LIPOPROTEIN GLOMERULOPATHY WITH NOVEL GENETIC VARIANT- CASE REPORT

Introduction:

Nephrotic syndrome is common in children. Kidney biopsy is done in only few cases of pediatric nephrotic syndrome, predominantly steroid resistant cases. Common causes of nephrotic syndrome in children are minimal change disease, FSGS, c1q nephropathy. Very rarely it is caused by lipoprotein glomerulopathy. Worldwide, only 200 cases of lipoprotein glomerulopathy have been reported so far. We report first case of lipoprotein glomerulopathy from south India, also report the mutation in APOE gene c.502C>T(p.Arg168Cys) variant for the first time and this is the youngest patient to develop this disease. To our knowledge, this variant of APOE gene has not been reported so far in literature.

Methods:

Four-year-old male child, resident of Kurnool, Andhra Pradesh, India, born out of a non-consanguineous married couple, presented to hospital with pedal edema, facial puffiness and abdominal distension in April 2024. Evaluation revealed – hypertension (blood pressure 130/90mmHg), pitting pedal edema, ascites and periorbital puffiness. Urine examination showed 4+ protein on dipstick, 4-6 RBC/HPF, 24-hour urine protein 6.5grams/day, serum albumin was 1.5g/dl, serum cholesterol was 300mg/dl, serum triglycerides 960mg/dl, HDL was 22mg/dl, ultrasound examination showed normal sized kidneys, serum creatinine was 0.6mg/dl, eGFR was 96ml/min/1.73m2. No family history of kidney diseases.  Diagnosis of nephrotic syndrome was made and he was started on prednisolone 2mg/kg/day, Furosemide and advised fluid and salt restriction. After 6 weeks of steroid therapy, there was persistent edema so repeat evaluation was done which showed 24 hours urinary protein of 5g/day and serum albumin of 1.5g/dl. In view of persistent nephrotic state despite 6 weeks of steroid, a diagnosis of steroid resistant nephrotic syndrome was made with provisional diagnosis – FSGS. Hence kidney biopsy was done. 

Renal biopsy showed glomeruli which appear enlarged with dilated glomerular capillaries (dilation of capillaries is accompanied by mesangiolysis) containing pale acellular having a vague laminated appearance suspicious of lipoprotein thrombi. Occasional tufts show vacuolated appearance of these thrombi. These thrombi are pale on H&E stain, weakly PAS positive, Silver negative and pale blue on Masson Trichrome stain. There was mild mesangial hyper cellularity.  The basement membranes appear mildly thickened in all and focally duplicated forming tram track appearance and mesangial cell interposition in occasional tufts.

 Immunofluorescence revealed no significant immune deposits. Electron microscopy revealed foot process flattening of ninety percent of the loops and markedly dilated capillary loops. These are distended with granular material, focally showing linear arrangements and ill-defined finger print appearance. Few capillary loops showed identical material in the lamina densa. Genetic testing was done. Whole exome sequencing revealed heterozygous missense variant in exon 4 of APOE gene mutation on chromosome 19(c.502C>T(p.Arg168Cys)). Immunosuppression was stopped and child was treated with atorvastatin 20mg + Fenofibrate 80mg, Telmisartan 20mg once daily. Three weeks after starting Fenofibrate, lipid profile was normalised (cholesterol 120mg/dl, triglycerides 130mg/dl). Two months later, proteinuria also decreased (500mg/day) and GFR became stable (serum creatinine 0.5mg/dl).

Results:

LipoProtein Glomerulopathy (LPG) is a rare disorder of lipid metabolism leading to lipoprotein deposition in glomeruli causing proteinuria and renal injury. It is caused by mutation in APOE gene. About 200 cases of LPG have been reported worldwide, most of them are from China and Japan, about 10 cases have been reported from North America, with gene sequencing including APOE Kyoto, APOE Chicago, APOE Las Vegas, APOE Tokyo/Maebashi, APOE Modena, APOE Osaka/Kurashik. This disease has predilection for males and presents with proteinuria/ nephrotic syndrome, commonly seen in adults and rarely in children. Most cases presents with elevated serum triglycerides and hypertension. GFR will be normal at presentation. There can be incomplete penetrance of the gene mutation in some family members not having dyslipidaemia. There is mutation at LDL receptor binding site of APOE gene which impairs triglyceride rich lipoprotein catabolism, leading to lipoprotein deposition in glomeruli. The positively charged lipoprotein has affinity for negatively charged glomerular basement membrane. Precursor of lipoprotein thrombi assemble in sub endothelium and build up in glomerular capillary as a downstream effect.

Light microscopy shows enlarged glomerulus filled with lipoprotein thrombi, which look pale on H and E, PAS, but positive for oil red O. Mesangial proliferation and segmental sclerosis are also seen. Immunofluorescence was negative. On Electron microscopy, lipoprotein thrombi from lamellated fingerprint appearance was seen along with osmiophilic substances in the subendothelium.

The following mutations have been documented for LPG:

APOE Tokyo/Maebashi mutation: p.Leu162_Lys164del 

APOE Kyoto                                : p. Arg25Cys 

APOE Chicago                           :  p.Arg165Pro 

APOE Las Vegas                       :  p.Leu159Pro 

APOE Modena                           : p.Arg150Cys 

APOE Osaka/Kurashiki              :  p.Arg176Pro

Present patient APOE                : P Arg168Cys

Fibrates are the mainstay of treatment. LDL apheresis, protein A immunoadsorption have been tried with limited success. Statins alone, although can cause normalisation of lipid profile, but cannot cause improvement in proteinuria. Similarly, ACEi/ARB alone do not cause improvement in proteinuria. LPG does not resolve spontaneously without treatment and it recurs post renal transplant also.

LPG is rarely seen outside China and Japan. To our knowledge, this is the first case reported from south India and the genetic variant p.Arg168Cys has not been reported so far worldwide. This case illustrates importance of electron microscopy and genetic testing in cases of nephrotic syndrome in children, especially with steroid resistance and very high level of triglycerides at presentation. Diagnosis is critical in these cases as treatment is different from the other causes of nephrotic syndrome in children. Without treatment, prognosis is poor. By reporting this case, we hope to raise awareness of this rare disease.

Conclusions:

It is difficult to clinically differentiate LPG from other causes of nephrotic syndrome. Accurate diagnosis leads to cure of disease, whereas without diagnosis, ESRD is the final outcome. This disease is underreported outside China and Japan and all the genetic variants of APOE gene causing the disease are yet to be identified. By reporting the first case from south India, and also the genetic variant  p. Arg168Cys of APOE gene, we hope to raise awareness of this rare disease and importance of genetic testing in nephrotic child. 

To our knowledge, this APOE mutation c.502C>T (p. Arg168Cys) has not been reported in literature and is the youngest patient to develop this disease.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.