|Year : 2005 | Volume
| Issue : 3 | Page : 367-374
|A Case of Adolescent Renal Failure
Department of Nephrology, Riyadh Medical Complex, Riyadh, Saudi Arabia
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|How to cite this article:|
Kumar R. A Case of Adolescent Renal Failure. Saudi J Kidney Dis Transpl 2005;16:367-74
| Case Presentation|| |
This patient was admitted for first time in 1990 under the pediatrics nephrology services, when she was 12 years old. Her presenting symptoms were failure to thrive, polyuria, polydypsia and nocturia since six years of age and repeated episodes of carpopedal spasms for few weeks before hospitalization. Physical examination revealed a short stature female, whose height and weight were well below the 3 rd centile for her age, suggestive of severe growth retardation. There was no edema and her blood pressure was 100/60 mmHg. Her other general physical and systemic examination was within normal limits. She had three brothers and two sisters at this point of time and no one was affected by any form of renal disease.
Investigations revealed hemoglobin 9.3gm/dl, white blood cell counts 7.5x10 9 /L with normal differential. Blood urea nitrogen 28 mmol/L, serum creatinine 282 umol/L, calcium 1.3 mmol/L, phosphorus 1.8 mmol/L, alkaline phosphatase 1590 U/L and parathyroid hormone level 2999 pmol/L. Urinalysis showed traces of protein and few pus cells/ high power field on microscopic examination. Twenty four hours proteinuria was 270 mg. Ultrasound examination of the abdomen [Figure - 1] showed right kidney measuring 7 centimeters and left kidney of 7.5 centimeters. There was loss of cortico-medullary differentiation and increase in echogenicity of both kidneys. Micturiting cystouretherogram did not show any evidence of vesicoureteric reflux. Technetium 99 renal scan demonstrated very poor perfusion in both kidneys. Skeletal survey documented pathological fracture of neck of right femur, upper end of left fibula and coxa vera deformity of both hips, suggestive of severe renal osteo-dystrophy. Thin section CT scan of abdomen [Figure - 2] showed bilateral small kidneys with increase in echogenicity and loss of corticomedullary differentiation. No cyst was detected in medullary area of either kidney on CT scan.
Renal biopsy done in 1990 showed 25 glomeruli, out of which 15 glomeruli were completely hyalinized. The remaining showed variable degree of periglomerular fibrosis. The glomerular tuft showed prominent mesangium associated with slight increase in mesangeal matrix as well as cellularity. There was marked loss of tubules with replacement by fibrosis. Some of the tubules showed early cystic dilatation. Within the interstitium there was lymphocytic infiltration. Electron microscopic examination of glomerulus showed marked irregular expansion of mesangium associated with increase in mesangial matrix as well as cellularity. No electron dense deposits were seen. Capillary basement membrane was of normal thickness. The histological diagnosis given by the renal pathologist was advanced renal disease.
A diagnosis of chronic renal failure (CRF) of uncertain etiology was made and she was started on conservative management of CRF. She reached end stage renal disease (ESRD) in 1994 (at the age of 16 years) and was referred to adult nephrology services for renal replacement therapy. She was started on continuous ambulatory peritoneal dialysis (CAPD) and was followed up in our CAPD clinic regularly. She remained stable on CAPD for almost 10 years, when she was shifted to hemodialysis due to malfunction of CAPD catheter in 2004. She was transplanted in June 2004 (patient's age then was 26 years) with live unrelated kidney donor and is doing well on triple immunosuppressant, having normal renal function.
When she was being followed up in our CAPD clinic, many members of her family were found to have chronic renal failure, hence all family members were evaluated in details. Pedigree pattern [Figure - 3] of this family showed that patient's father had two wives and 18 children, 9 from each wife. One of the marriage was consanguineous, whereas other wife was not related to the husband, but children from both wives were affected by the disease. In addition to the index case, three brothers and one sister were affected by the disease in this family. Parents of the affected children were clinically normal. Both male and female children were affected by the disease in equal proportion. There was no vertical transmission of the disease. So, this pedigree pattern was classical of autosomal recessive disease. All affected family members presented with polyuria, polydypsia, growth retardation, normal blood pressure, lack of edema and chronic renal failure. The affected sister of the index case also showed classical findings of retinitis pigmentosa on fundus examination [Figure - 4]. All affected children demonstrated small kidneys with increase in echogenicity, loss of cortico-medullary differentiation and absence of visible cyst on renal imaging studies [Figure - 5]. All diseased family members developed ESRD, requiring renal replacement therapy by 20 years of age. All of them received live unrelated renal transplant and are doing very well with normal renal function. In view of autosomal recessive mode of inheritance, clinical features of chronic tubulointerstitial disease, onset of ESRD in second decade of life, retinitis pigmentosa in a family member, a diagnosis of Juvenile Nephronophthisis was made in this family.
| Discussion|| |
Nephronophthisis (NPH) is an autosomal recessive disorder, characterized by polyuria, polydypsia, anemia and the development of ESRD in the second decade of life. It represents the most frequent genetic cause of uremia in children with a prevalence rate of 0.13 per 10,000 live births.  It has been estimated that, NPH accounts for 2.4% cases of end stage renal disease in children in the United States.  This frequency may be an underestimate, as studies from Europe have reported a higher frequency of 15%.  At north Italy Transplant Program, among 438 children who received renal transplant between 1980 & 1998, approximately 20 % were affected by NPH. 
| Genetics|| |
In the past, NPH was considered to be a heterogeneous disorder possibly resulting from a single autosomal recessive gene defect, but recently, mutations in four genes have been discovered. ,,
The first identified gene named as NPHP1 is mapped on the long arm of chromosome 2 (2q13) and encodes for a protein nephrocystin.  A large homozygous deletion of 250 kb within this region was demonstrated in 60-70% of cases, which is responsible for the juvenile form of nephronophthisis.  Among the different forms of NPH, juvenile nephronophthisis is the commonest. These patients invariably progress to ESRD, which typically develops before 20 years of age.  Three recent studies from Italy,  Germany,  and Finland  collectively described 300 patients with clinical features of NPH, 6070% of whom shared the molecular diagnosis of NPHP1.
NPHP2 gene is mapped on the long arm of chromosome 9 (9q21) and encodes for a protein termed as inversin. Patients with mutation in NPHP2 gene develop ESRD by 5 years of age and are classified as having infantile NPH. Although, in a recent report by Otto et al,  among seven affected families, all children in five families who were affected by the disease, developed ESRD by 30 months of age.
Mutation in NPHP3 gene cause an adolescent form of NPH. This gene is mapped on the long arm of chromosome 3 (3q21) which encodes a 1330 amino acids protein. Mutation in this gene is responsible for NPH, where renal disease occurs either alone or in association with hepatic fibrosis or tapeto-retinal degeneration. Median age at onset of ESRD is 19 years in this form of NPH. 
Gene locus for NPHP4 has been mapped to the short arm of chromosome 11 (11p36) and this gene encodes a protein named as nephroretinin. This minor variant of NPH, has a juvenile onset of disease and may be associated with retinitis pigmentosa.
| Pathogenesis|| |
The exact pathogenesis of renal cyst formation in NPH is not clear. Nephrocystin and inversin has been presumed to be localized to the primary cilia of renal tubular epithelial cells. In addition, nephrocystin interacts with inversin and proteins encoded by NPHP3 and NPHP4 gene as well as other proteins known to underlie cell-cell and cell-matrix signaling. , A hypothesis for the pathogenesis of cyst formation in NPH is that, gene mutations alter the structure of nephrocystin, inversin and other proteins encoded by NPHP3 and NPHP4 genes. These altered proteins result in defective ciliary functions leading to inability of renal tubular cells to correctly sense luminal flow rates.  Abnormal kidney's attempt to compensate for perceived altered tubular flow results in, dysregulated tissue growth, and therefore leading to renal cyst formation.
| Clinical Features|| |
In the early phase of the disease, major symptoms are in the form of polyuria and polydypsia. These symptoms are related to structural defects of the renal tubules, leading to reduction in urine concentrating ability and sodium conservation. Urinary abnormalities such as proteinuria and hematuria, are minimal. Anemia, growth retardation and renal osteodystrophy are frequent early features and become progressively serious as ESRD develops. Age of onset of ESRD is determined partly by the type and severity of the genetic defect, but in the majority of cases, develops within the first two decades of life. The kidneys maintain a normal or slightly reduced size and demonstrate increased medullary echogenicity with diminished corticomedullary differentiation on imaging studies. Solitary or multiple cysts of variable sizes may be seen at the corticomedullary junction.
| Associated Disorders|| |
- Senior Loken syndrome in which tapetoretinal degeneration is associated with NPH is seen in 18% of cases, and has been linked to the genetic area of the NPHP3 gene. ,
- Juobert syndrome in which NPH is associated with coloboma of optic nerve and cerebellar vermis aplasia.
- Cogen syndrome where NPH occurs in combination with ocular motor aprexia.
- Laber's congenital amaurosis occurs early in life and affected children are blind from birth. Other associated eye abnormalities are cataract, coloboma, amblyopia and nystagmus.
- Hepatic involvement is characterized by hepatosplenomegaly and portal fibrosis.
| Pathology|| |
The kidneys in these disorders are moderately small with irregular granular capsular surface. On cut section, the cortex and medulla are both thinned out. Multiple cysts of variable sizes are visible at the corticomedullary junction and in the medulla. Medullary cysts appear late in the course of the disease and are absent at the early stage. Up to 25% of NPH kidneys have no grossly visible cysts.  As no cysts could be seen in any affected member of this family, they probably belong to this category. Renal histology is non-specific and changes are restricted to the tubules and the interstitium. Groups of atrophic tubules with thickened tubular basement membrane alternate with groups of dilated or collapsed tubules. The interstitium shows moderate degree of inflammatory cells infiltration with interstitial fibrosis. The glomeruli are often normal initially, but secondary glomerular sclerosis and periglomerular fibrosis occur in advanced disease. Renal biopsy in the index case showed all the above findings consistent with a diagnosis of NPH.
| Diagnosis|| |
Clinical presentation of NPH is relatively non-specific and the diagnosis is often delayed. Hence the diagnosis is made by inference from the family history of autosomal recessive pattern, polyuria, bland urinary sediment and the presence of small, hyperechogenic kidneys with indistinct corticomedullary border on renal imaging studies.
Traditionally, multiple medullary cysts have been regarded as the hallmark for the diagnosis of NPH, but in up-to 25% of patients these cysts may be absent. Thin section (1-2 mm thickness) CT scan has been found to be more sensitive to detect these medullary cysts than ultrasonography.  Homogeneous or multilayered thickening of the tubular basement membrane, on electron microscopy is highly suggestive of NPH. Other tubular and interstitial changes seen on renal histology are nonspecific. Finally molecular genetic testing offers the only technique for definitive diagnosis of NPH. Hildebrandt et al  has recently proposed an algorithm for molecular diagnosis of NPH that addresses four important diagnostic issues:
- Detection of the classical homozygous deletion of 250 kb on chromosome 2 (2q13), the location of NPHP1 gene, by lack of amplification by PCR, of genomic DNA markers. This test permits accurate diagnosis in 62% of patients.
- Detection of rare smaller homozygous deletion of NPHP1.
- Testing for a heterozygous deletion.
- Potential exclusion of linkage to NPHP1.
The diagnosis is also supported by the presence of associated disorders.
| Differential Diagnosis|| |
NPH should be differentiated from reflux nephropathy, urinary tract obstruction, polycystic kidney disease and medullary sponge kidney.
These disorders however are associated with specific diagnostic findings on renal imaging; caliectasis with focal parenchymal scarring in reflux nephropathy, hydronephrosis in urinary tract obstruction and multiple bilateral cysts with enlarged kidneys in polycystic kidney disease are pathognomonic on renal imaging. There is no dilatation of pelvicalyceal system in NPH. The principle method for the diagnosis of medullary sponge kidney is excretory urography, which demonstrate the presence of medullary nephrocalcinosis and linear, cystic areas in the medullary pyramids. Ultrasonogram and CT scan findings are more sensitive in showing medullary calcification, but they are less specific than the excretory urographic findings.
| Treatment|| |
There is no specific treatment for NPH, except correction of water and electrolytes disturbances. Calcium and vitamin D supplements should be started in early course of the disease to prevent the onset of renal osteodystrophy. Dialysis followed by transplantation is the best possible therapy, when patients reach ESRD. There is no recurrence of NPH in the transplant kidney.
| Audience Discussion Forum|| |
Chairman-Dr. Mohammed Al Sunaid: Thank you Dr. Kumar for your presentation and now the floor is open for questions and discussion.
Dr. Shaheen: what about the outcome of renal transplantation in these cases?
Dr. Kumar: There is a recent study published in NDT journal about renal transplantation in medullary cystic kidney diseases with five years post transplant follow up. The graft survival at one year was excellent compared to other patients, while the two and five years graft survival rates were equal to other transplanted patients.
Dr. Sunaid: The kidney biopsy in your case was done despite the advanced stage of CRF, so what was the reason to do the kidney biopsy at this stage?
Dr. Kumar: This was discussed with our colleagues, in the pediatric department. Remember that at that time the serum creatinine was around 280 µmol/l and kidney size was around 7 cm, and we did an extensive work up to find out the cause of CRF, although one colleague was hesitant to do the renal biopsy in such small kidney, knowing that it does not contribute in the diagnosis as there is bound to be extensive fibrosis.
Dr. Shaheen: Do you have information about the presence of any abnormality in the cerebral vascular bed in those patients?
Dr. Kumar: Actually this case was presented as CRF, growth retardation and renal osteodystrophy. There was no evidence of mental retardation in any effected children and imaging studies has not been done for the exploration of the presence of brain vascular malformation.
Dr. Shaheen: I am asking about brain vascular malformation because I have one patient who had the same disease, and she developed post transplant severe brain hemorrhage and died with functioning graft.
Dr. N. Turaif: First I would like to congratulate you about this very good scientific work that you did, in order to identify the disease in this family. In your review did you find any reason why some of these patients develop retinitis pigmentosa? Is it due to protein abnormalities due to nephron defect system?
Dr. Kumar: I reviewed the literature in detail and I did not find any specific genetic protein defect that can explain the retinitis pigmentosa, although, it is possible that there may be some genetic disease that affects vessels in other areas that may be responsible for this retinal change. When we discussed this family with the molecular genetics team at King Fahd National Center for children's cancer, we were keen to get the genetic map result before this presentation. This however, takes too long to establish. I suppose it is possible that further work could be done that may identify a protein defect that can explain the retinitis pigmentosa. But I did not find in the literature any report in this regard.
Dr. Sunaid: Knowing that it is a rare disease and mainly reported from Western countries and USA, did you find any local or regional data about this disease?
Dr. Kumar: Yes, there are some cases reported from the region. My colleague Dr. Mirza is a co-author of three cases of juvenile nephronophthisis published in the American Journal of Kidney Disease.  And there are some other reports from the region.
Dr. F. Al Kanhal: The reason we present this case is to highlight that may be this disease is underestimated in our community, and to give the message that we should always consider nephronophthisis in the differential diagnosis of unknown etiology of CRF in children and adolescents.
Dr Sunaid: I would like to thank Dr. Kumar again for this presentation, and thanks to the audience.
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Department of Nephrology, Riyadh Medical Complex, P.O. Box 2897, Riyadh 11196
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]
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