried out suspending mycophenolate and initiation of azathioprine, other infectious etiologies causing graft dysfunction were ruled out. Since then, his renal function was established at G3aA1T, but progressively he began to present a significant increase in proteinuria in the subnephrotic range to a maximum value of 2655 mg/24h, nephrotic syndrome, infectious and autoimmune pathologies and dysproteinemias were ruled out. For this reason, a second biopsy was performed in September 2024, finding findings of other changes not considered by acute or chronic rejection, with findings of interstitial fibrosis and tubular atrophy grade II considered as BANFF category: 5 and 6, but within the histopathological findings there is expansion of the mesangial matrix, associated with mesangial hypercellularity with positivity for IgG and C3, so it is required to complement with electron microscopy study for Discard organized deposits, see image 1. Electron microscopy highlights the presence of nodular areas of electrondense material without characteristics of immune complexes. There is no organized material that suggests fibrils, thyroglobulin or amyloid, there is podocyte effacement of 70% of the capillary surface, consistent with nodular pattern glomerulosclerosis and secondary podocytopathy, image 1. To optimize antiproteinuric therapeutic management, ARA II was changed from losartan to irbesartan and iSGLT2 was initiated. The results obtained were important, in the control the reduction of almost 50% of proteinuria and stabilization of azoates stands out. See Table 1

Discussion:

Nodular glomerulosclerosis is a pattern of histological lesion that was classically associated with diabetes and was first described in 1936 by Kimmelstiel and Wilson (7). Nodular glomerulosclerosis is also associated with various entities, so it is important to make an adequate clinical-pathological correlation (8). Among other factors associated with this pathology are obesity and smoking, described in 1999 and 2002 (9)(10). In the same way, other entities such as membranoproliferative glomerulonephritis, glomerulopathies associated with dysproteinemia, fibronectin-associated glomerulonephritis, type III collagen glomerulopathy, hypoxic or ischemic pathologies and cystic fibrosis should be ruled out, although it is highlighted that the reports are extremely infrequent, corresponding to 0.45-0.5% of biopsies and scarcely reported in meta-analyses around 95 cases (11). Due to the impact on its correlation with various cardiovascular risk factors, the nomenclature of non-diabetic metabolic nodular glomerulosclerosis has been proposed. This condition is more frequent in men than women, with an average age of 60 years, with progressive renal dysfunction and findings in urinalysis given by proteinuria and microhematuria. It may also present with nephrotic syndrome or subnephrotic proteinuria associated with microhematuria (12). As for the largest reports in the medical literature on idiopathic nodular glomerulosclerosis (IDG) in native kidneys, the one by Yang et al. stands out, which presents 122 cases in a period recorded from 1999 to August 2023. In this registry, most were men, the average age was 62 years, most were smokers, obese and with high blood pressure. 60% had nephrotic syndrome (13). As for the appearance of post-transplant glomerular disease, it can be divided into recurrent or de novo, with recurrences of primary glomerulopathies being more frequent in renal transplantation than de novo appearance. The clinical expression is similar to that presented in native kidneys and the appearance of these has a negative impact on graft survival (14). Among the most common recurrent glomerulopathies in kidney transplantation are focal segmental glomerulosclerosis, IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulosclerosis (2). In the few cases reported worldwide, there is the reported Mohamed Nasreen in a 35-year-old kidney transplant patient in whom he had the appearance of GNI 3 years after transplantation with loss of the kidney graft, who underwent a second kidney transplant with a new recurrence of GNI from the second transplant with subsequent progression to renal failure.  evidencing the relevance and severity of this pathology (15).

Similarly, it is important to note that the case presented is atypical in terms of demographic profile, which occurs in a young adult and appears after kidney transplantation, which does not have any risk factor associated with the appearance of this pathology. Regarding therapeutic management, it is evident that there is a favorable clinical response with the establishment of ARB II at the maximum tolerated dose, as well as the inclusion of the SGLT2 inhibitor, proving its benefits again. It is known that immunosuppressive drugs such as calcineurin inhibitors and steroids can contribute to the development of post-transplant diabetes, with pathophysiological pathways shared with diabetic nephropathy that lead to glomerular ischemia and overexpression of TGF-B, which may contribute to the appearance of GNI (16).

GNI is a pattern of glomerular lesion that is predominantly seen in men and manifests clinically with nephrotic syndrome or significant proteinuria. However, its diagnosis represents a challenge, as it requires the careful exclusion of other underlying pathologies, especially diabetic nephropathy and depositional diseases, such as amyloidosis or plasma cell dyscrasias. The precise identification of this entity is essential, since its prognosis may be conditioned by non-traditional risk factors, such as high blood pressure, smoking, and obesity. In the context of kidney transplantation, is an extremely rare entity, but of great clinical relevance due to its potential negative impact on graft survival. The recurrence or de novo appearance of this pathology in the renal graft may be associated with a progressive deterioration of renal function and the eventual loss of the transplanted organ. Therefore, it is essential to maintain a high index of suspicion in the presence of proteinuria or nephrotic syndrome in transplant patients, even in the absence of classic risk factors. The diagnostic approach should be comprehensive, including detailed histopathological studies and exhaustive clinical and biochemical evaluations to rule out secondary etiologies. should be considered within the differential diagnosis of nodular glomerular lesions, especially in non-diabetic patients and in the context of kidney transplantation. Timely detection and appropriate management can contribute to improving the prognosis and quality of life of affected patients. More multicenter studies and case reports are needed to better understand the course, prognosis, and best therapeutic strategies for this rare entity.